TW201335150A

TW201335150A - Substituted benzylpyrazoles

Info

Publication number: TW201335150A
Application number: TW101149104A
Authority: TW
Inventors: 瑪利安伊奇庫克; 安妮明格; 安亞里奇特; 漢斯布里安; 克努特爾斯; 維拉彼得; 傑爾哈德希梅斯特; 史蒂芬普雷克爾; 萌塔薇恩安無瑞安斯托佛安茲; 克里西汀史德曼; 賽門荷爾頓; 馬克珍勾拿茲; 克里雅普修
Original assignee: 拜耳知識產權公司; 拜耳製藥公司
Priority date: 2011-12-21
Filing date: 2012-12-21
Publication date: 2013-09-01

Abstract

Compounds of formula (I) and their use as pharmaceutical.

Description

經取代之苯甲基吡唑 Substituted benzylpyrazole

本發明係關於經取代之苯甲基吡唑化合物、其製造方法及其用途。 The present invention relates to substituted benzylpyrazole compounds, processes for their preparation, and uses thereof.

癌細胞之最基本特徵之一在於其維持慢性增殖之能力，而在正常組織中，進入細胞***週期且在整個細胞***週期內進展的過程受到嚴密控制以確保細胞數目恆定且維持正常組織功能。增殖控制損失被強調為癌症之六種標誌之一[Hanahan D及Weinberg RA,Cell 100,57,2000；Hanahan D及Weinberg RA,Cell 144,646,2011]。 One of the most basic features of cancer cells is their ability to maintain chronic proliferation, whereas in normal tissues, the process of entering the cell division cycle and progressing throughout the cell division cycle is tightly controlled to ensure a constant number of cells and maintain normal tissue function. Proliferation control losses are highlighted as one of the six hallmarks of cancer [Hanahan D and Weinberg RA, Cell 100, 57, 2000; Hanahan D and Weinberg RA, Cell 144, 646, 2011].

真核細胞***週期(或細胞週期)藉由經歷經協調及調節之一系列事件來確保基因體重複及將其分配至子細胞中。細胞週期分為四個連續階段： The eukaryotic cell division cycle (or cell cycle) ensures that the genome repeats and distributes it into daughter cells by undergoing a series of events that are coordinated and regulated. The cell cycle is divided into four consecutive phases:

1. G1階段表示DNA複製前之時間，期間細胞生長且對外部刺激敏感。 1. The G1 phase indicates the time before DNA replication, during which cells grow and are sensitive to external stimuli.

2.在S階段，細胞複製其DNA，且 2. In the S phase, the cell replicates its DNA, and

3.在G2階段，為進入有絲***做準備。 3. In the G2 phase, prepare for mitosis.

4.在有絲***期(M階段)，重複染色體分離，由自微管構造之紡錘體裝置支撐，且完成細胞***為兩個子細胞的過程。 4. During the mitotic phase (M phase), the chromosome separation is repeated, supported by a spindle device constructed from a microtubule, and the process of cell division into two daughter cells is completed.

為了確保為將染色體準確分佈至子細胞所需之極高保真性，嚴格調節且控制細胞週期進程。為週期進展所必需之酶必須在準確時間被活化且一旦已經過相應階段即亦再次被關閉。若偵測到DNA損害或尚未完成DNA複製或紡錘體裝置之產生，則相應控制點(「檢查點」)終止或延遲細胞週期之進展。有絲***檢查點(亦稱作紡錘體檢查點或紡錘體組裝檢查點)控制紡錘體裝置之微管與重複染色體之著絲點(微管之連接位點)的準確連接。只要未連接之著絲點存在且產生等待信號以使***細胞有時間來確保每一著絲點均連接至紡錘體極且糾正連接錯誤，則該有絲***檢查點即為活性的。因此，有絲***檢查點防止有絲***細胞完成具有未連接或錯誤連接之染色體之細胞***[Suijkerbuijk SJ及Kops GJ,Biochem.Biophys.Acta 1786,24,2008；Musacchio A及Salmon ED,Nat.Rev.Mol.Cell.Biol.8,379,2007]。一旦以正確雙極(兩極性)方式連接所有著絲點與有絲***紡錘體極，則滿足檢查點且細胞進入細胞***後期且繼續進行有絲***。 To ensure the high fidelity required to accurately distribute chromosomes to daughter cells, cell cycle progression is tightly regulated and controlled. The enzyme necessary for the progression of the cycle must be activated at the exact time and once again the corresponding phase is closed. If DNA damage is detected or DNA replication or spindle device production has not been completed, the corresponding control point ("checkpoint") terminates or delays the progression of the cell cycle. A mitotic checkpoint (also known as a spindle checkpoint or spindle assembly checkpoint) controls the exact attachment of the microtubules of the spindle device to the centromere of the repeating chromosome (the junction of the microtubules). The mitotic checkpoint is active as long as the unattached centromere is present and a wait signal is generated to allow the dividing cells to have time to ensure that each centromere is attached to the spindle pole and corrects the connection error. Thus, mitotic checkpoints prevent mitotic cells from completing cell division with unconnected or misligated chromosomes [Suijkerbuijk SJ and Kops GJ, Biochem. Biophys. Acta 1786, 24, 2008; Musacchio A and Salmon ED, Nat. Rev. Mol. Cell. Biol. 8, 379, 2007]. Once all of the centromere and mitotic spindle poles are connected in the correct bipolar (bipolar) manner, the checkpoint is met and the cells enter the late stage of cell division and continue mitosis.

有絲***檢查點係由大量基本蛋白質之複雜網狀結構建立，該等基本蛋白質包括MAD(有絲***阻滯缺陷，MAD 1-3)及Bub(未受苯并咪唑抑制之Budding，Bub 1-3)家族之成員、Mps1激酶、cdc20以及其他組分[綜述於Bolanos-Garcia VM及Blundell TL,Trends Biochem.Sci.36,141,2010中]，其中有許多在增殖細胞(例如癌細胞)及組織中過度表現[Yuan B等人，Clin.Cancer Res.12,405,2006]。未滿足之有絲***檢查點的主要功能在於保持細胞***後期促進複合體/細胞週期體(anaphase-promoting complex/cyclosome(APC/C))處於非活性狀態。一旦檢查點得以滿足，則 APC/C泛素-接合酶靶向細胞週期素B及保全素(securin)以進行蛋白水解降解，導致成對染色體分離且自有絲***中退出。 Mitotic checkpoints are established by a complex network of basic proteins including MAD (mitotic retardation defects, MAD 1-3) and Bub (Budding, Bub 1-3 not inhibited by benzimidazole) family. Members, Mps1 kinase, cdc20, and other components [reviewed in Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci. 36, 141, 2010], many of which are overexpressed in proliferating cells (eg, cancer cells) and tissues [ Yuan B et al., Clin. Cancer Res. 12, 405, 2006]. The primary function of unmet mitotic checkpoints is to maintain the anaphase-promoting complex/cyclosome (APC/C) in an inactive state. Once the checkpoint is met, then APC/C ubiquitin-nectin targets cyclin B and securin for proteolytic degradation, resulting in paired chromosome segregation and withdrawal from mitosis.

Ser/Thr激酶Bub1之非活性突變在以微管去穩定藥物處理酵母釀酒酵母(S.cerevisiae)細胞時防止有絲***進展延遲，此導致將Bub1識別為有絲***檢查點蛋白[Roberts BT等人，Mol.Cell Biol.,14,8282,1994]。大量近期的出版物提供證據表明Bub1在有絲***期間具有多重作用，此已由Elowe綜述[Elowe S,Mol.Cell.Biol.31,3085,2011]。特定而言，Bub1為與重複染色體之著絲點結合且可能充當骨架蛋白以構成有絲***檢查點複合體的第一有絲***檢查點蛋白之一。此外，經由組蛋白H2A之磷酸化作用，Bub1使蛋白shugoshin定位於染色體之著絲粒區域以防止成對染色體過早分離[Kawashima等人，Science 327,172,2010]。另外，連同Thr-3磷酸化之組蛋白H3一起，shugoshin蛋白充當包括蛋白存活素、borealin、INCENP及Aurora B之染色體過客複合體的結合位點。染色體過客複合體在有絲***檢查點機制內被視作張力感測器，其解散錯誤形成之微管-著絲點連接，諸如同極性(兩個姊妹著絲點連接至一個紡錘體極)或單極性(一個著絲點連接至兩個紡錘體極)連接[Watanabe Y,Cold Spring Harb.Symp.Quant.Biol.75,419,2010]。 The inactive mutation of Ser/Thr kinase Bub1 prevents delayed mitotic progression when microtubule destabilizing drug-treated yeast S. cerevisiae cells, which results in the recognition of Bub1 as a mitotic checkpoint protein [Roberts BT et al., Mol. Cell Biol., 14, 8282, 1994]. A number of recent publications provide evidence that Bub1 has multiple roles during mitosis, as reviewed by Elowe S [Elowe S, Mol. Cell. Biol. 31, 3085, 2011]. In particular, Bub1 is one of the first mitotic checkpoint proteins that bind to the centromere of a repetitive chromosome and may act as a backbone protein to form a mitotic checkpoint complex. Furthermore, via phosphorylation of histone H2A, Bub1 localizes the protein shugoshin to the centromere region of the chromosome to prevent premature separation of pairs of chromosomes [Kawashima et al, Science 327, 172, 2010]. In addition, together with the Thr-3 phosphorylated histone H3, the shugush protein acts as a binding site for the chromosomal passenger complex including the protein survivin, borealin, INCENP and Aurora B. The chromosomal passenger complex is considered a tension sensor within the mitotic checkpoint mechanism, which dissipates the erroneously formed microtubule-wire point connections, such as the same polarity (two sisters are connected to a spindle pole) or Polarity (a centromere is attached to two spindle poles) is connected [Watanabe Y, Cold Spring Harb. Symp. Quant. Biol. 75, 419, 2010].

不完全之有絲***檢查點功能與異倍數性及腫瘤發生相關[Weaver BA及Cleveland DW,Cancer Res.67,10103, 2007；King RW,Biochim Biophys Acta 1786,4,2008]。相比之下，已認識到有絲***檢查點之完全抑制導致腫瘤細胞中有嚴重之染色體錯誤分離且誘發細胞凋亡[Kops GJ等人，Nature Rev.Cancer 5,773,2005；Schmidt M及Medema RH,Cell Cycle 5,159,2006；Schmidt M及Bastians H,Drug Res.Updates 10,162,2007]。因此，經由對有絲***檢查點組分(諸如Bub1激酶)之藥理學抑制作用消除有絲***檢查點表示一種新的治療增殖性病症之方式，該等增殖性病症包括與不受控制之細胞增殖相關的實體腫瘤，諸如癌瘤、肉瘤、白血病及淋巴惡性病或其他病症。 Incomplete mitotic checkpoint function is associated with heteroploidy and tumorigenesis [Weaver BA and Cleveland DW, Cancer Res. 67, 10103, 2007; King RW, Biochim Biophys Acta 1786, 4, 2008]. In contrast, it has been recognized that complete inhibition of mitotic checkpoints results in severe chromosomal error separation and induction of apoptosis in tumor cells [Kops GJ et al, Nature Rev. Cancer 5, 773, 2005; Schmidt M and Medema RH, Cell Cycle 5, 159, 2006; Schmidt M and Bastians H, Drug Res. Updates 10, 162, 2007]. Thus, elimination of a mitotic checkpoint via pharmacological inhibition of a mitotic checkpoint component, such as Bub1 kinase, represents a novel means of treating a proliferative disorder, including entities associated with uncontrolled cell proliferation. Tumors, such as carcinomas, sarcomas, leukemias, and lymphoid malignancies or other conditions.

本發明係關於抑制Bub1激酶之化學化合物。 The present invention relates to chemical compounds that inhibit Bub1 kinase.

既定之抗有絲***藥物(諸如長春花生物鹼類、紫杉烷或埃博黴素(epothilone))活化有絲***檢查點，藉由使微管動力學穩定或失去穩定而誘發有絲***阻滯。此阻滯防止重複染色體分離而形成兩個子細胞。有絲***之阻滯延長迫使細胞退出有絲***而無細胞質***(有絲***滑移或適應)或迫使細胞發生有絲***災變，導致細胞死亡[Rieder CL及Maiato H,Dev.Cell 7,637,2004]。相比之下，Bub1之抑制劑防止有絲***檢查點之建立及/或功能發揮，此最終導致嚴重之染色體錯誤分離，誘導細胞凋亡及細胞死亡。 A given anti-mitotic drug (such as a vinca alkaloid, taxane or epothilone) activates a mitotic checkpoint to induce mitotic arrest by stabilizing or destabilizing microtubule dynamics. This block prevents repeated chromosome segregation and forms two daughter cells. Prolongation of mitotic arrest forces cells to exit mitosis without cytokinesis (mitotic slip or adaptation) or force mitotic catastrophe in cells, leading to cell death [Rieder CL and Maiato H, Dev. Cell 7, 637, 2004]. In contrast, inhibitors of Bub1 prevent the establishment and/or function of mitotic checkpoints, which ultimately leads to severe chromosomal error separation, induction of apoptosis and cell death.

該等發現表明Bub1抑制劑應具有關於治療溫血動物(諸如人)之與失控增殖細胞過程增強相關聯之增殖性病症的治療價值，該等增殖性病症諸如有癌症、炎症、關節炎、病毒性疾病、心血管疾病或真菌性疾病。 These findings indicate that the Bub1 inhibitor should have a proliferative disorder associated with enhanced process progression of uncontrolled proliferating cells in a warm-blooded animal, such as a human. Therapeutic value, such as cancer, inflammation, arthritis, viral disease, cardiovascular disease or fungal disease.

由於尤其在人類或動物體內不同器官之組織中由失控增殖細胞過程表現之癌症疾病因已存在充分的藥物療法而仍未被認為為受控疾病的事實，因此強烈需要提供其他新的治療上適用之藥物，較佳抑制新標靶且提供新的治療選擇。 Since cancer diseases manifested by uncontrolled proliferating cell processes in tissues of different organs, especially in humans or animals, are still not considered to be controlled diseases due to the existence of adequate drug therapy, there is a strong need to provide other new therapeutic applications. The drug preferably inhibits new targets and provides new therapeutic options.

在bub1激酶抑制劑領域中，迄今尚無相關技術狀態公開。然而，在與腫瘤學領域完全無關之sGC刺激劑領域中存在先前技術，例如WO1012/003405，其揭示用於完全不同目的之結構相關化合物，此取決於預防、管控及治療病症之作用，該等病症諸如有肺高血壓、動脈高血壓、心臟衰竭、動脈粥樣硬化、炎症、栓塞、腎纖維化及衰竭、肝硬化、***障礙及其他心血管病症。 In the field of bub1 kinase inhibitors, no relevant state of the art has been disclosed so far. However, there are prior art in the field of sGC stimulants that are completely unrelated to the field of oncology, such as WO 1012/003405, which discloses structurally related compounds for completely different purposes, depending on the role of prevention, management and treatment of the condition, such Conditions such as pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, embolism, renal fibrosis and failure, cirrhosis, erectile dysfunction and other cardiovascular conditions.

因此，Bub1抑制劑表示應作為單一藥劑或與其他藥物組合補充治療選擇之重要化合物。 Thus, a Bub1 inhibitor represents an important compound that should be used as a single agent or in combination with other drugs to supplement treatment options.

根據第一態樣，本發明係關於式(I)化合物， According to a first aspect, the invention relates to a compound of formula (I),

其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³彼此獨立地為氫、1-6C-烷氧基、鹵素、2-6C-烯基、3-6C-環烷基、1-6C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-6C-烷氧基，視情況經以下取代：(c1)1至2個OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)-S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為(a)氫；(b)2-6C-羥烷基； (c)，其中*為連接點； (d)-C(O)-(1-6C-烷基)；(e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為氫、1-6C-烷基、2-6C-烯基、1-6C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-6C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-6C-烷基，R¹¹、R¹²彼此獨立地為氫、1-6C-烷基、2-6C-羥烷基或(1-4C-烷基)-SO₂-(1-4C-烷基)，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Wherein R ¹ /R ² are independently of each other hydrogen, halogen or phenyl-S-, and R ^{3 is} independently of each other hydrogen, 1-6C-alkoxy, halogen, 2-6C-alkenyl, 3-6C-ring Alkyl, 1-6C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxy; (c) 1-6C-alkoxy, optionally Substituted by: (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; (c4) 1-4C-alkyl-S(O)-; (c5) 1-4C-alkyl-S(O) ₂ -; (c6)-S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is (a) hydrogen; (b) 2-6C-hydroxyalkyl; c) Where * is the point of attachment; (d) -C(O)-(1-6C-alkyl); (e)-C(O)-(1-6C-alkylene)-O-(1-6C -alkyl); (f)-C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R ⁶ is Hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is hydrogen, 1-6C-alkyl, 2-6C-alkenyl, 1- 6C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen or 1-6C-alkyl, m is 1-4, and R ⁹ and R ¹⁰ are independently hydrogen or 1- 6C-alkyl, R ¹¹ and R ¹² are each independently hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl or (1-4C-alkyl)-SO ₂ -(1-4C-alkyl R ¹³ is hydrogen or 1-4C-alkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N-oxide, tautomer or stereoisomer Salt.

根據第二態樣，本發明係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素，R³彼此獨立地為氫、1-6C-烷氧基、鹵素、2-6C-烯基、3-6C-環烷基、1-6C-鹵烷氧基，n為1-3， R⁴為(a)氫；(b)羥基；(c)1-4C-烷氧基(視情況經(c1)1至2個 OH、(c2)NR⁹R¹⁰取代)；(d)，其中*為連接點； R⁵為(a)氫；(b)2-6C-羥烷基；(c)，其中* 為連接點；(d)-C(O)-(1-6C-烷基)；(e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-46C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²，R⁷為氫、1-6C-烷基、2-6C-烯基、1-6C-烷氧基、3-6C-環烷基、NR⁹R¹⁰，R⁸為氫、1-6C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫、1-6C-烷基，R¹¹、R¹²彼此獨立地為氫、1-6C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 According to a second aspect, the invention relates to a compound of formula (I), wherein R ¹ /R ² are independently of one another hydrogen, halogen, and R ^{3 is} independently of each other hydrogen, 1-6C-alkoxy, halogen, 2- 6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxyl; (c) 1-4C-alkoxy Base (as appropriate by (c1) 1 to 2 OH, (c2) NR ⁹ R ¹⁰ substituted); (d) Where * is the point of attachment; R ⁵ is (a) hydrogen; (b) 2-6C-hydroxyalkyl; (c) Where * is the point of attachment; (d) -C(O)-(1-6C-alkyl); (e)-C(O)-(1-6C-alkylene)-O-(1-6C -alkyl); (f)-C(O)-(1-46C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R ⁶ is Hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , R ⁷ is hydrogen, 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-6C-cycloalkyl NR ⁹ R ¹⁰ , R ⁸ is hydrogen, 1-6C-alkyl, m is 1-4, R ⁹ and R ¹⁰ are each independently hydrogen, 1-6C-alkyl, and R ¹¹ and R ¹² are independently of each other. It is hydrogen, 1-6C-alkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣為如技術方案第1項之式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³獨立地為氫、鹵素、1-4C-烷氧基、3-6C-環烷基、1-4C-鹵烷氧基或C(O)OH， n為1-3，R⁴為(a)氫；(b)羥基；(c)1-4C-烷氧基，視情況經以下取代：(c1)1至2個OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為氫，R⁶為氫、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為2-4C-烯基、1-4C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-4C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-4C-烷基，R¹¹、R¹²彼此獨立地為氫、1-4C-烷基、2-6C-羥烷基或 (1-4C-烷基)-SO₂-(1-4C-烷基)，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the present invention is a compound of the formula (I) according to the first aspect of the invention, wherein R ¹ /R ² are independently of each other hydrogen, halogen or phenyl-S-, and R ^{3 is} independently hydrogen, halogen, 1-4C-alkoxy, 3-6C-cycloalkyl, 1-4C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxyl; (c) 1-4C-alkoxy, optionally substituted by (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; (c4) 1-4C-alkyl-S(O)-; (c5) 1-4C-alkyl-S(O) ₂ -; (c6)S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is hydrogen, R ⁶ is hydrogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is 2-4C-alkenyl, 1-4C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen Or 1-4C-alkyl, m is 1-4, R ⁹ and R ¹⁰ are each independently hydrogen or 1-4C-alkyl, and R ¹¹ and R ¹² are each independently hydrogen, 1-4C-alkyl, 2-6C-hydroxyalkyl or (1-4C-alkyl)-SO ₂ -(1-4C-alkyl), R ¹³ is hydrogen or 1-4C-alkyl, or an N-oxide of the compound, a salt, tautomer or stereoisomer or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣為如技術方案第1項之式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³獨立地為氫、鹵素、1-4C-烷氧基、3-6C-環烷基、1-4C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-4C-烷氧基，視情況經以下取代：(c1)OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為氫，R⁶為氫、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為2-4C-烯基、1-4C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-4C-烷基，m為1，R⁹、R¹⁰彼此獨立地為氫或1-4C-烷基，R¹¹、R¹²彼此獨立地為氫、1-4C-烷基、2-4C-羥烷基或(1-4C-烷基)-SO₂-(1-4C-烷基)，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the present invention is a compound of the formula (I) according to the first aspect of the invention, wherein R ¹ /R ² are independently of each other hydrogen, halogen or phenyl-S-, and R ^{3 is} independently hydrogen, halogen, 1-4C-alkoxy, 3-6C-cycloalkyl, 1-4C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxyl; (c) 1-4C-alkoxy, optionally substituted by: (c1) OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; (c4) 1-4C- alkyl-S(O)-; (c5) 1-4C-alkyl-S(O) ₂ -; (c6)S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is hydrogen, R ⁶ is hydrogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is 2-4C-alkenyl, 1-4C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen Or 1-4C-alkyl, m is 1, R ⁹ and R ¹⁰ are each independently hydrogen or 1-4C-alkyl, and R ¹¹ and R ¹² are independently of each other hydrogen, 1-4C-alkyl, 2- 4C-hydroxyalkyl or (1-4C-alkyl)-SO ₂ -(1-4C-alkyl), R ¹³ is hydrogen or 1-4C-alkyl, or the N-oxide, salt of the compound, A tautomer or a stereoisomer or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³彼此獨立地為氫、1-4C-烷氧基、鹵素、2-4C-烯基、3-6C-環烷基、1-4C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-4C-烷氧基，視情況經以下取代：(c1)1至2個OH； (c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)-S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為(a)氫；(b)2-4C-羥烷基； (c)，其中*為連接點； (d)-C(O)-(1-4C-烷基)；(e)-C(O)-(1-4C-伸烷基)-O-(1-4C-烷基)；(f)-C(O)-(1-4C-伸烷基)-O-(1-4C-伸烷基)-O-(1-4C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為氫、1-4C-烷基、2-4C-烯基、1-4C-烷氧基、3-4C-環烷基或NR⁹R¹⁰， R⁸為氫或1-4C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-4C-烷基，R¹¹、R¹²彼此獨立地為氫、1-4C-烷基、2-4C-羥烷基或(1-4C-烷基)-SO₂-(1-4C-烷基)，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention pertains to compounds of formula (I), wherein R ¹ /R ² are, independently of each other, hydrogen, halogen or phenyl-S-, R ³ independently of one another hydrogen, 1-4C-alkoxy , halogen, 2-4C-alkenyl, 3-6C-cycloalkyl, 1-4C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) Hydroxy; (c) 1-4C-alkoxy, optionally substituted by: (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; C4) 1-4C-alkyl-S(O)-; (c5) 1-4C-alkyl-S(O) ₂ -; (c6)-S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is (a) hydrogen; (b) 2-4C-hydroxyalkyl; c) Where * is the point of attachment; (d) -C(O)-(1-4C-alkyl); (e)-C(O)-(1-4C-alkylene)-O-(1-4C -alkyl); (f)-C(O)-(1-4C-alkylene)-O-(1-4C-alkylene)-O-(1-4C-alkyl), R ⁶ is Hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is hydrogen, 1-4C-alkyl, 2-4C-alkenyl, 1- 4C-alkoxy, 3-4C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen or 1-4C-alkyl, m is 1-4, and R ⁹ and R ¹⁰ are independently hydrogen or 1- 4C-alkyl, R ¹¹ and R ¹² are each independently hydrogen, 1-4C-alkyl, 2-4C-hydroxyalkyl or (1-4C-alkyl)-SO ₂ -(1-4C-alkyl R ¹³ is hydrogen or 1-4C-alkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N-oxide, tautomer or stereoisomer Salt.

本發明之另一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素，R³彼此獨立地為氫、1-4C-烷氧基、鹵素、2-4C-烯基、3-6C-環烷基、鹵烷氧基，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-4C-烷氧基，視情況經(c1)1至2 個OH、(c2)NR⁹R¹⁰取代；(d)，其中*為連接點， R⁵為(a)氫；(b)2-4C-羥烷基；(c)，其中* 為連接點；(d)-C(O)-(1-4C-烷基)；(e)-C(O)-(1-4C-伸烷基)-O-(1-4C-烷基)； (f)-C(O)-(1-4C-伸烷基)-O-(1-4C-伸烷基)-O-(1-4C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²，R⁷為氫、1-4C-烷基、2-4C-烯基、1-4C-烷氧基、3-6C-環烷基、NR⁹R¹⁰，R⁸為氫、1-4C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫、1-4C-烷基，R¹¹、R¹²彼此獨立地為氫、1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention relates to a compound of formula (I), wherein R ¹ /R ² are independently of each other hydrogen, halogen, and R ^{3 is} independently of each other hydrogen, 1-4C-alkoxy, halogen, 2-4C - alkenyl, 3-6C-cycloalkyl, haloalkoxy, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxy; (c) 1-4C-alkoxy, optionally (c1) 1 to 2 OH, (c2) NR ⁹ R ¹⁰ substituted; (d) Where * is the point of attachment, R ⁵ is (a) hydrogen; (b) 2-4C-hydroxyalkyl; (c) Where * is the point of attachment; (d)-C(O)-(1-4C-alkyl); (e)-C(O)-(1-4C-alkylene)-O-(1-4C -alkyl); (f)-C(O)-(1-4C-alkylene)-O-(1-4C-alkylene)-O-(1-4C-alkyl), R ⁶ is Hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , R ⁷ is hydrogen, 1-4C-alkyl, 2-4C-alkenyl, 1-4C-alkoxy, 3-6C-cycloalkyl , NR ⁹ R ¹⁰ , R ⁸ is hydrogen, 1-4C-alkyl, m is 1-4, R ⁹ and R ¹⁰ are each independently hydrogen, 1-4C-alkyl, and R ¹¹ and R ¹² are independently of each other. It is hydrogen, 1-4C-alkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素，R³獨立地為氫、1-4C-烷氧基，n為1-3，R⁴為(b)羥基；(c)1-4C-烷氧基，視情況經(c1)1至2個 OH、(c2)NR⁹R¹⁰取代；(d)，其中*為連接點，R⁵為氫，R⁶為氫、氰基、C(O)NR¹¹R¹²，R⁷為2-4C-烯基、1-4C-烷氧基、3-6C-環烷基、NR⁹R¹⁰，R⁸為氫、1-4C-烷基， m為1-4，R⁹、R¹⁰彼此獨立地為氫、1-4C-烷基，R¹¹、R¹²為氫，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention pertains to compounds of formula (I), wherein R ¹ /R ² are independently of one another hydrogen, halogen, R ^{3 is} independently hydrogen, 1-4C-alkoxy, n is 1-3, R ⁴ is (b) hydroxy; (c) 1-4C-alkoxy, optionally substituted by (c1) 1 to 2 OH, (c2)NR ⁹ R ¹⁰ ; (d) Wherein * is a point of attachment, R ⁵ is hydrogen, R ⁶ is hydrogen, cyano, C(O)NR ¹¹ R ¹² , R ⁷ is 2-4C-alkenyl, 1-4C-alkoxy, 3-6C -cycloalkyl, NR ⁹ R ¹⁰ , R ⁸ is hydrogen, 1-4C-alkyl, m is 1-4, R ⁹ and R ¹⁰ are independently of each other hydrogen, 1-4C-alkyl, R ¹¹ , R ¹² is hydrogen, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素，R³獨立地為氫、1-4C-烷氧基，n為1；R⁴為(b)羥基；(c)1-4C-烷氧基，視情況經(c1)OH、(c2) NR⁹R¹⁰取代；(d)，其中*為連接點， R⁵為氫，R⁶為氫、氰基、C(O)NR¹¹R¹²，R⁷為2-4C-烯基、1-4C-烷氧基、3-6C-環烷基、NR⁹R¹⁰，R⁸為氫、1-4C-烷基，m為1，R⁹、R¹⁰彼此獨立地為氫、1-4C-烷基，R¹¹、R¹²為氫，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention relates to a compound of formula (I), wherein R ¹ /R ² are independently of one another hydrogen, halogen, R ^{3 is} independently hydrogen, 1-4C-alkoxy, n is 1; R ⁴ Is (b) hydroxy; (c) 1-4C-alkoxy, optionally substituted by (c1) OH, (c2) NR ⁹ R ¹⁰ ; (d) Wherein * is the point of attachment, R ⁵ is hydrogen, R ⁶ is hydrogen, cyano, C(O)NR ¹¹ R ¹² , R ⁷ is 2-4C-alkenyl, 1-4C-alkoxy, 3-6C -cycloalkyl, NR ⁹ R ¹⁰ , R ⁸ is hydrogen, 1-4C-alkyl, m is 1, R ⁹ and R ¹⁰ are each independently hydrogen, 1-4C-alkyl, and R ¹¹ and R ¹² are Hydrogen, or an N-oxide, salt, tautomer or stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣為如技術方案第1項之式(I)化合物，其中 R¹/R²彼此獨立地為氫、氟、氯或苯基-S-，R³為氫、氟、甲氧基、乙氧基、環丙基、二氟甲氧基、2,2,2-三氟乙氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)視情況經-S(O)₂NH₂取代之甲氧基；(d)視情況經羥基或-N(CH₃)₂、-SCH₃、-S(O)CH₃或-S(O)₂CH₃取代之乙氧基；(e)經-SCH₃、-S(O)CH₃或-S(O)₂CH₃取代之丙氧基； (f)，其中*為連接點； (g)，其中*為連接點； (h)氰基；(i)-S(O)₂CH₃；(k)-S(O)₂CH(CH₃)₂，R⁵為氫，R⁶為氫、氰基、C(O)NH₂、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為乙烯基、甲氧基、乙氧基、環丙基或-N(CH₃)₂，R⁸為氫、甲基或乙基，m為1， R⁹、R¹⁰為氫或甲基，R¹¹為氫，R¹²為甲基、-CH₂-CH₂-OH、-CH₂-CH₂-SO₂-CH₃，R¹³為氫或乙基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the present invention is a compound of the formula (I) according to the first aspect of the invention, wherein R ¹ /R ² are independently of each other hydrogen, fluorine, chlorine or phenyl-S-, and R ³ is hydrogen or fluorine. Methoxy, ethoxy, cyclopropyl, difluoromethoxy, 2,2,2-trifluoroethoxy or C(O)OH, n is 1-3, and R ⁴ is (a) hydrogen; (b) a hydroxyl group; (c) a methoxy group substituted with -S(O) ₂ NH _{2 as appropriate} ; (d) optionally via a hydroxyl group or -N(CH ₃ ) ₂ , -SCH ₃ , -S(O) CH ₃ or -S(O) ₂ CH ₃ substituted ethoxy; (e) propoxy substituted with -SCH ₃ , -S(O)CH ₃ or -S(O) ₂ CH ₃ ; (f) Where * is the connection point; (g) Where * is the point of attachment; (h) cyano; (i)-S(O) ₂ CH ₃ ; (k)-S(O) ₂ CH(CH ₃ ) ₂ , R ⁵ is hydrogen and R ⁶ is hydrogen , cyano, C(O)NH ₂ , C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is vinyl, methoxy, ethoxy, cyclopropyl Or -N(CH ₃ ) ₂ , R ⁸ is hydrogen, methyl or ethyl, m is 1, R ⁹ , R ¹⁰ is hydrogen or methyl, R ¹¹ is hydrogen, R ¹² is methyl, -CH ₂ - CH ₂ -OH, -CH ₂ -CH ₂ -SO ₂ -CH ₃ , R ¹³ is hydrogen or ethyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N- a salt of an oxide, a tautomer or a stereoisomer.

本發明之另一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、氟或氯，R³為氫、甲氧基或乙氧基，n為1，R⁴為(a)羥基、(b)甲氧基、或(c)乙氧基(視情況經羥基或-N(CH₃)₂取代)、(d)(其中*為連接點)， R⁵為氫，R⁶為氫、氰基、C(O)NH₂，R⁷為乙烯基、甲氧基、乙氧基、環丙基，R⁸為氫、甲基，m為1，R⁹、R¹⁰為甲基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention pertains to compounds of formula (I), wherein R ¹ /R ² are, independently of one another, hydrogen, fluoro or chloro, R ³ is hydrogen, methoxy or ethoxy, n is 1, R ⁴ Is (a) hydroxy, (b) methoxy, or (c) ethoxy (optionally substituted by hydroxy or -N(CH ₃ ) ₂ ), (d) (where * is the point of attachment), R ⁵ is hydrogen, R ⁶ is hydrogen, cyano, C(O)NH ₂ , R ⁷ is vinyl, methoxy, ethoxy, cyclopropyl, and R ⁸ is hydrogen Methyl, m is 1, R ⁹ , R ¹⁰ are methyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N-oxide, tautomer or stereo a salt of an isomer.

本發明之另一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-， R³彼此獨立地為氫、1-6C-烷氧基、鹵素、2-6C-烯基、3-6C-環烷基、1-6C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(c)1-6C-烷氧基，視情況經以下取代：(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)S(O)₂NR⁹R¹⁰； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為(a)氫；(b)2-6C-羥烷基； (c)，其中*為連接點； (d)-C(O)-(1-6C-烷基)；(e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH， R⁷為氫、1-6C-烷基、2-6C-烯基、1-6C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-6C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-6C-烷基，R¹¹、R¹²彼此獨立地為氫、1-6C-烷基、2-6C-羥烷基或2-(甲磺醯基)乙基，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention pertains to compounds of formula (I), wherein R ¹ /R ² are, independently of one another, hydrogen, halogen or phenyl-S-, R ³ independently of one another hydrogen, 1-6C-alkoxy , halogen, 2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy or C(O)OH, n is 1-3, and R ⁴ is (c)1-6C-alkane An oxy group, optionally substituted by: (c3) 1-4C-alkyl-S-; (c4) 1-4C-alkyl-S(O)-; (c5) 1-4C-alkyl-S ( O) ₂ -; (c6) S(O) ₂ NR ⁹ R ¹⁰ ; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is (a) hydrogen; (b) 2-6C-hydroxyalkyl; c) Where * is the point of attachment; (d) -C(O)-(1-6C-alkyl); (e)-C(O)-(1-6C-alkylene)-O-(1-6C -alkyl); (f)-C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R ⁶ is Hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is hydrogen, 1-6C-alkyl, 2-6C-alkenyl, 1- 6C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen or 1-6C-alkyl, m is 1-4, and R ⁹ and R ¹⁰ are independently hydrogen or 1- 6C-alkyl, R ¹¹ and R ¹² are each independently hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl or 2-(methylsulfonyl)ethyl, R ¹³ is hydrogen or 1-4C An alkyl group, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之又一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³彼此獨立地為氫、1-6C-烷氧基、鹵素、2-6C-烯基、3-6C-環烷基、1-6C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(c)1-6C-烷氧基，視情況經以下取代：(c1)1至2個OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； R⁵為(a)氫；(b)2-6C-羥烷基； (c)，其中*為連接點； (d)-C(O)-(1-6C-烷基)；(e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為氫、1-6C-烷基、2-6C-烯基、1-6C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-6C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-6C-烷基，R¹¹、R¹²彼此獨立地為氫、1-6C-烷基、2-6C-羥烷基或2-(甲磺醯基)乙基，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 A further aspect of the invention relates to a compound of formula (I), wherein R ¹ /R ² are, independently of one another, hydrogen, halogen or phenyl-S-, R ³ independently of one another hydrogen, 1-6C-alkoxy , halogen, 2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (c) 1-6C-alkoxy, as the case may be substituted by: (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; (c4) 1-4C -alkyl-S(O)-; (c5) 1-4C-alkyl-S(O) ₂ -; (c6)S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Where * is the point of attachment; R ⁵ is (a) hydrogen; (b) 2-6C-hydroxyalkyl; (c) Where * is the point of attachment; (d) -C(O)-(1-6C-alkyl); (e)-C(O)-(1-6C-alkylene)-O-(1-6C -alkyl); (f)-C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R ⁶ is Hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is hydrogen, 1-6C-alkyl, 2-6C-alkenyl, 1- 6C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen or 1-6C-alkyl, m is 1-4, and R ⁹ and R ¹⁰ are independently hydrogen or 1- 6C-alkyl, R ¹¹ and R ¹² are each independently hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl or 2-(methylsulfonyl)ethyl, R ¹³ is hydrogen or 1-4C An alkyl group, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣係關於式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³彼此獨立地為氫、1-6C-烷氧基、鹵素、2-6C-烯基、3-6C-環烷基、1-6C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-6C-烷氧基，視情況經以下取代：(c1)1至2個OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為 (c)，其中*為連接點； (e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為氫、1-6C-烷基、2-6C-烯基、1-6C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-6C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-6C-烷基，R¹¹、R¹²彼此獨立地為氫、1-6C-烷基、2-6C-羥烷基或2-(甲磺醯基)乙基，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention pertains to compounds of formula (I), wherein R ¹ /R ² are, independently of each other, hydrogen, halogen or phenyl-S-, R ³ independently of one another hydrogen, 1-6C-alkoxy , halogen, 2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) Hydroxy; (c) 1-6C-alkoxy, optionally substituted by: (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; C4) 1-4C-alkyl-S(O)-; (c5) 1-4C-alkyl-S(O) ₂ -; (c6)S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Where * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is (c) Where * is the point of attachment; (e) -C(O)-(1-6C-alkylene)-O-(1-6C-alkyl); (f)-C(O)-(1-6C -alkyl)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R ⁶ is hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , C( O) OR ¹³ or C(O)NHOH, R ⁷ is hydrogen, 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ R ⁸ is hydrogen or 1-6C-alkyl, m is 1-4, R ⁹ and R ¹⁰ are each independently hydrogen or 1-6C-alkyl, and R ¹¹ and R ¹² are independently hydrogen and 1- 6C-alkyl, 2-6C-hydroxyalkyl or 2-(methylsulfonyl)ethyl, R ¹³ is hydrogen or 1-4C-alkyl, or the N-oxide, salt, tautomer of the compound a body or a stereoisomer or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣係關於如技術方案第1項之式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³彼此獨立地為氫、1-6C-烷氧基、鹵素、2-6C-烯基、3-6C-環烷基、1-6C-鹵烷氧基或C(O)OH，n為1-3， R⁴為(a)氫；(c)1-6C-烷氧基，視情況經以下取代：(c1)1至2個OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)-S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點， R⁵為 (c)，其中*為連接點； (e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，R⁶為氫、-C(O)NH-(1-3C-烷基)-OH、-C(O)NH-(1-3C烷基)-SO₂-(1-3C-烷基)或C(O)NHOH，R⁷為氫、1-6C-烷基、2-6C-烯基、1-6C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-6C-烷基， m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-6C-烷基，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the present invention relates to the compound of the formula (I) according to the first aspect of the invention, wherein R ¹ /R ² are independently of each other hydrogen, halogen or phenyl-S-, and R ^{3 is} independently hydrogen, 1-6C-alkoxy, halogen, 2-6C-alkenyl, 3-6C-cycloalkyl, 1-6C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is ( a) hydrogen; (c) 1-6C-alkoxy, optionally substituted by: (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S- (c4)1-4C-alkyl-S(O)-; (c5)1-4C-alkyl-S(O) ₂ -; (c6)-S(O) ₂ NR ⁹ R ¹⁰ ; (d ) Where * is the connection point; (e) Where * is the connection point and R ⁵ is (c) Where * is the point of attachment; (e) -C(O)-(1-6C-alkylene)-O-(1-6C-alkyl); (f)-C(O)-(1-6C -alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R ⁶ is hydrogen, -C(O)NH-(1-3C-alkyl)- OH, -C(O)NH-(1-3C alkyl)-SO ₂ -(1-3C-alkyl) or C(O)NHOH, R ⁷ is hydrogen, 1-6C-alkyl, 2-6C - alkenyl, 1-6C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen or 1-6C-alkyl, m is 1-4, and R ⁹ and R ¹⁰ are independent of each other Is hydrogen or 1-6C-alkyl, R ¹³ is hydrogen or 1-4C-alkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N-oxide, a tautomer or a salt of a stereoisomer.

本發明之另一態樣係關於選自由以下各物組成之群之式(I)化合物：2-[1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-乙氧基-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-環丙基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-乙烯基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲腈；2-[5-環丙基-1-(4-甲氧基苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2,6-二氯苯甲基)-4-甲基-1H-吡唑-3-基]- 5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2-氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2,6-二氯苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(二甲胺基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；{3-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]氧雜環丁烷-3-基}甲醇；2-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)乙醇；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲醯胺；2,4-二氯-3-({5-環丙基-3-[5-甲氧基-4-(吡啶-4-基胺基)嘧啶-2-基]-4-甲基-1H-吡唑-1-基}甲基)苯甲酸；或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention pertains to a compound of formula (I) selected from the group consisting of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5- Oxy-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino) )-1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[1- (2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[ 5-ethoxy-1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; -(1-Benzyl-5-cyclopropyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-(1 -benzylmethyl-5-vinyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-({2-[1 -(2-fluorobenzyl)-5-methoxy-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile; 2-[ 5-cyclopropyl-1-(4-methoxybenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine ;2-[5-cyclopropyl-1-(2,6-dichlorobenzyl)-4-methyl-1 H -pyrazol-3-yl]- 5-methoxy- N- (pyridine -4-base) Piperidin-4-amine; 2- [5-cyclopropyl-1- (2-fluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5-methoxy - N - (pyridin-4-yl)pyrimidine-4-amine; 2-[1-(2,6-dichlorobenzyl)-5-methoxy-4-methyl-1 H -pyrazol-3-yl ]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl) -4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1- (4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol ;2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2 - (dimethylamino) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; {3 - [({2- [5-cyclopropyl-1- (4-ethoxy -2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl Oxetane-3-yl}methanol; 2-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl -1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)ethanol; 4-({2-[1-(2-fluorobenzyl) -5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino Pyridine-3-carboxamide; 2,4-dichloro-3-({5-cyclopropyl-3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2- -4--4-methyl-1 H -pyrazol-1-yl}methyl)benzoic acid; or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N-oxide a tautomer or a salt of a stereoisomer.

本發明之另一態樣為選自由以下各物組成之群之式(I)化合物：2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基硫基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；1-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲磺醯胺；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體1；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲基硫基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；[3-({[2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-基]氧基}甲基)氧雜環丁烷-3-基]甲醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺； 4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼醯胺；2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-甲腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼腈；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-(甲磺醯基)-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-(異丙磺醯基)-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸乙酯；2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺； 4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；2-[5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺對映異構體1；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲亞磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-1-[4-(二氟甲氧基)-2,6-二氟苯甲基]-4-甲基-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-4-甲基-1-[2,3,5,6-四氟-4-(2,2,2-三氟乙氧基)苯甲基]-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺； 4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸；4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-甲基菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-羥基菸鹼醯胺；4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention is a compound of formula (I) selected from the group consisting of 2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenyl) Thio)benzyl]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5-cyclopropyl- 1-(4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2-(methylthio)ethoxy ] - N - (pyridin-4-yl) pyrimidin-4-amine; 1 - ({2- [5-cyclopropyl-1- (4-ethoxy-2,6-difluorobenzyl) - 4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methanesulfonamide; 5-[({2-[5 -cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamine A pyrimidin-5-yl}oxy)methyl]pyrrolidin-2-one enantiomer 1; 5-[({2-[5-cyclopropyl-1-(4-ethoxy)- 2,6-Difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl] Pyrrolidin-2-one enantiomer 2; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H - pyrazol-3-yl] -5- [3- (methylthio) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; [3 - ({[2- {5- Cyclopropyl-1-[4-ethoxy 2-fluoro-6- (phenylthio) benzyl] -4-methyl -1 H - pyrazol-3-yl} -4- (pyridin-4-ylamino) pyrimidin-5-yl ]oxy}methyl)oxetan-3-yl]methanol; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4- methyl -1 H - pyrazol-3-yl] -5- [3- (methanesulfonamide acyl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({2 -[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidine 4-yl}amino) nicotine decylamine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl -1 H -pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinium amide; 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl -1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino)-1-(4) -ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4 -amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4- (pyridin-4-ylamino)pyrimidine-5-carbonitrile; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4 -methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl }amino)nicotinonitrile; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyridyl Zyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) nicotinic acid ethyl ester; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2) ,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinonitrile; 2-[5-cyclopropyl-1-( 4-ethoxy-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- (methanesulfonamide acyl) - N - (pyridin-4-yl Pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl ] -5- (isopropyl sulfonylurea yl) - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({2- [5-cyclopropyl-1- (4-ethoxy -2 ,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino) ethyl nicotinic acid; 2-[4-ethyl-1- (2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-( {2-[4-Ethyl-1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino Ethyl nicotinic acid; 2-[5-cyclopropyl-1-(4-cyclopropyl-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl ] -5-methoxy - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5- Propyl-1- (4-ethoxy-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- [2- (methyl sulfinyl group ) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5-cyclopropyl-1- (4-ethoxy-2,6-difluorobenzyl) - 4-methyl -1 H - pyrazol-3-yl] -5- [2- (methyl sulfinyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine enantiomer iso Construct 1; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5 - [2- (methyl sulfinyl-yl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine enantiomer 2; 2- [5-cyclopropyl-1- (4 -ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[3-(methylsulfinyl)propoxy] -N -(pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H - pyrazol-3-yl] -5- [2- (methanesulfonyl acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- {5-propyl-1 -[4-(Difluoromethoxy)-2,6-difluorobenzyl]-4-methyl-1 H -pyrazol-3-yl}-5-methoxy- N- (pyridine- 4-yl)pyrimidin-4-amine; 2-{5-cyclopropyl-4-methyl-1-[2,3,5,6-tetrafluoro-4-(2,2,2-trifluoroethyl) Oxy)benzyl]-1 H -pyrazol-3-yl}-5-methoxy- N- (pyridine 4-yl)pyrimidine-4-amine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy)- 2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinic acid; 4-({2-[4-ethyl 1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic acid; 4-( {2-[5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy 4-yl} amino) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4 - ({2- [5-cyclopropyl-1- (4-ethoxyphenyl -2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino) -N -methylnicotinium amide; 4-( {2-[5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy 4-yl} amino) - N - (2- hydroxyethyl) niacinamide; 4 - ({2- [5-cyclopropyl-1- (4-ethoxy-2,6 - difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] amino} pyrimidin-4-yl) - N - (2- hydroxyethyl) niacinamide; 4- ( {2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl Yl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4- ( {2-[5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl } amino) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4 - ({2- [5-cyclopropyl-1- (4-ethoxy-2,6 Difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) -N -hydroxynicotinium amide; 4-({ 2-[4-Ethyl-1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) Nicotinamide, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣為選自由以下各物組成之群之式(I)化合物：2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基硫基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；1-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲磺醯胺；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體1；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲基硫基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺； [3-({[2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-基]氧基}甲基)氧雜環丁烷-3-基]甲醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼醯胺；2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-甲腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸乙酯； 2-[5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲亞磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-1-[4-(二氟甲氧基)-2,6-二氟苯甲基]-4-甲基-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-4-甲基-1-[2,3,5,6-四氟-4-(2,2,2-三氟乙氧基)苯甲基]-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-甲基菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基- 1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-羥基菸鹼醯胺，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention is a compound of formula (I) selected from the group consisting of 2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenyl) Thio)benzyl]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5-cyclopropyl- 1-(4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2-(methylthio)ethoxy ] - N - (pyridin-4-yl) pyrimidin-4-amine; 1 - ({2- [5-cyclopropyl-1- (4-ethoxy-2,6-difluorobenzyl) - 4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methanesulfonamide; 5-[({2-[5 -cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamine A pyrimidin-5-yl}oxy)methyl]pyrrolidin-2-one enantiomer 1; 5-[({2-[5-cyclopropyl-1-(4-ethoxy)- 2,6-Difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl] Pyrrolidin-2-one enantiomer 2; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H - pyrazol-3-yl] -5- [3- (methylthio) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; [3 - ({[2- {5- Cyclopropyl-1-[4-ethoxy 2-fluoro-6-(phenylthio)benzyl]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidine-5- 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4 - methyl - -1 H - pyrazol-3-yl] -5- [3- (methanesulfonamide acyl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({ 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy Pyrimidin-4-yl}amino)nicotinium amide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl yl -1 H - pyrazol-3-yl] amino} pyrimidin-4-yl) niacinamide; 2- [5-cyclopropyl-1- (4-methoxybenzyl) -4- Methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino)-1-( 4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine- 4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4 -(pyridin-4-ylamino)pyrimidine-5-carbonitrile; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)- 4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl }amino)nicotinonitrile; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyridyl Zyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) nicotinic acid ethyl ester; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2) ,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinonitrile; 4-({2-[5-cyclopropyl 1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino) ethyl nicotinic acid ; 2-[5-cyclopropyl-1-(4-cyclopropyl-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy yl - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5-cyclopropyl-1- (4-ethoxy-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- [2- (methyl sulfinyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5- Propyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[3-(methylsulfinyl) ) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5-cyclopropyl-1- (4-ethoxy-2,6-difluorobenzyl) - 4-methyl -1 H - pyrazol-3-yl] -5- [2- (methanesulfonyl acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- { 5-cyclopropyl-1-[4-(difluoromethoxy)-2,6-difluorobenzyl ]-4-methyl-1 H -pyrazol-3-yl}-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-{5-cyclopropyl-4- Methyl-1-[2,3,5,6-tetrafluoro-4-(2,2,2-trifluoroethoxy)benzyl]-1 H -pyrazol-3-yl}-5- Methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl) -4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic acid; 4-({2-[5-cyclopropyl-1 -(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)- N- [2-(methylsulfonyl)ethyl]nicotinium amide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl) -4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino) -N -methylnicotinium amide; 4-({2-[5-cyclopropyl-1 -(4-ethoxy-2,6-difluorobenzyl)-4-methyl- 1H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)- N- (2-hydroxyethyl)nicotinium amide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl yl -1 H - pyrazol-3-yl] amino} pyrimidin-4-yl) - N - (2- hydroxyethyl) niacinamide; 4 - ({2- [5-propyl-1 -(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-A Amino} pyrimidin-4-yl oxy) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4 - ({2- [5-cyclopropyl-1- (4-B methyl-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] amino} pyrimidin-4-yl) - N - [2- (methanesulfonyl acyl) Ethyl]nicotine decylamine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyridyl Zyridin-3-yl]-5-methoxypyrimidin-4-yl}amino) -N -hydroxynicotinium amide, or an N-oxide, a salt, a tautomer or a stereoisomer thereof Or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣為選自由以下各物組成之群之式(I)化合物：2-[1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-乙氧基-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N- (吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-環丙基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-乙烯基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲腈；2-[5-環丙基-1-(4-甲氧基苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2,6-二氯苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2-氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2,6-二氯苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(二甲胺基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；{3-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]氧雜環丁烷-3-基}甲醇；2-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)乙醇；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲醯胺；2,4-二氯-3-({5-環丙基-3-[5-甲氧基-4-(吡啶-4-基胺基)嘧啶-2-基]-4-甲基-1H-吡唑-1-基}甲基)苯甲酸；2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基硫基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；1-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲磺醯胺；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體1；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲基硫基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺； [3-({[2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-基]氧基}甲基)氧雜環丁烷-3-基]甲醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼醯胺；2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-甲腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼腈；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-(甲磺醯基)-N-(吡啶-4-基)嘧啶-4-胺； 2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-(異丙磺醯基)-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸乙酯；2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；2-[5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺對映異構體1；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲亞磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4- 胺；2-{5-環丙基-1-[4-(二氟甲氧基)-2,6-二氟苯甲基]-4-甲基-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-4-甲基-1-[2,3,5,6-四氟-4-(2,2,2-三氟乙氧基)苯甲基]-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸；4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-甲基菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基) 乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-羥基菸鹼醯胺；4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention is a compound of formula (I) selected from the group consisting of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy 4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino) 1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[1-( 2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5 -ethoxy-1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2- (1-Benzyl-5-cyclopropyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-(1- Benzyl-5-vinyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-({2-[1- (2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile; 2-[ 5-cyclopropyl-1-(4-methoxybenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine ;2-[5-cyclopropyl-1-(2,6-dichlorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridine -4-yl)pyrimidine 4-amine; 2-[5-cyclopropyl-1-(2-fluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- ( Pyridin-4-yl)pyrimidine-4-amine; 2-[1-(2,6-dichlorobenzyl)-5-methoxy-4-methyl-1 H -pyrazol-3-yl] -5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl) 4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-( 4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-( Dimethylamino)ethoxy]-N-(pyridin-4-yl)pyrimidine-4-amine; {3-[({2-[5-cyclopropyl-1-(4-ethoxy-2) ,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl]oxy Heterocyclobutane-3-yl}methanol; 2-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)ethanol; 4-({2-[1-(2-fluorobenzyl)-) 5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine- 3-methanamine; 2,4-dichloro-3-({5-cyclopropyl-3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]- 4-methyl-1 H -pyrazol-1-yl}methyl)benzoic acid; 2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenylthio) Benzyl]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5-cyclopropyl-1- (4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2-(methylthio)ethoxy]- N- (pyridin-4-yl)pyrimidine-4-amine; 1-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4- Methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methanesulfonamide; 5-[({2-[5-ring] Propyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino) Pyrimidine-5-yl}oxy)methyl]pyrrolidin-2-one enantiomer 1; 5-[({2-[5-cyclopropyl-1-(4-ethoxy-2, 6-Difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl]pyrrolidine 2-keto enantiomer 2; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole 3-yl] -5- [3- (methylthio) propoxy] - N - (pyrazol 4-yl)pyrimidine-4-amine; [3-({[2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenylthio))benzyl) ]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidin-5-yl]oxy}methyl)oxetan-3-yl Methanol; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5- [3- (methanesulfonyl acyl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({2- [5-cyclopropyl-1- (4-ethoxy -2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinamide; 4-( {2-[5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl "amino" nicotine decylamine; 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1 H -pyrazol-3-yl]-5- Oxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino)-1-(4-ethoxy-2,6-difluorobenzyl)- 4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4) -ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-carbonitrile; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzene) Yl) -4-methyl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) nicotinic nitrile; 4 - ({2- [5-cyclopropyl - 1-(4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) Ethyl nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole- 3-yl]pyrimidin-4-yl}amino)nicotinonitrile; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl -1 H - pyrazol-3-yl] -5- (methanesulfonamide acyl) - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5-cyclopropyl-1- (4- ethoxy-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- (isopropyl sulfonylurea yl) - N - (pyridin-4-yl) Pyrimidin-4-amine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole- 3-yl]pyrimidin-4-yl}amino) ethyl nicotinic acid; 2-[4-ethyl-1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazole- 3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-({2-[4-ethyl-1-(2-fluorobenzyl)-5 -methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) nicotinic acid ethyl ester; 2-[5-cyclopropyl-1-(4- Cyclopropyl-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3 -yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzene ) -4-methyl -1 H - pyrazol-3-yl] -5- [2- (methyl sulfinyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4 Amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[ 2- (methyl sulfinyl-yl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine enantiomer 1; 2- [5-cyclopropyl-1- (4-b methyl-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- [2- (methyl sulfinyl) ethoxy] - N - ( Pyridin-4-yl)pyrimidine-4-amine enantiomer 2; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl yl -1 H - pyrazol-3-yl] -5- [3- (methyl sulfinyl-yl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5- Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2-(methylsulfonyl) ) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- {5-cyclopropyl-1- [4- (difluoromethoxy) -2,6-difluorophenyl Methyl]-4-methyl-1 H -pyrazol-3-yl}-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-{5-cyclopropyl- 4-methyl-1-[2,3,5,6-tetrafluoro-4-(2,2,2-trifluoroethyl) Yl) benzyl] -1 H - pyrazol-5-methoxy-3-yl} - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({2- [5- cyclopropyloxy 1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amine Nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole- 3-yl]pyrimidin-4-yl}amino)nicotinic acid; 4-({2-[4-ethyl-1-(2-fluorobenzyl)-5-methoxy-1 H -pyridyl) Zin-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6) - difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - [2- (methanesulfonyl acyl) Ethyl]nicotine decylamine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyridyl Zyridin-3-yl]pyrimidin-4-yl}amino) -N -methylnicotinium amide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6) - difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - (2- hydroxyethyl) nicotine Indoleamine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl) ] pyrimidin-4-yl} amino) - N - (2- hydroxyethyl) niacinamide; 4- ( {2-[5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy 4-yl} amino) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4 - ({2- [5-cyclopropyl-1- (4-ethoxyphenyl methyl-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] amino} pyrimidin-4-yl) - N - [2- (methanesulfonyl acyl) acetate Nicotinamide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole 3-yl]-5-methoxypyrimidin-4-yl}amino) -N -hydroxynicotinium amide; 4-({2-[4-ethyl-1-(2-fluorobenzyl) -5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinium amide, or N-oxide, salt, mutual An isomer or a stereoisomer or a salt of the N-oxide, tautomer or stereoisomer.

本發明之另一態樣為選自由以下各物組成之群之式(I)化合物：2-[1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-乙氧基-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-環丙基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-乙烯基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶- 4-基)嘧啶-4-胺；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲腈；2-[5-環丙基-1-(4-甲氧基苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2,6-二氯苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2-氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2,6-二氯苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(二甲胺基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；{3-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]氧雜環丁烷-3-基}甲醇；2-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)乙醇；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲醯胺；2,4-二氯-3-({5-環丙基-3-[5-甲氧基-4-(吡啶-4-基胺基)嘧啶-2-基]-4-甲基-1H-吡唑-1-基}甲基)苯甲酸；2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基硫基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；1-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲磺醯胺；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體1；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲基硫基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；[3-({[2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-基]氧基}甲基)氧雜環丁烷-3-基]甲醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼醯胺；2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-甲腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸乙酯；2-[5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4- 胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲亞磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-1-[4-(二氟甲氧基)-2,6-二氟苯甲基]-4-甲基-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-4-甲基-1-[2,3,5,6-四氟-4-(2,2,2-三氟乙氧基)苯甲基]-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-甲基菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺； 4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-羥基菸鹼醯胺，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 Another aspect of the invention is a compound of formula (I) selected from the group consisting of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy 4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino) 1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[1-( 2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5 -ethoxy-1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2- (1-Benzyl-5-cyclopropyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-(1- Benzyl-5-vinyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-({2-[1- (2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile; 2-[ 5-cyclopropyl-1-(4-methoxybenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine ;2-[5-cyclopropyl-1-(2,6-dichlorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridine -4-yl)pyrimidine 4-amine; 2-[5-cyclopropyl-1-(2-fluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- ( Pyridin-4-yl)pyrimidine-4-amine; 2-[1-(2,6-dichlorobenzyl)-5-methoxy-4-methyl-1 H -pyrazol-3-yl] -5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl) 4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-( 4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-( Dimethylamino)ethoxy]-N-(pyridin-4-yl)pyrimidine-4-amine; {3-[({2-[5-cyclopropyl-1-(4-ethoxy-2) ,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl]oxy Heterocyclobutane-3-yl}methanol; 2-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)ethanol; 4-({2-[1-(2-fluorobenzyl)-) 5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine- 3-methanamine; 2,4-dichloro-3-({5-cyclopropyl-3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]- 4-methyl-1 H -pyrazol-1-yl}methyl)benzoic acid; 2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenylthio) Benzyl]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5-cyclopropyl-1- (4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2-(methylthio)ethoxy]- N- (pyridin-4-yl)pyrimidine-4-amine; 1-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4- Methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methanesulfonamide; 5-[({2-[5-ring] Propyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino) Pyrimidine-5-yl}oxy)methyl]pyrrolidin-2-one enantiomer 1; 5-[({2-[5-cyclopropyl-1-(4-ethoxy-2, 6-Difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl]pyrrolidine 2-keto enantiomer 2; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole 3-yl] -5- [3- (methylthio) propoxy] - N - (pyrazol 4-yl)pyrimidine-4-amine; [3-({[2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenylthio))benzyl) ]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidin-5-yl]oxy}methyl)oxetan-3-yl Methanol; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5- [3- (methanesulfonyl acyl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({2- [5-cyclopropyl-1- (4-ethoxy -2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinamide; 4-( {2-[5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl "amino" nicotine decylamine; 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1 H -pyrazol-3-yl]-5- Oxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino)-1-(4-ethoxy-2,6-difluorobenzyl)- 4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4) -ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-carbonitrile; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorophenyl) 4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinonitrile; 4-({2-[5-cyclopropyl- 1-(4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) Ethyl nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole- 3-yl]pyrimidin-4-yl}amino)nicotinonitrile; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)- 4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino) ethyl nicotinic acid; 2-[5-cyclopropyl-1-(4-cyclopropyl-2, 6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5 -cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2-(methyl sulfin acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5-cyclopropyl-1- (4-ethoxy-2,6-difluorophenyl methyl ) -4-methyl -1 H - pyrazol-3-yl] -5- [3- (methyl sulfinyl-yl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2- (methanesulfonamide acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2 -{5-cyclopropyl-1-[4-(difluoromethoxy)-2,6-difluorobenzyl]-4-methyl-1 H -pyrazol-3-yl}-5- Methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-{5-cyclopropyl-4-methyl-1-[2,3,5,6-tetrafluoro-4-( 2,2,2-trifluoroethoxy)benzyl]-1 H -pyrazol-3-yl}-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; -({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5- Methoxypyrimidin-4-yl}amino)nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4 - methyl - -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4 -({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidine-4 -yl}amino) -N -methylnicotinate guanamine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4 - methyl - -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - (2- hydroxyethyl) niacinamide; 4 - ({2- [5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino ) - N - (2- hydroxyethyl) niacinamide; 4 - ({2- [5-cyclopropyl-1- (4-ethoxyphenyl -2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - [2- (methyl Sulfhydryl)ethyl]nicotinium amide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl- 1 H - pyrazol-3-yl] amino} pyrimidin-4-yl) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4 - ({2- [5- cyclopropyloxy 1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amine N -hydroxynicotinium amide, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or a salt of the N-oxide, tautomer or stereoisomer.

本發明之又一態樣為：2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺及4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲腈。 A further aspect of the invention is: 2-[1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridine 4-yl)pyrimidine-4-amine and 4-({2-[1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxy Pyrimidin-4-yl}amino)pyridine-3-carbonitrile.

本發明之一態樣為如實例中所述之式(I)化合物，其特徵在於其在如技術方案第5項中所主張之標題中之名稱及其結構，以及在實例化合物中特定揭示之所有殘基的子組合。 One aspect of the invention is a compound of formula (I) as described in the examples, which is characterized by its name in the title as claimed in claim 5 and its structure, as well as the particular disclosure in the example compounds. Sub-combination of all residues.

本發明之另一態樣為用於其合成之中間物。 Another aspect of the invention is an intermediate for its synthesis.

若如本文揭示之本發明實施例係關於式(I)化合物，則應瞭解彼等實施例係指如申請專利範圍及實例中之任一者中所揭示之式(I)化合物。 If an embodiment of the invention as disclosed herein relates to a compound of formula (I), it is to be understood that the examples refer to a compound of formula (I) as disclosed in any one of the claims and examples.

本發明之另一態樣為式(I)化合物，其中R¹、R²彼此獨立地為氫或鹵素(尤其為氟、氯、溴)。 Another aspect of the invention is a compound of formula (I), wherein R ¹ , R ² are, independently of each other, hydrogen or halogen (especially fluorine, chlorine, bromine).

本發明之另一態樣為式(I)化合物，其中R¹、R²為氟或氯。 Another aspect of the invention is a compound of formula (I), wherein R ¹ , R ² are fluoro or chloro.

本發明之另一態樣為式(I)化合物，其中R¹、R²為氟。 Another aspect of the invention is a compound of formula (I), wherein R ¹ , R ² are fluoro.

本發明之另一態樣為式(I)化合物，其中R¹、R²為-S-苯基。 Another aspect of the invention is a compound of formula (I), wherein R ¹ , R ² are -S-phenyl.

本發明之另一態樣為式(I)化合物，其中R³為氫、1-4C-烷氧基、鹵素、1-4C-烷基、2-4C-烯基或3-6C-環烷基。 Another aspect of the invention is a compound of formula (I), wherein R ³ is hydrogen, 1-4C-alkoxy, halogen, 1-4C-alkyl, 2-4C-alkenyl or 3-6C-cycloalkane base.

本發明之又一態樣為式(I)化合物，其中R³為氫或1-4C-烷氧基。 Yet another aspect is a compound of formula (I) of the present invention, wherein R ³ is hydrogen or 1-4C- alkoxy.

本發明之又一態樣為式(I)化合物，其中R³為-C(O)OH。 A further aspect of the invention is a compound of formula (I), wherein R ³ is -C(O)OH.

本發明之另一態樣為式(I)化合物，其中R³為鹵素、1-4C-烷基、2-4C-烯基或3-6C-環烷基。 Another aspect is a compound of formula (I) of the present invention, wherein R ³ is halogen, 1-4C-alkyl, 2-4C-alkenyl or 3-6C- cycloalkyl.

本發明之另一態樣為式(I)化合物，其中R³相對於R¹或R²位於鄰位或間位。 Another aspect of the invention is a compound of formula (I), wherein R ³ is in the ortho or meta position relative to R ¹ or R ² .

本發明之另一態樣為式(I)化合物，其中R³相對於R¹或R²位於鄰位。 Another aspect of the invention is a compound of formula (I), wherein R ³ is ortho to R ¹ or R ² .

本發明之另一態樣為式(I)化合物，其中R³相對於苯環與苯甲基亞甲基之連接點位於對位。 Another aspect is a compound of the present invention of formula (I), wherein R ³ and the phenyl ring relative to the point of attachment of methyl benzyl sulfoxide in the para position.

本發明之另一態樣為式(I)化合物，其中 R¹、R²為氟且R³為1-4C-烷氧基。 Another aspect of the invention is a compound of formula (I), wherein R ¹ , R ² are fluoro and R ³ is 1-4C-alkoxy.

本發明之又一態樣為式(I)化合物，其中n為1。 A further aspect of the invention is a compound of formula (I) wherein n is 1.

本發明之另一態樣為式(I)化合物，其中n為3。 Another aspect of the invention is a compound of formula (I), wherein n is 3.

本發明之另一態樣為式(I)化合物，其中m為1。 Another aspect of the invention is a compound of formula (I), wherein m is 1.

本發明之又一態樣為式(I)化合物，其中R⁴為羥基、1-4C烷氧基(視情況經羥基或NR⁹R¹⁰取代)、-S-(1-4C-烷基)、-S(O)-(1-4C-烷基)、-SO₂-(1-4C-烷基)或 (其中*為連接點)。 A further aspect of the invention is a compound of formula (I), wherein R ⁴ is hydroxy, 1-4C alkoxy (optionally substituted by hydroxy or NR ⁹ R ¹⁰ ), -S-(1-4C-alkyl) , -S(O)-(1-4C-alkyl), -SO ₂ -(1-4C-alkyl) or (where * is the connection point).

本發明之另一態樣為式(I)化合物，其中R⁴為-S-(1-4C-烷基)、-S(O)-(1-4C-烷基)、-SO₂-(1-4C-烷基)。 Another aspect of the invention is a compound of formula (I), wherein R ⁴ is -S-(1-4C-alkyl), -S(O)-(1-4C-alkyl), -SO ₂ -( 1-4C-alkyl).

本發明之又一態樣為式(I)化合物，其中R⁴為羥基、1-4C烷氧基(視情況經羥基或NR⁹R¹⁰取代)或 (其中*為連接點)。 A further aspect of the invention is a compound of formula (I), wherein R ⁴ is hydroxy, 1-4C alkoxy (optionally substituted with hydroxy or NR ⁹ R ¹⁰ ) or (where * is the connection point).

本發明之另一態樣為式(I)化合物，其中R⁴為氫；(c)1-6C-烷氧基，視情況經以下取代：1至2個OH、NR⁹R¹⁰、1-4C-烷基-S-、1-4C-烷基-S(O)-、1-4C-烷基-S(O)₂-、S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點。 Another aspect of the invention is a compound of formula (I), wherein R ⁴ is hydrogen; (c) 1-6C-alkoxy, optionally substituted by 1 to 2 OH, NR ⁹ R ¹⁰ , 1 4C-alkyl-S-, 1-4C-alkyl-S(O)-, 1-4C-alkyl-S(O) ₂ -, S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) , where * is the connection point.

本發明之另一態樣為式(I)化合物，其中R⁴為氫、視情況經1-4C-烷基-S-、1-4C-烷基-S(O)-、1-4C-烷基-S(O)₂-、S(O)₂NR⁹R¹⁰取代之1-6C-烷氧基。 Another aspect of the invention is a compound of formula (I), wherein R ⁴ is hydrogen, optionally 1-4C-alkyl-S-, 1-4C-alkyl-S(O)-, 1-4C- Alkyl-S(O) ₂ -, S(O) ₂ NR ⁹ R ¹⁰ substituted 1-6C-alkoxy.

本發明之另一態樣為式(I)化合物，其中R⁴為氫。 Another aspect of the invention is a compound of formula (I), wherein R ⁴ is hydrogen.

本發明之另一態樣為式(I)化合物，其中 R⁵為(c)，其中*為連接點； (e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)。 Another aspect of the invention is a compound of formula (I), wherein R ⁵ is (c) Where * is the point of attachment; (e) -C(O)-(1-6C-alkylene)-O-(1-6C-alkyl); (f)-C(O)-(1-6C -alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl).

本發明之另一態樣為式(I)化合物，其中R⁵為氫。 Another aspect is a compound of formula (I) of the present invention, wherein R ⁵ is hydrogen.

本發明之另一態樣為式(I)化合物，其中R⁶為氫、氰基或(CO)NR¹¹R¹²。 Another aspect of the invention is a compound of formula (I), wherein R ⁶ is hydrogen, cyano or (CO)NR ¹¹ R ¹² .

本發明之另一態樣為式(I)化合物，其中R⁶為氫、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH。 Another aspect of the invention is a compound of formula (I), wherein R ⁶ is hydrogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH.

本發明之另一態樣為式(I)化合物，其中R⁶為C(O)NR¹¹R¹²。 Another aspect of the invention is a compound of formula (I), wherein R ⁶ is C(O)NR ¹¹ R ¹² .

本發明之又一態樣為式(I)化合物，其中R⁶為C(O)OR¹³。 A further aspect of the invention is a compound of formula (I), wherein R ⁶ is C(O)OR ¹³ .

本發明之又一態樣為式(I)化合物，其中R⁶為氫或-C(O)NH-OH、-C(O)NH-(1-3C-烷基)-OH或-C(O)NH-(1-3C-烷基)-SO₂-(1-3C-烷基)，尤其為氫或-C(O)NH-OH、-C(O)NH-(CH₂)₂-OH、-C(O)NH-(CH₂-)₂-SO₂-CH₃。 A further aspect of the invention is a compound of formula (I), wherein R ⁶ is hydrogen or -C(O)NH-OH, -C(O)NH-(1-3C-alkyl)-OH or -C( O) NH-(1-3C-alkyl)-SO ₂ -(1-3C-alkyl), especially hydrogen or -C(O)NH-OH, -C(O)NH-(CH ₂ ) ₂ -OH, -C(O)NH-(CH ₂ -) ₂ -SO ₂ -CH ₃ .

本發明之又一態樣為式(I)化合物，其中R⁶位於吡啶之3-位置。 Compound further aspect of the present invention of formula (I), wherein R ^{6 is} located at the 3-position of the pyridine.

本發明之另一態樣為式(I)化合物，其中R⁷為1-4C-烷基。 Another aspect is a compound of formula (I) of the present invention, wherein R ⁷ is 1-4C- alkyl.

本發明之一態樣為式(I)化合物，其中R⁷為2-4C-烯基、1-4C-烷氧基、3-6C-環烷基、NR⁹R¹⁰，尤其為乙烯基、甲氧基、乙氧基、環丙基或-N(CH₃)₂。 One aspect of the invention is a compound of formula (I), wherein R ⁷ is 2-4C-alkenyl, 1-4C-alkoxy, 3-6C-cycloalkyl, NR ⁹ R ¹⁰ , especially vinyl, Methoxy, ethoxy, cyclopropyl or -N(CH ₃ ) ₂ .

本發明之一態樣為式(I)化合物，其中R⁷為氫。 One aspect of the present invention is a sample of formula (I) compounds wherein R ⁷ is hydrogen.

本發明之另一態樣為式(I)化合物，其中R⁸為氫或甲基且R⁷不為氫。 Another aspect of the invention is a compound of formula (I), wherein R ⁸ is hydrogen or methyl and R ^{7 is} not hydrogen.

本發明之另一態樣為式(I)化合物，其中R⁸為氫或甲基、乙基且R⁷不為氫，R⁹、R¹⁰為氫或甲基。 Another aspect is a compound of the present invention of formula (the I), wherein R ⁸ is hydrogen or a methyl group, an ethyl group and R ⁷ is not hydrogen, R ^9, R ¹⁰ is hydrogen or methyl.

本發明之另一態樣為式(I)化合物，其中R¹¹為氫且R¹²為氫、(1-3C-烷基)、1-3C-羥烷基或(1-3C-烷基)-SO₂-(1-3C-烷基)，尤其為氫、甲基、羥乙基或2-甲磺醯基乙基。 Another aspect of the invention is a compound of formula (I), wherein R ¹¹ is hydrogen and R ¹² is hydrogen, (1-3C-alkyl), 1-3C-hydroxyalkyl or (1-3C-alkyl) -SO ₂ -(1-3C-alkyl), especially hydrogen, methyl, hydroxyethyl or 2-methylsulfonylethyl.

本發明之另一態樣為式(I)化合物，其中R¹³為氫或乙基。 Another aspect of the present invention is a sample of formula (I) compounds wherein R ¹³ is hydrogen or ethyl.

本發明之另一態樣為式(I)化合物，其中R¹³為氫。 Another aspect of the invention is a compound of formula (I), wherein R ¹³ is hydrogen.

本發明之又一態樣為式(I)化合物，其中R¹³為1-3C-烷基，尤其為乙基。 Yet another aspect is a compound of formula (I) of the present invention, wherein R ¹³ is 1-3C- alkyl, especially ethyl.

定義definition

除非另外說明，否則如本文所述視情況經取代之組分可在任何可能的位置彼此獨立地經取代一或多次。當任何變數在任何組分中出現一次以上時，每一定義均為獨立的。 Unless otherwise stated, optionally substituted components as described herein may be substituted one or more times independently of one another at any possible position. Each definition is independent when any variable occurs more than once in any component.

除非申請專利範圍中另外定義，否則下文定義之組分可視情況經選自以下之取代基相同或不同地取代一或多次：羥基、鹵素、氰基、1-6C-烷基、1-4C-鹵烷基、1-6C-烷氧基、-NR⁹R¹⁰、氰基、(=O)、-C(O)NR¹¹R¹²、-C(O)OR¹³、-NHC(O)R¹²、-NHS(O)₂R¹²。經鹵素取代多次之烷基組分亦包括經完全鹵化之烷基部分，諸如CF₃。 Unless otherwise defined in the scope of the patent application, the components defined below may optionally be substituted one or more times with substituents selected from the group consisting of hydroxyl, halogen, cyano, 1-6C-alkyl, 1-4C. -haloalkyl, 1-6C-alkoxy, -NR ⁹ R ¹⁰ , cyano, (=O), -C(O)NR ¹¹ R ¹² , -C(O)OR ¹³ , -NHC(O) R ¹² , -NHS(O) ₂ R ¹² . The alkyl component substituted a plurality of halogens also includes a fully halogenated alkyl moiety such as CF ₃ .

若一個組分由一個以上部分組成，例如-O-(1-6C烷基)-(3-7C-環烷基)，則可能的取代基之位置可位於任何適合位置之任何該等部分處。該組分開頭處之連字符標記與分子剩餘部分之連接點。若一個環經取代，則取代基可位於該環之任何適合位置，若適合則亦可位於環氮原子上。 If a component consists of more than one moiety, such as -O-(1-6C alkyl)-(3-7C-cycloalkyl), the position of the possible substituents may be at any such moiety at any suitable position. . The point at which the hyphen at the beginning of the component is attached to the remainder of the molecule. If a ring is substituted, the substituent may be at any suitable position on the ring and, if appropriate, on the ring nitrogen atom.

術語「包含」在本說明書中使用時包括「由......組成」。 The term "comprising" is used in this specification to include "by... to make".

若在描述中涉及「如上文提及」或「上文提及」，則係指本說明書中任何前面章頁中所作之任何揭示。 References to "as mentioned above" or "mentioned above" in the description refer to any disclosure made in any of the preceding chapters of this specification.

在本發明之意義內，「適合」意謂在化學上有可能藉由屬於熟習此項技術者知識範圍內之方法來達成。 Within the meaning of the present invention, "suitable" means chemically possible by means of methods within the knowledge of those skilled in the art.

「1-6C-烷基」為具有1至6個碳原子之直鏈或分支鏈烷基。實例為甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基及第三丁基、戊基、己基，較佳具有1至4個碳原子(1-4C-烷基)，更佳具有1至3個碳原子(1-3C-烷基)。本文提及之具有另一碳原子數目之其他烷基組分應考慮其鏈之不同長度而如上文提及來定義。含有烷基鏈作為組分兩個其他部分之間的橋接部分(通常稱作「伸烷基」部分)的彼等組分部分係與上文關於烷基之定義一致地來定義，包括較佳鏈長度，例如亞甲基、伸乙基、伸正丙基、伸異丙基、伸正丁基、伸異丁基、伸第三丁基。 The "1-6C-alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and tert-butyl, pentyl, hexyl, preferably having 1 to 4 carbon atoms (1 -4C-alkyl), more preferably 1 to 3 carbon atoms (1-3C-alkyl). Other alkyl components mentioned herein having another number of carbon atoms should be defined as mentioned above, taking into account the different lengths of the chains. The component portion of the bridging moiety (generally referred to as the "alkylene" moiety) containing the alkyl chain as the component is defined in accordance with the definition above for the alkyl group, including preferably. Chain length, such as methylene, ethyl, propyl, isopropyl, butyl, butyl, and butyl.

「2-6C-烯基」為具有2至6個碳原子之直鏈或分支鏈烯基。實例為丁-2-烯基、丁-3-烯基(高烯丙基)、丙-1-烯基、丙-2-烯基(烯丙基)及乙烯基(ethenyl)(乙烯基(vinyl))。 The "2-6C-alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms. Examples are but-2-enyl, but-3-enyl (homoallyl), prop-1-enyl, prop-2-enyl (allyl) and ethenyl (vinyl ( Vinyl)).

「單-或二-1-4C-烷胺基」基團除氮原子以外還獨立地含有上文提及1-4C-烷基中之一或兩者。實例為甲胺基、乙胺基、異丙胺基、二甲胺基、二乙胺基及二異丙胺基。 The "mono- or di-1-4C-alkylamino" group independently contains one or both of the above-mentioned 1-4C-alkyl groups in addition to the nitrogen atom. Examples are methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino and diisopropylamino.

本發明含義內之「鹵素」為碘、溴、氯或氟，本發明含義內之「鹵素」較佳為氯或氟，若在合成中需要鹵素原子作為離去基，則碘或溴為較佳。 The "halogen" within the meaning of the present invention is iodine, bromine, chlorine or fluorine, and "halogen" within the meaning of the present invention is preferably chlorine or fluorine, if a halogen atom is required in the synthesis. As the leaving group, iodine or bromine is preferred.

「1-6C-鹵烷基」為具有1至6個碳原子之直鏈或分支鏈烷基，其中至少一個氫經鹵素原子取代。實例為氯甲基或2-溴乙基。對於經部分或完全氟化之C1-C4-烷基而言，考慮以下經部分或完全氟化之基團，例如氟甲基、二氟甲基、三氟甲基、氟乙基、1,1-二氟乙基、1,2-二氟乙基、1,1,1-三氟乙基、四氟乙基及五氟乙基，其中二氟甲基、三氟甲基或1,1,1-三氟乙基較佳。所有可能之經部分或完全氟化之1-6C-烷基均被認為由術語1-6C-鹵烷基所涵蓋。 The "1-6C-haloalkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms in which at least one hydrogen is substituted by a halogen atom. Examples are chloromethyl or 2-bromoethyl. For partially or fully fluorinated C1-C4-alkyl groups, consider the following partially or fully fluorinated groups such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1, 1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl and pentafluoroethyl, wherein difluoromethyl, trifluoromethyl or 1, 1,1-Trifluoroethyl is preferred. All possible partially or fully fluorinated 1-6C-alkyl groups are considered to be encompassed by the term 1-6C-haloalkyl.

「1-6C-羥烷基」為具有1至6個碳原子之直鏈或分支鏈烷基，其中至少一個氫原子經羥基取代。實例為羥甲基、1-羥乙基、2-羥乙基、1,2-二羥乙基、3-羥丙基、2-羥丙基、2,3-二羥丙基、3-羥基-2-甲基-丙基、2-羥基-2-甲基-丙基、1-羥基-2-甲基-丙基。 The "1-6C-hydroxyalkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms in which at least one hydrogen atom is substituted with a hydroxyl group. Examples are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 3- Hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl.

「1-6C-烷氧基」表示除氧原子以外還含有具有1至6個碳原子之直鏈或分支鏈烷基的基團。可提及之實例為己氧基、戊氧基、丁氧基、異丁氧基、第二丁氧基、第三丁氧基、丙氧基、異丙氧基、乙氧基及甲氧基，較佳為甲氧基、乙氧基、丙氧基、異丙氧基。除非另外說明，否則烷氧基可經羥基、鹵素取代一或多次。 The "1-6C-alkoxy group" means a group having a linear or branched alkyl group having 1 to 6 carbon atoms in addition to the oxygen atom. Examples which may be mentioned are hexyloxy, pentyloxy, butoxy, isobutoxy, second butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy The group is preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group. Unless otherwise stated, an alkoxy group may be substituted one or more times with a hydroxyl group or a halogen.

「1-6C-鹵烷氧基」表示除氧原子以外還含有具有1至6個碳原子之直鏈或分支鏈烷基的基團，其中至少一個氫經鹵素原子取代。實例為-O-CFH₂、-O-CF₂H、-O-CF₃、-O-CH₂-CFH₂、-O-CH₂-CF₂H、-O-CH₂-CF₃。較佳為-O- CF₂H、-O-CF₃、-O-CH₂-CF₃。 The "1-6C-haloalkoxy group" means a group having a linear or branched alkyl group having 1 to 6 carbon atoms in addition to the oxygen atom, wherein at least one hydrogen is substituted by a halogen atom. Examples are -O-CFH ₂ , -O-CF ₂ H, -O-CF ₃ , -O-CH ₂ -CFH ₂ , -O-CH ₂ -CF ₂ H, -O-CH ₂ -CF ₃ . Preferred is -O-CF ₂ H, -O-CF ₃ , -O-CH ₂ -CF ₃ .

「3-7C-環烷基」代表環丙基、環丁基、環戊基、環己基或環庚基，較佳為環丙基。 The "3-7C-cycloalkyl group" represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, preferably a cyclopropyl group.

NR⁹R¹⁰基團例如包括NH₂、N(H)CH₃、N(CH₃)₂、N(H)CH₂CH₃及N(CH₃)CH₂CH₃。 The NR ⁹ R ¹⁰ group includes, for example, NH ₂ , N(H)CH ₃ , N(CH ₃ ) ₂ , N(H)CH ₂ CH ₃ and N(CH ₃ )CH ₂ CH ₃ .

C(O)NR¹¹R¹²基團例如包括C(O)NH₂、C(O)N(H)CH₃、C(O)N(CH₃)₂、C(O)N(H)CH₂CH₃、C(O)N(CH₃)CH₂CH₃或C(O)N(CH₂CH₃)₂。若R¹¹或R¹²不為氫，則其可經羥基取代。 The C(O)NR ¹¹ R ¹² group includes, for example, C(O)NH ₂ , C(O)N(H)CH ₃ , C(O)N(CH ₃ ) ₂ , C(O)N(H)CH ₂ CH ₃ , C(O)N(CH ₃ )CH ₂ CH ₃ or C(O)N(CH ₂ CH ₃ ) ₂ . If R ¹¹ or R ^{12 is} not hydrogen, it may be substituted with a hydroxyl group.

在本發明化合物之特性之情形下，術語「藥物動力學概況」意謂一個單一參數或其組合，包括如在一項適合實驗中量測之滲透性、生物可用性、曝露量及藥力學參數(諸如藥理學效應之持續時間或幅度)。具有改良藥物動力學概況之化合物例如可以較低劑量使用以達成相同效應，可達成較長之持續作用時間或可達成兩種效應之組合。 In the context of the properties of the compounds of the invention, the term "pharmacokinetic profile" means a single parameter or a combination thereof, including permeability, bioavailability, exposure, and pharmacokinetic parameters as measured in a suitable assay ( Such as the duration or magnitude of pharmacological effects). Compounds with improved pharmacokinetic profiles can be used, for example, in lower doses to achieve the same effect, with a longer duration of action or a combination of both effects.

本發明化合物之鹽包括所有無機及有機酸加成鹽及鹼鹽，尤其為所有醫藥學上可接受之無機及有機酸加成鹽及鹼鹽，特別為藥學上常用之所有醫藥學上可接受之無機及有機酸加成鹽及鹼鹽。 The salts of the compounds of the present invention include all inorganic and organic acid addition salts and base salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts and base salts, especially all pharmaceutically acceptable pharmaceuticals. Inorganic and organic acid addition salts and alkali salts.

本發明之一態樣為本發明化合物之鹽，包括所有無機及有機酸加成鹽，尤其為所有醫藥學上可接受之無機及有機酸加成鹽，特別為藥學上常用之所有醫藥學上可接受之無機及有機酸加成鹽。本發明之另一態樣為與二羧酸及三羧酸形成之鹽。 An aspect of the invention is a salt of a compound of the invention, including all inorganic and organic acid addition salts, especially all pharmaceutically acceptable inorganic and organic acid addition salts, especially for all pharmaceutically acceptable pharmaceuticals Acceptable inorganic and organic acid addition salts. Another aspect of the invention is a salt formed with a dicarboxylic acid and a tricarboxylic acid.

酸加成鹽之實例包括(但不限於)鹽酸鹽、氫溴酸鹽、磷酸鹽、硝酸鹽、硫酸鹽、胺磺酸鹽、甲酸鹽、乙酸鹽、丙酸鹽、檸檬酸鹽、D-葡糖酸鹽、苯甲酸鹽、2-(4-羥基苯甲醯基)苯甲酸鹽、丁酸鹽、水楊酸鹽、磺基水楊酸鹽、乳酸鹽、順丁烯二酸鹽、月矽酸鹽、蘋果酸鹽、反丁烯二酸鹽、丁二酸鹽、草酸鹽、丙二酸鹽、丙酮酸鹽、乙醯乙酸鹽、酒石酸鹽、硬脂酸鹽、苯磺酸鹽、甲苯磺酸鹽、甲烷磺酸鹽、三氟甲烷磺酸鹽、3-羥基-2-萘甲酸鹽、苯磺酸鹽、萘二磺酸鹽及三氟乙酸鹽。 Examples of acid addition salts include, but are not limited to, hydrochloride, hydrobromide, phosphate, nitrate, sulfate, amine sulfonate, formate, acetate, propionate, citrate, D-gluconate, benzoate, 2-(4-hydroxybenzylidene) benzoate, butyrate, salicylate, sulfosalicylic acid salt, lactate, butene Diacid salt, laurate, malate, fumarate, succinate, oxalate, malonate, pyruvate, acetoacetate, tartrate, stearate , besylate, tosylate, methanesulfonate, trifluoromethanesulfonate, 3-hydroxy-2-naphthoate, benzenesulfonate, naphthalene disulfonate and trifluoroacetate.

鹼鹽之實例包括(但不限於)鋰鹽、鈉鹽、鉀鹽、鈣鹽、鋁鹽、鎂鹽、鈦鹽、葡甲胺鹽、銨鹽、視情況衍生自NH₃或具有1至16個C原子之有機胺的鹽，諸如乙胺、二乙胺、三乙胺、乙基二異丙基胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己基胺、二甲胺基乙醇、普魯卡因(procaine)、二苯甲基胺、N-甲基嗎啉、精胺酸、離胺酸、乙二胺、N-甲基哌啶及胍之鹽。 Examples of base salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, titanium salts, meglumine salts, ammonium salts, optionally derived from NH ₃ or having from 1 to 16 a salt of an organic amine of a C atom, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, A salt of procaine, benzhydrylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and guanidine.

鹽包括水不溶性鹽且尤其包括水溶性鹽。 Salts include water insoluble salts and include, in particular, water soluble salts.

根據熟習此項技術者，本發明之式(I)化合物以及其鹽例如在以結晶形式分離時可含有不同量之溶劑。因此，本發明範疇內包括本發明式(I)化合物之所有溶劑合物及尤其所有水合物，以及本發明式(I)化合物之鹽的所有溶劑合物及尤其所有水合物。 The compounds of formula (I) of the present invention, as well as salts thereof, may contain varying amounts of solvent, for example, when isolated in crystalline form, according to those skilled in the art. Accordingly, all solvates and especially all hydrates of the compounds of the formula (I) according to the invention, as well as all solvates of the salts of the compounds of the formula (I) according to the invention, and in particular all hydrates, are included within the scope of the invention.

本發明中之術語「組合」係如熟習此項技術者所知來使用且可呈現為固定組合、非固定組合或分裝部分之套組。 The term "combination" as used in the present invention is used as known to those skilled in the art and can be presented as a set of fixed combinations, non-fixed combinations or dispensing portions.

本發明中之「固定組合」係如熟習此項技術者所知來使用且被定義為其中所述第一活性成分與所述第二活性成分一起存在於一個單位劑量或單一整體中之組合。「固定組合」之一個實例為其中所述第一活性成分與所述第二活性成分存在於混雜物中以用於同時投藥(諸如存在於一種調配物中)之醫藥組合物。「固定組合」之另一實例為其中所述第一活性成分與所述第二活性成分存在於一個單位中而未經混雜之醫藥組合。 A "fixed combination" in the present invention is used as known to those skilled in the art and is defined as a combination wherein the first active ingredient and the second active ingredient are present together in one unit dose or in a single unit. An example of a "fixed combination" is a pharmaceutical composition wherein the first active ingredient and the second active ingredient are present in a hybrid for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the second active ingredient are present in one unit without being mixed.

本發明中之非固定組合或「分裝部分之套組」係如熟習此項技術者所知來使用且被定義為其中所述第一活性成分與所述第二活性成分存在於一個以上單位中之組合。非固定組合或分裝部分之套組的一個實例為其中所述第一活性成分與所述第二活性成分單獨存在之組合。非固定組合或分裝部分之套組的各組分可單獨、相繼、同時、同步或按時間順序交錯地來投藥。 The non-fixed combination or "packaged portion" of the present invention is used as known to those skilled in the art and is defined as wherein the first active ingredient and the second active ingredient are present in more than one unit. The combination in the middle. An example of a set of non-fixed combinations or dispensing portions is one in which the first active ingredient and the second active ingredient are present separately. The components of the set of non-fixed combinations or dispensing portions can be administered separately, sequentially, simultaneously, simultaneously or chronologically.

本發明之式(I)化合物與如下文定義之抗癌劑的任何如此之組合均為本發明之實施例。 Any such combination of a compound of formula (I) of the invention with an anticancer agent as defined below is an embodiment of the invention.

術語「(化學療法)抗癌劑」包括(但不限於)：131I-chTNT、阿倍瑞克(abarelix)、阿比特龍(abiraterone)、阿柔比星(aclarubicin)、阿地介白素(aldesleukin)、阿侖單抗(alemtuzumab)、亞利崔托寧(alitretinoin)、六甲蜜胺(altretamine)、胺魯米特(aminoglutethimide)、胺柔比星(amrubicin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、阿哥拉賓(arglabin)、三氧化二砷、天冬醯胺酶 (asparaginase)、阿紮胞苷(azacitidine)、巴利昔單抗(basiliximab)、BAY 80-6946、BAY 1000394、貝洛替康(belotecan)、苯達莫司汀(bendamustine)、貝伐單抗(bevacizumab)、貝沙羅汀(bexarotene)、比卡魯胺(bicalutamide)、比生群(bisantrene)、博萊黴素(bleomycin)、硼替佐米(bortezomib)、布舍瑞林(buserelin)、白消安(busulfan)、卡巴他賽(cabazitaxel)、亞葉酸鈣(calcium folinate)、左亞葉酸鈣(calcium levofolinate)、卡西他濱(capecitabine)、卡鉑(carboplatin)、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡妥索單抗(catumaxomab)、塞內昔布(celecoxib)、西莫介白素(celmoleukin)、西妥昔單抗(cetuximab)、苯丁酸氮芥(chlorambucil)、氯地孕酮(chlormadinone)、氮芥(chlormethine)、順鉑(cisplatin)、克拉屈濱(cladribine)、氯膦酸(clodronic acid)、氯法拉濱(clofarabine)、克瑞特培(crisantaspase)、環磷醯胺(cyclophosphamide)、環丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、達卡巴嗪(dacarbazine)、更生黴素(dactinomycin)、阿法達貝泊汀(darbepoetin alfa)、達沙替尼(dasatinib)、道諾黴素(daunorubicin)、地西他濱(decitabine)、地加瑞克(degarelix)、地尼介白素(denileukin diftitox)、地諾單抗(denosumab)、地洛瑞林(deslorelin)、二溴螺氯銨(dibrospidium chloride)、多烯紫杉醇(docetaxel)、去氧氟尿苷(doxifluridine)、小紅莓(doxorubicin)、小紅莓+雌酮 (estrone)、艾庫組單抗(eculizumab)、依決洛單抗(edrecolomab)、依利醋銨(elliptinium acetate)、伊屈潑帕(eltrombopag)、內皮生長抑素(endostatin)、依諾他濱(enocitabine)、表柔比星(epirubicin)、環硫雄醇(epitiostanol)、阿法依泊汀(epoetin alfa)、倍他依泊汀(epoetin beta)、依鉑(eptaplatin)、艾日布林(eribulin)、埃羅替尼(erlotinib)、***(estradiol)、雌莫司汀(estramustine)、依託泊苷(etoposide)、依維莫司(everolimus)、依西美坦(exemestane)、法屈唑(fadrozole)、非格司汀(filgrastim)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟他胺(flutamide)、福美司坦(formestane)、福莫司汀(fotemustine)、氟維司群(fulvestrant)、硝酸鎵(gallium nitrate)、加尼瑞克(ganirelix)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥珠單抗(gemtuzumab)、氧化型谷胱甘肽(glutoxim)、戈舍瑞林(goserelin)、組織胺二鹽酸鹽、組胺瑞林(histrelin)、羥基碳醯胺(hydroxycarbamide)、I-125晶種、伊班膦酸(ibandronic acid)、替伊莫單抗(ibritumomab tiuxetan)、伊達比星(idarubicin)、異環磷醯胺(ifosfamide)、伊馬替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、干擾素α、干擾素β、干擾素γ、伊匹單抗(ipilimumab)、伊立替康(irinotecan)、伊沙匹隆(ixabepilone)、蘭瑞肽(lanreotide)、拉帕替尼(lapatinib)、來那度胺(lenalidomide)、來格司亭(lenograstim)、香菇多糖(lentinan)、來曲唑(letrozole)、亮丙瑞林(leuprorelin)、左旋咪唑(levamisole)、麥角乙脲(lisuride)、洛鉑(lobaplatin)、洛莫司汀(lomustine)、氯尼達明(lonidamine)、馬索羅酚(masoprocol)、甲羥孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美法侖(melphalan)、美雄烷(mepitiostane)、巰基嘌呤(mercaptopurine)、甲胺喋呤(methotrexate)、甲氧沙林(methoxsalen)、胺基乙醯丙酸甲酯(Methyl aminolevulinate)、***(methyltestosterone)、米伐木肽(mifamurtide)、米替福新(miltefosine)、米鉑(miriplatin)、二溴甘露醇(mitobronitol)、丙脒腙(mitoguazone)、二溴衛矛醇(mitolactol)、絲裂黴素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、奈達鉑(nedaplatin)、奈拉濱(nelarabine)、尼羅替尼(nilotinib)、尼魯米特(nilutamide)、尼妥珠單抗(nimotuzumab)、尼莫司汀(nimustine)、二胺硝吖啶(nitracrine)、奧伐組單抗(ofatumumab)、奧美拉唑(omeprazole)、奧普瑞介白素(oprelvekin)、奧沙利鉑(oxaliplatin)、p53基因療法、太平洋紫杉醇(paclitaxel)、帕利夫明(palifermin)、鈀-103晶種、帕米膦酸(pamidronic acid)、盤尼圖單抗(panitumumab)、帕佐泮尼(pazopanib)、培門冬酶(pegaspargase)、PEG-倍他依泊汀(PEG-epoetin beta)(甲氧基PEG-倍他依泊汀)、乙二醇化非格司亭(pegfilgrastim)、聚乙二醇化干擾素α2b、培美曲塞(pemetrexed)、噴他佐辛(pentazocine)、噴司他汀(pentostatin)、培洛黴素(peplomycin)、培磷醯胺(perfosfamide)、畢西巴尼(picibanil)、吡柔比星(pirarubicin)、普樂沙福(plerixafor)、普卡黴素(plicamycin)、聚胺葡糖(poliglusam)、聚磷酸***、多醣-K、卟吩姆鈉(porfimer sodium)、普拉曲沙(pralatrexate)、潑尼莫司汀(prednimustine)、丙卡巴肼(procarbazine)、喹高利特(quinagolide)、鐳-223氯化物(radium-223 chloride)、雷洛昔芬(raloxifene)、雷替曲塞(raltitrexed)、雷莫司汀(ranimustine)、雷佐生(razoxane)、來伐替尼(refametinib)、瑞戈非尼(regorafenib)、利塞膦酸(risedronic acid)、利妥昔單抗(rituximab)、羅米地辛(romidepsin)、羅米司亭(romiplostim)、沙格司亭(sargramostim)、西普亮塞-T(sipuleucel-T)、西佐喃(sizofiran)、索布佐生(sobuzoxane)、甘胺雙唑鈉(sodium glycididazole)、索拉非尼(sorafenib)、鏈脲佐菌素(streptozocin)、舒尼替尼(sunitinib)、他拉泊芬(talaporfin)、他米巴羅汀(tamibarotene)、他莫昔芬(tamoxifen)、他索納明(tasonermin)、替西介白素(teceleukin)、喃氟啶(tegafur)、喃氟啶+吉莫斯特(gimeracil)+奧替拉西(oteracil)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、西羅莫司(temsirolimus)、替尼泊苷(teniposide)、睪酮(testosterone)、替曲膦 (tetrofosmin)、沙立度胺(thalidomide)、噻替派(thiotepa)、胸腺法新(thymalfasin)、硫鳥嘌呤(tioguanine)、托珠單抗(tocilizumab)、拓朴替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲貝替定(trabectedin)、曲妥珠單抗(trastuzumab)、曲奧舒凡(treosulfan)、維甲酸(tretinoin)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、曲磷胺(trofosfamide)、色胺酸(tryptophan)、烏苯美司(ubenimex)、伐柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽(vapreotide)、維羅非尼(vemurafenib)、長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春氟寧(vinflunine)、長春瑞濱(vinorelbine)、伏立諾他(vorinostat)、伏氯唑(vorozole)、釔-90玻璃微球體、淨司他丁(zinostatin)、淨司他丁斯酯(zinostatin stimalamer)、唑來膦酸(zoledronic acid)、左柔比星(zorubicin)。 The term "(chemotherapy) anticancer agent" includes (but is not limited to): 131I-chTNT, abarelix, abiraterone, aclarubicin, adesleukin (aldesleukin) ), alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, Anastrozole, arglabin, arsenic trioxide, aspartate (asparaginase), azacitidine (azacitidine), basiliximab, BAY 80-6946, BAY 1000394, belototecan, bendamustine, bevacizumab (bevacizumab), bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, white Busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur Carmustine, catummaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil Chlorambucil), chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, cretite Crisantaspase), cyclophosphamide, cyproterone, cytarabine, Dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, dexamethasone Degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, go Doxyl chlorouridine (doxifluridine), cranberry (doxorubicin), cranberry + estrone (estrone), eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enoxabine (enocitabine), epirubicin, epititocolol, epoetin alfa, epoetin beta, eptaplatin, eribulin (eribulin), erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, Facrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, Fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, oxidized glutathione Glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamine Hydroxycarbamide), I-125 seed, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib , imiquimod, imiprosulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone ), lanreotide, lapatinib, Lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride , lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan ( Melphalan), mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, Mifamurtide, miltefosine, miribatin, mitobronitol, mitoguazone, mitrosorbol, mitomycin Mitomycin), mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nicotine Nimotuzumab, nimustine, nitracrine, Austria Fauna monoclonal antibody (ofatumumab), omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin , palladium-103 seed crystal, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-beta epoxide (PEG) -epoetin beta) (methoxy PEG-beta epoxide), PEGylated pegfilgrastim, Pegylated interferon alpha 2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, bisiba Picibanil, pirarubicin, plerixafor, plicamycin, pigolusam, estradiol polyphosphate, polysaccharide-K, 卟姆姆Porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, radium-223 chloride, thunder Raloxifene, raltitrexed, ranimustine, razoxane, revametinib, regorafenib, risedronate Risedronic acid), rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, west Sizofiran, sobuzuxane, sodium glycididazole, sorafenib, streptozotocin (str Eptozocin), sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, ticlopyr ( Teceleukin), tegafur, fluridine + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus , teniposide, testosterone, tetrofosmin (tetrofosmin), thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, tortoise Toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, troose Trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib , vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, Vorinostat, vorozole, strontium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, Zorubicin.

本發明之化合物及其鹽可以互變異構體形式存在，該等互變異構體包括於本發明之實施例中。 The compounds of the present invention and salts thereof may exist in tautomeric forms, and such tautomers are included in the examples of the present invention.

本發明之化合物可視其結構而定以不同立體異構形式存在。該等形式包括構型異構體或視情況包括構形異構體(對映異構體及/或非對映異構體，包括滯轉異構體之彼等對映異構體及/或非對映異構體)。因此，本發明包括對映異構體、非對映異構體以及其混合物。可藉由此項技術中已知之方法自彼等對映異構體及/或非對映異構體混合物分離出純立體異構形式，該等方法較佳為層析方法，尤其為使用非對掌性或對掌性相之高壓液相層析(HPLC)。本發明另外包括上述立體異構體之所有混合物(與比率無關)，包括外消旋體。 The compounds of the invention may exist in different stereoisomeric forms depending on their structure. Such forms include configurational isomers or, where appropriate, conformational isomers (enantiomers and/or diastereomers, including the enantiomers of the atropisomers and/or Or diastereomers). Accordingly, the invention includes enantiomers, diastereomers, and mixtures thereof. From the enantiomers and/or diastereomeric mixtures by methods known in the art The pure stereoisomeric forms are isolated, preferably chromatographic methods, especially high pressure liquid chromatography (HPLC) using a non-pivoting or palmitic phase. The invention additionally includes all mixtures of the above stereoisomers (independent of the ratio), including racemates.

本發明之某些化合物及鹽可以不同結晶形式(多晶型物)存在，該等形式在本發明之範疇內。 Certain compounds and salts of the present invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.

此外，本發明涵蓋可在生物系統中轉化為式(I)化合物或其鹽的式(I)化合物及其鹽之衍生物(生物前驅體或前藥)。該生物系統例如為哺乳動物有機體，尤其為人類個體。生物前驅體例如藉由代謝過程而轉化為式(I)化合物或其鹽。 Furthermore, the invention encompasses derivatives (bioprecursors or prodrugs) of a compound of formula (I) and a salt thereof which can be converted to a compound of formula (I) or a salt thereof in a biological system. The biological system is, for example, a mammalian organism, especially a human individual. The biological precursor is converted to a compound of the formula (I) or a salt thereof, for example, by a metabolic process.

現已發現，本發明之該等化合物具有驚人且有利之性質，且此構成本發明之基礎。 It has now been found that the compounds of the invention have surprising and advantageous properties and this forms the basis of the invention.

特定言之，已令人驚訝地發現，本發明之該等化合物可有效抑制Bub1激酶，且因此可用於治療或預防以下疾病：失控之細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎性反應之疾病；或伴有失控之細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎性反應之疾病，特定言之為其中失控之細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎性反應由Bub1激酶介導之疾病，諸如血液腫瘤、實體腫瘤及/或其轉移，例如白血病及骨髓發育不良症候群、惡性淋巴瘤、頭頸部腫瘤(包括腦腫瘤及腦轉移)、胸部腫瘤(包括非小細胞肺腫瘤及小細胞肺腫瘤)、胃腸腫瘤、內分泌腫瘤、***腫瘤及其他婦科腫瘤、泌尿腫瘤(包括腎腫瘤、膀胱腫瘤及前列腺腫瘤)、皮膚腫瘤及肉瘤及/或其轉移。 In particular, it has surprisingly been found that such compounds of the invention are effective in inhibiting Bub1 kinase and are therefore useful in the treatment or prevention of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response or inappropriate a disease in which an inflammatory response is caused by cells; or a disease accompanied by uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response, particularly in the case of uncontrolled cell growth, proliferation, and/or survival, Improper cellular immune response or inappropriate cellular inflammatory response by Bub1 kinase-mediated diseases such as hematological tumors, solid tumors and/or metastases thereof, such as leukemia and myelodysplastic syndromes, malignant lymphomas, head and neck tumors (including brain tumors and Brain metastasis), chest tumors (including non-small cell lung tumors and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary tumors (including kidney tumors, bladder tumors and the forefront) Adenocarcinoma), skin tumors and sarcomas and/or their metastases.

用於合成如下文所述之技術方案第1項至第5項之化合物的中間物以及其用於合成技術方案第1項至第5項之化合物的用途為本發明之另一態樣。較佳中間物為如下文揭示之中間物實例。 The use of an intermediate for the synthesis of the compounds of the first to fifth aspects of the technical means as described below and the compounds thereof for use in the synthesis schemes 1 to 5 is another aspect of the invention. Preferred intermediates are examples of intermediates as disclosed below.

通用程序General procedure

本發明之化合物可根據以下流程1至16來製備。 The compounds of the present invention can be prepared according to the following Schemes 1 to 16.

下文所述之流程及程序說明本發明通式(I)化合物之合成途徑且不欲具限制性。對於熟習此項技術者而言顯然可以各種方式改變如流程中所例示之轉化順序。因此，流程中所例示之轉化順序不欲具限制性。另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R⁵、R⁶、R⁷或R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 The schemes and procedures described below illustrate the synthetic route of the compounds of formula (I) of the present invention and are not intended to be limiting. It will be apparent to those skilled in the art that the order of transformation as exemplified in the process can be varied in various ways. Therefore, the order of transformations exemplified in the process is not intended to be limiting. In addition, interconversion of any substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

流程1中描述一種製備通式(Ia)之化合物之途徑。 A route for the preparation of compounds of formula (Ia) is described in Scheme 1.

流程1(若RProcess 1 (if R ⁷⁷ =O烷基)=O alkyl)

流程1：製備通式(Ia)之化合物之途徑，其中R¹、R²、R³、R⁴、R⁶及R⁸具有如上文關於通式(I)所給出之含義。X表示F、Cl、Br、I、酸或酸酯，諸如4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼(酸頻哪醇酯)。R^A表示烷基。 Scheme 1: A route for the preparation of a compound of formula (Ia) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁸ have the meanings given above in relation to formula (I). X represents F, Cl, Br, I, Acid or Acid esters such as 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaboron ( Acid pinacol ester). R ^A represents an alkyl group.

另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R⁶及R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 In addition, interconversion of any of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

化合物A、B及C可自市場上購得或可根據可自公開領域獲悉之程序來製備，此可由熟習此項技術者所理解。在後續段落中描述特定實例。 Compounds A, B, and C are either commercially available or can be prepared according to procedures that are known from the publicly available art, as will be appreciated by those skilled in the art. Specific examples are described in subsequent paragraphs.

經適當取代之苯甲基肼(A)可與經適當取代之草乙酸酯(B)在適合溶劑系統(諸如乙酸及二噁烷)中在0℃至各自的溶劑沸點範圍內之溫度下反應，較佳在90℃下進行反應，以得到通式(1-1)之1-苯甲基-5-羥基-1H-吡唑-3-羧酸酯中間物。可分離甲基或乙基醚1-18作為副產物。 The appropriately substituted benzyl hydrazine (A) can be suitably substituted with the oxalic acid acetate (B) in a suitable solvent system (such as acetic acid and dioxane) at a temperature ranging from 0 ° C to the boiling point of the respective solvent. The reaction is preferably carried out at 90 ° C to obtain a 1-benzyl-5-hydroxy-1 H -pyrazole-3-carboxylate intermediate of the formula (1-1). The methyl or ethyl ether 1-18 can be isolated as a by-product.

通式(1-1)之中間物可藉由在適合鹼(諸如碳酸鉀)存在下，在適合溶劑系統(諸如丙酮)中，在0℃與各自的溶劑沸點之間的溫度下與適合烷基化劑(諸如碘甲烷)反應而轉化為通式(1-2)之中間物，較佳在室溫下進行該反應。 The intermediate of the formula (1-1) can be reacted with a suitable alkane in the presence of a suitable base such as potassium carbonate in a suitable solvent system such as acetone at a temperature between 0 ° C and the boiling point of the respective solvent. The base compound (such as methyl iodide) is reacted to convert to an intermediate of the formula (1-2), preferably at room temperature.

通式(1-2)之中間物在適合溶劑系統(諸如甲苯)中，在0℃與各自的溶劑沸點之間的溫度下用藉由向市售三甲基鋁中添加氯化銨而當場製備之試劑甲基氯鋁醯胺處理，較佳在80℃下進行該反應，且用適合溶劑系統(諸如甲醇)淬滅以形成所要之通式(1-3a)之中間物。 The intermediate of formula (1-2) is used in a suitable solvent system (such as toluene) at a temperature between 0 ° C and the boiling point of the respective solvent by adding ammonium chloride to commercially available trimethylaluminum. The reagents prepared are methylammonium amide treatment, preferably carried out at 80 ° C, and quenched with a suitable solvent system such as methanol to form the desired intermediate of formula (1-3a).

通式(1-3a)之中間物可藉由在適合鹼(諸如哌啶)存在下，在適合溶劑系統(諸如3-甲基丁-1-醇)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(1-4)之經適當取代之3,3-雙(二甲胺基)丙腈(諸如3,3-雙(二甲胺基)-2-甲氧基丙腈)反應而轉化為通式(1-5a)之中間物，較佳在100℃下進行該反應。 The intermediate of formula (1-3a) can be used in a suitable solvent system (such as 3-methylbutan-1-ol) in the presence of a suitable base such as piperidine, at room temperature to An appropriately substituted 3,3-bis(dimethylamino)propionitrile (such as 3,3-bis(dimethylamino)-2) at a temperature within the boiling range of the solvent from the formula (1-4) -Methoxypropionitrile) is converted to an intermediate of the formula (1-5a), preferably at 100 °C.

通式(1-5a)之中間物可在適合鹼(諸如2-甲基丙-2-醇鈉)及適合鈀催化劑(諸如(1E,4E)-1,5-二苯基戊-1,4-二烯-3-酮-鈀)存在下，在適合配位體(諸如1'-聯萘-2,2'-二基雙(二苯基磷烷))存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-溴吡啶)反應，較佳在100℃下進行該反應，以得到通式(Ia)之化合物。或者，可使用以下鈀催化劑：烯丙基氯化鈀二聚體、二氯雙(苯甲腈)鈀(II)、乙酸鈀(II)、氯化鈀(II)、肆(三苯基膦)鈀(0)、參(二苯亞甲基丙酮)二鈀(0)或以下配位體：外消旋-2,2'-雙(二苯膦基)-1,1'-聯萘、外消旋-BINAP、1,1'-雙(二苯膦基)二茂鐵、雙(2-二苯膦基苯基)醚、二第三丁基甲基四氟硼酸鏻、2-(二第三丁基膦基)聯苯、三第三丁基四氟硼酸鏻、三-2-呋喃基膦、參(2,4-二第三丁基苯基)亞磷酸酯、三鄰甲苯基膦、(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)。 The intermediate of the formula (1-5a) may be in a suitable base such as sodium 2-methylpropan-2-ol and a suitable palladium catalyst such as (1 E , 4 E )-1,5-diphenylpentane- In the presence of 1,4-dien-3-one-palladium, in the presence of a suitable ligand such as 1'-binaphthyl-2,2'-diylbis(diphenylphosphino), suitable In a solvent system (such as N,N -dimethylformamide), a suitable 4-halopyridine (such as 4-bromopyridine) of the formula (C) at a temperature ranging from room temperature to the boiling point of the respective solvent The reaction is preferably carried out at 100 ° C to obtain a compound of the formula (Ia). Alternatively, the following palladium catalysts can be used: allyl palladium chloride dimer, dichlorobis(benzonitrile)palladium(II), palladium(II) acetate, palladium(II) chloride, ruthenium (triphenylphosphine) Palladium (0), ginseng (diphenylmethyleneacetone) dipalladium (0) or the following ligand: racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl , racemic-BINAP, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyltetrafluoroborate, 2-(two Tertiary butylphosphino)biphenyl, tris-tert-butyltetrafluoroborate, tris-2-furylphosphine, bis(2,4-di-t-butylphenyl)phosphite, tri-o-tolyl Phosphine, (9,9-dimethyl-9 H -dibenzopipene-4,5-diyl) bis(diphenylphosphine).

或者，通式(1-5a)之中間物可在適合鹼(諸如三乙胺)、適合活化劑(諸如N,N-二甲基吡啶-4-胺)及適合銅鹽(諸如乙酸銅(II))存在下，在適合溶劑系統(諸如三氯甲烷)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合酸或酸頻哪醇酯(諸如(2-氟吡啶-4-基)酸反應，較佳在室溫下進行該反應，以得到通式(Ia)之化合物。 Alternatively, the intermediate of formula (1-5a) may be in a suitable base such as triethylamine, a suitable activator such as N , N -dimethylpyridin-4-amine, and a suitable copper salt such as copper acetate ( In the presence of II)), in a suitable solvent system (such as chloroform), suitable for the general formula (C) at temperatures ranging from room temperature to the boiling point of the respective solvent Acid or Acid pinacol ester (such as (2-fluoropyridin-4-yl) The reaction is preferably carried out at room temperature to obtain a compound of the formula (Ia).

或者，通式(1-5a)之中間物可在適合鹼(諸如氫化鈉)存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-氟吡啶)反應，較佳在90℃下進行該反應，以得到通式(Ia)之化合物。 Alternatively, the intermediate of formula (1-5a) may be in the presence of a suitable base such as sodium hydride in a suitable solvent system such as N,N -dimethylformamide at room temperature to the respective solvent The reaction is carried out at a temperature within the boiling point range with a suitable 4-halopyridine of the formula (C), such as 4-fluoropyridine, preferably at 90 ° C to give a compound of the formula (Ia).

流程2(若RProcess 2 (if R ⁷⁷ =烯基或環烷基)= alkenyl or cycloalkyl)

流程2：製備通式(Ib)之化合物之途徑，其中R¹、R²、R³、R⁴、R⁶及R⁸具有如上文關於通式(I)所給出之含義。X表示F、Cl、Br、I、酸或酸酯，諸如4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼(酸頻哪醇酯)。OR^B表示離去基，諸如三氟甲磺酸酯基。 Scheme 2: A route for the preparation of a compound of the formula (Ib) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁸ have the meanings given above for the formula (I). X represents F, Cl, Br, I, Acid or Acid esters such as 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaboron ( Acid pinacol ester). OR ^B represents a leaving group such as a triflate group.

化合物C可自市場上購得或可根據可自公開領域獲悉之程序來製備，此可由熟習此項技術者所理解。在後續段落中描述特定實例。 Compound C is commercially available or can be prepared according to procedures known from the public domain, as will be appreciated by those skilled in the art. Specific examples are described in subsequent paragraphs.

通式(1-1)之中間物可藉由在適合鹼(諸如吡啶)存在下，在適合溶劑系統(諸如二氯甲烷)中，在0℃與各自的溶劑沸點之間的溫度下與適合磺酸衍生物(諸如三氟甲磺酸酐)反應而轉化為通式(1-6)之中間物，較佳在室溫下進行該反應。 The intermediate of the formula (1-1) can be suitably used in the presence of a suitable base such as pyridine in a suitable solvent system such as dichloromethane at a temperature between 0 ° C and the boiling point of the respective solvent. The sulfonic acid derivative (such as trifluoromethanesulfonic anhydride) is converted to an intermediate of the formula (1-6) by reaction, preferably at room temperature.

通式(1-6)之中間物可藉由在適合鹼(諸如碳酸鈉)及適合鈀催化劑(諸如肆(三苯基膦)鈀(0))存在下，在適合溶劑系統(諸如1,2-二甲氧基乙烷)中，在室溫至各自的溶劑沸點範圍內之溫度下與酸或酸頻哪醇酯(諸如環丙基酸)反應而轉化為通式(1-7a)之中間物，較佳在75℃下進行該反應。 The intermediate of the formula (1-6) can be in a suitable solvent system (such as 1, in the presence of a suitable base such as sodium carbonate and a suitable palladium catalyst such as ruthenium (triphenylphosphine) palladium (0). In 2-dimethoxyethane), at a temperature ranging from room temperature to the boiling point of the respective solvent Acid or Acid pinacol ester (such as cyclopropyl The acid is converted into an intermediate of the formula (1-7a), preferably at 75 °C.

通式(1-7a)之中間物在適合溶劑系統(諸如甲苯)中，在0℃與各自的溶劑沸點之間的溫度下用藉由向市售三甲基鋁中添加氯化銨而當場製備之試劑甲基氯鋁醯胺處理，較佳在80℃下進行該反應，且用適合溶劑系統(諸如甲醇)淬滅以形成所要之通式(1-3b)之中間物。 The intermediate of formula (1-7a) is used on the spot in a suitable solvent system (such as toluene) at a temperature between 0 ° C and the boiling point of the respective solvent by adding ammonium chloride to commercially available trimethylaluminum. The reagents prepared are methylammonium amide treatment, preferably carried out at 80 ° C, and quenched with a suitable solvent system such as methanol to form the desired intermediate of formula (1-3b).

通式(1-3b)之中間物可藉由在適合鹼(諸如哌啶)存在下，在適合溶劑系統(諸如3-甲基丁-1-醇)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(1-4)之經適當取代之3,3-雙(二甲胺基)丙腈(諸如3,3-雙(二甲胺基)-2-甲氧基丙腈)反應而轉化為通式(1-5b)之中間物，較佳在100℃下進行該反應。 The intermediate of formula (1-3b) can be at room temperature to the boiling point of the respective solvent in the presence of a suitable base such as piperidine in a suitable solvent system such as 3-methylbutan-1-ol. An appropriately substituted 3,3-bis(dimethylamino)propionitrile (such as 3,3-bis(dimethylamino)-2-methoxyl of the formula (1-4) at a temperature within the range The propionitrile is converted to an intermediate of the formula (1-5b) by reaction, preferably at 100 °C.

通式(1-5b)之中間物可在適合鹼(諸如2-甲基丙-2-醇鈉)及適合鈀催化劑(諸如(1E,4E)-1,5-二苯基戊-1,4-二烯-3-酮-鈀)存在下，在適合配位體(諸如1'-聯萘-2,2'-二基雙(二苯基磷烷))存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-溴吡啶)反應，較佳在100℃下進行該反應，以得到通式(Ib)之化合物。或者，可使用以下鈀催化劑：烯丙基氯化鈀二聚體、二氯雙(苯甲腈)鈀(II)、乙酸鈀 (II)、氯化鈀(II)、肆(三苯基膦)鈀(0)、參(二苯亞甲基丙酮)二鈀(0)或以下配位體：外消旋-2,2'-雙(二苯膦基)-1,1'-聯萘、外消旋-BINAP、1,1'-雙(二苯膦基)二茂鐵、雙(2-二苯膦基苯基)醚、二第三丁基甲基四氟硼酸鏻、2-(二第三丁基膦基)聯苯、三第三丁基四氟硼酸鏻、三-2-呋喃基膦、參(2,4-二第三丁基苯基)亞磷酸酯、三鄰甲苯基膦、(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)。 The intermediate of the formula (1-5b) may be in a suitable base such as sodium 2-methylpropan-2-ol and a suitable palladium catalyst such as (1 E , 4 E )-1,5-diphenylpentane- In the presence of 1,4-dien-3-one-palladium, in the presence of a suitable ligand such as 1'-binaphthyl-2,2'-diylbis(diphenylphosphino), suitable In a solvent system (such as N,N -dimethylformamide), a suitable 4-halopyridine (such as 4-bromopyridine) of the formula (C) at a temperature ranging from room temperature to the boiling point of the respective solvent The reaction is preferably carried out at 100 ° C to obtain a compound of the formula (Ib). Alternatively, the following palladium catalysts can be used: allyl palladium chloride dimer, dichlorobis(benzonitrile)palladium(II), palladium(II) acetate, palladium(II) chloride, ruthenium (triphenylphosphine) Palladium (0), ginseng (diphenylmethyleneacetone) dipalladium (0) or the following ligand: racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl , racemic-BINAP, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyltetrafluoroborate, 2-(two Tertiary butylphosphino)biphenyl, tris-tert-butyltetrafluoroborate, tris-2-furylphosphine, bis(2,4-di-t-butylphenyl)phosphite, tri-o-tolyl Phosphine, (9,9-dimethyl-9 H -dibenzopipene-4,5-diyl) bis(diphenylphosphine).

或者，通式(1-5b)之中間物可在適合鹼(諸如三乙胺)、適合活化劑(諸如N,N-二甲基吡啶-4-胺)及適合銅鹽(諸如乙酸銅(II))存在下，在適合溶劑系統(諸如三氯甲烷)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合酸或酸頻哪醇酯(諸如(2-氟吡啶-4-基)酸)反應，較佳在室溫下進行該反應，以得到通式(Ib)之化合物。 Alternatively, the intermediate of formula (1-5b) may be in a suitable base such as triethylamine, a suitable activator such as N , N -dimethylpyridin-4-amine, and a suitable copper salt such as copper acetate ( In the presence of II)), in a suitable solvent system (such as chloroform), suitable for the general formula (C) at temperatures ranging from room temperature to the boiling point of the respective solvent Acid or Acid pinacol ester (such as (2-fluoropyridin-4-yl) The acid reaction is preferably carried out at room temperature to give a compound of the formula (Ib).

或者，通式(1-5b)之中間物可在適合鹼(諸如氫化鈉)存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-氟吡啶)反應，較佳在90℃下進行該反應，以得到通式(Ib)之化合物。 Alternatively, the intermediate of formula (1-5b) can be in the presence of a suitable base such as sodium hydride in a suitable solvent system such as N,N-dimethylformamide at room temperature to the respective solvent The reaction is carried out at a temperature within the boiling point range with a suitable 4-halopyridine of the formula (C), such as 4-fluoropyridine, preferably at 90 ° C to give a compound of the formula (Ib).

流程3(若RProcess 3 (if R ⁷⁷ =N(烷基)=N(alkyl) ₂₂ ))

流程3：製備通式(Ic)之化合物之途徑，其中R¹、R²、R³、R⁴、R⁶及R⁸具有如上文關於通式(I)所給出之含義。X表示F、Cl、Br、I、酸或酸酯，諸如4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼(酸頻哪醇酯)。R^C與R^D表示烷基，尤其為1-4C烷基，其中烷基殘基可相同或不同。 Scheme 3: A route for the preparation of a compound of formula (Ic) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁸ have the meanings given above in relation to formula (I). X represents F, Cl, Br, I, Acid or Acid esters such as 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaboron ( Acid pinacol ester). R ^C and R ^D represent an alkyl group, especially a 1-4C alkyl group, wherein the alkyl residues may be the same or different.

中間物(1-8)可根據Bioorg Med Chem Lett,2001,11/6,781-784中所述之程序來製備。 The intermediate (1-8) can be prepared according to the procedure described in Bioorg Med Chem Lett, 2001, 11/6, 781-784.

通式(1-8)之中間物可藉由在適合鹼(諸如氫化鋰)存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在0℃與各自的溶劑沸點之間的溫度下與適合烷基化劑(諸如碘甲烷)反應而轉化為通式(1-9)之中間物，較佳在室溫下進行該反應。 The intermediate of the formula (1-8) can be used in a solvent system (such as N,N-dimethylformamide) in the presence of a suitable base such as lithium hydride at 0 ° C with the respective solvent. The intermediate is converted to the intermediate of the formula (1-9) by reaction with a suitable alkylating agent such as methyl iodide at a temperature between the boiling points, preferably at room temperature.

通式(1-9)之中間物可藉由在適合溶劑系統(諸如甲醇)中，在0℃與各自的溶劑沸點之間的溫度下，在1與10巴(bar)之間的壓力下與氨反應而轉化為通式(1-10)之中間物，較佳在50℃下進行該反應且較佳在密封容器中進行該反應。 The intermediate of formula (1-9) can be at a pressure between 1 and 10 bar at a temperature between 0 ° C and the boiling point of the respective solvent in a suitable solvent system such as methanol. It is converted to an intermediate of the formula (1-10) by reaction with ammonia, preferably at 50 ° C and preferably carried out in a sealed vessel.

通式(1-10)之中間物在適合溶劑系統(諸如四氫呋喃) 中，在適合鹼(諸如吡啶)存在下，在0℃與各自的溶劑沸點之間的溫度下用三氟甲磺酸酐處理，較佳在室溫下進行該反應，以形成所要之通式(1-11)之中間物。 The intermediate of the formula (1-10) is in a suitable solvent system (such as tetrahydrofuran) The reaction is carried out with trifluoromethanesulfonic anhydride at a temperature between 0 ° C and the boiling point of the respective solvent in the presence of a suitable base such as pyridine, preferably at room temperature to form the desired formula ( 1-11) The intermediate.

通式(1-11)之中間物可藉由在適合溶劑系統(諸如相應醇，例如甲醇)中，在室溫與各自的溶劑沸點之間的溫度下與適合醇鹽(諸如甲醇鈉)反應，較佳在室溫下進行該反應，且隨後在適合酸(諸如乙酸)存在下，在室溫至各自的溶劑沸點範圍內之溫度下用適合銨源(諸如氯化銨)處理，較佳在50℃下進行該反應，從而轉化為通式(1-3c)之中間物。 The intermediate of formula (1-11) can be reacted with a suitable alkoxide (such as sodium methoxide) at a temperature between room temperature and the boiling point of the respective solvent in a suitable solvent system such as the corresponding alcohol, such as methanol. Preferably, the reaction is carried out at room temperature and then treated with a suitable ammonium source (such as ammonium chloride) at a temperature ranging from room temperature to the boiling point of the respective solvent in the presence of a suitable acid such as acetic acid. The reaction is carried out at 50 ° C to be converted into an intermediate of the formula (1-3c).

通式(1-3c)之中間物可藉由在適合鹼(諸如哌啶)存在下，在適合溶劑系統(諸如3-甲基丁-1-醇)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(1-4)之經適當取代之3,3-雙(二甲胺基)丙腈(諸如3,3-雙(二甲胺基)-2-甲氧基丙腈)反應而轉化為通式(1-5c)之中間物，較佳在100℃下進行該反應。 The intermediate of formula (1-3c) can be at room temperature to the boiling point of the respective solvent in the presence of a suitable base such as piperidine in a suitable solvent system such as 3-methylbutan-1-ol. An appropriately substituted 3,3-bis(dimethylamino)propionitrile (such as 3,3-bis(dimethylamino)-2-methoxyl of the formula (1-4) at a temperature within the range The propionitrile reaction is converted to an intermediate of the formula (1-5c), preferably at 100 °C.

通式(1-5c)之中間物可在適合鹼(諸如2-甲基丙-2-醇鈉)及適合鈀催化劑(諸如(1E,4E)-1,5-二苯基戊-1,4-二烯-3-酮-鈀)存在下，在適合配位體(諸如1'-聯萘-2,2'-二基雙(二苯基磷烷))存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-溴吡啶)反應，較佳在100℃下進行該反應，以得到通式(Ic)之化合物。或者，可使用以下鈀催化劑：烯丙基氯化鈀二聚體、二氯雙(苯甲腈)鈀(II)、乙酸鈀(II)、氯化鈀(II)、肆(三苯基膦)鈀(0)、參(二苯亞甲基丙酮)二鈀(0)或以下配位體：外消旋-2,2'-雙(二苯膦基)-1,1'-聯萘、外消旋-BINAP、1,1'-雙(二苯膦基)二茂鐵、雙(2-二苯膦基苯基)醚、二第三丁基甲基四氟硼酸鏻、2-(二第三丁基膦基)聯苯、三第三丁基四氟硼酸鏻、三-2-呋喃基膦、參(2,4-二第三丁基苯基)亞磷酸酯、三鄰甲苯基膦、(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)。 The intermediate of the formula (1-5c) may be in a suitable base such as sodium 2-methylpropan-2-ol and a suitable palladium catalyst such as (1 E , 4 E )-1,5-diphenylpentane- In the presence of 1,4-dien-3-one-palladium, in the presence of a suitable ligand such as 1'-binaphthyl-2,2'-diylbis(diphenylphosphino), suitable In a solvent system (such as N,N-dimethylformamide), a suitable 4-halopyridine (such as 4-bromopyridine) of formula (C) at a temperature ranging from room temperature to the boiling point of the respective solvent The reaction is preferably carried out at 100 ° C to give a compound of the formula (Ic). Alternatively, the following palladium catalysts can be used: allyl palladium chloride dimer, dichlorobis(benzonitrile)palladium(II), palladium(II) acetate, palladium(II) chloride, ruthenium (triphenylphosphine) Palladium (0), ginseng (diphenylmethyleneacetone) dipalladium (0) or the following ligand: racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl , racemic-BINAP, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyltetrafluoroborate, 2-(two Tertiary butylphosphino)biphenyl, tris-tert-butyltetrafluoroborate, tris-2-furylphosphine, bis(2,4-di-t-butylphenyl)phosphite, tri-o-tolyl Phosphine, (9,9-dimethyl-9 H -dibenzopipene-4,5-diyl) bis(diphenylphosphine).

或者，通式(1-5c)之中間物可在適合鹼(諸如三乙胺)、適合活化劑(諸如N,N-二甲基吡啶-4-胺)及適合銅鹽(諸如乙酸銅(II))存在下，在適合溶劑系統(諸如三氯甲烷)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合酸或酸頻哪醇酯(諸如(2-氟吡啶-4-基)酸)反應，較佳在室溫下進行該反應，以得到通式(Ic)之化合物。 Alternatively, the intermediate of formula (1-5c) may be in a suitable base such as triethylamine, a suitable activator such as N , N -dimethylpyridin-4-amine, and a suitable copper salt such as copper acetate ( In the presence of II)), in a suitable solvent system (such as chloroform), suitable for the general formula (C) at temperatures ranging from room temperature to the boiling point of the respective solvent Acid or Acid pinacol ester (such as (2-fluoropyridin-4-yl) The acid reaction is preferably carried out at room temperature to give a compound of the formula (Ic).

或者，通式(1-5c)之中間物可在適合鹼(諸如氫化鈉)存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-氟吡啶)反應，較佳在90℃下進行該反應，以得到通式(Ic)之化合物。 Alternatively, the intermediate of formula (1-5c) may be in the presence of a suitable base such as sodium hydride in a suitable solvent system such as N,N-dimethylformamide at room temperature to the respective solvent The reaction is carried out at a temperature within the boiling point range with a suitable 4-halopyridine of the formula (C), such as 4-fluoropyridine, preferably at 90 ° C to give a compound of the formula (Ic).

通式(Id)之化合物亦可根據流程4中所示之程序來合成。 Compounds of formula (Id) can also be synthesized according to the procedure shown in Scheme 4.

流程4Process 4

流程4：製備通式(Id)之化合物之替代性途徑，其中R¹、R²、R³、R⁴、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。X表示F、Cl、Br、I、酸或酸酯，諸如4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼(酸頻哪醇酯)。 Scheme 4 : An alternative route for the preparation of a compound of formula (Id) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ have the same as given above for formula (I) meaning. X represents F, Cl, Br, I, Acid or Acid esters such as 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaboron ( Acid pinacol ester).

X'表示F、Cl、Br、I或磺酸酯基，例如三氟甲磺酸酯基或對甲苯磺酸酯基。 X' represents F, Cl, Br, I or a sulfonate group such as a triflate group or a p-toluenesulfonate group.

另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R⁶、R⁷及R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 In addition, interconversion of any of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

化合物C、D、E、F及G可自市場上購得或可根據可自公開領域獲悉之程序來製備，此可由熟習此項技術者參考下文而理解。 Compounds C, D, E, F, and G are commercially available or can be prepared according to procedures known from the public domain, as understood by those skilled in the art from the following.

通式D之中間物可藉由在適合溶劑系統(諸如***)中，在0℃與各自的溶劑沸點之間的溫度下與適合有機金屬化合物(諸如溴(乙基)鎂)反應而轉化為通式(1-12)之中間物，較佳在回流下進行該反應。 The intermediate of formula D can be converted to a suitable organometallic compound (such as bromo(ethyl)magnesium) by reaction in a suitable solvent system (such as diethyl ether) at a temperature between 0 ° C and the boiling point of the respective solvent. The intermediate of the formula (1-12) is preferably subjected to the reaction under reflux.

通式(1-12)之中間物可藉由在適合鹼(諸如雙-(三甲基矽烷基)醯胺鋰)存在下，在適合溶劑系統(諸如***)中，在-78℃與室溫之間的溫度下與適合草酸酯(E)(諸如草酸二乙酯)反應而轉化為通式(1-13)之中間物，較佳在室溫下進行該反應。 The intermediate of the formula (1-12) can be used in a suitable solvent system (such as diethyl ether) at -78 ° C in the presence of a suitable base such as lithium bis-(trimethyldecyl) guanide The intermediate is converted to the intermediate of the formula (1-13) by reaction with a suitable oxalate (E) such as diethyl oxalate at a temperature between the temperatures, preferably at room temperature.

通式(1-13)之化合物藉由在適合溶劑系統(諸如乙醇) 中，在室溫至各自的溶劑沸點範圍內之溫度下用第三丁基肼羧酸酯(F)處理而轉化為通式(1-14)之中間物，較佳在各自的溶劑之沸點下進行該反應。 a compound of the formula (1-13) by a suitable solvent system (such as ethanol) The intermediates of the formula (1-14) are preferably converted to the intermediates of the formula (1-14) by treatment with a third butyl hydrazine carboxylate (F) at a temperature ranging from room temperature to the boiling point of the respective solvent, preferably at the boiling point of the respective solvent. The reaction is carried out underneath.

通式(1-14)之化合物藉由在適合溶劑系統(諸如二噁烷)中，在0℃至室溫之溫度範圍內在酸性條件(諸如鹽酸)下反應而轉化為通式(1-15)之中間物，較佳在室溫下進行該反應。 The compound of the formula (1-14) is converted to the formula (1-15) by reaction under acidic conditions (such as hydrochloric acid) in a suitable solvent system such as dioxane at a temperature ranging from 0 ° C to room temperature. The intermediate is preferably carried out at room temperature.

或者，通式(1-13)之化合物可藉由在適合溶劑系統(諸如乙醇)中，在室溫至各自的溶劑沸點範圍內之溫度下用肼處理而直接轉化為通式(1-15)之中間物，較佳在各自的溶劑之沸點下進行該反應。 Alternatively, the compound of the formula (1-13) can be directly converted to the formula (1-15) by treatment with hydrazine in a suitable solvent system such as ethanol at a temperature ranging from room temperature to the boiling point of the respective solvent. The intermediate is preferably subjected to the reaction at the boiling point of the respective solvent.

通式(1-15)之中間物可在適合溶劑系統(諸如四氫呋喃)中，在適合鹼(諸如氫化鈉)存在下，在0℃至各自的溶劑沸點範圍內之溫度下與通式(G)之經適當取代之苯甲基鹵化物或磺酸苯甲酯(諸如苯甲基溴化物)反應，較佳在室溫下進行該反應，以得到通式(1-7a)之化合物。 The intermediate of the formula (1-15) can be combined with the formula (G in a suitable solvent system such as tetrahydrofuran in the presence of a suitable base such as sodium hydride at a temperature ranging from 0 ° C to the boiling point of the respective solvent. The reaction of the appropriately substituted benzyl halide or benzyl sulfonate (such as benzyl bromide) is preferably carried out at room temperature to give a compound of the formula (1-7a).

通式(1-7a)之中間物在適合溶劑系統(諸如甲苯)中，在0℃與各自的溶劑沸點之間的溫度下用藉由向市售三甲基鋁中添加氯化銨而當場製備之試劑甲基氯鋁醯胺處理，較佳在80℃下進行該反應，且用適合溶劑系統(諸如甲醇)淬滅，以形成所要之通式(1-3b)之中間物。 The intermediate of formula (1-7a) is used on the spot in a suitable solvent system (such as toluene) at a temperature between 0 ° C and the boiling point of the respective solvent by adding ammonium chloride to commercially available trimethylaluminum. The reagents prepared are methylammonium amide treatment, preferably carried out at 80 ° C, and quenched with a suitable solvent system such as methanol to form the desired intermediate of formula (1-3b).

通式(1-3b)之中間物可藉由在適合鹼(諸如哌啶)存在下，在適合溶劑系統(諸如3-甲基丁-1-醇)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(1-4)之經適當取代之 3,3-雙(二甲胺基)丙腈(諸如3,3-雙(二甲胺基)-2-甲氧基丙腈)反應而轉化為通式(1-5b)之中間物，較佳在100℃下進行該反應。 The intermediate of formula (1-3b) can be at room temperature to the boiling point of the respective solvent in the presence of a suitable base such as piperidine in a suitable solvent system such as 3-methylbutan-1-ol. Substituted at a temperature within the range and appropriately substituted with the formula (1-4) Conversion of 3,3-bis(dimethylamino)propionitrile (such as 3,3-bis(dimethylamino)-2-methoxypropionitrile) to an intermediate of formula (1-5b), The reaction is preferably carried out at 100 °C.

通式(1-5b)之中間物可在適合鹼(諸如2-甲基丙-2-醇鈉)及適合鈀催化劑(諸如(1E,4E)-1,5-二苯基戊-1,4-二烯-3-酮-鈀)存在下，在適合配位體(諸如1'-聯萘-2,2'-二基雙(二苯基磷烷))存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-溴吡啶)反應，較佳在100℃下進行該反應，以得到通式(Id)之化合物。或者，可使用以下鈀催化劑：烯丙基氯化鈀二聚體、二氯雙(苯甲腈)鈀(II)、乙酸鈀(II)、氯化鈀(II)、肆(三苯基膦)鈀(0)、參(二苯亞甲基丙酮)二鈀(0)或以下配位體：外消旋-2,2'-雙(二苯膦基)-1,1'-聯萘、外消旋-BINAP、1,1'-雙(二苯膦基)二茂鐵、雙(2-二苯膦基苯基)醚、二第三丁基甲基四氟硼酸鏻、2-(二第三丁基膦基)聯苯、三第三丁基四氟硼酸鏻、三-2-呋喃基膦、參(2,4-二第三丁基苯基)亞磷酸酯、三鄰甲苯基膦、(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)。 The intermediate of the formula (1-5b) may be in a suitable base such as sodium 2-methylpropan-2-ol and a suitable palladium catalyst such as (1 E , 4 E )-1,5-diphenylpentane- In the presence of 1,4-dien-3-one-palladium, in the presence of a suitable ligand such as 1'-binaphthyl-2,2'-diylbis(diphenylphosphino), suitable In a solvent system (such as N,N-dimethylformamide), a suitable 4-halopyridine (such as 4-bromopyridine) of formula (C) at a temperature ranging from room temperature to the boiling point of the respective solvent The reaction is preferably carried out at 100 ° C to give a compound of the formula (Id). Alternatively, the following palladium catalysts can be used: allyl palladium chloride dimer, dichlorobis(benzonitrile)palladium(II), palladium(II) acetate, palladium(II) chloride, ruthenium (triphenylphosphine) Palladium (0), ginseng (diphenylmethyleneacetone) dipalladium (0) or the following ligand: racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl , racemic-BINAP, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyltetrafluoroborate, 2-(two Tertiary butylphosphino)biphenyl, tris-tert-butyltetrafluoroborate, tris-2-furylphosphine, bis(2,4-di-t-butylphenyl)phosphite, tri-o-tolyl Phosphine, (9,9-dimethyl-9 H -dibenzopipene-4,5-diyl) bis(diphenylphosphine).

或者，通式(1-5b)之中間物可在適合鹼(諸如三乙胺)、適合活化劑(諸如N,N-二甲基吡啶-4-胺)及適合銅鹽(諸如乙酸銅(II))存在下，在適合溶劑系統(諸如三氯甲烷)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合酸或酸頻哪醇酯(諸如(2-氟吡啶-4-基)酸)反應，較佳在室溫下進行該反應，以得到通式(Id)之化合物。 Alternatively, the intermediate of formula (1-5b) may be in a suitable base such as triethylamine, a suitable activator such as N , N -dimethylpyridin-4-amine, and a suitable copper salt such as copper acetate ( In the presence of II)), in a suitable solvent system (such as chloroform), suitable for the general formula (C) at temperatures ranging from room temperature to the boiling point of the respective solvent Acid or Acid pinacol ester (such as (2-fluoropyridin-4-yl) The acid reaction is preferably carried out at room temperature to give a compound of the formula (Id).

或者，通式(Id)之化合物可經由根據流程5中所示之程序進行去苯甲基化且隨後進行苯甲基化而由通式(Id-1)之其他化合物(其為其中R³=甲氧基或乙氧基之式(Id)之化合物)來合成。 Alternatively, a compound of formula (Id) can be debenzylated by a procedure according to Scheme 5 and subsequently subjected to benzylation from other compounds of formula (Id-1), which are R ³ = a compound of the formula (Id) wherein methoxy or ethoxy is synthesized.

流程5Process 5

流程5：製備通式(Id)之化合物之途徑，其中R¹、R²、R³、R⁴、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。X'表示F、Cl、Br、I或磺酸酯基。另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R⁶、R⁷及R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 Scheme 5: A route for the preparation of a compound of the formula (Id) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ have the meanings given above for the formula (I). X' represents F, Cl, Br, I or a sulfonate group. In addition, interconversion of any of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

化合物G可自市場上購得或可根據可自公開領域獲悉之程序來製備，此可由熟習此項技術者在下文中參考以上流程1而理解。 Compound G is commercially available or can be prepared according to procedures available from the public domain, as understood by those skilled in the art in reference to Scheme 1 above.

通式(Id-1)之化合物藉由在適合溶劑(諸如二氯乙烷)中，在室溫至各自的溶劑沸點範圍內之溫度下用適合酸系統(諸如三氟乙酸與三氟甲烷磺酸之混合物)處理而轉化為通式(1-16)之中間物，較佳在室溫下進行該反應。 The compound of the formula (Id-1) is used in a suitable solvent (such as trifluoroacetic acid and trifluoromethanesulfonate) at a temperature ranging from room temperature to the boiling point of the respective solvent in a suitable solvent such as dichloroethane. The mixture of acids is converted to an intermediate of the formula (1-16), preferably at room temperature.

通式(1-16)之中間物可在適合溶劑系統(諸如四氫呋喃)中，在適合鹼(諸如氫化鈉)存在下，在室溫至各自的溶劑沸點範圍內之溫度下與通式(G)之經適當取代之苯甲基鹵化物或磺酸苯甲酯(諸如苯甲基溴化物)反應，較佳在室溫下進行該反應，以得到通式(Id)之化合物。 The intermediate of the formula (1-16) can be combined with the formula (G in a suitable solvent system such as tetrahydrofuran in the presence of a suitable base such as sodium hydride at a temperature ranging from room temperature to the boiling point of the respective solvent. The reaction of the appropriately substituted benzyl halide or benzyl sulfonate (such as benzyl bromide) is preferably carried out at room temperature to give a compound of the formula (Id).

通式(Ie)、(Ie-1)及(If)之化合物可根據流程6中所示之程序由通式(Id-2)之化合物(其為其中R⁴=甲氧基之式(Ib)之化合物)來合成。 The compounds of the formulae (Ie), (Ie-1) and (If) can be obtained from the compound of the formula (Id-2) according to the procedure shown in Scheme 6 (which is the formula wherein R ⁴ = methoxy (Ib) )) to synthesize.

流程6Process 6

流程6 經由使通式(Id-2)之化合物去甲基化以得到通式(Ie)之化合物且隨後醚化以得到通式(If)之化合物來製備通式(If)之化合物的方法，其中R¹、R²、R³、R⁴、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R⁶、R⁷或R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 Process 6 for preparing a compound of the formula (If) by demethylating a compound of the formula (Id-2) to give a compound of the formula (Ie) and subsequently etherifying to give a compound of the formula (If) Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ have the meanings given above in relation to formula (I). In addition, interconversion of any substituent R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ or R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

通式H之化合物可自市場上購得，其中X表示離去基(諸如Cl、Br或I)，或X表示芳基磺酸酯基(諸如對甲苯磺酸酯基)或表示烷基磺酸酯基(諸如甲烷磺酸酯基或三氟甲烷磺酸酯基(三氟甲磺酸酯基))。R^F表示烷基(獨立地視情況經烷氧基、OH、NR⁹R¹⁰、SO₂NR⁹R¹⁰取代一或多次)、雜芳基或環烷基。 Compounds of formula H are commercially available wherein X represents a leaving group such as Cl, Br or I, or X represents an aryl sulfonate group such as p-toluenesulfonate or represents an alkyl sulfonate. An acid ester group such as a methanesulfonate group or a trifluoromethanesulfonate group (triflate group). R ^F represents an alkyl group (independently substituted one or more times by alkoxy group, OH, NR ⁹ R ¹⁰ , SO ₂ NR ⁹ R ¹⁰ ), a heteroaryl group or a cycloalkyl group.

通式(Id-2)之化合物藉由在適合溶劑(諸如1-甲基吡咯啶-2-酮)中，在適合鹼(諸如碳酸鉀)存在下，在室溫至各自的溶劑沸點範圍內之溫度下用適合去甲基化劑(諸如苯硫酚)處理而轉化為通式(Ie)之化合物，較佳在190℃下進行該反應。在R¹與R²為氟之情形下，可分離出副產物Ie-1。 The compound of the formula (Id-2) is present in a suitable solvent such as 1-methylpyrrolidin-2-one in the presence of a suitable base such as potassium carbonate at room temperature to the boiling point of the respective solvent The compound is converted to the compound of the formula (Ie) by treatment with a demethylating agent (such as thiophenol) at a temperature, preferably at 190 °C. In the case where R ¹ and R ² are fluorine, the by-product Ie-1 can be isolated.

通式(Ie)之化合物隨後在適合溶劑(諸如N,N-二甲基甲醯胺)中，在適合鹼(諸如碳酸鉀)存在下，在室溫至各自的溶劑沸點範圍內之溫度下與如上文提及之通式(H)之化合物反應，較佳在室溫下進行該反應，以得到通式(If)之化合物。 The compound of the formula (Ie) is then placed in a suitable solvent such as N,N -dimethylformamide at a temperature ranging from room temperature to the boiling point of the respective solvent in the presence of a suitable base such as potassium carbonate. The reaction is preferably carried out at room temperature by reaction with a compound of the formula (H) as mentioned above to give a compound of the formula (If).

通式(Ig)之化合物可根據流程7中所示之程序轉化為通式(Ih)之化合物。 The compound of the formula (Ig) can be converted to the compound of the formula (Ih) according to the procedure shown in Scheme 7.

流程7Process 7

流程7：經由通式(Ig)之化合物製備通式(Ih)之化合物之途徑，其中R¹、R²、R³、R⁴、R⁵、R⁷及R⁸具有如上文關於通式(I)所給出之含義。另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R⁵、R⁷或R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 Scheme 7: A route for the preparation of a compound of formula (Ih) via a compound of formula (Ig) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ have the formula above ( I) The meaning given. In addition, interconversion of any substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ or R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

通式(Ig)之中間物在酸條件(諸如濃硫酸)下，在0℃與各自的溶劑沸點之間的溫度下發生部分水解，較佳在室溫下進行該反應，以形成所要之通式(Ih)之化合物。 The intermediate of the formula (Ig) is partially hydrolyzed under acidic conditions (such as concentrated sulfuric acid) at a temperature between 0 ° C and the boiling point of the respective solvent, preferably at room temperature to form the desired pass. a compound of formula (Ih).

通式(Ie)之化合物可根據流程8中所示之程序轉化為通式(Ii)之化合物。 The compound of the formula (Ie) can be converted to the compound of the formula (Ii) according to the procedure shown in Scheme 8.

流程8Process 8

在此序列之步驟2期間，殘餘物可能會經歷改質，例如還原反應。 During step 2 of this sequence, the residue may undergo upgrading, such as a reduction reaction.

流程8：經由通式(Id-3)之中間物將通式(Ie)之化合物轉化為通式(Ii)之化合物的方法，其中R¹、R²、R³、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。O-R'''表示適合離去基，例如三氟甲基磺酸酯基、九氟丁基磺醯氧基。 Process 8: A process for converting a compound of the formula (Ie) to a compound of the formula (Ii) via an intermediate of the formula (Id-3), wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ has the meaning as given above for the general formula (I). O-R''' indicates a suitable leaving group such as a trifluoromethylsulfonate group or a nonafluorobutylsulfonyloxy group.

另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁶、R⁷或R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 In addition, the interconversion of any substituent R ¹ , R ² , R ³ , R ⁶ , R ⁷ or R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

通式(Ie)之化合物可藉由在適合溶劑(諸如二氯甲烷)中，在適合鹼(諸如吡啶)存在下，在室溫至各自的溶劑沸點範圍內之溫度下與適合磺酸衍生物(諸如三氟甲烷磺酸酐或1,1,2,2,3,3,4,4,4-九氟丁烷-1-磺醯基氟化物)反應而轉化為通式(Id-3)之中間物，較佳在室溫下進行該反應。 The compound of the formula (Ie) can be substituted with a suitable sulfonic acid derivative in a suitable solvent such as dichloromethane in the presence of a suitable base such as pyridine at a temperature ranging from room temperature to the boiling point of the respective solvent. Conversion to the general formula (Id-3) by reaction such as trifluoromethanesulfonic anhydride or 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride The intermediate is preferably subjected to the reaction at room temperature.

通式(Id-3)之中間物隨後可在適合Pd-催化劑(諸如乙酸鈀(II))連同適合配位體(諸如丙烷-1,3-二基雙(二苯基磷烷))一起存在下，在室溫至各自的溶劑沸點範圍內之溫度下，在適合溶劑(諸如N,N-二甲基甲醯胺(DMF))中與適合氫化物來源(諸如三乙基矽烷)反應，較佳在60℃下進行該反應，以得到通式(Ii)之化合物。 The intermediate of formula (Id-3) can then be combined with a suitable Pd-catalyst (such as palladium(II) acetate) along with a suitable ligand such as propane-1,3-diylbis(diphenylphosphane) In the presence of a suitable hydride source (such as triethyl decane) in a suitable solvent such as N,N -dimethylformamide (DMF) at room temperature to the temperature within the boiling point of the respective solvent The reaction is preferably carried out at 60 ° C to give a compound of the formula (Ii).

通式(Ii)之化合物(其為其中R⁴=氫之式(Id)化合物)可根據流程9中所示之程序轉化為通式(Ij及Ik)之化合物。 A compound of the formula (Ii) which is a compound of the formula (Id) wherein R ⁴ = hydrogen can be converted into a compound of the formula (Ij and Ik) according to the procedure shown in Scheme 9.

流程9Process 9

流程9：將通式(Ii)之化合物轉化為通式(Ik)及(Ij)之化合物的方法，其中R¹、R²、R³、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。R^5a表示1-6C-烷基(獨立地視情況經1-3C-烷氧基、羥基取代一或多次)，且X在下文中如上文流程1所定義或例如為1,3,2-二氧硫雜環戊烷2-氧化物。R^5b表示醯基部分，諸如-C(O)-(1-6C-烷基)、-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)、-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，且Z表示鹵素、羥基或-O-R^5b。 Process 9: A process for the conversion of a compound of the formula (Ii) to a compound of the formula (Ik) and (Ij), wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ have the same meaning as above The meaning given by formula (I). R ^5a represents 1-6C-alkyl (independently substituted one or more times by 1-3C-alkoxy, hydroxy, as appropriate), and X is hereinafter defined as in Scheme 1 above or, for example, 1,3,2- Dioxathiolane 2-oxide. R ^5b represents a thiol moiety such as -C(O)-(1-6C-alkyl), -C(O)-(1-6C-alkylene)-O-(1-6C-alkyl), -C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), and Z represents halogen, hydroxy or -OR ^5b .

另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R^5a、R^5b、R⁶、R⁷或R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 In addition, interconversion of any substituent R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ or R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

通式(Ii)之化合物可藉由在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在適合鹼(諸如碳酸銫)存在下，在室溫至各自的溶劑沸點範圍內之溫度下與適合鹵烷基或二氧硫雜環戊烷2-氧化物(諸如1,3,2-二氧硫雜環戊烷2-氧化物)反應而轉化為通式(Ij)之化合物，較佳在60℃下進行該反應。 The compound of the formula (Ii) can be used in a suitable solvent system (such as N , N -dimethylformamide) in the presence of a suitable base such as cesium carbonate at room temperature to the boiling point of the respective solvent. Conversion to a haloalkyl or dioxathiolane 2-oxide (such as 1,3,2-dioxathiolane 2-oxide) at a temperature to convert it to the formula (Ij) The compound is preferably subjected to the reaction at 60 °C.

通式(Ii)之化合物可藉由在適合溶劑(諸如二氯甲烷)中，在適合鹼(諸如N,N-二乙基乙胺)存在下，在室溫至各自的溶劑沸點範圍內之溫度下與適合碳酸衍生物(諸如羧酸鹵化物，例如羧酸氯化物或羧酸酐)反應而轉化為通式(Ik)之化合物，較佳在室溫下進行該反應。 The compound of the formula (Ii) can be used in a suitable solvent such as dichloromethane in the presence of a suitable base such as N,N -diethylethylamine at room temperature to the boiling point of the respective solvent. The compound is converted to the compound of the formula (Ik) by reaction with a suitable carbonic acid derivative such as a carboxylic acid halide such as a carboxylic acid chloride or a carboxylic anhydride at a temperature, preferably at room temperature.

通式(1-17)之化合物可根據流程10中所示之程序轉化為通式(1-4)之化合物。 The compound of the formula (1-17) can be converted into the compound of the formula (1-4) according to the procedure shown in Scheme 10.

流程10Process 10

流程10：將通式(I-17)之化合物轉化為通式(1-4)之化合物之方法，其中R⁴具有關於通式(I)所給出之含義。 Process 10: A process for converting a compound of the formula (I-17) into a compound of the formula (1-4), wherein R ⁴ has the meaning given for the formula (I).

通式(1-17)之化合物可藉由在室溫至各自的溶劑沸點範圍內之溫度下與適合的經取代之氰基烷基(諸如甲氧基乙腈)反應而轉化為通式(1-4)之化合物，較佳在80℃下進行該反應。 The compound of the formula (1-17) can be converted to the formula (1) by reaction with a suitable substituted cyanoalkyl group such as methoxyacetonitrile at a temperature ranging from room temperature to the boiling point of the respective solvent. The compound of -4) is preferably subjected to the reaction at 80 °C.

通式(1-19)之化合物可根據流程11中所示之程序轉化為為通式(G)之化合物。 The compound of the formula (1-19) can be converted into a compound of the formula (G) according to the procedure shown in Scheme 11.

流程11Process 11

流程11：將通式(1-19)之化合物轉化為通式(G)之化合物之方法，其中R¹、R²及R³具有關於通式(I)所給出之含義。X'表示F、Cl、Br、I或磺酸酯基，例如三氟甲基磺酸酯基或對甲苯磺酸酯基。 Process 11: A process for converting a compound of the formula (1-19) into a compound of the formula (G) wherein R ¹ , R ² and R ³ have the meanings given for the formula (I). X' represents F, Cl, Br, I or a sulfonate group such as a trifluoromethylsulfonate group or a p-toluenesulfonate group.

通式(1-19)之化合物可藉由在適合溶劑系統(諸如THF)中，在-78℃至各自的溶劑沸點範圍內之溫度下與適合還原劑(諸如硼烷)反應而轉化為通式(1-20)之化合物，較佳在室溫下進行該反應。 The compound of the formula (1-19) can be converted into a reaction by reacting with a suitable reducing agent such as borane in a suitable solvent system such as THF at a temperature ranging from -78 ° C to the boiling point of the respective solvent. The compound of the formula (1-20) is preferably subjected to the reaction at room temperature.

通式(1-20)之化合物可藉由在適合溶劑(諸如酸性酸)中，在0℃至各自的溶劑沸點範圍內之溫度下與適合鹵化或磺醯化劑(諸如溴化氫)反應而轉化為通式(G)之化合物，較佳在室溫下進行該反應。 The compound of the formula (1-20) can be reacted with a suitable halogenation or sulfonating agent such as hydrogen bromide in a suitable solvent such as an acidic acid at a temperature ranging from 0 ° C to the boiling point of the respective solvent. Further, the compound which is converted into the formula (G) is preferably subjected to the reaction at room temperature.

通式(1-21)之化合物可根據中流程12中所示之程序轉化為通式(1-23)之化合物。 The compound of the formula (1-21) can be converted according to the procedure shown in the scheme 12 It is a compound of the formula (1-23).

流程12Process 12

流程12：將通式(1-21)之化合物轉化為通式(1-23)之化合物之方法，其中R¹與R²具有關於通式(I)所給出之含義。X'表示F、Cl、Br、I或磺酸酯基，例如三氟甲基磺酸酯基或對甲苯磺酸酯基。 Process 12: A process for converting a compound of the formula (1-21) into a compound of the formula (1-23) wherein R ¹ and R ² have the meanings given for the formula (I). X' represents F, Cl, Br, I or a sulfonate group such as a trifluoromethylsulfonate group or a p-toluenesulfonate group.

通式(1-21)之化合物可藉由在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在適合鹼(諸如碳酸銫)存在下，在室溫至各自的溶劑沸點範圍內之溫度下與適合二氟甲基化劑(諸如氯(二氟)乙酸鈉)反應而轉化為通式(1-22)之化合物，較佳在100℃下進行該反應。 The compound of the formula (1-21) can be used in a suitable solvent system (such as N,N-dimethylformamide) in the presence of a suitable base such as cesium carbonate at room temperature to the boiling point of the respective solvent. The compound is converted to the compound of the formula (1-22) by reaction with a suitable difluoromethylating agent (such as sodium chloro(difluoro)acetate) at a temperature within the range, preferably at 100 °C.

通式(1-22)之化合物可藉由在適合溶劑(諸如酸性酸)中，在0℃至各自的溶劑沸點範圍內之溫度下與適合鹵化或磺醯化劑(諸如溴化氫)反應而轉化為通式(1-23)之化合物，較佳在室溫下進行該反應。 The compound of the formula (1-22) can be reacted with a suitable halogenating or sulfonating agent such as hydrogen bromide in a suitable solvent such as an acidic acid at a temperature ranging from 0 ° C to the boiling point of the respective solvent. Further, the compound is converted into the compound of the formula (1-23), and the reaction is preferably carried out at room temperature.

通式(1-7b)之化合物可根據流程13中所示之程序轉化為通式(Id-4)之化合物。 The compound of the formula (1-7b) can be converted to the compound of the formula (Id-4) according to the procedure shown in Scheme 13.

流程13Process 13

流程13：製備通式(Id-4)之化合物之替代性途徑，其中R¹、R²、R⁴、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。X表示F、Cl、Br、I、酸或酸酯，諸如4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼(酸頻哪醇酯)。 Scheme 13 : An alternative route for the preparation of a compound of the formula (Id-4) wherein R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ and R ⁸ have the meanings given above for the formula (I) . X represents F, Cl, Br, I, Acid or Acid esters such as 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaboron ( Acid pinacol ester).

X"表示Cl、Br、I或磺酸酯基，例如三氟甲基磺酸酯基。 X" represents Cl, Br, I or a sulfonate group such as a triflate group.

R^E表示烷基、環烷基、烯基或芳基。 R ^E represents an alkyl group, a cycloalkyl group, an alkenyl group or an aryl group.

另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R⁴、R⁶、R⁷及R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 In addition, interconversion of any of the substituents R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ and R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

化合物C可自市場上購得或可根據可自公開領域獲悉之程序來製備，此可由熟習此項技術者參考下文而理解。 Compound C is commercially available or can be prepared according to procedures known from the public domain, as understood by those skilled in the art with reference to the following.

通式(1-7b)之中間物可藉由在適合鹼(諸如碳酸鈉)及適合鈀催化劑(諸如肆(三苯基膦)鈀(0))存在下，在適合溶劑系統(諸如1,2-二甲氧基乙烷)中，在室溫至各自的溶劑沸點範圍內之溫度下與酸或酸頻哪醇酯(諸如環丙基酸)反應而轉化為通式(1-7c)之中間物，較佳在75℃下進行該反應。 The intermediate of the formula (1-7b) can be in a suitable solvent system (such as 1, in the presence of a suitable base such as sodium carbonate and a suitable palladium catalyst such as ruthenium (triphenylphosphine) palladium (0). In 2-dimethoxyethane), at a temperature ranging from room temperature to the boiling point of the respective solvent Acid or Acid pinacol ester (such as cyclopropyl The acid is converted into an intermediate of the formula (1-7c), preferably at 75 °C.

通式(1-7c)之中間物在適合溶劑系統(諸如甲苯)中，在0℃與各自的溶劑沸點之間的溫度下用藉由向市售三甲基鋁中添加氯化銨而當場製備之試劑甲基氯鋁醯胺處理，較佳在80℃下進行該反應，且用適合溶劑系統(諸如甲醇)淬滅以形成所要之通式(1-3d)之中間物。 The intermediate of the formula (1-7c) is used in a suitable solvent system (such as toluene) at a temperature between 0 ° C and the boiling point of the respective solvent by adding ammonium chloride to commercially available trimethylaluminum. The prepared reagent is methylammonium amide treatment, preferably carried out at 80 ° C, and quenched with a suitable solvent system such as methanol to form the intermediate of the desired formula (1-3d).

通式(1-3d)之中間物可藉由在適合鹼(諸如哌啶)存在下，在適合溶劑系統(諸如3-甲基丁-1-醇)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(1-4)之經適當取代之3,3-雙(二甲胺基)丙腈(諸如3,3-雙(二甲胺基)-2-甲氧基丙腈)反應而轉化為通式(1-5d)之中間物，較佳在100℃下進行該反應。 The intermediate of formula (1-3d) can be at room temperature to the boiling point of the respective solvent in the presence of a suitable base such as piperidine in a suitable solvent system such as 3-methylbutan-1-ol. An appropriately substituted 3,3-bis(dimethylamino)propionitrile (such as 3,3-bis(dimethylamino)-2-methoxyl of the formula (1-4) at a temperature within the range The propionitrile is converted to an intermediate of the formula (1-5d), preferably at 100 °C.

通式(1-5d)之中間物可在適合鹼(諸如2-甲基丙-2-醇鈉)及適合鈀催化劑(諸如(1E,4E)-1,5-二苯基戊-1,4-二烯-3-酮- 鈀)存在下，在適合配位體(諸如1'-聯萘-2,2'-二基雙(二苯基磷烷))存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-溴吡啶)反應，較佳在100℃下進行該反應，以得到通式(Id-4)之化合物。或者，可使用以下鈀催化劑：烯丙基氯化鈀二聚體、二氯雙(苯甲腈)鈀(II)、乙酸鈀(II)、氯化鈀(II)、肆(三苯基膦)鈀(0)、參(二苯亞甲基丙酮)二鈀(0)或以下配位體：外消旋-2,2'-雙(二苯膦基)-1,1'-聯萘、外消旋-BINAP、1,1'-雙(二苯膦基)二茂鐵、雙(2-二苯膦基苯基)醚、二第三丁基甲基四氟硼酸鏻、2-(二第三丁基膦基)聯苯、三第三丁基四氟硼酸鏻、三-2-呋喃基膦、參(2,4-二第三丁基苯基)亞磷酸酯、三鄰甲苯基膦、(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)。 The intermediate of the formula (1-5d) may be in a suitable base such as sodium 2-methylpropan-2-ol and a suitable palladium catalyst such as (1 E , 4 E )-1,5-diphenylpentane- In the presence of 1,4-dien-3-one-palladium, in the presence of a suitable ligand such as 1'-binaphthyl-2,2'-diylbis(diphenylphosphino), suitable In a solvent system (such as N,N-dimethylformamide), a suitable 4-halopyridine (such as 4-bromopyridine) of formula (C) at a temperature ranging from room temperature to the boiling point of the respective solvent The reaction is preferably carried out at 100 ° C to obtain a compound of the formula (Id-4). Alternatively, the following palladium catalysts can be used: allyl palladium chloride dimer, dichlorobis(benzonitrile)palladium(II), palladium(II) acetate, palladium(II) chloride, ruthenium (triphenylphosphine) Palladium (0), ginseng (diphenylmethyleneacetone) dipalladium (0) or the following ligand: racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl , racemic-BINAP, 1,1'-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, di-tert-butylmethyltetrafluoroborate, 2-(two Tertiary butylphosphino)biphenyl, tris-tert-butyltetrafluoroborate, tris-2-furylphosphine, bis(2,4-di-t-butylphenyl)phosphite, tri-o-tolyl Phosphine, (9,9-dimethyl-9 H -dibenzopipene-4,5-diyl) bis(diphenylphosphine).

或者，通式(1-5d)之中間物可在適合鹼(諸如三乙胺)、適合活化劑(諸如N,N-二甲基吡啶-4-胺)及適合銅鹽(諸如乙酸銅(II))存在下，在適合溶劑系統(諸如三氯甲烷)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合酸或酸頻哪醇酯(諸如(2-氟吡啶-4-基)酸)反應，較佳在室溫下進行該反應，以得到通式(Id-4)之化合物。 Alternatively, the intermediate of formula (1-5d) may be in a suitable base such as triethylamine, a suitable activator such as N , N -dimethylpyridin-4-amine, and a suitable copper salt such as copper acetate ( In the presence of II)), in a suitable solvent system (such as chloroform), suitable for the general formula (C) at temperatures ranging from room temperature to the boiling point of the respective solvent Acid or Acid pinacol ester (such as (2-fluoropyridin-4-yl) The acid reaction is preferably carried out at room temperature to give a compound of the formula (Id-4).

或者，通式(1-5d)之中間物可在適合鹼(諸如氫化鈉)存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-氟吡啶)反應，較佳在90℃下進行該反應，以得到通式(Id-4)之化合物。 Alternatively, the intermediate of formula (1-5d) may be in the presence of a suitable base such as sodium hydride in a suitable solvent system such as N,N-dimethylformamide at room temperature to the respective solvent Suitable for 4-halogen at the temperature within the boiling point range and formula (C) The reaction is carried out by a pyridine (such as 4-fluoropyridine), preferably at 90 ° C to give a compound of the formula (Id-4).

通式(1-3b)之化合物可根據流程14中所示之程序轉化為通式(Id)之化合物。 The compound of the formula (1-3b) can be converted to the compound of the formula (Id) according to the procedure shown in Scheme 14.

流程14Process 14

流程14：製備通式(Id)之化合物之替代性途徑，其中R¹、R²、R³、R⁴、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。X表示F、Cl、Br、I、酸或酸酯，諸如4,4,5,5-四甲基-2-苯基-1,3,2-二氧硼(酸頻哪醇酯)。 Scheme 14 : An alternative route for the preparation of a compound of formula (Id) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ have the same as given above for formula (I) meaning. X represents F, Cl, Br, I, Acid or Acid esters such as 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaboron ( Acid pinacol ester).

通式(1-3b)之中間物可藉由在適合鹼(諸如甲醇鈉)存在下，在適合溶劑系統(諸如甲醇)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(1-24)之經適當取代之3-甲氧基丙烯腈(諸如(乙氧基亞甲基)丙二腈)反應而轉化為通式(1-5b)之中間物，較佳在65℃下進行該反應。 The intermediate of the formula (1-3b) can be synthesized by using a suitable base (such as sodium methoxide) in a suitable solvent system (such as methanol) at a temperature ranging from room temperature to the boiling point of the respective solvent. (1-24) an appropriately substituted 3-methoxyacrylonitrile (such as (ethoxymethylene) malononitrile) is converted to an intermediate of the formula (1-5b), preferably at 65. The reaction was carried out at °C.

或者，通式(1-5b)之中間物可在適合鹼(諸如氫化鈉)存在下，在適合溶劑系統(諸如N,N-二甲基甲醯胺)中，在室溫至各自的溶劑沸點範圍內之溫度下與通式(C)之適合4-鹵基吡啶(諸如4-氟吡啶)反應，較佳在90℃下進行該反應，以得到通式(Id)之化合物。 Alternatively, the intermediate of formula (1-5b) can be in the presence of a suitable base such as sodium hydride in a suitable solvent system such as N,N-dimethylformamide at room temperature to the respective solvent The reaction is carried out at a temperature within the boiling point range with a suitable 4-halopyridine of the formula (C), such as 4-fluoropyridine, preferably at 90 ° C to give a compound of the formula (Id).

通式(Il)之化合物可根據中流程15中所示之程序轉化為通式(Im)及(In)之化合物。 The compound of the formula (Il) can be converted into a compound of the formula (Im) and (In) according to the procedure shown in Scheme 15.

流程15Process 15

流程15：經由通式(Im)之化合物之氧化製備通式(In)之化合物的方法，其中R¹、R²、R³、R⁶、R⁷及R⁸具有如上文關於通式(I)所給出之含義。p可為1至6。另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁶、R⁷及R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第3版，Wiley 1999)。在後續段落中描述特定實例。 Process 15 : Process for the preparation of a compound of the formula (In) via oxidation of a compound of the formula (Im), wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ have the formula (I) above ) the meaning given. p can be from 1 to 6. In addition, interconversion of any of the substituents R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

通式(IL)之化合物藉由在適合溶劑(諸如氯仿)中，在0℃至各自的溶劑沸點範圍內之溫度下用適合氧化劑(諸如3-氯過氧苯甲酸)處理而轉化為通式(Im)之化合物，較佳在0℃下進行該反應。 The compound of the formula (IL) is converted to the formula by treatment with a suitable oxidizing agent such as 3-chloroperoxybenzoic acid in a suitable solvent such as chloroform at a temperature ranging from 0 ° C to the boiling point of the respective solvent. The compound of (Im) is preferably subjected to the reaction at 0 °C.

通式(Im)之化合物可藉由在適合溶劑(諸如四氫呋喃)中，在0℃至各自的溶劑沸點範圍內之溫度下用適合氧化劑(諸如過氧化氫)及試劑偶氮二甲酸二乙酯處理而轉化為通式(In)之化合物，較佳在50℃下進行該反應。 The compound of the formula (Im) can be used with a suitable oxidizing agent (such as hydrogen peroxide) and a reagent diethyl azodicarboxylate in a suitable solvent such as tetrahydrofuran at a temperature ranging from 0 ° C to the boiling point of the respective solvent. The compound is converted into a compound of the formula (In) by treatment, preferably at 50 °C.

通式(Ip)之化合物可根據流程16中所示之程序轉化為通式(Iqj)及(Ir)之化合物。 The compound of formula (Ip) can be converted to the compounds of formula (Iqj) and (Ir) according to the procedure shown in Scheme 16.

流程16Process 16

流程16：經由通式(Iq)之化合物製備通式(Ir)之化合物之途徑，其中R¹、R²、R³、R⁴、R⁵、R⁷及R⁸具有如上文關於通式(I)所給出之含義。另外，可在所例示之轉化之前及/或之後達成任何取代基R¹、R²、R³、R⁴、R⁵、R⁷及R⁸之相互轉化。該等改變可為諸如引入保護基、使保護基裂解、使官能基還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知之其他反應。該等轉化包括引入允許取代基進一步相互轉化之官能基的彼等轉化。適當保護基及其引入及裂解為熟習此項技術者所熟知(參見例如T.W.Greene及P.G.M.Wuts之Protective Groups in Organic Synthesis，第 3版，Wiley 1999)。在後續段落中描述特定實例。 Scheme 16: A route for the preparation of a compound of formula (Ir) via a compound of formula (Iq) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ have the formula above ( I) The meaning given. In addition, interconversion of any of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ can be achieved before and/or after the exemplified transformation. Such alterations can be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reaction known to those skilled in the art. Such transformations include the introduction of such transformations that allow the functional groups of the substituents to further interconvert. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

通式(Ip)之中間物藉由在適合溶劑(諸如四氫呋喃及甲醇)中，在0℃至各自的溶劑沸點範圍內之溫度下用適合鹼(諸如氫氧化鈉)處理而轉化為式(Iq)，較佳在室溫下進行該反應。 The intermediate of the formula (Ip) is converted to the formula (Iq by treatment with a suitable base such as sodium hydroxide in a suitable solvent such as tetrahydrofuran and methanol at a temperature ranging from 0 ° C to the boiling point of the respective solvent. The reaction is preferably carried out at room temperature.

通式(Iq)之中間物藉由在適合溶劑(諸如N,N-二甲基甲醯胺)中，在0℃至各自的溶劑沸點範圍內之溫度下在添加適合鹼(諸如N,N-二異丙基乙基胺)及適合偶合試劑(諸如(苯并***-1-基氧基)三吡咯啶基六氟磷酸鏻)下，用適合胺(諸如2-胺基乙基甲基碸)處理而轉化為式(Ir)，較佳在室溫下進行該反應。 The intermediate of the formula (Iq) is added to a suitable base (such as N , N ) in a suitable solvent such as N,N -dimethylformamide at a temperature ranging from 0 ° C to the boiling point of the respective solvent. -diisopropylethylamine) and a suitable coupling reagent (such as (benzotriazol-1-yloxy)tripyrrolidinium hexafluorophosphate) with a suitable amine (such as 2-aminoethylethyl) The reaction is converted to the formula (Ir), preferably at room temperature.

熟習此項技術者已知，若起始或中間化合物上存在多個反應中心，則可能有必要用保護基暫時阻斷一或多個反應中心以允許某一反應可特定地在所要之反應中心處進行。關於多種經證實保護基之使用的詳細描述例如見於T.W.Greene,Protective Groups in Organic Synthesis,John Wiley & Sons,1999，第3版或P.Kocienski,Protecting Groups,Thieme Medical Publishers,2000中。 It is known to those skilled in the art that if multiple reaction centers are present on the starting or intermediate compound, it may be necessary to temporarily block one or more reaction centers with a protecting group to allow a reaction to be specifically at the desired reaction center. At the place. A detailed description of the use of various proven protecting groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 3rd edition or P. Kocienski, Protecting Groups, Thieme Medical Publishers, 2000.

以本身已知之方式分離及純化本發明之化合物，例如在真空下蒸餾出溶劑且自適合溶劑再結晶出所獲得之殘餘物或使其經受常用純化方法之一，諸如在適合載體材料上層析。此外，對具有足夠鹼性或酸性官能基之本發明化合物進行逆相製備型HPLC可導致形成鹽，諸如在具有足夠鹼性之本發明化合物情形下例如形成三氟乙酸鹽或甲酸鹽，或在具有足夠酸性之本發明化合物情形下例如形成銨鹽。此類型之鹽可藉由熟習此項技術者已知之各種方法分別轉化為其游離鹼或游離酸形式，或用作後續生物分析中之鹽。另外，在分離本發明化合物期間之乾燥方法可能未完全移除痕量共溶劑(尤其諸如甲酸或三氟乙酸)而產生溶劑合物或包合複合物。熟習此項技術者將意識到何種溶劑合物或包合複合物可被接受而用於後續生物分析中。應瞭解，如本文所述分離之特定形式的本發明化合物(例如，鹽、游離鹼、溶劑合物、包合複合物)並非必定為該化合物可用於生物分析來定量特定生物活性之唯一形式。 The compounds of the invention are isolated and purified in a manner known per se, for example by distilling off the solvent under vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the usual purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC of a compound of the invention having a sufficiently basic or acidic functional group can result in the formation of a salt, such as in the case of a compound of the invention having sufficient basicity, for example, to form a trifluoroacetate or formate, Or, in the case of a compound of the invention having sufficient acidity, for example, an ammonium salt is formed. Salts of this type can be converted to their free base or free acid form, respectively, by various methods known to those skilled in the art, or used as salts in subsequent biological assays. Additionally, the drying process during the isolation of the compounds of the invention may not completely remove trace cosolvents (especially such as formic acid or trifluoroacetic acid) to produce solvates or inclusion complexes. Those skilled in the art will recognize which solvates or inclusion complexes are acceptable for use in subsequent bioassays. It will be appreciated that a particular form of a compound of the invention (e.g., a salt, a free base, a solvate, an inclusion complex) isolated as described herein is not necessarily the only form in which the compound can be used in biological assays to quantify a particular biological activity.

本發明之式(I)化合物之鹽可藉由將游離化合物溶解於含有所要酸或鹼、或隨後向其中添加所要酸或鹼之適合溶劑(例如酮(諸如丙酮、甲基乙基酮或甲基異丁基酮)、醚(諸如***、四氫呋喃或二噁烷)、氯化烴(諸如二氯甲烷或氯仿)或低分子量脂族醇(諸如甲醇、乙醇或異丙醇))中來獲得。在鹽製備中可視關於一元或多元酸或鹼而定且視需要何種鹽而定以等莫耳定量比或不同於此之比率來採用酸或鹼。藉由過濾、再沈澱、用鹽之非溶劑沈澱析出或藉由蒸發溶劑來獲得鹽。所獲之鹽可轉化為游離化合物，該等游離化合物又可轉化為鹽。以此方式，可藉由熟習此項技術者已知之方法將例如在工業規模製造中可作為加工產品獲得之醫藥學上不可接受之鹽轉化為醫藥學上可接受之鹽。尤其較佳為實例部分中所用之鹽酸鹽及方法。 The salt of the compound of the formula (I) of the present invention can be prepared by dissolving the free compound in a suitable solvent containing the desired acid or base, or subsequently adding the desired acid or base (for example, a ketone (such as acetone, methyl ethyl ketone or nail) Obtained in isobutyl ketone), ether (such as diethyl ether, tetrahydrofuran or dioxane), chlorinated hydrocarbon (such as dichloromethane or chloroform) or low molecular weight aliphatic alcohol (such as methanol, ethanol or isopropanol) . The acid or base may be employed in the salt preparation depending on the mono- or polybasic acid or base and depending on which salt is desired, in a molar ratio or a ratio different from this. The salt is obtained by filtration, reprecipitation, precipitation with a non-solvent of the salt or by evaporation of the solvent. The salt obtained can be converted to a free compound which in turn can be converted into a salt. In this manner, a pharmaceutically unacceptable salt obtainable as a processed product, for example, in industrial scale manufacturing, can be converted to a pharmaceutically acceptable salt by methods known to those skilled in the art. Particularly preferred are the hydrochlorides and methods used in the Examples section.

可例如藉由不對稱合成，藉由在合成中使用對掌性起始化合物及藉由分離合成中所獲之對映異構與非對映異構混合物來獲得本發明化合物及鹽之純非對映異構體及純對映異構體。 Can be used, for example, by asymmetric synthesis, by using the palm of the hand in the synthesis The compounds and the enantiomers and diastereomeric mixtures obtained in the synthesis are isolated to obtain the pure diastereomers and pure enantiomers of the compounds and salts of the invention.

可藉由熟習此項技術者已知之方法將對映異構及非對映異構混合物分離成純對映異構體及純非對映異構體。非對映異構混合物較佳藉由結晶(尤其為分步結晶)或層析來分離。對映異構混合物可例如藉由與對掌性助劑形成非對映異構體、解析所獲非對映異構體且移除對掌性助劑來分離。作為對掌性助劑，例如可使用對掌性酸(諸如杏仁酸)來分離對映異構鹼，且可使用對掌性鹼經由形成非對映異構鹽來分離對映異構酸。此外，可分別使用對掌性酸或對掌性醇作為對掌性助劑而分別自醇之對映異構混合物或酸之對映異構混合物來形成非對映異構衍生物，諸如非對映異構酯。另外，非對映異構複合物或非對映異構籠形物可用於分離對映異構混合物。或者，可在層析中使用對掌性分離管柱來分離對映異構混合物。另一分離對映異構體之適合方法為酶促分離。 The enantiomeric and diastereomeric mixtures can be separated into the pure enantiomers and the pure diastereomers by methods known to those skilled in the art. The diastereomeric mixture is preferably isolated by crystallization (especially by fractional crystallization) or chromatography. The enantiomeric mixture can be isolated, for example, by forming a diastereomer with the palmitic auxiliary, resolving the resulting diastereomer and removing the palmitic auxiliary. As a palmitic adjuvant, for example, a palmitic acid such as mandelic acid can be used to separate the enantiomeric base, and the enantiomeric acid can be separated by formation of a diastereomeric salt using a palmitic base. In addition, diastereomeric derivatives, such as non-isomeric derivatives, may be formed, respectively, using an enantiomeric mixture of an alcohol or an enantiomeric mixture of an acid, either as a palmitic acid or as a palmitic auxiliary, respectively. Enantiomeric ester. Additionally, diastereomeric complexes or diastereomeric clathrates can be used to separate the enantiomeric mixtures. Alternatively, the separation column can be used in chromatography to separate the enantiomeric mixture. Another suitable method for separating the enantiomers is enzymatic separation.

本發明之一個較佳態樣為根據實例製備技術方案第l項至第5項之化合物的方法。 A preferred aspect of the present invention is a process for preparing a compound according to items 1 to 5 according to the examples.

式(I)化合物可視情況轉化為其鹽，或式(I)化合物之鹽可視情況轉化為游離化合物。熟習此項技術者常用相應方法。 The compound of formula (I) may optionally be converted to its salt, or the salt of the compound of formula (I) may optionally be converted to the free compound. Those skilled in the art often use corresponding methods.

式(I)化合物可視情況轉化為其N-氧化物。N-氧化物亦可藉助於中間物引入。N-氧化物可藉由在適當溶劑(諸如二氯甲烷)中，在諸如0℃至40℃之適合溫度(其中室溫通常較佳)下以氧化劑(諸如間氯過苯甲酸)處理適當前驅體來製備。熟習此項技術者常用其他用於形成N-氧化物之相應方法。 The compound of formula (I) can optionally be converted to its N-oxide. The N-oxide can also be introduced by means of an intermediate. N-oxide can be used in a suitable solvent (such as two In methyl chloride, it is prepared by treating an appropriate precursor with an oxidizing agent such as m-chloroperbenzoic acid at a suitable temperature such as 0 ° C to 40 ° C, wherein room temperature is generally preferred. Other methods for forming N-oxides are commonly used by those skilled in the art.

商業效用Commercial utility

如上文提及，已令人驚訝地發現本發明之化合物可有效地抑制Bub1，最終導致細胞凋亡及細胞死亡，且因此可用於治療或預防以下疾病：失控之細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎性反應之疾病；或伴有失控之細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎性反應之疾病，特定言之為其中失控之細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎性反應由Bub1介導之疾病，諸如良性及惡性瘤形成，更詳言之為血液腫瘤、實體腫瘤及/或其轉移，例如白血病及骨髓發育不良症候群、惡性淋巴瘤、頭頸部腫瘤(包括腦腫瘤及腦轉移)、胸部腫瘤(包括非小細胞肺腫瘤及小細胞肺腫瘤)、胃腸腫瘤、內分泌腫瘤、***腫瘤及其他婦科腫瘤、泌尿腫瘤(包括腎腫瘤、膀胱腫瘤及***腫瘤)、皮膚腫瘤及肉瘤及/或其轉移，尤其為血液腫瘤、實體腫瘤及/或以下的腫瘤之轉移：***、膀胱、骨、腦、中樞及周邊神經系統、子宮頸、結腸、內分泌腺(例如甲狀腺及腎上腺皮質)、內分泌腫瘤、子宮內膜、食道、腸胃腫瘤、生殖細胞、腎臟、肝臟、肺、喉及咽下部、間皮瘤、卵巢、胰腺、***、直腸、腎、小腸、軟組織、胃、皮膚、睪丸、輸尿管、***及外陰，以及惡性瘤形成，包括該等器官中之原發腫瘤及遠端器官中之相應繼發腫瘤(「腫瘤轉移」)。血液腫瘤例如可用以下例示：侵襲性及惰性形式之白血病及淋巴瘤，即非霍奇金氏疾病(non-Hodgkins disease)、慢性及急性骨髓白血病(CML/AML)、急性淋巴母細胞白血病(ALL)、霍奇金氏疾病(Hodgkins disease)、多發性骨髓瘤及T-細胞淋巴瘤。亦包括骨髓發育不良症候群、漿細胞瘤形成、副腫瘤症候群及未知原發性位點之癌症以及AIDS相關惡性腫瘤。 As mentioned above, it has been surprisingly found that the compounds of the invention are effective in inhibiting Bub1, ultimately leading to apoptosis and cell death, and are therefore useful in the treatment or prevention of uncontrolled cell growth, proliferation and/or survival. Diseases that are inappropriate for cellular immune responses or inappropriate cellular inflammatory responses; or diseases associated with uncontrolled cell growth, proliferation, and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in the case of uncontrolled cell growth , proliferation and/or survival, inappropriate cellular immune response or inappropriate cell inflammatory response by Bub1 mediated diseases such as benign and malignant neoplasia, more specifically hematological tumors, solid tumors and/or their metastases, such as leukemia and Myelodysplastic syndrome, malignant lymphoma, head and neck tumors (including brain tumors and brain metastases), chest tumors (including non-small cell lung tumors and small cell lung tumors), gastrointestinal tumors, endocrine tumors, breast tumors and other gynecological tumors, Urological tumors (including kidney tumors, bladder tumors, and prostate tumors), skin tumors and sarcomas, and/or their metastases Especially for the metastasis of hematological tumors, solid tumors and/or the following tumors: breast, bladder, bone, brain, central and peripheral nervous system, cervix, colon, endocrine glands (eg thyroid and adrenal cortex), endocrine tumors, uterus Endometrium, esophagus, gastrointestinal tumor, germ cell, kidney, liver, lung, larynx and hypopharyngeal, mesothelioma, ovary, pancreas, prostate, rectum, kidney, small intestine, soft Tissue, stomach, skin, testicles, ureters, vagina and vulva, as well as malignant neoplasia, including primary tumors in these organs and corresponding secondary tumors in distal organs ("tumor metastasis"). Hematological tumors can be exemplified, for example, by invasive and inert forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML/AML), acute lymphoblastic leukemia (ALL). ), Hodgkins disease, multiple myeloma, and T-cell lymphoma. Also included are myelodysplastic syndromes, plasmacytoma formation, paraneoplastic syndromes, and cancers of unknown primary sites, as well as AIDS-related malignancies.

本發明之一個態樣為式(I)化合物用於治療子宮頸癌、乳癌、卵巢癌、非小細胞肺癌(NSCLC)、***癌、結腸癌、胰腺癌、骨肉瘤、急性骨髓性白血病、伯基特淋巴瘤(Burkitt lymphoma)、多發性骨髓瘤、黑素瘤之用途。 One aspect of the invention is a compound of formula (I) for use in the treatment of cervical cancer, breast cancer, ovarian cancer, non-small cell lung cancer (NSCLC), prostate cancer, colon cancer, pancreatic cancer, osteosarcoma, acute myeloid leukemia, Use of Burkitt lymphoma, multiple myeloma, melanoma.

本發明之一個態樣為式(I)化合物用於治療子宮頸癌、非小細胞肺癌(NSCLC)、***癌、結腸癌、黑素瘤之用途。 One aspect of the invention is the use of a compound of formula (I) for the treatment of cervical cancer, non-small cell lung cancer (NSCLC), prostate cancer, colon cancer, melanoma.

本發明之另一態樣為式(I)化合物用於治療子宮頸腫瘤、NSCLC、***癌、結腸癌及黑素瘤之用途以及一種治療子宮頸腫瘤、NSCLC、***癌、結腸癌及黑素瘤之方法，其包含投與有效量之式(I)化合物。本發明之另一態樣為式(I)化合物用於治療子宮頸腫瘤之用途以及一種治療子宮頸腫瘤之方法，其包含投與有效量之式(I)化合物。 Another aspect of the invention is the use of a compound of formula (I) for the treatment of cervical tumors, NSCLC, prostate cancer, colon cancer and melanoma, and a treatment for cervical tumors, NSCLC, prostate cancer, colon cancer and melanin A method of neoplasia comprising administering an effective amount of a compound of formula (I). Another aspect of the invention is the use of a compound of formula (I) for the treatment of cervical tumors and a method of treating a cervical tumor comprising administering an effective amount of a compound of formula (I).

因此，根據本發明之一態樣，本發明係關於如本文所述及定義之通式I化合物或該化合物之N-氧化物、鹽、互變異構體或立體異構體，或該N-氧化物、互變異構體或立體異構體之鹽，尤其為其醫藥學上可接受之鹽或其混合物，其係用於治療或預防疾病，尤其用於治療疾病。 Thus, according to one aspect of the invention, the invention relates to a compound of formula I as described and defined herein or an N-oxide, salt, interconversion of the compound Isomer or stereoisomer, or a salt of the N-oxide, tautomer or stereoisomer, especially a pharmaceutically acceptable salt thereof or a mixture thereof, for use in the treatment or prevention of a disease Especially for the treatment of diseases.

因此，本發明之另一特定態樣為上文所述之通式I化合物或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽(尤其為其醫藥學上可接受之鹽)或其混合物之用途，其係用於預防或治療過度增殖性病症或對誘導細胞凋亡具反應性之病症，尤其用於治療過度增殖性病症或對誘導細胞凋亡具反應性之病症。 Thus, another particular aspect of the invention is a compound of formula I as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof (especially for its pharmaceutical use) Use of a physiologically acceptable salt or a mixture thereof for preventing or treating a hyperproliferative disorder or a condition responsive to induction of apoptosis, particularly for treating a hyperproliferative disorder or for inducing apoptosis Reactive disease.

如本文所用，術語「不當」在本發明之情形下，尤其在「不當細胞免疫反應或不當細胞發炎性反應」之情形下，應理解為較佳意謂反應低於正常反應或高於正常反應，且伴發、造成或引起該等疾病病變。 As used herein, the term "improper" is used in the context of the present invention, particularly in the context of "inappropriate cellular immune response or inappropriate cellular inflammatory response", and is preferably understood to mean that the reaction is lower than normal or higher than normal. And accompanying, causing or causing lesions of such diseases.

用途較佳在於治療或預防疾病，尤其為治療，其中該等疾病為血液腫瘤、實體腫瘤及/或其轉移。 The use is preferably in the treatment or prevention of diseases, especially in the treatment, wherein the diseases are hematological tumors, solid tumors and/or metastases thereof.

治療過度增殖性病症之方法Method for treating hyperproliferative disorders

本發明係關於一種使用本發明化合物及其組合物治療哺乳動物過度增殖性病症之方法。化合物可用於使細胞增殖及/或細胞***得以抑制、阻斷、減少、降低等及/或產生細胞凋亡。該方法包含向有此需要之哺乳動物(包括人類)投與有效治療該病症之量的本發明化合物或其醫藥學上可接受之鹽、異構體、多晶型物、代謝物、水合物、溶劑合物或酯等。過度增殖性病症包括(但不限於)例如牛皮癬、瘢痕瘤及影響皮膚之其他增生；良性***增生(BPH)；實體腫瘤，諸如乳癌、呼吸道癌、腦癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮膚癌、頭頸癌、甲狀腺癌、副甲狀腺癌及其遠端轉移。彼等病症亦包括淋巴瘤、肉瘤及白血病。 The present invention relates to a method of treating a hyperproliferative disorder in a mammal using the compounds of the invention and compositions thereof. The compounds are useful for inhibiting, blocking, reducing, reducing, etc., and/or producing apoptosis of cell proliferation and/or cell division. The method comprises administering to a mammal, including a human, in need thereof, a compound of the invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate thereof, in an amount effective to treat the condition , solvates or esters, and the like. Hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids, and other hyperplasia affecting the skin; benign prostatic hyperplasia (BPH); Solid tumors, such as breast cancer, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis. These conditions also include lymphoma, sarcoma and leukemia.

乳癌之實例包括(但不限於)侵襲性乳腺管癌、侵襲性小葉癌、乳腺管原位癌及小葉原位癌。 Examples of breast cancer include, but are not limited to, invasive breast ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

呼吸道癌之實例包括(但不限於)小細胞肺癌及非小細胞肺癌，以及支氣管腺瘤及胸膜肺母細胞瘤。 Examples of respiratory cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.

腦癌之實例包括(但不限於)腦幹及下丘腦神經膠質瘤、小腦及大腦星形細胞瘤、神經管胚細胞瘤、室管膜瘤以及神經外胚層及松果體腫瘤。 Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and cerebral astrocytoma, chorioblastoma, ependymoma, and neuroectoderm and pineal tumors.

***官腫瘤包括(但不限於)***癌及睪丸癌。女性生殖器官腫瘤包括(但不限於)子宮內膜癌、子宮頸癌、卵巢癌、***癌及外陰癌以及子宮肉瘤。 Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer and vulvar cancer, and uterine sarcoma.

消化道腫瘤包括(但不限於)肛門癌、結腸癌、結腸直腸癌、食道癌、膽囊癌、胃癌、胰腺癌、直腸癌、小腸癌及唾液腺癌。 Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.

泌尿道腫瘤包括(但不限於)膀胱癌、陰莖癌、腎癌、腎盂癌、輸尿管癌、尿道癌及人類乳頭狀腎癌。 Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

眼癌包括(但不限於)眼內黑素瘤及視網膜胚細胞瘤。 Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

肝癌之實例包括(但不限於)肝細胞癌(有或無纖維板層變異之肝細胞癌)、膽管癌(肝內膽管癌)及混合型肝細胞膽管癌。 Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocyte cholangiocarcinoma.

皮膚癌包括(但不限於)鱗狀細胞癌、卡波西氏肉瘤 (Kaposi's sarcoma)、惡性黑素瘤、默克細胞皮膚癌(Merkel cell skin cancer)及非黑素瘤皮膚癌。 Skin cancer includes, but is not limited to, squamous cell carcinoma, Kaposi's sarcoma (Kaposi's sarcoma), malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

頭頸癌包括(但不限於)喉癌、下咽癌、鼻咽癌、口咽癌、唇及口腔癌以及鱗狀細胞癌。淋巴瘤包括(但不限於)AIDS相關淋巴瘤、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、皮膚T-細胞淋巴瘤、伯基特淋巴瘤、霍奇金氏疾病及中樞神經系統淋巴瘤。 Head and neck cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and central nervous system lymph tumor.

肉瘤包括(但不限於)軟組織肉瘤、骨肉瘤、惡性纖維組織細胞瘤、淋巴肉瘤及橫紋肌肉瘤。 Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

白血病包括(但不限於)急性骨髓白血病、急性淋巴母細胞白血病、慢性淋巴球性白血病、慢性骨髓性白血病及毛細胞白血病。 Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

該等病症在人類中已得到良好表徵，且在其他哺乳動物中亦以類似病源學存在，且可藉由投與本發明之醫藥組合物來治療。 Such conditions have been well characterized in humans and are also present in similar pathogens in other mammals and can be treated by administration of the pharmaceutical compositions of the invention.

如本文通篇所述之術語「治療」係以習知含義使用，例如處理或護理個體以達到對抗、減輕、減少、緩解、改善疾病或病症(諸如癌瘤)之病狀等之目的。 The term "treatment" as used throughout the text is used in the conventional sense, for example, to treat or care for an individual for the purpose of combating, alleviating, reducing, alleviating, ameliorating the condition of a disease or condition, such as a cancer, and the like.

治療激酶病症之方法Method of treating a kinase disorder

本發明亦提供治療與異常有絲***原細胞外激酶活性相關之病症的方法，該等病症包括(但不限於)中風、心臟衰竭、肝腫大、心肥大、糖尿病、阿茲海默氏病(Alzheimer's disease)、囊腫性纖維化、異種移植排斥反應之症狀、敗血性休克或哮喘。 The invention also provides methods of treating disorders associated with aberrant mitogen-extracellular kinase activity, including but not limited to stroke, heart failure, hepatomegaly, cardiac hypertrophy, diabetes, Alzheimer's disease (Alzheimer's) Disease), cystic fibrosis, symptoms of xenograft rejection, septic shock or asthma.

可使用有效量之本發明化合物來治療該等病症，包括上文【先前技術】部分中提及之彼等疾病(例如癌症)。儘管如此，無論作用機制及/或激酶與病症之間的關係如何，該等癌症及其他疾病均可用本發明之化合物來治療。 An effective amount of a compound of the invention can be used to treat such conditions, including those diseases (e.g., cancer) as mentioned in the [Prior Art] section above. Nonetheless, regardless of the mechanism of action and/or the relationship between the kinase and the condition, such cancers and other diseases can be treated with the compounds of the invention.

片語「異常激酶活性」或「異常酪胺酸激酶活性」包括編碼激酶之基因或該基因所編碼之多肽的任何異常表現或活性。該異常活性之實例包括(但不限於)基因或多肽之過度表現；基因擴增；產生組成性活性或活性過高之激酶活性的突變；基因突變、缺失、取代、添加等。 The phrase "abnormal kinase activity" or "abnormal tyrosine kinase activity" includes any abnormal expression or activity of a gene encoding a kinase or a polypeptide encoded by the gene. Examples of such abnormal activities include, but are not limited to, overexpression of a gene or polypeptide; gene amplification; mutations that produce constitutively active or hyperactive kinase activity; gene mutations, deletions, substitutions, additions, and the like.

本發明亦提供抑制激酶活性、尤其有絲***原細胞外激酶活性之方法，該方法包含投與有效量之本發明化合物，包括其鹽、多晶型物、代謝物、水合物、溶劑合物、前藥(例如酯)及其非對映異構形式。可抑制細胞中(例如活體外)或哺乳動物個體(尤其為需要治療之人類患者)細胞中之激酶活性。 The invention also provides a method of inhibiting kinase activity, particularly mitogen extracellular kinase activity, comprising administering an effective amount of a compound of the invention, including salts, polymorphs, metabolites, hydrates, solvates thereof, Drugs such as esters and their diastereomeric forms. It can inhibit kinase activity in cells (e.g., in vitro) or in mammalian individuals (especially in human patients in need of treatment).

治療血管生成病症之方法Method of treating angiogenic disorders

本發明亦提供治療與過度及/或異常血管生成相關之病症及疾病的方法。 The invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.

血管生成之不當及異位表現可對有機體有害。大量病理學病狀與額外血管之生長有關。該等病症包括例如糖尿病性視網膜病變、缺血性視網膜-靜脈阻塞及早產兒視網膜病變[Aiello等人，New Engl.J.Med.1994,331,1480；Peer等人，Lab.Invest.1995,72,638]、年齡相關之黃斑變性[AMD；參見Lopez等人，Invest.Opththalmol.Vis.Sci. 1996,37,855]、新生血管性青光眼、牛皮癬、晶狀體後顯微組織增生、血管纖維瘤、炎症、類風濕性關節炎(RA)、再狹窄、支架內再狹窄、血管移植再狹窄等。另外，與癌性及贅生性組織相關之血液供應增加促進生長，導致腫瘤快速擴大及轉移。此外，腫瘤中新血管及***之生長為反叛細胞提供逃脫途徑，從而促進癌症轉移及由此引起之擴散。因此，可使用本發明之化合物例如藉由抑制及/或減少血管形成；藉由使內皮細胞增殖或涉及血管生成之其他類型細胞增殖得以抑制、阻斷、減少、降低等，以及促使該等細胞類型之細胞死亡或細胞凋亡來治療及/或預防任何前述血管生成病症。 Improper angiogenesis and ectopic performance can be harmful to organisms. A large number of pathological conditions are associated with the growth of additional blood vessels. Such conditions include, for example, diabetic retinopathy, ischemic retinal-venous obstruction, and retinopathy of prematurity [Aiello et al, New Engl. J. Med. 1994 , 331, 1480; Peer et al, Lab. Invest. 1995 , 72, 638 Age-related macular degeneration [AMD; see Lopez et al, Invest. Opththalmol. Vis. Sci. 1996 , 37, 855], neovascular glaucoma, psoriasis, post-lens microscopic hyperplasia, angiofibroma, inflammation, rheumatoid Arthritis (RA), restenosis, in-stent restenosis, restenosis of vascular grafts, etc. In addition, increased blood supply associated with cancerous and neoplastic tissues promotes growth, leading to rapid tumor expansion and metastasis. In addition, the growth of new blood vessels and lymphatic vessels in tumors provides an escape pathway for rebel cells, thereby promoting cancer metastasis and its spread. Thus, the compounds of the invention may be used, for example, by inhibiting and/or reducing angiogenesis; by inhibiting, blocking, reducing, reducing, etc., proliferation of endothelial cells or other types of cell proliferation involved in angiogenesis, and promoting such cells Types of cell death or apoptosis to treat and/or prevent any of the aforementioned angiogenic disorders.

適於該方法之疾病較佳為血液腫瘤、實體腫瘤及/或其轉移。 Diseases suitable for this method are preferably hematological tumors, solid tumors and/or metastases thereof.

本發明之化合物尤其可用於治療及預防(亦即預防)，尤其用於治療腫瘤生長及轉移，尤其在已預先治療腫瘤生長或未預先治療腫瘤生長之所有適應症及階段的實體腫瘤中。 The compounds of the invention are especially useful for the treatment and prophylaxis (i.e., prophylaxis), particularly for the treatment of tumor growth and metastasis, particularly in solid tumors where all indications and stages of tumor growth have not been previously treated or have not been previously treated for tumor growth.

本發明化合物之醫藥組合物Pharmaceutical composition of the compound of the present invention

本發明亦係關於含有一或多種本發明化合物之醫藥組合物。該等組合物可用於藉由投藥至有此需要之患者來達成所需之藥理學作用。適於本發明目的之患者為需要治療特定病狀或疾病之哺乳動物，包括人類。 The invention also relates to pharmaceutical compositions containing one or more compounds of the invention. Such compositions can be used to achieve the desired pharmacological effect by administering to a patient in need thereof. A patient suitable for the purposes of the present invention is a mammal, including a human, in need of treatment for a particular condition or disease.

因此，本發明包括包含醫藥學上可接受之載劑或助劑及醫藥學有效量之本發明化合物或其鹽的醫藥組合物。 Accordingly, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier or adjuvant and a pharmaceutically effective amount of a compound of the invention or a salt thereof.

本發明之另一態樣為一種包含醫藥學有效量之式(I)化合物及醫藥學上可接受之助劑的醫藥組合物，其係用於治療上文提及之疾病，尤其用於治療血液腫瘤、實體腫瘤及/或其轉移。 Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable adjuvant for the treatment of the above mentioned diseases, especially for treatment Hematological tumors, solid tumors, and/or their metastases.

醫藥學上可接受之載劑或助劑較佳為在與活性成分之有效活性一致之濃度下對患者無毒且無害之載劑，以使得可歸於載劑之任何副作用均不會破壞活性成分之有益作用。載劑及助劑為有助於組合物適合投藥之所有種類的添加劑。 The pharmaceutically acceptable carrier or adjuvant is preferably a carrier that is non-toxic and non-toxic to the patient at a concentration consistent with the effective activity of the active ingredient so that any side effects attributable to the carrier do not destroy the active ingredient. Beneficial effect. Carriers and auxiliaries are all types of additives which aid in the suitability of the composition for administration.

化合物之醫藥學有效量較佳為對所治療之特定病狀產生一定效果或產生預期影響之量。 The pharmaceutically effective amount of the compound is preferably an amount which produces a certain effect or produces the desired effect on the particular condition being treated.

本發明之化合物可與此項技術中熟知之醫藥學上可接受之載劑或助劑一起，使用包括速釋、緩釋及延時釋放製劑之任何有效習知單位劑型經口、非經腸、經局部、經鼻、經眼部(ophthalmically)、經眼、經舌下、經直腸、經***及其類似途徑來投與。 The compounds of the present invention can be administered orally, parenterally, in any effective conventional unit dosage form including immediate release, sustained release and extended release formulations, together with pharmaceutically acceptable carriers or adjuvants well known in the art. It is administered topically, nasally, ophthalmically, transocularly, sublingually, transrectally, transvaginally, and the like.

對於經口投藥而言，可將化合物調配成固體或液體製劑，諸如膠囊、丸劑、錠劑、片劑、***劑、熔融劑、散劑、溶液、懸浮液或乳液，且可根據此項技術中已知用於製造醫藥組合物之方法來製備。固體單位劑型可為膠囊，其可為含有例如界面活性劑、潤滑劑以及諸如乳糖、蔗糖、磷酸鈣及玉米澱粉之惰性填充劑之助劑的普通硬殼或軟殼明膠型膠囊。 For oral administration, the compound can be formulated into a solid or liquid preparation such as a capsule, a pill, a lozenge, a tablet, a buccal, a flux, a powder, a solution, a suspension or an emulsion, and according to the technology It is known to prepare a method for producing a pharmaceutical composition. The solid unit dosage form can be a capsule which can be a conventional hard or soft shell gelatin type capsule containing an adjuvant such as a surfactant, a lubricant, and an inert filler such as lactose, sucrose, calcium phosphate, and corn starch.

在另一實施例中，可將本發明化合物與習知錠劑基質 (諸如乳糖、蔗糖及玉米澱粉)連同與以下各物組合一起製成錠劑：黏合劑，諸如***膠(acacia)、玉米澱粉或明膠；旨在輔助錠劑在投藥後分解及溶解之崩解劑，諸如馬鈴薯澱粉、褐藻酸、玉米澱粉及瓜爾膠(guar gum)、黃蓍膠、***膠；旨在改良錠劑顆粒流動性且防止錠劑材料黏附於錠劑壓模及衝頭表面之潤滑劑，例如滑石、硬脂酸或硬脂酸鎂、硬脂酸鈣或硬脂酸鋅；旨在增強錠劑之美觀品質且使其更能為患者所接受之染料、著色劑及調味劑，諸如薄荷、冬青油或櫻桃調味劑。用於口服液體劑型之適當賦形劑包括磷酸二鈣及稀釋劑，諸如水及醇，例如乙醇、苯甲醇及聚乙烯醇，其中添加或不添加醫藥學上可接受之界面活性劑、懸浮劑或乳化劑。各種其他物質可以包衣形式存在或以其他方式改變劑量單位之物理形式。舉例而言，錠劑、丸劑或膠囊可經蟲膠、糖或其兩者包覆。 In another embodiment, the compounds of the invention may be formulated with conventional lozenge matrices (such as lactose, sucrose, and corn starch) together with a combination of the following: a binder, such as acacia, corn starch or gelatin; is intended to aid in the disintegration of the tablet after decomposition and dissolution after administration. Agents such as potato starch, alginic acid, corn starch and guar gum, tragacanth, gum arabic; aim to improve the flowability of tablet particles and prevent the tablet material from sticking to the tablet mold and punch surface Lubricants, such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate; dyes, colorants and flavourings designed to enhance the aesthetic qualities of lozenges and make them more acceptable to patients An agent such as peppermint, wintergreen oil or cherry flavoring. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols such as ethanol, benzyl alcohol and polyvinyl alcohol with or without the addition of pharmaceutically acceptable surfactants, suspending agents Or an emulsifier. Various other materials may be present in the form of a coating or otherwise alter the physical form of the dosage unit. For example, a lozenge, pill or capsule may be coated with shellac, sugar or both.

分散性散劑及顆粒適於製備水性懸浮液。其提供活性成分與分散劑或濕潤劑、懸浮劑及一或多種防腐劑之混合物。適合之分散劑或濕潤劑及懸浮劑由上文已提及之彼等試劑例示。亦可存在其他賦形劑，例如上文所述之彼等甜味劑、調味劑及著色劑。 Dispersible powders and granules are suitable for the preparation of aqueous suspensions. It provides a mixture of the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the reagents already mentioned above. Other excipients, such as those described above, such as sweeteners, flavoring agents, and coloring agents, may also be present.

本發明之醫藥組合物亦可呈水包油乳液之形式。油相可為植物油(諸如液體石蠟)或植物油混合物。適合乳化劑可為(1)天然存在之樹膠，諸如***膠及黃蓍膠；(2)天然存生之磷脂，諸如大豆及卵磷脂；(3)衍生自脂肪酸及己醣醇酐之酯或偏酯，例如脫水山梨糖醇單油酸酯；(4)該等偏酯與氧化乙烯之縮合產物，例如聚氧乙烯脫水山梨糖醇單油酸酯。乳液亦可含有甜味劑及調味劑。 The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (such as liquid paraffin) or a vegetable oil mixture. Suitable emulsifiers can be (1) naturally occurring gums such as acacia and tragacanth; (2) naturally occurring phospholipids such as soy and lecithin; (3) esters derived from fatty acids and hexitol anhydrides or Partial esters, such as sorbitan monooleate; (4) the partial A condensation product of an ester with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The lotion may also contain sweeteners and flavoring agents.

油性懸浮液可藉由使活性成分懸浮於諸如花生油、橄欖油、芝麻油或椰子油之植物油或諸如液體石蠟之礦物油中來調配。油性懸浮液可含有增稠劑，諸如蜂蠟、硬石蠟或十六烷醇。懸浮液亦可含有一或多種防腐劑，例如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯；一或多種著色劑；一或多種調味劑；及一或多種甜味劑，諸如蔗糖或糖精。 An oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil or mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, for example ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin.

糖漿及酏劑可用諸如甘油、丙二醇、山梨糖醇或蔗糖之甜味劑來調配。該等調配物亦可含有緩和劑及防腐劑(諸如對羥基苯甲酸甲酯及對羥基苯甲酸丙酯)以及調味劑及著色劑。 Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent and preservative (such as methylparaben and propylparaben) as well as flavoring and coloring agents.

本發明之化合物亦可以化合物較佳於生理學上可接受之稀釋劑以及醫藥學載劑中之可注射劑型非經腸(亦即，經皮下、靜脈內、眼內、滑膜內、肌肉內或腹膜內)投與，該醫藥學載劑可為添加或不添加醫藥學上可接受之界面活性劑(諸如皂或清潔劑)、懸浮劑(諸如果膠、卡波姆(carbomer)、甲基纖維素、羥丙基甲基纖維素或羧甲基纖維素)或乳化劑及其他醫藥學佐劑之無菌液體或液體混合物，該液體諸如水、生理鹽水、右旋糖水溶液及相關糖溶液；醇，諸如乙醇、異丙醇或十六烷醇；二醇，諸如丙二醇或聚乙二醇；甘油縮酮，諸如2,2-二甲基-1,1-二氧雜環戊烷-4-甲醇；醚，諸如聚(乙二醇)400；油、脂肪酸、脂肪酸酯或脂肪酸甘油酯或乙醯化脂肪酸甘油酯。 The compound of the present invention may also be a parenteral (i.e., subcutaneous, intravenous, intraocular, intrasynovial, intramuscular) injectable form of the compound in a physiologically acceptable diluent and a pharmaceutically acceptable carrier. Or intraperitoneally, the pharmaceutical carrier may be with or without the addition of a pharmaceutically acceptable surfactant (such as a soap or detergent), a suspending agent (such as a gum, a carbomer, a a sterile liquid or liquid mixture of a cellulosic, hydroxypropylmethylcellulose or carboxymethylcellulose) or emulsifier and other pharmaceutical adjuvants such as water, physiological saline, aqueous dextrose and related sugar solutions An alcohol such as ethanol, isopropanol or cetyl alcohol; a diol such as propylene glycol or polyethylene glycol; a glycerol ketal such as 2,2-dimethyl-1,1-dioxolane- 4-methanol; ethers such as poly(ethylene glycol) 400; oils, fatty acids, fatty acid esters or fatty acid glycerides or acetylated fatty acid glycerides.

可用於本發明之非經腸調配物中之說明性油為石油、動物油、植物油或合成來源之油，例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄欖油、石蠟油及礦物油。適合之脂肪酸包括油酸、硬脂酸、異硬脂酸及肉豆蔻酸。適合之脂肪酸酯為例如油酸乙酯及肉豆蔻酸異丙酯。適合之皂類包括脂肪酸鹼金屬鹽、銨鹽及三乙醇胺鹽且適合之清潔劑包括陽離子型清潔劑，例如二甲基二烷基鹵化銨、烷基鹵化吡錠及烷基胺乙酸鹽；陰離子型清潔劑，例如烷基、芳基及烯烴磺酸酯，烷基、烯烴、醚及單酸甘油酯硫酸酯，及磺基丁二酸酯；非離子型清潔劑，例如脂肪胺氧化物、脂肪酸烷醇醯胺及聚(氧乙烯-氧丙烯)，或者氧化乙烯或氧化丙烯共聚物；及兩性清潔劑，例如烷基-β-胺基丙酸酯及2-烷基咪唑啉四級銨鹽；以及混合物。 Illustrative oils useful in parenteral formulations of the invention are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal salts, ammonium salts and triethanolamine salts of fatty acids and suitable detergents include cationic detergents such as dimethyldialkylammonium halide, alkylhalide pyrene and alkylamine acetate; Anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents such as fatty amine oxides , fatty acid alkanolamines and poly(oxyethylene-oxypropylene), or ethylene oxide or propylene oxide copolymers; and amphoteric detergents such as alkyl-β-aminopropionate and 2-alkylimidazoline Ammonium salt; and mixture.

本發明之非經腸組合物通常在溶液中含有約0.5重量%至約25重量%之活性成分。亦可有利地使用防腐劑及緩衝劑。為最小化或消除對注射部位之刺激，該等組合物可含有較佳具有約12至約17之親水親油平衡值(HLB)的非離子性界面活性劑。該調配物中界面活性劑之量較佳在約5重量%至約15重量%之範圍內。界面活性劑可為具有以上HLB之單一組分或可為兩種或兩種以上具有所要HLB之組分的混合物。 The parenteral compositions of the present invention typically comprise from about 0.5% to about 25% by weight of active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation to the injection site, the compositions may contain a nonionic surfactant preferably having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant in the formulation is preferably in the range of from about 5% by weight to about 15% by weight. The surfactant may be a single component having the above HLB or a mixture of two or more components having the desired HLB.

用於非經腸調配物中之說明性界面活性劑為聚乙烯脫水山梨糖醇脂肪酸酯類(例如脫水山梨糖醇單油酸酯)及氧化乙烯與藉由氧化丙烯與丙二醇縮合所形成之疏水性基質的高分子量加合物。 Illustrative surfactants for use in parenteral formulations are polyethylene sorbitan fatty acid esters (such as sorbitan monooleate) and the hydrophobicity of ethylene oxide with condensation of propylene oxide with propylene glycol. Sexual matrix High molecular weight adducts.

醫藥組合物可呈無菌可注射水性懸浮液之形式。該等懸浮液可根據已知方法使用適合之分散劑或濕潤劑及懸浮劑來調配，該等懸浮劑諸如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、褐藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及***膠，分散劑或濕潤劑可為天然存在之磷脂，諸如卵磷脂；氧化烯與脂肪酸之縮合產物，例如聚氧乙烯硬脂酸酯；氧化乙烯與長鏈脂族醇之縮合產物，例如十七伸乙氧基十六烷醇；氧化乙烯與衍生自脂肪酸及己醣醇之偏酯的縮合產物，諸如聚氧乙烯山梨糖醇單油酸酯；或氧化乙烯與衍生自脂肪酸及己醣醇酐之偏酯的縮合產物，例如聚氧乙烯脫水山梨糖醇單油酸酯。 The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. These suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, alginic acid Sodium, polyvinylpyrrolidone, tragacanth and acacia, dispersing or wetting agents may be naturally occurring phospholipids, such as lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; ethylene oxide a condensation product with a long-chain aliphatic alcohol, such as hepta-ethoxyethoxy cetyl alcohol; a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitan monooleate Or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyoxyethylene sorbitan monooleate.

無菌可注射製劑亦可為於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液。可使用之稀釋劑及溶劑為例如水、林格氏溶液(Ringer's solution)、等張氯化鈉溶液及等張葡萄糖溶液。另外，無菌不揮發性油通常用作溶劑或懸浮介質。出於此目的，可使用包括合成單甘油酯或二甘油酯之任何溫和不揮發性油。另外，諸如油酸之脂肪酸亦可用於製備可注射劑。 The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any mild, fixed oil comprising synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

本發明之組合物亦可以用於直腸投與藥物之栓劑形式來投與。該等組合物可藉由將藥物與適合之無刺激性賦形劑混合來製備，該賦形劑在常溫下為固體但在直腸溫度下為液體且因此在直腸中將熔融以釋放藥物。該等物質例如為可可脂及聚乙二醇。 The compositions of the invention may also be administered in the form of suppositories for rectal administration of the drug. The compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and thus will melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.

用於非經腸投藥之控釋調配物包括此項技術中已知之脂質體、聚合微球及聚合凝膠調配物。 Controlled release formulations for parenteral administration include liposomes, polymeric microspheres, and polymeric gel formulations known in the art.

可能需要或必需經由機械傳遞裝置將醫藥組合物引入患者體內。用於傳遞藥劑之機械傳遞裝置的構造及使用為此項技術中所熟知。例如用於將藥物直接投與至腦中之直接投藥技術通常涉及將藥物傳遞導管置入患者之腦室系統中以繞過血腦屏障。一種此類用於將藥劑輸送至身體特定解剖學區域之可植入式傳遞系統描述於美國專利第5,011,472號(1991年4月30日頒佈)中。 It may be necessary or necessary to introduce a pharmaceutical composition into a patient via a mechanical delivery device. The construction and use of mechanical delivery devices for delivering medicaments are well known in the art. For example, direct dosing techniques for administering drugs directly into the brain typically involve placing a drug delivery catheter into the ventricular system of the patient to bypass the blood brain barrier. One such implantable delivery system for delivering a medicament to a particular anatomical region of the body is described in U.S. Patent No. 5,011,472, issued Apr. 30, 1991.

本發明之組合物視必需或需要時亦可含有其他習知醫藥學上可接受之混配成分(通常稱為載劑或稀釋劑)。可使用將該等組合物製備成適當劑型之習知程序。 The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients (commonly referred to as carriers or diluents) as necessary or desired. Conventional procedures for preparing such compositions into suitable dosage forms can be used.

該等成分及程序包括以下文獻中所述之彼等成分及程序，該等文獻各自以引用的方式併入本文中：Powell,M.F.等人，「Compendium of Excipients for Parenteral Formulations」PDA Journal of Pharmaceutical Science & Technology 1998,52(5),238-311；Strickley,R.G「Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States(1999)-Part-1」PDA Journal of Pharmaceutical Science & Technology 1999,53(6),324-349；及Nema,S.等人，「Excipients and Their Use in Injectable Products」PDA Journal of Pharmaceutical Science & Technology 1997,51(4),166-171。 Such components and procedures include those components and procedures described in the following documents, each of which is incorporated herein by reference: Powell, MF et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998 , 52(5), 238-311; Strickley, RG "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999 , 53(6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997 , 51(4), 166-171.

適當時可用於調配適於其預期投藥途徑之組合物的常用醫藥成分包括：酸化劑(實例包括(但不限於)乙酸、檸檬酸、反丁烯二酸、鹽酸、硝酸)；鹼化劑(實例包括(但不限於)氨溶液、碳酸銨、二乙醇胺、單乙醇胺、氫氧化鉀、硼酸鈉、碳酸鈉、氫氧化鈉、三乙醇胺(triethanolamine)、三乙醇胺(trolamine))；吸附劑(實例包括(但不限於)粉末狀纖維素及活性炭)；氣溶膠推進劑(實例包括(但不限於)二氧化碳、CCl₂F₂、F₂ClC-CClF₂及CClF₃)；排氣劑(實例包括(但不限於)氮氣及氬氣)；抗真菌防腐劑(實例包括(但不限於)苯甲酸、對羥基苯甲酸丁酯、對羥基苯甲酸乙酯、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、苯甲酸鈉)；抗菌防腐劑(實例包括(但不限於)氯化苯甲烴銨、苄索氯銨(benzethonium chloride)、苯甲醇、氯化十六烷基吡錠、氯丁醇、苯酚、苯乙醇、硝酸苯汞及硫柳汞(thimerosal))；抗氧化劑(實例包括(但不限於)抗壞血酸、抗壞血基棕櫚酸酯、丁基化羥基甲氧苯、丁基化羥基甲苯、次磷酸、單硫代甘油、沒食子酸丙酯、抗壞血酸鈉、亞硫酸氫鈉、甲醛合次硫酸氫鈉、焦亞硫酸鈉)；黏合物質(實例包括(但不限於)嵌段聚合物、天然及合成橡膠、聚丙烯酸酯、聚胺基甲酸酯、聚矽氧、聚矽氧烷及苯乙烯-丁二烯共聚物)； 緩衝劑(實例包括(但不限於)偏磷酸鉀、磷酸氫二鉀、乙酸鈉、無水檸檬酸鈉及二水合檸檬酸鈉)；載劑(實例包括(但不限於)***膠糖漿、芳香糖漿、芳香酏劑、櫻桃糖漿、可可糖漿、橙糖漿、糖漿、玉米油、礦物油、花生油、芝麻油、抑菌性氯化鈉注射液及抑菌注射用水)；螯合劑(實例包括(但不限於)乙二胺四乙酸二鈉及乙二胺四乙酸)；著色劑(實例包括(但不限於)FD&C紅色3號、FD&C紅色20號、FD&C黃色6號、FD&C藍色2號、D&C綠色5號、D&C橙色5號、D&C紅色8號、焦糖及氧化鐵紅)；澄清劑(實例包括(但不限於)膨潤土)；乳化劑(實例包括(但不限於)***膠、聚西托醇(cetomacrogol)、十六烷醇、單硬脂酸甘油酯、卵磷脂、脫水山梨糖醇單油酸酯、聚氧乙烯50單硬脂酸酯)；囊封劑(實例包括(但不限於)明膠及鄰苯二甲酸乙酸纖維素)；調味劑(實例包括(但不限於)大茴香油、肉桂油、可可豆、薄荷腦、橙油、胡椒薄荷油及香草精)；保濕劑(實例包括(但不限於)甘油、丙二醇及山梨糖醇)；水磨劑(實例包括(但不限於)礦物油及甘油)；油(實例包括(但不限於)花生油、礦物油、橄欖油、花生油、芝麻油及植物油)； 軟膏基質(實例包括(但不限於)羊毛脂、親水性軟膏、聚乙二醇軟膏、石蠟油、親水性石蠟油、白色軟膏、黃色軟膏及玫瑰水軟膏)；穿透增強劑(經皮傳遞)(實例包括(但不限於)一元醇或多元醇、一價醇或多價醇、飽和或不飽和脂肪醇、飽和或不飽和脂肪酯、飽和或不飽和二羧酸、精油、磷脂醯基衍生物、腦磷脂、萜、醯胺、醚、酮及脲)；增塑劑(實例包括(但不限於)鄰苯二甲酸二乙酯及甘油)；溶劑(實例包括(但不限於)乙醇、玉米油、棉籽油、甘油、異丙醇、礦物油、油酸、花生油、純化水、注射用水、無菌注射用水及無菌灌注用水)；硬化劑(實例包括(但不限於)十六烷醇、十六烷酯蠟、微晶蠟、石蠟、硬脂醇、白蠟及黃蠟)；栓劑基質(實例包括(但不限於)可可脂及聚乙二醇(混合物))；界面活性劑(實例包括(但不限於)氯化苯甲烴銨、壬苯醇醚10、辛苯聚醇9(oxtoxynol 9)、聚山梨醇酯80、十二烷基硫酸鈉及脫水山梨糖醇單棕櫚酸酯)；懸浮劑(實例包括(但不限於)瓊脂、膨潤土、卡波姆、羧甲基纖維素鈉、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、高嶺土、甲基纖維素、黃蓍膠及維格姆(veegum))；甜味劑(實例包括(但不限於)阿斯巴甜糖(aspartame)、右旋糖、甘油、甘露糖醇、丙二醇、糖精鈉、山梨糖醇及蔗糖)；錠劑抗黏劑(實例包括(但不限於)硬脂酸鎂及滑石)；錠劑黏合劑(實例包括(但不限於)***膠、褐藻酸、羧甲基纖維素鈉、可壓縮糖、乙基纖維素、明膠、液體葡萄糖、甲基纖維素、非交聯聚乙烯吡咯啶酮及預膠凝化澱粉)；錠劑及膠囊稀釋劑(實例包括(但不限於)磷酸氫鈣、高嶺土、乳糖、甘露糖醇、微晶纖維素、粉末狀纖維素、沈澱碳酸鈣、碳酸鈉、磷酸鈉、山梨糖醇及澱粉)；錠劑包衣劑(實例包括(但不限於)液體葡萄糖、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、甲基纖維素、乙基纖維素、鄰苯二甲酸乙酸纖維素及蟲膠)；錠劑直接壓縮賦形劑(實例包括(但不限於)磷酸氫鈣)；錠劑崩解劑(實例包括(但不限於)褐藻酸、羧甲基纖維素鈣、微晶纖維素、泊拉可林鉀(polacrillin potassium)、交聯聚乙烯吡咯啶酮、褐藻酸鈉、乙醇酸澱粉鈉及澱粉)；錠劑滑動劑(實例包括(但不限於)膠狀二氧化矽、玉米澱粉及滑石)；錠劑潤滑劑(實例包括(但不限於)硬脂酸鈣、硬脂酸鎂、礦物油、硬脂酸及硬脂酸鋅)；錠劑/膠囊遮光劑(實例包括(但不限於)二氧化鈦)；錠劑拋光劑(實例包括(但不限於)巴西棕櫚蠟(carnuba wax)及白蠟)； 增稠劑(實例包括(但不限於)蜂蠟、十六烷醇及石蠟)；張力劑(實例包括(但不限於)右旋糖及氯化鈉)；增黏劑(實例包括(但不限於)褐藻酸、膨潤土、卡波姆、羧甲基纖維素鈉、甲基纖維素、聚乙烯吡咯啶酮、褐藻酸鈉及黃蓍膠)；及濕潤劑(實例包括(但不限於)十七伸乙氧基十六烷醇、卵磷脂、山梨糖醇單油酸酯、聚氧乙烯山梨糖醇單油酸酯及聚氧乙烯硬脂酸酯)。 Common pharmaceutical ingredients that may be used to formulate compositions suitable for the intended route of administration, as appropriate, include: acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalizing agents ( Examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trilamine, and adsorbents (examples) Including, but not limited to, powdered cellulose and activated carbon; aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl ₂ F ₂ , F ₂ ClC-CClF ₂ and CClF ₃ ); venting agents (examples include (but not limited to) nitrogen and argon); antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, p-hydroxybenzene Propyl propylate, sodium benzoate); antibacterial preservatives (examples include, but are not limited to, benzethonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol , phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal (thime Rosal)); antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxymethoxybenzene, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, gallic acid Propyl ester, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binders (examples include (but not limited to) block polymers, natural and synthetic rubbers, polyacrylates, polyamines Acid esters, polyoxyxides, polyoxyalkylenes, and styrene-butadiene copolymers; buffers (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and Hydrated sodium citrate); carrier (examples include (but not limited to) gum arabic syrup, aromatic syrup, aromatic tincture, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic Sodium chloride injection and bacteriostatic water for injection); chelating agents (examples include (but not limited to) disodium edetate and ethylenediaminetetraacetic acid); colorants (examples include (but are not limited to) FD&C red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue 2 No., D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, Caramel and Iron Oxide Red); clarifying agent (examples include (but not limited to) bentonite); emulsifiers (examples include (but not limited to) gum arabic , cetomacrogol (cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include (but not limited to) gelatin and cellulose acetate phthalate); flavoring agents (examples include (but not limited to) anise oil, cinnamon oil, cocoa beans, menthol, orange oil, peppermint oil and vanilla extract); Humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol); water-grinding agents (examples include, but are not limited to, mineral oil and glycerin); oils (examples include (but are not limited to) peanut oil, mineral oil, olives Oil, peanut oil, sesame oil and vegetable oil); ointment base (examples include (but not limited to) lanolin, hydrophilic ointment, polyethylene glycol ointment, paraffin oil, hydrophilic paraffin oil, white ointment, yellow ointment and rose water ointment) ; penetration enhancers (transdermal delivery) (examples include (but are not limited to) one yuan Or a polyol, a monovalent or polyvalent alcohol, a saturated or unsaturated fatty alcohol, a saturated or unsaturated fatty ester, a saturated or unsaturated dicarboxylic acid, an essential oil, a phospholipid derivative, a cephalin, a guanidine, a guanamine, Ether, ketone and urea); plasticizers (examples include (but not limited to) diethyl phthalate and glycerin); solvents (examples include (but are not limited to) ethanol, corn oil, cottonseed oil, glycerin, isopropyl Alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and water for aseptic perfusion); hardener (examples include (but are not limited to) cetyl alcohol, cetyl ester wax, microcrystalline wax, Paraffin, stearyl alcohol, white wax and yellow wax); suppository base (examples include but not limited to cocoa butter and polyethylene glycol (mixture)); surfactants (examples include (but are not limited to) benzalkonium chloride , nonoxynol ether 10, octetoxynol 9 (polyoxylol 80), polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (examples include (but not limited to) Agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxy Propyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum; sweeteners (examples include (but are not limited to) aspartame, dextrose, Glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose); tablet anti-adhesives (examples include, but are not limited to, magnesium stearate and talc); tablet adhesives (examples include (but are not limited to) ) gum arabic, alginic acid, sodium carboxymethyl cellulose, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose, non-crosslinked polyvinylpyrrolidone and pregelatinized starch; ingot And capsule diluents (examples include, but are not limited to, calcium hydrogen phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol, and starch Tablet coating agent (examples include, but are not limited to) liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, ortho-benzene Cellulose acetate diacetate and shellac); tablets directly compress excipients (examples include (but are not limited to) Calcium hydrogen phosphate); tablet disintegrant (examples include, but are not limited to, alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose, poracrillin potassium, crosslinked polyvinylpyrrolidone , sodium alginate, sodium starch glycolate and starch); lozenge slip agents (examples include, but are not limited to, colloidal ceria, corn starch and talc); lozenge lubricants (examples include (but are not limited to) hard Calcium citrate, magnesium stearate, mineral oil, stearic acid and zinc stearate); lozenge/capsule opacifiers (examples include, but not limited to, titanium dioxide); lozenge polishes (examples include (but are not limited to) Carnituba wax and white wax; thickeners (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin); tonicity agents (examples include, but are not limited to, dextrose and sodium chloride) Adhesives (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth); Wetting agent (examples include, but are not limited to, heptadecyl ethoxy cetyl alcohol, lecithin, sorbitol monooleate, polyoxyethylene mountain Pearitol monooleate and polyoxyethylene stearate).

本發明之醫藥組合物可說明如下：無菌靜脈內溶液：可使用無菌可注射水來製備所需本發明化合物之5 mg/mL溶液，且若必要則調整pH值。將該溶液用無菌5%右旋糖稀釋至1-2 mg/mL以供投藥且以靜脈內輸注方式經約60分鐘投與。 The pharmaceutical composition of the present invention can be illustrated as follows: Sterile intravenous solution : A sterile injectable water can be used to prepare a 5 mg/mL solution of the desired compound of the present invention, and the pH is adjusted if necessary. The solution was diluted to 1-2 mg/mL with sterile 5% dextrose for administration and administered by intravenous infusion over about 60 minutes.

靜脈內投藥之凍乾粉末：無菌製劑可用以下各物來製備：(i)100 mg至1000 mg呈凍乾粉末形式之所需本發明化合物，(ii)32 mg/mL至327 mg/mL檸檬酸鈉及(iii)300 mg至3000 mg葡聚糖40。調配物經無菌可注射鹽水或5%右旋糖復原至10 mg/mL至20 mg/mL之濃度，其經鹽水或5%右旋糖進一步稀釋至0.2 mg/mL至0.4 mg/mL且經15分鐘至60分鐘藉由靜脈內推注或靜脈內輸注來投與。 Lyophilized powder for intravenous administration : Sterile preparations can be prepared by (i) 100 mg to 1000 mg of the desired compound of the invention in lyophilized powder form, (ii) 32 mg/mL to 327 mg/mL lemon Sodium and (iii) 300 mg to 3000 mg dextran 40. The formulation is reconstituted in sterile injectable saline or 5% dextrose to a concentration of 10 mg/mL to 20 mg/mL, which is further diluted to 0.2 mg/mL to 0.4 mg/mL via saline or 5% dextrose. 15 minutes to 60 minutes are administered by intravenous bolus or intravenous infusion.

肌肉內懸浮液：可製備以下溶液或懸浮液用於肌肉內注射：50 mg/mL所需本發明之水不溶性化合物 Intramuscular suspension : The following solutions or suspensions can be prepared for intramuscular injection: 50 mg/mL of the desired water insoluble compound of the invention

5 mg/mL羧甲基纖維素鈉 5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80 4 mg/mL TWEEN 80

9 mg/mL氯化鈉 9 mg/mL sodium chloride

9 mg/mL苯甲醇。 9 mg/mL benzyl alcohol.

硬殼膠囊：藉由將標準兩件式硬明膠膠囊各自用100 mg粉末狀活性成分、150 mg乳糖、50 mg纖維素及6 mg硬脂酸鎂填充來製備大量單位膠囊。 Hard shell capsules : A large number of unit capsules were prepared by filling standard two-part hard gelatin capsules with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

軟明膠膠囊：製備活性成分於易消化油(諸如大豆油、棉籽油或橄欖油)中之混合物，且藉助於正排量泵將其注射至熔融明膠中以形成含有100 mg活性成分之軟明膠膠囊。將膠囊洗滌且乾燥。可將活性成分溶解於聚乙二醇、甘油及山梨糖醇之混合物中來製備水可混溶之藥物混合物。 Soft gelatin capsules : prepare a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil and inject it into molten gelatin by means of a positive displacement pump to form a soft gelatin containing 100 mg of active ingredient. capsule. The capsules were washed and dried. The water-miscible drug mixture can be prepared by dissolving the active ingredient in a mixture of polyethylene glycol, glycerin and sorbitol.

錠劑：藉由習知程序製備大量錠劑，以使得劑量單位為100 mg活性成分、0.2 mg膠狀二氧化矽、5 mg硬脂酸鎂、275 mg微晶纖維素、11 mg澱粉及98.8 mg乳糖。可應用適當水性及非水性包衣來增加可口性、改良美觀性及穩定性或延緩吸收。 Lozenges : A large number of tablets are prepared by conventional procedures such that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal cerium oxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 Mg lactose. Appropriate aqueous and non-aqueous coatings can be applied to increase palatability, improve aesthetics and stability, or delay absorption.

速釋錠劑/膠囊：該等劑型為藉由習知及新穎方法製備之固體口服劑型。該等單位劑型係在無水情況下口服以便藥物之快速溶解及傳遞。將活性成分混入含有諸如糖、明膠、果膠及甜味劑之成分的液體中。藉由冷凍乾燥及固態萃取技術使該等液體固化成固體錠劑或囊片。可將藥物化合物與具黏彈性及熱彈性之糖及聚合物或發泡組分一起壓縮以產生預定用於在無需水之情況下速釋之多孔基質。 Immediate Release Lozenges/Capsules : These dosage forms are solid oral dosage forms prepared by conventional and novel methods. These unit dosage forms are administered orally in the absence of water for rapid dissolution and delivery of the drug. The active ingredient is incorporated into a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. The liquids are solidified into solid lozenges or caplets by freeze drying and solid state extraction techniques. The pharmaceutical compound can be compressed with a viscoelastic and thermoelastic sugar and polymer or foaming component to produce a porous matrix intended for immediate release without the need for water.

劑量及投藥Dosage and administration

基於已知用於評估適用於治療過度增殖性病症及血管生成病症之化合物的標準實驗室技術，藉由標準毒性測試及用於測定對哺乳動物之以上鑑別病狀之治療的標準藥理學分析，以及藉由將該等結果與用於治療該等病狀之已知藥劑之結果相比較，可容易地測定用於治療各種預期適應症之本發明化合物的有效劑量。治療該等病狀之一所投與之活性成分的量可根據諸如以下之考慮因素而廣泛變化：所用特定化合物及劑量單位、投藥模式、療程、所治療患者之年齡及性別，及所治療病狀之性質及程度。 Based on standard laboratory techniques known for assessing compounds useful in the treatment of hyperproliferative disorders and angiogenic disorders, by standard toxicity testing and standard pharmacological assays for determining treatment of a condition above a mammal, And by comparing such results to the results of known agents for treating such conditions, an effective dosage of a compound of the invention for treating various contemplated indications can be readily determined. The amount of active ingredient administered to treat one of these conditions can vary widely depending on factors such as the particular compound and dosage unit employed, the mode of administration, the course of treatment, the age and sex of the patient being treated, and the condition being treated The nature and extent of the shape.

欲投與之活性成分之總量一般將為每日每公斤體重約0.001 mg至約200 mg且較佳為每日每公斤體重約0.01 mg至約20 mg之範圍內。臨床適用之給藥時程將在一天給藥一至三次至每四週給藥一次之範圍內。另外，「藥物假期」(其間在一定時期內不給與患者藥物)可有益於藥理學作用與耐受性之間的整體平衡。單位劑量可含有約0.5 mg至約1500 mg活性成分且可每日投與一或多次或一天投與不到一次。藉由注射(包括靜脈內、肌肉內、皮下及非經腸注射)及使用輸注技術投藥之平均每日劑量較佳為每公斤總體重0.01至200 mg。平均每日經直腸劑量方案較佳為每公斤總體重0.01至200 mg。平均每日經***劑量方案較佳為每公斤總體重0.01至200 mg。平均每日經局部劑量方案較佳為0.1至200 mg，每天投與次數在一次至四次之間。經皮濃度較佳為維持0.01至200 mg/kg之每日劑量所需之濃度。平均每日吸入劑量方案較佳為每公斤總體重0.01至100 mg。 The total amount of active ingredient to be administered will generally range from about 0.001 mg to about 200 mg per kilogram of body weight per day and preferably from about 0.01 mg to about 20 mg per kilogram of body weight per day. The clinically applicable dosing schedule will be administered from one to three times a day to once every four weeks. In addition, the "drug holiday" (which does not give the patient's medication for a certain period of time) may be beneficial to the overall balance between pharmacological effects and tolerance. A unit dose may contain from about 0.5 mg to about 1500 mg of the active ingredient and may be administered one or more times a day or less than once a day. The average daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injection) and by infusion techniques is preferably from 0.01 to 200 mg per kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily vaginal dosage regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily topical dosage regimen is preferably from 0.1 to 200 mg and the number of administrations per day is between one and four times. The transdermal concentration is preferably required to maintain a daily dose of 0.01 to 200 mg/kg. degree. The average daily inhalation dosage regimen is preferably from 0.01 to 100 mg per kg of total body weight.

當然，各患者之特定初始及連續劑量方案將根據如主治診斷醫師所確定之病狀性質及嚴重程度、所用特定化合物之活性、患者之年齡及一般狀況、投藥時間、投藥途徑、藥物之***速率、藥物組合及其類似因素而變化。所要治療模式及本發明化合物或其醫藥學上可接受之鹽或酯或組合物之劑量數可由熟習此項技術者使用習知治療測試來確定。 Of course, the specific initial and continuous dosing regimen for each patient will be based on the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and general condition of the patient, the time of administration, the route of administration, and the rate of drug excretion. , drug combinations and similar factors vary. The number of doses of the desired mode of treatment and the compound of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional therapeutic tests.

組合療法Combination therapy

本發明之化合物可以單一藥劑之形式或與一或多種其他藥劑組合投與，其中該組合不會引起不可接受之不良作用。彼等組合醫藥劑可為例如用於治療血液腫瘤、實體腫瘤及/或其轉移的具有抗增殖作用之其他藥劑，及/或用於治療不良副作用之藥劑。本發明亦係關於該等組合。 The compounds of the invention may be administered in the form of a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse effects. The combination pharmaceutical agents may be, for example, other agents having anti-proliferative effects for the treatment of hematological tumors, solid tumors and/or their metastases, and/or agents for treating adverse side effects. The invention is also related to such combinations.

適於與本發明組合物一起使用之其他抗過度增殖劑包括(但不限於)在Goodman及Gilman之The Pharmacological Basis of Therapeutics(第9版)，編者Molinoff等人，由McGraw-Hill出現，第1225-1287頁(1996)(其以引用的方式併入本文)中已知用於治療贅生性疾病之彼等化合物，尤其為如上文定義之(化學療法)抗癌劑。該組合可視情形為非固定組合或固定劑量組合。 Other anti-hyperproliferative agents suitable for use with the compositions of the present invention include, but are not limited to, The Pharmacological Basis of Therapeutics (9th Edition) by Goodman and Gilman, edited by Molinoff et al., appearing by McGraw-Hill, 1225 Compounds for the treatment of neoplastic diseases, especially anti-cancer agents as defined above (chemotherapy), are known from page 1287 (1996), which is incorporated herein by reference. The combination may be a non-fixed combination or a fixed dose combination, as the case may be.

特定藥理學或醫藥學性質之測試方法為熟習此項技術者所熟知。 Test methods for specific pharmacological or pharmaceutical properties are well known to those skilled in the art.

本文所述之實例測試實驗用於說明本發明且本發明不限於所給實例。 The example test experiments described herein are illustrative of the invention and the invention is not limited to the examples given.

如熟習此項技術者將瞭解，本發明不限於本文所述之特定實施例，而涵蓋如隨附申請專利範圍所定義在本發明精神及範疇內之該等實施例的所有修改。 It will be appreciated by those skilled in the art that the present invention is not limited to the specific embodiments described herein, and all modifications of such embodiments are intended to be within the spirit and scope of the invention as defined by the appended claims.

以下實例更詳細說明本發明而非對其加以限制。製備未明確描述之其他本發明化合物可以類似方式來製備。 The following examples illustrate the invention in more detail and are not limiting thereof. Other compounds of the invention not specifically described may be prepared in a similar manner.

實例中提及之化合物及其鹽表示本發明之較佳實施例，而且申請專利範圍涵蓋如用特定實例所揭示之式(I)化合物殘餘物的所有子組合。 The compounds and salts thereof mentioned in the examples represent preferred embodiments of the invention, and the scope of the patent application covers all subcombinations of the residues of the compounds of formula (I) as disclosed by the specific examples.

實驗部分中之術語「根據」係以欲「類似於......」使用所提及之程序的含義來使用。 The term "base" in the experimental section is used in the sense of "similar to..." using the procedures mentioned.

實驗部分Experimental part

下表列舉此段及中間物實例及實例部分中所用之縮寫，只要其在正文中未作解釋。 The following table lists the abbreviations used in this paragraph and the intermediate examples and examples, as long as they are not explained in the text.

其他縮寫具有其本身為熟習此項技術者所常用之含義。 Other abbreviations have their own meaning as commonly used by those skilled in the art.

本申請案中所述之本發明之各種態樣由以下實例來說明，該等實例不欲以任何方式限制本發明。 Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

特定實驗描述Specific experimental description

以下特定實驗描述中之NMR峰形式在其在光譜中出現時進行描述，且尚未考慮可能之高階效應。採用微波輻射之反應可由視情況配備有機器人裝置之Biotage Initator^®微波爐來進行。所報導之使用微波加熱之反應時間意欲理解為達到指定反應溫度後之固定反應時間。根據本發明方法產生之化合物及中間物可能會需要純化。有機化合物之純化為熟習此項技術者所熟知且可存在若干種純化該化合物的方式。在某些情形下可不必純化。在某些情形下，化合物可藉由結晶來純化。在某些情形下，可使用適合溶劑攪拌去除雜質。在某些情形下，可藉由例如使用例如來自Separtis之預裝填矽膠濾筒(諸如Isolute^® Flash矽膠或 Isolute^® Flash NH₂矽膠)與Isolera自動淨化器(Biotage)及溶離劑(諸如，例如己烷/乙酸乙酯或DCM/甲醇梯度)組合之層析(特定言之急驟管柱層析)來純化化合物。在某些情形下，化合物可藉由製備型HPLC來純化，該製備型HPLC例如使用配備有二極體陣列偵測器及/或線上電噴霧電離質譜儀之Waters自動淨化器與適合之預裝填逆相管柱及可含有諸如三氟乙酸、甲酸或氨水之添加劑的溶離劑(諸如水與乙腈之梯度)組合。在某些情形下，如上所述之純化方法可提供具有足夠鹼性或酸性官能基之呈鹽形式的彼等本發明化合物，諸如在具有足夠鹼性之本發明化合物之情形下，例如為三氟乙酸鹽或甲酸鹽，或在具有足夠酸性之本發明化合物之情形下，例如為銨鹽。此類型之鹽可經熟習此項技術者已知之各種方法分別轉化為其游離鹼或游離酸形式，或用作後續生物分析中之鹽。應瞭解，如本文所述分離之特定形式本發明化合物(例如，鹽、游離鹼等)並非必要為該化合物可用於生物分析來定量特定生物活性之唯一形式。 The NMR peak form in the specific experimental description below is described when it appears in the spectrum, and possible high order effects have not been considered. Using microwave irradiation of the reaction can be optionally equipped with a Biotage Initator ^® microwave to the robot apparatus. The reported reaction time using microwave heating is intended to be understood as the fixed reaction time after reaching the specified reaction temperature. Compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to those skilled in the art and there may be several ways to purify the compound. In some cases it may not be necessary to purify. In some cases, the compound can be purified by crystallization. In some cases, impurities may be removed using a suitable solvent agitation. In certain instances, for example, may be used, for example by filling silicone cartridge (Isolute ^® Flash such as a silicone or silicone Isolute ^® Flash NH ₂₎ with an automatic cleaner Isolera (a Biotage) and eluants from the pre Separtis (such as, e.g. The compound was purified by a combination of hexane/ethyl acetate or DCM/methanol gradient chromatography (specifically, flash column chromatography). In some cases, the compound can be purified by preparative HPLC using, for example, a Waters automatic purifier equipped with a diode array detector and/or an on-line electrospray ionization mass spectrometer with a suitable preload The reverse phase column and a dissolving agent (such as a gradient of water and acetonitrile) which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia are combined. In certain instances, the purification methods described above can provide such compounds of the invention in salt form with sufficiently basic or acidic functional groups, such as in the case of compounds of the invention having sufficient basicity, such as three Fluoroacetate or formate, or in the case of a compound of the invention having sufficient acidity, such as an ammonium salt. Salts of this type can be converted to their free base or free acid form, respectively, by various methods known to those skilled in the art, or as salts in subsequent biological assays. It will be appreciated that the particular form of the compound (e.g., salt, free base, etc.) isolated as described herein is not necessarily the only form in which the compound can be used in biological assays to quantify a particular biological activity.

以下實例中所報導之產率百分比係基於以最低莫耳量使用之起始組份。空氣及水分敏感性液體及溶液係經由注射器或套管轉移，且經橡膠隔墊引入反應容器中。商業級試劑及溶劑不經進一步純化即使用。術語「真空濃縮」係指在約15 mm Hg之最小壓力下使用Buchi旋轉蒸發器。所有溫度係未經校正以攝氏度(℃)報導。 The percent yields reported in the examples below are based on the starting components used in the lowest molar amount. The air and moisture sensitive liquids and solutions are transferred via a syringe or cannula and introduced into the reaction vessel via a rubber septum. Commercial grade reagents and solvents were used without further purification. The term "vacuum concentration" means the use of a Buchi rotary evaporator at a minimum pressure of about 15 mm Hg. All temperatures were uncorrected and reported in degrees Celsius (°C).

為了可更好地理解本發明，將陳述以下實例。該等實例僅為達成說明之目的，且並不應視為以任何方式限制本發明之範疇。本文中提及之所有公開案均以全文引用的方式併入本文中。 In order to better understand the present invention, the following examples will be set forth. Such instances It is for the purpose of illustration only and is not to be construed as limiting the scope of the invention in any way. All publications mentioned herein are hereby incorporated by reference in their entirety.

分析型LC-MS條件Analytical LC-MS conditions

後續特定實驗描述中給出之LC-MS資料係指(除非另外說明)以下條件： The LC-MS data given in the subsequent specific experimental description refers to (unless otherwise stated) the following conditions:

製備型HPLC條件Preparative HPLC conditions

後續特定實驗描述中之「藉由製備型HPLC純化」係指(除非另外說明)以下條件： "Purification by preparative HPLC" in the subsequent specific experimental description refers to (unless otherwise stated) the following conditions:

分析(分析前及分析後：方法B)：Analysis (before and after analysis: Method B):

製備：preparation:

對掌性HPLC條件Palm-like HPLC conditions

後續特定實驗描述中給出之對掌性HPLC資料係指以下條件： The palmar HPLC data given in the subsequent specific experimental description refers to the following conditions:

分析：analysis:

製備：preparation:

急驟管柱層析條件Rapid column chromatography conditions

如後續特定實驗描述中所述之「藉由(急驟)管柱層析純化」係指使用Biotage Isolera純化系統。關於技術說明參見www.biotage.com上之「Biotage product catalogue」。 The "purification by (flash) column chromatography" as described in the subsequent specific experimental description refers to the use of the Biotage Isolera purification system. For technical instructions, see "Biotage product catalogue" on www.biotage.com.

旋光條件測定Optical rotation condition determination

在589 nm波長、20℃、1.0000 g/100mL濃度、10 s積分時間、100.00 mm薄膜厚度下於二甲亞碸中量測旋光性。 The optical rotation was measured in dimethyl sulfoxide at 589 nm wavelength, 20 ° C, 1.0000 g/100 mL concentration, 10 s integration time, and 100.00 mm film thickness.

實例Instance 合成中間物Synthetic intermediate 中間物1-1-1Intermediate 1-1-1 製備1-(4-乙氧基-2,6-二氟苯甲基)-5-羥基-4-甲基-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-hydroxy-4-methyl-1 H -pyrazole-3-carboxylate

在氬氣氛圍下將4.65 g 2-甲基-3-側氧基丁二酸二乙酯(23.0 mmol，1.00 eq.)溶解於100 mL無水二噁烷中。添加2.1 mL冰醋酸及6.32 g(4-乙氧基-2,6-二氟苯甲基)肼二鹽酸鹽(23.00 mmol，1.00 eq.)。將混合物在90℃浴溫下攪拌16小時。真空蒸發反應混合物。將殘餘物與乙酸乙酯一起攪拌。濾除所得懸浮液且以乙酸乙酯洗滌。在40℃下真空乾燥濾餅。真空濃縮濾液且藉由急驟層析(己烷/乙酸乙酯-己烷0-100%之梯度)純化。將濾餅及急驟層析所得之純化化合物在乙酸乙酯中一起攪拌，濾除且提供3.95 g(11.3 mmol，49%)分析純的目標化合物。 4.65 g of diethyl 2-methyl-3-oxo-succinate (23.0 mmol, 1.00 eq.) was dissolved in 100 mL of anhydrous dioxane under argon. 2.1 mL of glacial acetic acid and 6.32 g of (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (23.00 mmol, 1.00 eq.) were added. The mixture was stirred at a bath temperature of 90 ° C for 16 hours. The reaction mixture was evaporated in vacuo. The residue was stirred with ethyl acetate. The resulting suspension was filtered off and washed with ethyl acetate. The filter cake was dried under vacuum at 40 °C. The filtrate was concentrated in vacuo and purified by flash chromatography eluting EtOAc The filter cake and the purified compound obtained by flash chromatography were stirred together in ethyl acetate and filtered to afford 3.95 g (11.3 mmol, 49%).

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=1.13-1.36(m,6H),1.97(s,3H),4.01(q,2H),4.14(q,2H),5.04(s,2H),6.65-6.73(m,2H),10.60(br,s,1H)。 ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.13-1.36 (m, 6H), 1.97 (s, 3H), 4.01 (q, 2H), 4.14 (q, 2H), 5.04 ( s, 2H), 6.65-6.73 (m, 2H), 10.60 (br, s, 1H).

根據相同程序製備以下中間物： The following intermediates were prepared according to the same procedure:

中間物1-2-1Intermediate 1-2-1 製備1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1 H -pyrazole-3-carboxylate

將3.95 g 1-(4-乙氧基-2,6-二氟苯甲基)-5-羥基-4-甲基-1H-吡唑-3-甲酸乙酯1-1-1(11.6 mmol，1.0 eq.)溶解於50 mL丙酮中。添加1.45 mL碘甲烷(23.2 mmol，2.0 eq.)及5.78 g(41.8 mmol，3.6 eq.)碳酸鉀且在室溫下攪拌24小時。添加1.45 mL碘甲烷(23.2 mmol，2.0 eq.)且將混合物在室溫下再攪拌24小時。經海沙濾除懸浮液且真空濃縮濾液。由DCM及水萃取殘餘物。以DCM萃取水層兩次。經硫酸鈉乾燥經合併之有機層且真空濃縮。藉由急驟層析純化殘餘物以產生2.29 g(6.46 mmol，55.7%)分析純的目標化合物。 3.95 g of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-hydroxy-4-methyl-1 H -pyrazole-3-carboxylate 1-1-1 (11.6 M, 1.0 eq.) was dissolved in 50 mL of acetone. 1.45 mL of methyl iodide (23.2 mmol, 2.0 eq.) and 5.78 g (41.8 mmol, 3.6 eq.) of potassium carbonate were added and stirred at room temperature for 24 hours. 1.45 mL of iodomethane (23.2 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature for additional 24 hours. The suspension was filtered off with sea sand and the filtrate was concentrated in vacuo. The residue was extracted from DCM and water. The aqueous layer was extracted twice with DCM. The combined organic layers were dried with sodium s The residue was purified by flash chromatography to yield 2.29 g (6.46 mmol, 55.

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=1.21(t,3H),1.27(t,3H),2.08(s,3H),3.83(s,3H),4.01(q,2H),4.17(q,2H),5.11(s,2H),6.68-6.75(m,2H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 1.21 (t, 3H), 1.27 (t, 3H), 2.08 (s, 3H), 3.83 (s, 3H), 4.01 (q, 2H), 4.17 (q, 2H), 5.11 (s, 2H), 6.68-6.75 (m, 2H).

中間物1-3-1Intermediate 1-3-1 製備1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-羰醯亞胺醯胺鹽酸鹽1：1 Preparation of 1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1 H -pyrazole-3-carbonylindoleamine amide hydrochloride 1 :1

在氮氣氛圍下將1.73 g氯化銨懸浮於37 mL無水甲苯中且冷卻至0℃浴溫。逐滴添加16.2 mL 2M三甲基鋁之庚烷溶液(32.3 mmol，5.0 eq.)。在室溫下攪拌混合物直至氣體排出消失。將2.29 g 1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-甲酸乙酯1-2-1(6.46 mmol，1.0 eq.)溶解於13 mL無水甲苯中且逐滴添加至反應混合物中且在80℃浴溫下攪拌24小時。將混合物經冰浴冷卻至0℃浴溫，添加35.6 mL甲醇且在室溫下攪拌一小時。濾除所得懸浮液且以洗滌甲醇。真空濃縮濾液且將殘餘物與DCM/甲醇9：1一起攪拌。濾除懸浮液。將濾餅以DCM/甲醇9：1洗滌兩次。真空濃縮濾液且隨後以DCM及飽和碳酸氫鈉水溶液萃取，經聚矽氧過濾器乾燥且真空濃縮以產生1.95 g(5.42 mmol，84%)分析純的目標化合物。 1.73 g of ammonium chloride was suspended in 37 mL of anhydrous toluene under a nitrogen atmosphere and cooled to a bath temperature of 0 °C. 16.2 mL of a 2 M solution of trimethylaluminum in heptane (32.3 mmol, 5.0 eq.) was added dropwise. The mixture was stirred at room temperature until the gas evolution disappeared. 2.29 g of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1 H -pyrazole-3-carboxylate 1-2-1 (6.46 mmol, 1.0 eq.) was dissolved in 13 mL of anhydrous toluene and added dropwise to the reaction mixture and stirred at a bath temperature of 80 ° C for 24 hours. The mixture was cooled to 0 ° C bath temperature in an ice bath, 35.6 mL methanol was added and stirred at room temperature for one hour. The resulting suspension was filtered off and washed with methanol. The filtrate was concentrated in vacuo and the residue was stirred with DCM / methanol 9:1. Filter off the suspension. The filter cake was washed twice with DCM/methanol 9:1. The filtrate was concentrated in vacuo then EtOAcqqqqqqqqqqqqqqqqq

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=1.27(t,3H),2.06(s,3H),3.88(s,3H),4.02(q,2H),5.16(s,2H),6.69-6.75(m,2H),8.79-9.05(m,4H)。 ^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.27 (t, 3H), 2.06 (s, 3H), 3.88 (s, 3H), 4.02 (q, 2H), 5.16 (s, 2H), 6.69-6.75 (m, 2H), 8.79-9.05 (m, 4H).

脒(中間物1-3-8)之替代性製備Alternative preparation of hydrazine (intermediate 1-3-8) 中間物1-3-8Intermediate 1-3-8 製備5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-羰醯亞胺醯胺鹽酸鹽1：1 Preparation of 5-(dimethylamino)-1-(2-fluorobenzyl)-1 H -pyrazole-3-carbonylindoleamine amide hydrochloride 1:1

將356 mg甲醇鈉(6.60 mmol，4.0 eq.)溶解於10 mL甲醇中。將403 mg 5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-甲腈1-11-1(1.65 mmol，1.0 eq.)溶解於20 mL甲醇中且逐滴添加。將混合物在室溫下攪拌一小時。添加111.2 mg氯化銨(2.08 mmol，1.26 eq.)及377 μL 100%乙酸(6.60 mmol，4.0 eq.)且在回流下攪拌24小時。添加111 mg氯化銨(2.08 mmol，1.26 eq.)及377 μL 100%乙酸(6.60 mmol，4.0 eq.)且在回流下再攪拌24小時。真空濃縮混合物。將殘餘物懸浮於乙腈中且濾除兩次。將濾餅溶解於DCM/甲醇1：1中且經二氧化矽管柱過濾以提供313 mg(1.19 mmol，72.6%)分析純的目標化合物。 356 mg of sodium methoxide (6.60 mmol, 4.0 eq.) was dissolved in 10 mL of methanol. Dissolve 403 mg of 5-(dimethylamino)-1-(2-fluorobenzyl)-1 H -pyrazole-3-carbonitrile 1-11-1 (1.65 mmol, 1.0 eq.) in 20 mL Add in methanol and dropwise. The mixture was stirred at room temperature for one hour. 111.2 mg of ammonium chloride (2.08 mmol, 1.26 eq.) and 377 μL of 100% acetic acid (6.60 mmol, 4.0 eq.) were added and stirred under reflux for 24 hours. 111 mg of ammonium chloride (2.08 mmol, 1.26 eq.) and 377 μL of 100% acetic acid (6.60 mmol, 4.0 eq.) were added and stirred under reflux for a further 24 hours. The mixture was concentrated in vacuo. The residue was suspended in acetonitrile and filtered twice. The filter cake was dissolved in DCM / methanol 1:1 and filtered thru a silica gel column to afford 313 mg (1.19 mmol, 72.

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=2.59(s,6H),5.34(s,2H),6.70(s,1H),6.97-7.04(m,1H),7.14(s,2H),7.29-7.39(m,1H),8.72-10.63(m,3H)。 ^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 2.59 (s, 6H), 5.34 (s, 2H), 6.70 (s, 1H), 6.97-7.04 (m, 1H), 7.14 ( s, 2H), 7.29-7.39 (m, 1H), 8.72-10.63 (m, 3H).

中間物1-4-1Intermediate 1-4-1 製備3,3-雙(二甲胺基)-2-甲氧基丙腈 Preparation of 3,3-bis(dimethylamino)-2-methoxypropionitrile

將360 g 1-第三丁氧基-N,N,N',N'-四甲基甲烷二胺(Bredereck試劑)(2068 mmol，1.0 eq.)及150.0 g甲氧基乙腈(2068 mmol，1.0 eq.)在80℃下攪拌18小時。真空濃縮反應混合物。藉由真空蒸餾純化殘餘物以產生117 g(687 mmol，33.0%)呈微黃色液體狀之分析純的目標化合物。 360 g of 1-t-butoxy- N , N , N' , N' -tetramethylmethanediamine (Bredereck's reagent) (2068 mmol, 1.0 eq.) and 150.0 g of methoxyacetonitrile (2068 mmol, 1.0 eq.) Stir at 80 ° C for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by vacuum distillation to yield 117 g (yield: EtOAc, EtOAc)

¹H-NMR(400 MHz,DMSO-d₆)：δ[ppm]=2.23(s,6H),2.29(s,6H),3.23(d,1H),3.36-3.41(s,3H),4.73(d,1H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.23 (s, 6H), 2.29 (s, 6H), 3.23 (d, 1H), 3.36-3.41 (s, 3H), 4.73 (d, 1H).

中間物1-5-1Intermediate 1-5-1 製備2-[1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-胺 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1 H -pyrazol-3-yl]-5-methoxy Pyrimidine-4-amine

將1.95 g 1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-羰醯亞胺醯胺鹽酸鹽1：1 1-3-1(5.42 mmol，1.0 eq)懸浮於19.7 mL無水3-甲基-1丁醇中。在氮氣氛圍下添加0.3 mL哌啶(3.0 mmol，0.56 eq)及3.09 g 3,3-雙(二甲胺基)-2-甲氧基丙腈1-4-1(18.0 mmol，3.30 eq)且在100℃浴溫下攪拌24小時。真空濃縮冷卻至室溫之反應混合物且藉由急驟層析純化以產生619 mg(1.13 mmol，21%)分析純的目標化合物。 1.95 g of 1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1 H -pyrazole-3-carbonylindoleamine hydrochloride Salt 1:1 1-3-1 (5.42 mmol, 1.0 eq) was suspended in 19.7 mL of anhydrous 3-methyl-1 butanol. 0.3 mL piperidine (3.0 mmol, 0.56 eq) and 3.09 g 3,3-bis(dimethylamino)-2-methoxypropionitrile 1-4-1 (18.0 mmol, 3.30 eq) were added under a nitrogen atmosphere. It was stirred at a bath temperature of 100 ° C for 24 hours. The reaction mixture was cooled to room temperature in vacuo and purified by flash chromatography to yield </RTI></RTI></RTI></RTI><RTIgt;

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=1.27(t,3H),2.15(s,3H),3.79(s,3H),3.83(s,3H),4.01(q,2H),5.05(s,2H),6.62-6.74(m,4H),7.81(s,1H)。 ¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (t, 3H), 2.15 (s, 3H), 3.79 (s, 3H), 3.83 (s, 3H), 4.01 (q, 2H), 5.05 (s, 2H), 6.62-6.74 (m, 4H), 7.81 (s, 1H).

根據相同程序，使用脒及中間物1-4-1製備以下中間物： The following intermediates were prepared according to the same procedure using hydrazine and intermediate 1-4-1:

中間物1-6-1Intermediate 1-6-1 製備1-苯甲基-5-{[(三氟甲基)磺醯基]氧基}-1H-吡唑-3-甲酸甲酯 Preparation of methyl 1-benzyl-5-{[(trifluoromethyl)sulfonyl]oxy}-1 H -pyrazole-3-carboxylate

在氮氣氛圍下將2.00 g 1-苯甲基-5-羥基-1H-吡唑-3-甲酸甲酯1-1-4(8.61 mmol，1.0 eq.)懸浮於16.6 mL無水DCM。隨後添加1.74 mL無水吡啶(21.5 mmol，2.5 eq.)及1.82 mL三氟甲烷磺酸酐(10.8 mmol，1.25 eq)且在室溫下攪拌3天。經短(5 g二氧化矽)急驟管柱濾除反應混合物且以DCM洗滌。真空濃縮濾液。以甲苯將殘餘物濃縮一次且藉由急驟層析純化以提供2.77 g(6.84 mmol，79%)分析純的目標化合物。 2.00 g of methyl 1-phenylmethyl-5-hydroxy-1 H -pyrazole-3-carboxylate 1-1-4 (8.61 mmol, 1.0 eq.) was suspended in 16.6 mL of dry DCM under nitrogen. Then 1.74 mL of anhydrous pyridine (21.5 mmol, 2.5 eq.) and 1.82 mL of trifluoromethanesulfonic anhydride (10.8 mmol, 1.25 eq) were added and stirred at room temperature for 3 days. The reaction mixture was filtered through a short (5 g EtOAc) column and washed with DCM. The filtrate was concentrated in vacuo. The residue was concentrated once with toluene and purified by flash chromatography to afford 2.77 g ( 6.

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=3.79(s,3H),5.43(s,2H),6.87(s,1H),7.16-7.21(m,2H),7.27-7.40(m,3H)。 ^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 3.79 (s, 3H), 5.43 (s, 2H), 6.87 (s, 1H), 7.16-7.21 (m, 2H), 7.27- 7.40 (m, 3H).

中間物1-7-1Intermediate 1-7-1 製備1-苯甲基-5-環丙基-1H-吡唑-3-甲酸甲酯 Preparation of methyl 1-benzyl-5-cyclopropyl-1 H -pyrazole-3-carboxylate

在氮氣氛圍下將2.57 g 1-苯甲基-5-{[(三氟甲基)磺醯基]氧基}-1H-吡唑-3-甲酸甲酯(7.06 mmol，1.0 eq.)溶解於51 mL無水1,2-二甲氧基乙烷中。添加1.52 g環丙基酸(17.6 mmol，2.5 eq.)、2.62 g碳酸鈉(24.7 mmol，3.5 eq.)及408 mg肆(三苯基膦)鈀(O)(0.353 mmol，0.05 eq.)且將混合物在75℃浴溫下攪拌24小時。隨後濾除混合物且以乙酸乙酯洗滌。真空濃縮濾液且藉由急驟層析純化殘餘物以產生1.61 g(5.39 mmol，76%)分析純的目標化合物。 2.57 g of methyl 1-phenylmethyl-5-{[(trifluoromethyl)sulfonyl]oxy}-1 H -pyrazole-3-carboxylate (7.06 mmol, 1.0 eq.) under a nitrogen atmosphere. Dissolved in 51 mL of anhydrous 1,2-dimethoxyethane. Add 1.52 g of cyclopropyl Acid (17.6 mmol, 2.5 eq.), 2.62 g of sodium carbonate (24.7 mmol, 3.5 eq.) and 408 mg of tris(triphenylphosphine)palladium(0) (0.353 mmol, 0.05 eq.) and mixture at 75 ° C Stir at room temperature for 24 hours. The mixture was then filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purifiedjjjjjjjjjj

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=0.59(dd,2H),0.83-0.89(m,2H),1.85(s,1H),3.72(s,3H),5.46(s,2H),6.40(d,1H),7.11-7.16(m,2H),7.22-7.35(m,3H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.59 (dd, 2H), 0.83-0.89 (m, 2H), 1.85 (s, 1H), 3.72 (s, 3H), 5.46 ( s, 2H), 6.40 (d, 1H), 7.11-7.16 (m, 2H), 7.22 - 7.35 (m, 3H).

根據如關於合成中間物1-6-1及1-7-1所述之相同程序製備以下中間物： The following intermediates were prepared according to the same procedure as described for the synthesis of intermediates 1-6-1 and 1-7-1:

中間物1-8-1Intermediate 1-8-1

根據Bioorg Med Chem Lett,2001,11/6,781-784中所述之程序進行5-胺基-1-(2-氟苯甲基)-1H-吡唑-3-甲酸乙酯之製備。 The preparation of ethyl 5-amino-1-(2-fluorobenzyl)-1 H -pyrazole-3-carboxylate was carried out according to the procedure described in Bioorg Med Chem Lett, 2001, 11/6, 781-784.

中間物1-9-1Intermediate 1-9-1 製備5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 5-(dimethylamino)-1-(2-fluorobenzyl)-1 H -pyrazole-3-carboxylate

將1.96 g 5-胺基-1-(2-氟苯甲基)-1H-吡唑-3-甲酸乙酯1-8-1(7.46 mmol，1.0 eq.)溶解於9.8 mL無水DMF中。在氮氣氛圍下，在0℃浴溫下添加237 mg氫化鋰(29.8 mmol，4.0 eq.)。將混合物在此溫度下攪拌一小時。隨後在0℃浴溫下添加3.7 mL碘甲烷(59.6 mmol，8.0 eq.)。隨後在室溫下將反應混合物攪拌三天。添加冰之後，將其攪拌30分鐘且隨後以乙酸乙酯萃取三次。將經合併之有機層以鹽水洗滌，經硫酸鈉乾燥且真空濃縮。藉由急驟層析純化殘餘物以得到1.35 g(4.49 mmol，60%)分析純的目標化合物。 1.96 g of ethyl 5-amino-1-(2-fluorobenzyl)-1 H -pyrazole-3-carboxylate 1-8-1 (7.46 mmol, 1.0 eq.) was dissolved in 9.8 mL of anhydrous DMF. . 237 mg of lithium hydride (29.8 mmol, 4.0 eq.) was added at a bath temperature of 0 ° C under a nitrogen atmosphere. The mixture was stirred at this temperature for one hour. Then 3.7 mL of methyl iodide (59.6 mmol, 8.0 eq.) was added at a bath temperature of 0 °C. The reaction mixture was then stirred at room temperature for three days. After the addition of ice, it was stirred for 30 minutes and then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was purified by flash chromatography to give 1.35 g ( 4.49 mmol, 60%)

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=1.22(t,3H),2.57(s,6H),4.19(d,2H),5.30(s,2H),6.40(s,1H),6.91-6.99(m,1H),7.10-7.23(m,2H),7.28-7.37(m,1H)。 ^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.22 (t, 3H), 2.57 (s, 6H), 4.19 (d, 2H), 5.30 (s, 2H), 6.40 (s, 1H), 6.91-6.99 (m, 1H), 7.10-7.23 (m, 2H), 7.28-7.37 (m, 1H).

根據相同程序，使用中間物1-20-1製備以下中間物： The following intermediates were prepared using the intermediate 1-20-1 according to the same procedure:

中間物1-10-1Intermediate 1-1-1 製備5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-甲醯胺 Preparation of 5-(dimethylamino)-1-(2-fluorobenzyl)-1 H -pyrazole-3-carboxamide

將1.34 g 5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-甲酸乙酯1-9-1(4.60 mmol，1.0 eq.)溶解於120 mL甲醇中。添加60 mL 7 N氨之甲醇溶液且將溶液在50℃浴溫下攪拌三天。再次添加60 mL 7 N氨之甲醇溶液且在50℃浴溫下再攪拌24小時。再次添加60 mL 7 N氨之甲醇溶液且在65℃浴溫攪拌24小時。真空濃縮溶液以提供1.33 g(5.07 mmol，定量)分析純的目標化合物。 1.34 g of ethyl 5-(dimethylamino)-1-(2-fluorobenzyl)-1 H -pyrazole-3-carboxylate 1-9-1 (4.60 mmol, 1.0 eq.) was dissolved in 120 In methanol. 60 mL of 7 N ammonia in methanol was added and the solution was stirred at 50 ° C bath temperature for three days. 60 mL of 7 N ammonia in methanol was added again and stirred at 50 ° C for a further 24 hours. 60 mL of 7 N ammonia in methanol was added again and stirred at 65 ° C for 24 hours. The solution was concentrated in vacuo to provide 1.33 g (5.

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=2.56(s,6H),5.26(s,2H),6.30(s,1H),6.88-6.98(m,1H),7.13(d,3H),7.27-7.40(m,2H)。 ¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 2.56 (s, 6H), 5.26 (s, 2H), 6.30 (s, 1H), 6.88-6.98 (m, 1H), 7.13 ( d, 3H), 7.27-7.40 (m, 2H).

中間物1-11-1Intermediate 1-11-1 製備5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-甲腈 Preparation of 5-(dimethylamino)-1-(2-fluorobenzyl)-1 H -pyrazole-3-carbonitrile

將1.33 g 5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-甲醯胺1-10-1(5.07 mmol，1.0 eq.)溶解於74 mL無水THF中。添加1.03 mL吡啶(12.7 mmol，2.50 eq.)。隨後逐滴添加1.79 mL三氟乙酸酐(12.7 mmol，2.50 eq.)。將反應混合物在室溫下攪拌24小時。隨後將反應混合物分配於水與乙酸乙酯之間。將經分離之水層以乙酸乙酯萃取兩次。經硫酸鈉乾燥經合併之有機層且真空濃縮。藉由急驟層析(己烷/乙酸乙酯)純化殘餘物以得到406 mg(1.66 mmol，33%)分析純的目標化合物。 1.33 g of 5-(dimethylamino)-1-(2-fluorobenzyl)-1 H -pyrazole-3-carboxamide 1-1-10 (5.07 mmol, 1.0 eq.) was dissolved in 74 mL of anhydrous THF. 1.03 mL of pyridine (12.7 mmol, 2.50 eq.) was added. Then 1.79 mL of trifluoroacetic anhydride (12.7 mmol, 2.50 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned between water and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried with sodium s The residue was purified by EtOAcqqqq elut elut elut elut

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=2.60(s,6H),5.31(s,2H),6.63(s,1H),7.03-7.11(m,1H),7.16(s,2H),7.29-7.41(m,1H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 2.60 (s, 6H), 5.31 (s, 2H), 6.63 (s, 1H), 7.03-7.11 (m, 1H), 7.16 ( s, 2H), 7.29-7.41 (m, 1H).

中間物1-12-1Intermediate 1-12-1 製備1-環丙基丙-1-酮 Preparation of 1-cyclopropylpropan-1-one

將198 mL 3M乙基溴化鎂之***溶液(596 mmol，1.0 eq.)冷卻至0℃且逐滴添加44.2 mL溶解於80 mL無水***中之環丙烷甲腈。將混合物在回流下攪拌6小時。將其經飽和氯化銨水溶液水解且在室溫下攪拌24小時。濾除所得懸浮液且以***洗滌。經硫酸鈉乾燥濾液且真空濃縮(在40℃浴溫及600毫巴(mbar)下)。真空蒸餾粗產物提供36.9 g(376 mmol，63%)分析純的目標化合物。 198 mL of 3M ethylmagnesium bromide in diethyl ether (596 mmol, 1.0 eq.) was cooled to 0 ° C and 44.2 mL of cyclopropanecarbonitrile dissolved in 80 mL of anhydrous diethyl ether was added dropwise. The mixture was stirred at reflux for 6 hours. This was hydrolyzed with a saturated aqueous solution of ammonium chloride and stirred at room temperature for 24 hours. The resulting suspension was filtered off and washed with diethyl ether. The filtrate was dried over sodium sulphate and concentrated in vacuo (br. at 40 <0>C and 600 mbar). The crude product was distilled in vacuo to afford 36.9 g (376 mmol, 63%).

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=0.73-0.84(m,4H),0.91(t,3H),1.91-2.02(m,1H),2.52(q,2H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.73 - 0.84 (m, 4H), 0.91 (t, 3H), 1.91-2.02 (m, 1H), 2.52 (q, 2H).

中間物1-13-1Intermediate 1-13-1 製備4-環丙基-3-甲基-2,4-二側氧基丁酸乙酯 Preparation of ethyl 4-cyclopropyl-3-methyl-2,4-dioxybutanoate

將165 mL 1 M雙(三甲基矽烷基)醯胺鋰之THF溶液(166 mmol，1.10 eq.)加入500 mL***中且冷卻至-78℃。將14.8 g 1-環丙基丙-1-酮1-12-1溶解於100 mL***中且在-78℃下逐滴添加。將混合物在-78℃下攪拌一小時且隨後逐滴添加24.5 mL草酸二乙酯。移除冷卻浴且將混合物在室溫下攪拌24小時。添加500 mL 1M氯化氫水溶液且以DCM萃取混合物，經聚矽氧過濾器硫酸鹽乾燥，且真空濃縮以提供27.2 g(137 mmol，91%)呈粗產物形式之目標化合物。粗產物不經進一步純化即用於下一步驟。 165 mL of 1 M bis(trimethyldecyl) guanamine lithium THF solution (166 mmol, 1.10 eq.) was added to 500 mL diethyl ether and cooled to -78 °C. 14.8 g of 1-cyclopropylpropan-1-one 1-12-1 was dissolved in 100 mL of diethyl ether and added dropwise at -78 °C. The mixture was stirred at -78 °C for one hour and then 24.5 mL of diethyl oxalate was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 24 hours. A solution of the title compound was obtained as a crude product. EtOAc (EtOAc) The crude product was used in the next step without further purification.

LC-MS：滯留時間：0.98 min LC-MS: residence time: 0.98 min

MS ES⁺：199.2[M+H]⁺ MS ES ⁺ :199.2[M+H] ⁺

中間物1-14-1Intermediate 1-14-1 製備1-第三丁基3-乙基5-環丙基-4-甲基-1H-吡唑-1,3-二甲酸酯/1-第三丁基5-乙基3-環丙基-4-甲基-1H-吡唑-1,5-二甲酸酯 Preparation of 1-tert-butyl 3-ethyl 5-cyclopropyl-4-methyl-1 H -pyrazole-1,3-dicarboxylate/1-tert-butyl 5-ethyl 3-ring Propyl-4-methyl-1 H -pyrazole-1,5-dicarboxylate

使49.2 g 4-環丙基-3-甲基-2,4-二側氧基丁酸乙酯1-13-1(248 mmol，1.0 eq.)及32.81 g肼基甲酸第三丁酯在200 mL乙醇中回流4小時。真空濃縮混合物。藉由急驟層析純化殘餘物以得到2.17 g(7.37 mmol，3.0%)分析純的目標化合物及69.6 g(236 mmol，95%)區位異構體混合物，其不經進一步純化即用於下一步驟。 49.2 g of 4-cyclopropyl-3-methyl-2,4- dihydrobutyric acid ethyl ester 1-13-1 (248 mmol, 1.0 eq.) and 32.81 g of tert -butyl carbazate were It was refluxed for 4 hours in 200 mL of ethanol. The mixture was concentrated in vacuo. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut eluting elut step.

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.71-0.81(m,2H),0.82-0.93(m,2H),1.24(q,3H),1.46(s,9H),1.73-1.89(m,1H),2.04(s,3H),4.25(dd,2H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.71-0.81 (m, 2H), 0.82-0.93 (m, 2H), 1.24 (q, 3H), 1.46 (s, 9H), 1.73-1.89 (m, 1H), 2.04 (s, 3H), 4.25 (dd, 2H).

中間物1-15-1Intermediate 1-15-1 製備5-環丙基-4-甲基-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 5-cyclopropyl-4-methyl-1 H -pyrazole-3-carboxylate

步驟1：製備鹽酸鹽 Step 1: Preparation of hydrochloride

將19.9 g 1-第三丁基3-乙基5-環丙基-4-甲基-1H-吡唑-1,3-二甲酸酯/1-第三丁基5-乙基3-環丙基-4-甲基-1H-吡唑-1,5-二甲酸酯之混合物1-14-1(67.5 mmol，1.0 eq.)與152 mL 4 M氯化氫之二噁烷溶液(608 mmol，9.0 eq.)在室溫下一起攪拌三天。濾除所得懸浮液且提供5.20 g(18.0 mmol，27%)分析純的目標化合物。 19.9 g of 1-tert-butyl 3-ethyl 5-cyclopropyl-4-methyl-1 H -pyrazole-1,3-dicarboxylate/1-tert-butyl 5-ethyl 3 a mixture of cyclopropyl-4-methyl-1 H -pyrazole-1,5-dicarboxylate 1-14-1 (67.5 mmol, 1.0 eq.) and 152 mL of 4 M hydrogen chloride in dioxane (608 mmol, 9.0 eq.) Stir for three days at room temperature. The resulting suspension was filtered off and 5.20 g (18.0 mmol, 27%).

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.62-0.72(m,2H),0.81-0.87(m,2H),1.24(t,3H),1.69-1.83(m,1H),2.16(s,3H),4.21(q,2H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.62-0.72 (m, 2H), 0.81-0.87 (m, 2H), 1.24 (t, 3H), 1.69-1.83 (m, 1H ), 2.16 (s, 3H), 4.21 (q, 2H).

步驟2：製備游離胺 Step 2: Preparation of free amine

將22.2 g 5-環丙基-4-甲基-1H-吡唑-3-甲酸乙酯鹽酸鹽(1：1)(67.6 mmol，1.0 eq.)溶解於乙酸乙酯中且在室溫下與飽和碳酸氫鈉水溶液一起攪拌30分鐘。分離各相。真空濃縮有機層以提供14.1 g(65.2 mmol，96%)分析純的目標化合物。 22.2 g of 5-cyclopropyl-4-methyl-1 H -pyrazole-3-carboxylic acid ethyl ester hydrochloride (1:1) (67.6 mmol, 1.0 eq.) was dissolved in ethyl acetate and in room It was stirred with a saturated aqueous solution of sodium hydrogencarbonate under warm for 30 minutes. Separate the phases. The organic layer was concentrated in vacuo to afford 14.1 g (65.2 mmol, 96%)

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=0.69(br,s,2H), 0.74-0.96(m,2H),1.25(br,s,3H),1.68-1.84(m,1H),2.09-2.25(m,3H),4.11-4.35(m,2H),12.62-13.20(m,1H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.69 (br, s, 2H), 0.74-0.96 (m, 2H), 1.25 (br, s, 3H), 1.68-1.84 (m) , 1H), 2.09-2.25 (m, 3H), 4.11-4.35 (m, 2H), 12.62-13.20 (m, 1H).

5-環丙基-4-甲基-1H-吡唑-3-甲酸乙酯鹽酸鹽之替代性製備 Alternative preparation of 5-cyclopropyl-4-methyl-1 H -pyrazole-3-carboxylic acid ethyl ester hydrochloride

向100 mL乙醇中之10.0 g 4-環丙基-3-甲基-2,4-二側氧基丁酸乙酯1-13-1(51 mmol，1.0 eq.)中添加3.16 g水合肼(80%，50.4 mmol，1.0 eq.)。在氮氣下將反應混合物在70℃下攪拌1 h。濾除固體且真空濃縮濾液。將殘餘物溶解於100 mL***中且添加50 mL 2 M***中之鹽酸。在室溫下攪拌2小時之後，濾除產物且在40℃下真空乾燥以得到7.40 g(32 mmol，66%)分析純的目標化合物。 3.16 g of hydrazine hydrate was added to 10.0 g of ethyl 4-cyclopropyl-3-methyl-2,4-di- oxyacetate 1-13-1 (51 mmol, 1.0 eq.) in 100 mL of ethanol. (80%, 50.4 mmol, 1.0 eq.). The reaction mixture was stirred at 70 ° C for 1 h under nitrogen. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 100 mL of diethyl ether and 50 mL of EtOAc EtOAc. After stirring at room temperature for 2 hours, the product was filtered and dried <RTI ID=0.0></RTI> to <RTIgt;</RTI><RTIgt;

中間物1-16-1Intermediate 1-16-1 製備2-(5-環丙基-4-甲基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺 Preparation of 2-(5-cyclopropyl-4-methyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine

將410 mg 2-[5-環丙基-1-(2-氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺2-1-10(0.952 mmol，1.0 eq.)溶解於1.1 mL無水二甲亞碸及1.4 mL無水2-甲基丙-2-醇中。添加6.56 mL 1M THF中之2-甲基丙-2-醇鉀(6.56 mmol，6.9 eq.)。以氧將混合物沖洗三次且在室溫下攪拌5小時。隨後將反應混合物分配於飽和氯化銨水溶液與乙酸乙酯之間。將經分離之水層以乙酸乙酯萃取三次。經硫酸鈉乾燥經合併之有機層且真空濃縮。藉由急驟層析純化殘餘物提供200 mg(0.62 mmol，65.1%)分析純的目標化合物。 410 mg of 2-[5-cyclopropyl-1-(2-fluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridine- 4-yl)pyrimidine-4-amine 2-1-10 (0.952 mmol, 1.0 eq.) was dissolved in 1.1 mL anhydrous dimethyl hydrazine and 1.4 mL anhydrous 2-methylpropan-2-ol. Add 6.56 mL of potassium 2-methylpropan-2-ol (6.56 mmol, 6.9 eq.) in 1M THF. The mixture was washed three times with oxygen and stirred at room temperature for 5 hours. The reaction mixture was then partitioned between saturated aqueous ammonium chloride and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried with sodium s The residue was purified by flash chromatography to afford 200 mg (0.62 mmol, 65.1%)

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.60-0.91(m,4H),1.69-1.90(m,1H),2.33(s,3H),3.97(s,3H),7.96(br,s,2H),8.23(s,1H),8.37(d,2H),9.29(s,1H),12.54(br,s,1H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.60-0.91 (m, 4H), 1.69-1.90 (m, 1H), 2.33 (s, 3H), 3.97 (s, 3H), 7.96 (br, s, 2H), 8.23 (s, 1H), 8.37 (d, 2H), 9.29 (s, 1H), 12.54 (br, s, 1H).

2-(5-環丙基-4-甲基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺之替代性製備：將880 mg 2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺(2.0 mmol，1.00 eq.)溶解於7.8 mL無水1,2-二氯乙烷中。在室溫下添加4.6 mL三氟乙酸(60 mmol，30 eq.)及1.8 mL三氟甲烷磺酸(20 mmol，10 eq.)。將反應混合物在75℃下攪拌2 h。在0℃下緩慢添加2M氫氧化鈉溶液。濾除固體，在50℃下真空乾燥以得到637 mg(1.96 mmol，98%)分析純的目標化合物。 Alternative preparation of 2-(5-cyclopropyl-4-methyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidin-4-amine: 880 mg of 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- ( Pyridin-4-yl)pyrimidine-4-amine (2.0 mmol, 1.00 eq.) was dissolved in 7.8 mL of anhydrous 1,2-dichloroethane. 4.6 mL of trifluoroacetic acid (60 mmol, 30 eq.) and 1.8 mL of trifluoromethanesulfonic acid (20 mmol, 10 eq.) were added at room temperature. The reaction mixture was stirred at 75 ° C for 2 h. A 2M sodium hydroxide solution was slowly added at 0 °C. The solid was filtered off and dried in vacuo to give 637 mg (1.

中間物1-17-1Intermediate 1-17-1 製備5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3-carboxylate

將588 mL THF中之46.9 g 5-環丙基-4-甲基-1H-吡唑-3-甲酸乙酯1-15-1(266 mmol，1.0 eq.)冷卻至0℃且以小份添加11.6 g氫化鈉(60%，290 mmol，1.2 eq.)。以250 mL THF稀釋所得懸浮液。緩慢添加66.7 g 2-(溴甲基)-5-乙氧基-1,3-二氟苯(266 mmol，1.1 eq.，市售)。在室溫下將反應混合物攪拌2小時。添加300 mL水且真空蒸發THF。將含水殘餘物以乙酸乙酯萃取三次。經聚矽氧過濾器乾燥經合併之有機層且真空濃縮。藉由急驟層析純化殘餘物以得到79.8 g(195 mmol，81%)89%純目標化合物。 46.9 g of 5-cyclopropyl-4-methyl-1 H -pyrazole-3-carboxylic acid ethyl ester 1-15-1 (266 mmol, 1.0 eq.) in 588 mL of THF was cooled to 0 ° C and small 11.6 g of sodium hydride (60%, 290 mmol, 1.2 eq.) was added. The resulting suspension was diluted with 250 mL of THF. 66.7 g of 2-(bromomethyl)-5-ethoxy-1,3-difluorobenzene (266 mmol, 1.1 eq., commercially available) was added slowly. The reaction mixture was stirred at room temperature for 2 hours. 300 mL of water was added and the THF was evaporated in vacuo. The aqueous residue was extracted three times with ethyl acetate. The combined organic layers were dried with EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography to afford 79.8 g (195 mmol, 81%)

¹H-NMR(400MHz，氯仿-d)：δ[ppm]=0.65-0.70(m,2H),0.96-1.03(m,2H),1.34-1.42(m,7H),1.47-1.52(m,1H),2.24(s,3H),3.97(q,3H),4.35(q,2H),5.46(s,2H),6.40-6.44(m,2H)。 ¹ H-NMR (400MHz, CHLOROFORM -d): δ [ppm] = 0.65-0.70 (m, 2H), 0.96-1.03 (m, 2H), 1.34-1.42 (m, 7H), 1.47-1.52 (m, 1H), 2.24 (s, 3H), 3.97 (q, 3H), 4.35 (q, 2H), 5.46 (s, 2H), 6.40-6.44 (m, 2H).

根據相同程序，使用中間物1-15-1及市售苯甲基鹵化物製備以下中間物： The following intermediates were prepared according to the same procedure using intermediates 1-15-1 and commercially available benzyl halides:

中間物1-19-1Intermediate 1-19-1 製備(2Z)-3-氰基-1-乙氧基-1-側氧基丁-2-烯-2-醇鉀 Preparation of potassium ( 2Z )-3-cyano-1-ethoxy-1-oxobutan-2-en-2-ol

將3.84 g 2-甲基丙-2-醇鉀(34.2 mmol，1.0 eq.)及723 mg 18-冠-6(2.74 mmol，0.08 eq.)溶解於THF中且在5分鐘內添加5.00 g草酸二乙酯(34.2 mmol，1.0 eq.)。將反應混合物加熱至60℃且在5分鐘內添加1.88 g丙腈(34.2 mmol，1.0 eq.)。將反應在60℃下攪拌1小時。濾除固體，在50℃下真空乾燥以得到5.11 g(26.4 mmol，77%)不經進一步純化即使用之粗產物。 3.84 g of potassium 2-methylpropan-2-ol (34.2 mmol, 1.0 eq.) and 723 mg of 18-crown-6 (2.74 mmol, 0.08 eq.) were dissolved in THF and 5.00 g of oxalic acid was added over 5 minutes. Diethyl ester (34.2 mmol, 1.0 eq.). The reaction mixture was heated to 60 ° C and 1.88 g of propionitrile (34.2 mmol, 1.0 eq.) was added over 5 min. The reaction was stirred at 60 ° C for 1 hour. The solid was filtered, dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt;

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=1.14(t,3H), 3.51(s,3H),3.97(q,2H)。 ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.14 (t, 3H), 3.51 (s, 3H), 3.97 (q, 2H).

中間物1-20-1Intermediate 1-20-1 製備5-胺基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 5-amino-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3-carboxylate

在室溫下將2.01 g(2Z)-3-氰基-1-乙氧基-1-側氧基丁-2-烯-2-醇鉀(10.9 mmol，1.0 eq.)溶解於二噁烷中且在2分鐘內添加1.34 mL三氟乙酸(17.4 mmol，1.6 eq.)。將漿料攪拌10分鐘且添加3.00 g(4-乙氧基-2,6-二氟苯甲基)二鹽酸肼(10.9 mmol，1.0 eq.)。將反應混合物在130℃下攪拌3小時。濾除所得固體且以二噁烷洗滌沖洗。將濾液分配於乙酸乙酯與水之間。將含水相以乙酸乙酯洗滌三次。將所收集之有機溶液以鹽水洗滌，經矽過濾器乾燥，真空濃縮且藉由急驟層析純化：1.10 g(2.42 mmol，22%)71%純目標化合物。 At room temperature, 2.01 g (2 Z) -3- cyano-1-ethoxy-1-oxo-2-en-2-side potassium alkoxide (10.9 mmol, 1.0 eq.) Was dissolved in dioxane 1.34 mL of trifluoroacetic acid (17.4 mmol, 1.6 eq.) was added to the alkane and over 2 min. The slurry was stirred for 10 minutes and 3.00 g of (4-ethoxy-2,6-difluorobenzyl)phosphonium dihydrochloride (10.9 mmol, 1.0 eq.) was added. The reaction mixture was stirred at 130 ° C for 3 hours. The resulting solid was filtered off and washed with dioxane. The filtrate was partitioned between ethyl acetate and water. The aqueous phase was washed three times with ethyl acetate. The collected organic solution was washed with brine, dried EtOAc EtOAc EtOAcjjjjjj

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=1.25-1.31(m,6H),1.99(s,3H),3.96-4.09(m,2H),4.25(q,2H),4.37- 4.88(m,2H),5.21(s,2H),6.70-6.75(m,2H),11.51(s,1H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.25-1.31 (m, 6H), 1.99 (s, 3H), 3.96 - 4.09 (m, 2H), 4.25 (q, 2H), 4.37- 4.88 (m, 2H), 5.21 (s, 2H), 6.70-6.75 (m, 2H), 11.51 (s, 1H).

中間物1-21-1Intermediate 1-21-1 製備[4-(二氟甲氧基)-2,6-二氟苯基]甲醇 Preparation of [4-(difluoromethoxy)-2,6-difluorophenyl]methanol

將500 mg 3,5-二氟-4-(羥甲基)苯酚(3.12 mmol，1.0 eq.)溶解於DMF中。添加523 mg氯(二氟)乙酸鈉(3.44 mmol，1.1 eq.)、1.22 g碳酸銫(3.75 mmol，1.2 eq)及0.20 mL水(10.9 mmol，3.5 eq.)。將反應混合物在100℃下攪拌隔夜。將反應混合物在水與乙酸乙酯之間分開。將水層以乙酸乙酯洗滌兩次。以鹽水洗滌經合併之有機層，經矽過濾器乾燥且真空濃縮。藉由急驟層析純化粗產物以得到161 mg(0.69 mmol，22%)56%純目標化合物。 500 mg of 3,5-difluoro-4-(hydroxymethyl)phenol (3.12 mmol, 1.0 eq.) was dissolved in DMF. 523 mg of sodium chloro(difluoro)acetate (3.44 mmol, 1.1 eq.), 1.22 g of cesium carbonate (3.75 mmol, 1.2 eq) and 0.20 mL of water (10.9 mmol, 3.5 eq.) were added. The reaction mixture was stirred at 100 ° C overnight. The reaction mixture was separated between water and ethyl acetate. The aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine, dried w... The crude product was purified by flash chromatography to give 161 mg (0.69 mmol, 22%)

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=4.42(d,2H),5.23(t,1H),6.92-7.04(m,2H),7.30(t,1H)。 ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 4.42 (d, 2H), 5.23 (t, 1H), 6.92-7.04 (m, 2H), 7.30 (t, 1H).

中間物1-22-1Intermediate 1-22-1 製備2-(溴甲基)-5-(二氟甲氧基)-1,3-二氟苯 Preparation of 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene

將162 mg[4-(二氟甲氧基)-2,6-二氟苯基]甲醇(0.769 mmol，1.0 eq.)溶解於0.348 mL溴化氫(2.12 mmol，2.8 eq.)中且在室溫下攪拌隔夜。以***稀釋反應混合物且攪拌5分鐘。將水層以***洗滌兩次。以鹽水洗滌經合併之有機層，經矽過濾器乾燥且真空濃縮以提供149 mg(0.51 mmol，67%)粗產物，其不經進一步純化即使用。 162 mg of [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (0.769 Methylene, 1.0 eq.) was dissolved in 0.348 mL of hydrogen bromide (2.12 mmol, 2.8 eq.) and stirred overnight at room temperature. The reaction mixture was diluted with ether and stirred for 5 min. The aqueous layer was washed twice with diethyl ether. The combined organics were washed with EtOAc EtOAc m.

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=4.60(s,2H),7.05-7.14(m,2H),7.33(t,1H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.60 (s, 2H), 7.05-7.14 (m, 2H), 7.33 (t, 1H).

根據如關於中間物1-22-1所述之相同程序，使用市售起始物質來製備以下中間物1-22-2。中間物1-22-2不經進一步純化即使用。 The following intermediates 1-22-2 were prepared according to the same procedure as described for Intermediate 1-22-1 using commercially available starting materials. Intermediate 1-22-2 was used without further purification.

中間物1-23-1Intermediate 1-23-1 製備5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 5-cyclopropyl-1-(4-cyclopropyl-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3-carboxylate

將1.0 g 1-(4-溴-2,6-二氟苯甲基)-5-環丙基-4-甲基-1H-吡唑-3-甲酸乙酯(2.51 mmol，1.0 eq.)溶解於40 mL甲苯中且添加0.280 g環丙基酸(3.26 mmol，1.3 eq.)、1.86 g磷酸鉀(8.77 mmol，3.5 eq.)、70 mg三環己基膦(0.25 mmol，0.10 eq.)及0.66 mL水。以氮沖洗反應混合物且添加28 mg乙酸鈀(0.125 mmol，0.050 eq.)。將反應混合物在100℃下攪拌隔夜。再次添加0.280 g環丙基酸(3.26 mmol，1.3 eq.)、1.86 g磷酸鉀(8.77 mmol，3.5 eq.)、70 mg三環己基膦(0.25 mmol，0.10 eq.)及0.66 mL水。以氮沖洗反應混合物且添加28 mg乙酸鈀(0.125 mmol，0.050 eq.)。將反應混合物在100℃下攪拌隔夜。添加水且將含水相以乙酸乙酯洗滌兩次。經矽過濾器乾燥經合併之有機層且真空濃縮。藉由急驟層析純化粗產物以得到652 mg(1.63 mmol，65%)分析純的目標化合物。 1.0 g of ethyl 1-(4-bromo-2,6-difluorobenzyl)-5-cyclopropyl-4-methyl-1 H -pyrazole-3-carboxylate (2.51 mmol, 1.0 eq. Dissolved in 40 mL of toluene and added 0.280 g of cyclopropyl Acid (3.26 mmol, 1.3 eq.), 1.86 g potassium phosphate (8.77 mmol, 3.5 eq.), 70 mg tricyclohexylphosphine (0.25 mmol, 0.10 eq.) and 0.66 mL water. The reaction mixture was flushed with nitrogen and 28 mg of palladium acetate (0.125 mmol, 0.050 eq.). The reaction mixture was stirred at 100 ° C overnight. Add 0.280 g of cyclopropyl again Acid (3.26 mmol, 1.3 eq.), 1.86 g potassium phosphate (8.77 mmol, 3.5 eq.), 70 mg tricyclohexylphosphine (0.25 mmol, 0.10 eq.) and 0.66 mL water. The reaction mixture was flushed with nitrogen and 28 mg of palladium acetate (0.125 mmol, 0.050 eq.). The reaction mixture was stirred at 100 ° C overnight. Water was added and the aqueous phase was washed twice with ethyl acetate. The combined organic layers were dried with EtOAc (EtOAc)EtOAc. The crude product was purified by flash chromatography to afford 652 mg (1.

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=0.63-0.67(m,2H),0.70-0-74(m,2H),0.91-1.03(m,4H),1.20(t,3H),1.54-1.65(m,1H),1.87-1.98(m,1H),2.12(s,3H),4.16(q,2H),5.36(s,2H),6.80-6.85(m,2H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.63 - 0.67 (m, 2H), 0.70 - 0 - 74 (m, 2H), 0.91-1.03 (m, 4H), 1.20 (t) , 3H), 1.54-1.65 (m, 1H), 1.87-1.98 (m, 1H), 2.12 (s, 3H), 4.16 (q, 2H), 5.36 (s, 2H), 6.80-6.85 (m, 2H) ).

中間物1-24-1Intermediate 1-24-1 製備4-胺基-2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-5-甲腈 Preparation of 4-amino-2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl] Pyrimidine-5-carbonitrile

在氮氣氛圍下將146 mg甲醇鈉(2.70 mmol，1.0 eq)在室溫下稀釋於20 mL甲醇中。隨後添加1.0 g 5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-羰醯亞胺醯胺鹽酸鹽1：1 1-3-6(2.70 mmol，1.0 eq)及329 mg(乙氧基亞甲基)丙二腈(2.70 mmol，1.0 eq)且將混合物在65℃浴溫下攪拌18小時。在冷卻至室溫後，真空濃縮反應混合物且經由HPLC(ACN/H₂O/0.2% NH₃)純化以產生284 mg(0.65 mmol，24%)分析純的目標化合物。 146 mg of sodium methoxide (2.70 mmol, 1.0 eq) was diluted in 20 mL of methanol at room temperature under a nitrogen atmosphere. Subsequently, 1.0 g of 5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3-carbonylindoleamine amide salt was added. Acid salt 1:1 1-3-6 (2.70 mmol, 1.0 eq) and 329 mg (ethoxymethylene)malononitrile (2.70 mmol, 1.0 eq) and the mixture was stirred at 65 ° C for 18 hours. . After cooling to room temperature, the reaction mixture was concentrated in vacuo and _{(ACN / H 2 O / 0.2} % NH 3) was purified by HPLC to yield 284 mg (0.65 mmol, 24% ) of analytically pure title compound.

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.64-0.71(m,2H),0.95-1.04(m,2H),1.27(t,3H),1.63(m,1H),2.25(s,3H),4.01(q,2H),5.34(s,2H),6.72(m,2H),7.76(br,s,2H),8.56(s,1H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.64-0.71 (m, 2H), 0.95-1.04 (m, 2H), 1.27 (t, 3H), 1.63 (m, 1H), 2.25 (s, 3H), 4.01 (q, 2H), 5.34 (s, 2H), 6.72 (m, 2H), 7.76 (br, s, 2H), 8.56 (s, 1H).

根據相同程序，使用上述起始物質製備以下中間物： The following intermediates were prepared according to the same procedure using the above starting materials:

中間物1-25-1Intermediate 1-25-1 製備2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-胺 Preparation of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]pyrimidin-4-amine

在氮氣氛圍下向10.1 g 5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-羰醯亞胺醯胺鹽酸鹽1：1 1-3-1(27.2 mmol，1.0 eq)於163 mL無水吡啶及4.10 mL 1,8-二氮雜雙環[5.4.0]十一-7-烯(27.2 mmol，1.0 eq)中之懸浮液中添加 7.94 g 3-乙氧基丙烯腈(81.7 mmol，3.30 eq)。將反應混合物在110℃下攪拌隔夜。在冷卻至室溫後，將混合物淨化至水中且以乙酸乙酯萃取三次。經Na₂SO₄乾燥經合併之有機層且真空濃縮。將殘餘物溶於DCM/MeOH 9：1中且藉由添加***使產物沈澱以產生4.20 g所要化合物1-25-1。真空濃縮母液，將殘餘物懸浮於乙酸乙酯中。藉由過濾收集所得沈澱物且以乙酸乙酯洗滌以額外產生1.90 g所要化合物1-25-1。總計6.10 g目標化合物(15.8 mmol，58%)。 To a solution of 10.1 g of 5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1 H -pyrazole-3-carbonylindoleamine hydrochloride under nitrogen atmosphere 1: 1 1-3-1 (27.2 mmol, 1.0 eq) suspended in 163 mL of anhydrous pyridine and 4.10 mL of 1,8-diazabicyclo [5.4.0]undec-7-ene (27.2 mmol, 1.0 eq) 7.94 g of 3-ethoxyacrylonitrile (81.7 mmol, 3.30 eq) was added to the solution. The reaction mixture was stirred at 110 ° C overnight. After cooling to room temperature, the mixture was purified into water and extracted three times with ethyl acetate. Dried over Na ₂ SO ₄ and concentrated in vacuo the combined organic layers. The residue was dissolved in DCM / MeOH 9:1 and the product was precipitated with diethyl ether to afford 4.20 g of the desired compound 1-25-1 . The mother liquor was concentrated in vacuo and the residue was taken in ethyl acetate. The resulting precipitate was collected by filtration and washed with ethyl acetate to give 1.90 g of the desired compound 1-25-1 . A total of 6.10 g of the target compound (15.8 mmol, 58%).

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.64-0.77(m,2 H),0.96-1.07(m,2 H),1.31(t,3 H),1.67(m,1 H),2.24(s,3 H),4.05(q,2 H),5.33(s,2 H),6.26(d,1 H),6.68-6.81(m,4 H),8.06(d,1 H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.64-0.77 (m, 2 H), 0.96-1.07 (m, 2 H), 1.31 (t, 3 H), 1.67 (m, 1 H), 2.24 (s, 3 H), 4.05 (q, 2 H), 5.33 (s, 2 H), 6.26 (d, 1 H), 6.68-6.81 (m, 4 H), 8.06 (d, 1 H).

中間物1-26-1Intermediate 1-26-1 製備2-乙基-3-側氧基丁二酸二乙酯 Preparation of diethyl 2-ethyl-3-oxo-succinate

在氬氣氛圍下將27.8 mL二異丙基醯胺鋰(50.0 mmol，1.00 eq,1.8 M於THF/庚烷/乙基苯中)溶解於50 mL無水THF中且冷卻至-75℃。將6.64 mL丁酸乙酯(50.0 mmol，1.00 eq)溶解於25 mL無水THF中且在-60至-75℃浴溫下添加至前述溶液中且在-75℃之浴溫下再攪拌1 h。將6.92 mL乙烷二酸二乙酯(51.0 mmol，1.02 eq)溶解於25 mL無水THF中且在-60至-75℃浴溫下添加至前述溶液中且在-75℃ 之浴溫下再攪拌30 min。使混合物可達到-20℃，在此溫度下添加6.47 mL乙酸(113.0 mmol，2.26 eq)，繼而添加100 mL水。隨後使混合物可達到室溫。將經分離之有機層以水洗滌一次，以碳酸氫鈉溶液洗滌一次且以鹽水洗滌一次，之後經硫酸鈉乾燥且真空濃縮。粗反應產物不經任何進一步純化即用於下一轉化。 27.8 mL of lithium diisopropylamide (50.0 mmol, 1.00 eq, 1.8 M in THF / heptane / ethylbenzene) was dissolved in 50 mL anhydrous THF and cooled to -75 ° C under argon. 6.64 mL of ethyl butyrate (50.0 mmol, 1.00 eq) was dissolved in 25 mL of anhydrous THF and added to the above solution at a bath temperature of -60 to -75 ° C and stirred at a bath temperature of -75 ° C for an additional 1 h. . 6.92 mL of diethyl ethanedicarboxylate (51.0 mmol, 1.02 eq) was dissolved in 25 mL of anhydrous THF and added to the above solution at -60 to -75 ° C bath temperature and at -75 ° C Stir for another 30 minutes at the bath temperature. The mixture was allowed to reach -20 ° C, at which temperature 6.47 mL of acetic acid (113.0 mmol, 2.26 eq) was added, followed by 100 mL of water. The mixture is then allowed to reach room temperature. The separated organic layer was washed once with water, once with sodium bicarbonate solution and once with brine then dried over sodium sulfate and concentrated in vacuo. The crude reaction product was used in the next transformation without any further purification.

中間物1-27-1Intermediate 1-27-1 製備1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-甲酸乙酯 Preparation of ethyl 1-(2-fluorobenzyl)-5-methoxy-1H-pyrazole-3-carboxylate

將21.58 g 1-(2-氟苯甲基)-5-羥基-1H-吡唑-3-甲酸乙酯1-1-2(81.66 mmol，1.0 eq)溶解於無水丙酮中。隨後添加10.17 mL碘甲烷(163.3 mmol，2.0 eq)及40.63 g碳酸鉀(294 mmol，3.6 eq)。濾除沈澱物且真空濃縮濾液。將殘餘物分配於DCM與水之間，分離水層且以DCM萃取兩次。經硫酸鎂乾燥經合併之有機層，濾除且真空濃縮以產生14.74 g(52.96 mmol，65%)粗目標化合物，其不經進一步純化即用於下一轉化。 21.58 g of ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate 1-1-2 (81.66 mmol, 1.0 eq) was dissolved in anhydrous acetone. Then 10.17 mL of methyl iodide (163.3 mmol, 2.0 eq) and 40.63 g of potassium carbonate (294 mmol, 3.6 eq) were added. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water. aqueous layer was separated and extracted twice with DCM. The combined organics were dried with EtOAc EtOAc EtOAcjjjjjjjj

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=1.23(t,3H),3.88(s,3H),4.20(q,2H),5.21(s,2H),6.19(s,1H),6.99- 7.38(m,4H)。 ¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.88 (s, 3H), 4.20 (q, 2H), 5.21. (s, 2H), 6.19 (s, 1H), 6.99- 7.38 (m, 4H).

實例化合物Example compound 實例2-1-1Example 2-1-1 製備2-[1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺 Preparation of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1 H -pyrazol-3-yl]-5-methoxy ki- N- (pyridin-4-yl)pyrimidine-4-amine

將619 mg 2-[1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-胺1-5-1(1.53 mmol，1.0 eq.)、445-38 mg 4-溴吡啶鹽酸鹽(1：1)(2.29 mmol，1.5 eq.)、190.15 mg(R)-(+)-2,2'-雙(二苯膦基)-1,1'-聯萘(305 mmol，0.2 eq.)、587 mg第三丁酸鈉(6.12 mmol，4.0 eq.)及419 mg參(二苯亞甲基丙酮)二鈀(0)(0.458 mmol，0.3 eq.)懸浮於10 mL無水DMF中且在氮氣氛圍下在110℃浴溫下攪拌24小時。將反應混合物分配於半飽和氯化銨水溶液與DCM之間。將經分離之水層以DCM萃取兩次。以鹽水洗滌經合併之有機層，經硫酸鈉乾燥且真空濃縮。藉由急驟層析(己烷(0-100%)/乙酸乙酯)純化殘餘物。以甲醇洗滌管柱以產生50%純目標化合物。將此與丙酮一起攪拌且濾除懸浮液。藉由對濾餅及濃縮濾液進行急驟層析及製備型HPLC進一步純化產生82 mg(0.15 mmol，10%)分析純的目標化合物。 619 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1 H -pyrazol-3-yl]-5- Methoxypyrimidine-4-amine 1-5-1 (1.53 mmol, 1.0 eq.), 445-38 mg 4-bromopyridine hydrochloride (1:1) (2.29 mmol, 1.5 eq.), 190.15 mg ( R )-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (305 mmol, 0.2 eq.), 587 mg sodium citrate (6.12 mmol, 4.0 eq. And 419 mg of stilbene (diphenylmethyleneacetone) dipalladium (0) (0.458 mmol, 0.3 eq.) were suspended in 10 mL of dry DMF and stirred under a nitrogen atmosphere at a bath temperature of 110 ° C for 24 hours. The reaction mixture was partitioned between a half saturated aqueous ammonium chloride solution and DCM. The separated aqueous layer was extracted twice with DCM. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by flash chromatography (EtOAc (EtOAc) The column was washed with methanol to yield a 50% pure target compound. This was stirred with acetone and the suspension was filtered off. Further purification by flash chromatography and preparative HPLC of the cake and concentrated filtrate afforded 82 mg (0.15 mmol, 10%) of the objective compound.

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=1.26(t,3H),2.21(s,3H),3.90(s,3H),3.95(s,3H),4.02(q,2H),5.11(s,2H),6.69-6.82(m,2H),8.02-8.12(m,2H),8.20(s,1H),8.26-8.36(m,2H),9.26(s,1H)。 ¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (t, 3H), 2.21 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.02 (q, 2H), 5.11 (s, 2H), 6.69-6.82 (m, 2H), 8.02-8.12 (m, 2H), 8.20 (s, 1H), 8.26-8.36 (m, 2H), 9.26 (s, 1H) .

根據如上文所述相同程序，使用邏輯上與下表中所示最終產物結構一致之起始物質來製備以下化合物： The following compounds were prepared according to the same procedure as described above using starting materials that are logically identical to the structure of the final product shown in the table below:

實例2-2-1Example 2-2-1 製備2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-醇 Preparation of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridine -4-ylamino)pyrimidine-5-ol

將310 mg 2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺2-1-12(0.629 mmol，1 eq.)溶解於27.2 mL無水1-甲基吡咯啶-2-酮中。添加348 mg碳酸鉀(2.52 mmol，4.0 eq.)、分子篩及97 μL苯硫酚(0.944 mmol，1.5 eq.)。將混合物在150℃浴溫下攪拌1小時。再次添加348 mg碳酸鉀(2.52 mmol，4.0 eq.)及97 μL苯硫酚(0.944 mmol，1.5 eq.)且將混合物在150℃浴溫下再攪拌一小時。隨後將反應混合物分配於半飽和氯化銨水溶液與乙酸乙酯之間。將經分離之水層以乙酸乙酯萃取兩次。經聚矽氧過濾器乾燥經合併之有機層且真空濃縮。藉由急驟層析純化殘餘物提供191 mg(0.36 mmol，56%)分析純的目標化合物。 310 mg 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5- Methoxy- N- (pyridin-4-yl)pyrimidine-4-amine 2-1-12 (0.629 mmol, 1 eq.) was dissolved in 27.2 mL of anhydrous 1-methylpyrrolidin-2-one. Add 348 mg potassium carbonate (2.52 mmol, 4.0 eq.), molecular sieve and 97 μL thiophenol (0.944 mmol, 1.5 eq.). The mixture was stirred at a bath temperature of 150 ° C for 1 hour. 348 mg of potassium carbonate (2.52 mmol, 4.0 eq.) and 97 μL of thiophenol (0.944 mmol, 1.5 eq.) were again added and the mixture was stirred at 150 ° C for one hour. The reaction mixture was then partitioned between a half-saturated aqueous ammonium chloride solution and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried with EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography to afford 191 mg (0.3.

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=0.69-0.79(m,2H),1.01-1.09(m,2H),1.30(t,3H),1.68-1.80(m,1H),2.27(s,3H),4.05(q,2H),5.35(s,2H),6.74-6.80(m,2H),8.01(s,1H),8.04-8.10(m,2H),8.27-8.34(m,2H),9.12(br,s,1H),10.58(br,s,1H)。 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=0.69-0.79 (m, 2H), 1.01-1.09 (m, 2H), 1.30 (t, 3H), 1.68-1.80 (m, 1H) ), 2.27 (s, 3H), 4.05 (q, 2H), 5.35 (s, 2H), 6.74-6.80 (m, 2H), 8.01 (s, 1H), 8.04-8.10 (m, 2H), 8.27- 8.34 (m, 2H), 9.12 (br, s, 1H), 10.58 (br, s, 1H).

使用上述程序分離以下副產物： The following by-products were separated using the above procedure:

實例2-2-2Example 2-2-2 2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-醇 2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenylthio)benzyl]-4-methyl-1 H -pyrazol-3-yl} -4-(pyridin-4-ylamino)pyrimidine-5-ol

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.63-0.77(m,2H),0.93-1.05(m,2H),1.21(t,3H),1.72-1.81(m,1H),2.21(s,3H),3.92(q,2H),5.46(s,2H),6.57(d,1H),6.90(dd,1H),7.14-7.32(m,5H),7.97(s,1H),8.01-8.09(m,2H),8.18-8.31(m,2H),9.10(s,1H),10.89(br,s,1H)。 ¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.63 - 0.77 (m, 2H), 0.93-1.05 (m, 2H), 1.21 (t, 3H), 1.72-1.81 (m, 1H) ), 2.21 (s, 3H), 3.92 (q, 2H), 5.46 (s, 2H), 6.57 (d, 1H), 6.90 (dd, 1H), 7.14-7.32 (m, 5H), 7.97 (s, 1H), 8.01-8.09 (m, 2H), 8.18-8.31 (m, 2H), 9.10 (s, 1H), 10.89 (br, s, 1H).

實例2-3-1Example 2-3-1 製備2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(二甲胺基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺 Preparation of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2 -(dimethylamino)ethoxy] -N- (pyridin-4-yl)pyrimidine-4-amine

將80 mg 2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-醇2-2-1(0.048 mmol，1.0 eq)溶解於1.9 mL無水DMF中且添加33.5 mg碳酸鉀(0.24 mmol，5.0 eq)及10.5 mg 2-氟-N,N-二甲基乙胺(0.073 mmol，1.5 eq)。將反應混合物在50℃下攪拌隔夜。隨後添加丁-2-酮且以鹽水洗滌有機層，經硫酸鈉乾燥且真空濃縮。藉由急驟層析及HPLC純化殘餘物提供10 mg(0.02 mmol，37%)分析純的目標化合物。 80 mg 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4- (Pyridin-4-ylamino)pyrimidin-5-ol 2-2-1 (0.048 mmol, 1.0 eq) was dissolved in 1.9 mL of dry DMF and added 33.5 mg of potassium carbonate (0.24 mmol, 5.0 eq) and 10.5 mg 2 -Fluoro- N , N -dimethylethylamine (0.073 mmol, 1.5 eq). The reaction mixture was stirred at 50 ° C overnight. The butan-2-one was then added and the org. The residue was purified by flash chromatography and HPLC to afford 10 mg ( EtOAc,

¹H-NMR(400MHz，甲醇-d4)：δ[ppm]=0.73-0.80(m,2H),1.05-1.13(m,2H),1.35(t,3H),1.66-1.76(m,1H),2.32(s,3H),2.82(s,6H),3.41(t,2H),4.01(q,2H),4.47(t,2H),5.47(s,2H),6.54-6.62(m,2H),8.18-8.26(m,3H),8.38(d,2H)。 ¹ H-NMR (400 MHz, methanol-d4): δ [ppm] = 0.73 - 0.80 (m, 2H), 1.05-1.13 (m, 2H), 1.35 (t, 3H), 1.66-1.76 (m, 1H) , 2.32 (s, 3H), 2.82 (s, 6H), 3.41 (t, 2H), 4.01 (q, 2H), 4.47 (t, 2H), 5.47 (s, 2H), 6.54-6.62 (m, 2H) ), 8.18-8.26 (m, 3H), 8.38 (d, 2H).

實例2-4-1Example 2-4-1 製備4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲醯胺 Preparation of 4-({2-[1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) Pyridine-3-carboxamide

在室溫下向126 mg 4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲腈2-1-7(0.294 mmol，1.0 eq.)中小心給予0.446 mL硫酸。將混合物在室溫下攪拌24小時。隨後將反應混合物滴入冰水中且以2 M氫氧化鈉水溶液設定至鹼性pH。以DCM/丙-2-醇4：1將此水層萃取三次。經硫酸鎂乾燥經合併之有機層且真空濃縮。自甲醇結晶提供37.0 mg(0.08 mmol，28%)分析純的目標化合物。 To 126 mg of 4-({2-[1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidine-4 at room temperature To the base -amino)pyridine-3-carbonitrile 2-1-7 (0.294 mmol, 1.0 eq.), 0.446 mL of sulfuric acid was carefully administered. The mixture was stirred at room temperature for 24 hours. The reaction mixture was then dropped into ice water and set to a basic pH with a 2 M aqueous sodium hydroxide solution. The aqueous layer was extracted three times with DCM / propan-2-ol 4:1. The combined organic layers were dried with EtOAc EtOAc. Crystallization from methanol provided 37.0 mg (0.08 mmol, 28%) of the objective compound.

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=3.95(d,6H),5.22(s,2H),6.26(s,1H),7.10-7.26(m,3H),7.29-7.40(m,1H),7.73-7.86(m,1H),8.22(s,1H),8.34-8.43(m,1H),8.46-8.54(m,1H),8.84-8.91(m,1H),9.08-9.16(m,1H),12.04-12.16(m,1H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 3.95 (d, 6H), 5.22 (s, 2H), 6.26 (s, 1H), 7.10-7.26 (m, 3H), 7.29- 7.40(m,1H), 7.73-7.86(m,1H), 8.22(s,1H),8.34-8.43(m,1H),8.46-8.54(m,1H),8.84-8.91(m,1H), 9.08-9.16 (m, 1H), 12.04-12.16 (m, 1H).

根據相同程序製備以下化合物： The following compounds were prepared according to the same procedure:

實例2-5-1Example 2-5-1 製備2,4-二氯-3-({5-環丙基-3-[5-甲氧基-4-(吡啶-4-基胺基)嘧啶-2-基]-4-甲基-1H-吡唑-1-基}甲基)苯甲酸 Preparation of 2,4-dichloro-3-({5-cyclopropyl-3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-4-methyl- 1 H -pyrazol-1-yl}methyl)benzoic acid

將200 mg 2-(5-環丙基-4-甲基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺1-16-1(0.62 mmol，1.0 eq.)、184.86 mg 3-(溴甲基)-2,4-二氯苯甲酸甲酯(0.62 mmol，1.0 eq.)及31.0 mg 60%於石蠟油中之氫化鈉懸浮於6.3 mL無水THF中且在室溫下攪拌20小時。將反應混合物分配於水與DCM/丙-2-醇4：1之間。以DCM/丙-2-醇4：1將經分離之水層萃取三次。經硫酸鈉乾燥經合併之有機層且真空濃縮。藉由對殘餘物進行急驟層析及製備型HPLC而純化提供37.5 mg(0.07 mmol，11%)分析純的目標化合物。 200 mg 2-(5-cyclopropyl-4-methyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine 1- 16-1 (0.62 mmol, 1.0 eq.), 184.86 mg of methyl 3-(bromomethyl)-2,4-dichlorobenzoate (0.62 mmol, 1.0 eq.) and 31.0 mg of 60% in paraffin oil The sodium hydride was suspended in 6.3 mL of anhydrous THF and stirred at room temperature for 20 hours. The reaction mixture was partitioned between water and DCM / propan-2-ol 4:1. The separated aqueous layer was extracted three times with DCM / propan-2-ol 4:1. The combined organic layers were dried with sodium s Purification by flash chromatography and preparative HPLC afforded 37.5 mg (0.07 mmol, 11%)

¹H-NMR(400MHz,DMSO-d₆)：δ[ppm]=0.67-0.74(m,2H),0.79-0.87(m,2H),1.75-1.86(m,1H),2.33(s,3H),4.01(s,3H),5.82(s,2H),7.38(d,1H),7.45(d,1H),8.44-8.52(m,5H)。 ^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 0.67-0.74 (m, 2H), 0.79-0.87 (m, 2H), 1.75-1.86 (m, 1H), 2.33 (s, 3H ), 4.01 (s, 3H), 5.82 (s, 2H), 7.38 (d, 1H), 7.45 (d, 1H), 8.44 - 8.52 (m, 5H).

實例2-6-1 製備2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺 Example 2-6-1 Preparation of 2-[5-Cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy - N -(pyridin-4-yl)pyrimidine-4-amine

將1.03 g 2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-胺(2.82 mmol，1.00 eq.)、603 mg 4-溴吡啶鹽酸鹽(1：1)(3.10 mmol，1.10 eq.)、245 mg(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯基膦)(0.423 mmol，0.15 eq.)、2.76 g碳酸銫(8.46 mmol，3.00 eq.)及63 mg二乙酸鈀(0.282 mmol，0.1 eq.)懸浮於10.8 mL無水DMF中且在氮氣氛圍下在105℃浴溫下攪拌兩小時。以水稀釋反應混合物且以DCM萃取粗產物。經矽過濾器乾燥經合併之有機層且真空濃縮。藉由急驟層析純化殘餘物，產生930 mg(1.95 mmol，69%)分析純的目標化合物。 1.03 g of 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidine-4- amine (. 2.82 mmol, 1.00 eq) , 603 mg 4- bromopyridine hydrochloride (1: 1) (3.10 mmol , 1.10 eq.), 245 mg (9,9- dimethyl -9 H - dibenzo Piper-4,5-diyl)bis(diphenylphosphine) (0.423 mmol, 0.15 eq.), 2.76 g cesium carbonate (8.46 mmol, 3.00 eq.) and 63 mg palladium diacetate (0.282 mmol, 0.1 eq) .) was suspended in 10.8 mL of anhydrous DMF and stirred under a nitrogen atmosphere at a bath temperature of 105 ° C for two hours. The reaction mixture was diluted with water and the crude was extracted with DCM. The combined organic layers were dried with EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography to afford 930 mg (1.

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.55-0.65(m,2H),0.92-0.98(m,2H),1.47-1.63(m,1H),2.25(s,3H),3.68(s,3H),3.96(s,3H),5.32(s,2H),6.79-6.93(m,2H),7.17-7.22(m,2H),8.01-8.12(m,2H),8.22(s,1H),8.29- 8.38(m,2H),9.27(s,1H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.55-0.65 (m, 2H), 0.92-0.98 (m, 2H), 1.47-1.63 (m, 1H), 2.25 (s, 3H ), 3.68 (s, 3H), 3.96 (s, 3H), 5.32 (s, 2H), 6.79-6.93 (m, 2H), 7.17-7.22 (m, 2H), 8.01-8.12 (m, 2H), 8.22 (s, 1H), 8.29 - 8.38 (m, 2H), 9.27 (s, 1H).

實例2-7-1 製備2-[5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)- 4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺 Example 2-7-1 Preparation of 2-[5-Cyclopropyl-1-(4-cyclopropyl-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl ]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine

在氮氣氛圍下將16.5 mg 2-[5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-胺1-17-3(0.040 mmol，1.0 eq.)及16.1 mg 4-氟吡啶鹽酸鹽(0.120 mmol，3.0 eq.)懸浮於0.19 mL無水DMF中。添加19.2 mg氫化鈉(60%純度)且在90℃下攪拌2 h。隨後將混合物分配於半水與乙酸乙酯之間。將水層以乙酸乙酯洗滌兩次。以鹽水洗滌經合併之有機層，經硫酸鈉乾燥且真空濃縮。藉由急驟層析純化粗產物以獲得5.7 mg(0.01 mmol，20%)分析純的目標化合物。 16.5 mg of 2-[5-cyclopropyl-1-(4-cyclopropyl-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl under nitrogen atmosphere 5-Methoxypyrimidine-4-amine 1-17-3 (0.040 mmol, 1.0 eq.) and 16.1 mg of 4-fluoropyridine hydrochloride (0.120 mmol, 3.0 eq.) were suspended in 0.19 mL of anhydrous DMF. . 19.2 mg of sodium hydride (60% purity) was added and stirred at 90 °C for 2 h. The mixture was then partitioned between half water and ethyl acetate. The aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m. The crude product was purified by flash chromatography to afford 5.7 mg (0.01 mmol, 20%).

¹H-NMR(400 MHz,DMSO-d6)：δ[ppm]=0.69-0.74(m,4H),0.92-1.08(m,4H),1.66-1.78(m,1H),1.89-2.01(m,1H),2.26(s,3H),3.94(s,3H),5.36(s,2H),6.73-6.96(m,2H),8.06(d,2H),8.18(s,1H),8.30(d,2H),9.21(s,1H)。 ¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.69 - 0.74 (m, 4H), 0.92-1.08 (m, 4H), 1.66-1.78 (m, 1H), 1.89-2.01 (m) , 1H), 2.26 (s, 3H), 3.94 (s, 3H), 5.36 (s, 2H), 6.73-6.96 (m, 2H), 8.06 (d, 2H), 8.18 (s, 1H), 8.30 ( d, 2H), 9.21 (s, 1H).

實例2-8-1 製備2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺 Example 2-8-1 Preparation of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl ] -5- [2- (methylsulfinyl acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine

將180 mg 2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基硫基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺(0.326 mmol，1.0 eq.)溶解於1.7 mL氯仿中且冷卻至0℃。將80.3 mg 3-氯過氧苯甲酸與反應混合物在0℃下攪拌30分鐘。以DCM稀釋反應混合物，且添加硫代硫酸鈉溶液(10%於水中)且攪拌5分鐘。分離各層且以DCM將水層洗滌兩次。以飽和碳酸氫鈉溶液洗滌經合併之有機層，經矽過濾器乾燥且真空濃縮。藉由急驟層析純化粗產物以得到136 mg外消旋物形式之分析純的目標化合物。 180 mg 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5- [2- (methylthio) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine (. 0.326 mmol, 1.0 eq) was dissolved in 1.7 mL of chloroform and cooled to 0 ℃. 80.3 mg of 3-chloroperoxybenzoic acid was stirred with the reaction mixture at 0 ° C for 30 minutes. The reaction mixture was diluted with DCM, and a sodium thiosulfate solution (10% in water) was added and stirred for 5 min. The layers were separated and the aqueous layer was washed twice with DCM. The combined organic layers were washed with aq. The crude product was purified by flash chromatography to afford 136 mg of the objective compound as a crystals.

¹H-NMR(300 MHz,DMSO-d6)：δ[ppm]=0.69-0.81(m,2H),1.01-1.13(m,2H),1.31(t,3H),1.70-1.83(m,1H),2.30(s,3H),2.70(s,3H),3.15-3.25(m,1H),3.31-3.41(m,1H),4.06(q,2H),4.51-4.70(m,2H),5.37(s,2H),6.71-6.85(m,2H),7.93-8.08(m,2H),8.28-8.44(m,3H),9.25 (s,1H)。 ¹ H-NMR (300 MHz, DMSO-d6): δ [ppm] = 0.69 - 0.81 (m, 2H), 1.01-1.13 (m, 2H), 1.31 (t, 3H), 1.70-1.83 (m, 1H) ), 2.30 (s, 3H), 2.70 (s, 3H), 3.15-3.25 (m, 1H), 3.31-3.41 (m, 1H), 4.06 (q, 2H), 4.51-4.70 (m, 2H), 5.37 (s, 2H), 6.71-6.85 (m, 2H), 7.93-8.08 (m, 2H), 8.28-8.44 (m, 3H), 9.25 (s, 1H).

實例2-8-2及2-8-3Examples 2-8-2 and 2-8-3

藉由對掌性HPLC將外消旋物2-8-1分離為兩種對映異構體：¹H-NMR(300 MHz,DMSO-d6)：δ[ppm]=0.69-0.74(m,2H),1.00-1.09(m,2H),1.27(t,3H),1.60-1.80(m,1H),2.27(s,3H),2.66(s,3H),3.08-3.23(m,1H),3.28-3.42(m,1H),4.01(q,2H),4.49-4.63(m,2H),5.33(s,2H),6.72-6.79(m,2H),7.89-8.12(m,2H),8.17-8.45(m,3H),9.23(s,1H)。 The racemate 2-8-1 was separated into the two enantiomers by palm chromatography: ¹ H-NMR (300 MHz, DMSO-d6): δ [ppm] = 0.69 - 0.74 (m, 2H), 1.00-1.09 (m, 2H), 1.27 (t, 3H), 1.60-1.80 (m, 1H), 2.27 (s, 3H), 2.66 (s, 3H), 3.08-3.23 (m, 1H) , 3.28-3.42 (m, 1H), 4.01 (q, 2H), 4.49-4.63 (m, 2H), 5.33 (s, 2H), 6.72-6.79 (m, 2H), 7.89-8.12 (m, 2H) , 8.17-8.45 (m, 3H), 9.23 (s, 1H).

α=-21.3°(10.0 mg/mL DMSO) α=-21.3° (10.0 mg/mL DMSO)

¹H-NMR(300 MHz,DMSO-d6)：δ[ppm]=0.69-0.74(m,2H),1.00-1.09(m,2H),1.27(t,3H),1.60-1.80(m,1H),2.27(s,3H),2.66(s,3H),3.08-3.23(m,1H),3.28-3.42(m,1H),4.01(q,2H),4.49-4.63(m,2H),5.33(s,2H),6.72-6.79(m,2H),7.89-8.12(m,2H),8.17-8.45(m,3H),9.23(s,1H)。 ¹ H-NMR (300 MHz, DMSO-d6): δ [ppm] = 0.69 - 0.74 (m, 2H), 1.00 - 1.09 (m, 2H), 1.27 (t, 3H), 1.60-1.80 (m, 1H) ), 2.27 (s, 3H), 2.66 (s, 3H), 3.08-3.23 (m, 1H), 3.28-3.42 (m, 1H), 4.01 (q, 2H), 4.49-4.63 (m, 2H), 5.33(s, 2H), 6.72-6.79 (m, 2H), 7.89-8.12 (m, 2H), 8.17-8.45 (m, 3H), 9.23 (s, 1H).

α=20.6°(10.3 mg/mL DMSO) α=20.6° (10.3 mg/mL DMSO)

根據與製備實例2-8-1中所用相同之程序製備以下化合物： The following compounds were prepared according to the same procedure as used in Preparation Example 2-8-1:

實例2-9-1 製備2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺 Example 2-9-1 Preparation of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl ] -5- [2- (methanesulfonyl acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine

在氮氣氛圍下將100 mg 2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺(2-8-1，0.176 mmol，1.0 eq.)懸浮於0.93 mL無水四氫呋喃中。添加90 μL過氧化氫(30%，0.879 mmol，5.0 eq.)及33 μL偶氮二甲酸二乙酯 (0.211 mmol，1.2 eq.)。將反應混合物在50℃下攪拌2小時且真空濃縮。藉由急驟層析純化粗產物以得到31.9 mg(0.05 mmol，31%)分析純的目標化合物。 100 mg of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl under nitrogen atmosphere ] -5- [2- (methylsulfinyl acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine (. 2-8-1,0.176 mmol, 1.0 eq) was suspended in 0.93 mL in anhydrous tetrahydrofuran. 90 μL of hydrogen peroxide (30%, 0.879 mmol, 5.0 eq.) and 33 μL of diethyl azodicarboxylate (0.211 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 50 <0>C for 2 h and concentrated in vacuo. The crude product was purified by flash chromatography to give 31.9 mg (0.05 mmol, 31%)

¹H-NMR(400 MHz,DMSO-d6)：δ[ppm]=0.68-0.81(m,2H),1.03-1.11(m,2H),1.31(t,3H),1.70-1.83(m,1H),2.30(s,3H),3.12(s,3H),3.75(t,2H),4.06(q,2H),4.60(t,2H),5.37(s,2H),6.69-6.88(m,2H),7.91-8.07(m,2H),8.33(s,1H),8.34-8.40(m,2H),8.89(s,1H)。 ¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.68-0.81 (m, 2H), 1.03-1.11 (m, 2H), 1.31 (t, 3H), 1.70-1.83 (m, 1H) ), 2.30 (s, 3H), 3.12 (s, 3H), 3.75 (t, 2H), 4.06 (q, 2H), 4.60 (t, 2H), 5.37 (s, 2H), 6.69-6.88 (m, 2H), 7.91-8.07 (m, 2H), 8.33 (s, 1H), 8.34-8.40 (m, 2H), 8.89 (s, 1H).

實例2-10-1Example 2-10-1 製備2-{5-環丙基-1-[4-(二氟甲氧基)-2,6-二氟苯甲基]-4-甲基-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺 Preparation of 2-{5-cyclopropyl-1-[4-(difluoromethoxy)-2,6-difluorobenzyl]-4-methyl-1 H -pyrazol-3-yl}- 5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine

將70 mg 2-(5-環丙基-4-甲基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺1-16-1(0.217 mmol，1.0 eq)溶解於0.52 mL THF中且冷卻至0℃。添加10.4 mg氫化鈉(60%，0.261 mmol，1.2 eq)。攪拌混合物5分鐘，隨後移除冰浴且添加65.2 mg 2-(溴甲基)-5-(二氟甲氧基)-1,3-二氟苯(0.239 mmol，1.1 eq)。在室溫下攪拌反應物4天。再次添加5 mg氫化鈉(60%，0.130 mmol，0.6 eq)及33 mg 2-(溴甲基)-5-(二氟甲氧基)-1,3-二氟苯(0.120 mmol，0.55 eq)。在室溫下攪拌反應物2小時。添加水且用乙酸乙酯萃取水層兩次。以鹽水洗滌所收集之有機層，用矽過濾器乾燥且真空濃縮。藉由急驟層析及HPLC純化粗產物以得到10 mg(0.02 mmol，8%)分析純的目標化合物。 70 mg of 2-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine 1-16 -1 (0.217 mmol, 1.0 eq) was dissolved in 0.52 mL THF and cooled to 0. 10.4 mg of sodium hydride (60%, 0.261 mmol, 1.2 eq) was added. The mixture was stirred for 5 minutes, then the ice bath was removed and 65.2 mg of 2-(bromomethyl)-5-(difluoromethoxy)-l-difluorobenzene (0.239 mmol, 1.1 eq). The reaction was stirred at room temperature for 4 days. Add 5 mg of sodium hydride (60%, 0.130 mmol, 0.6 eq) and 33 mg of 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.120 mmol, 0.55 eq) ). The reaction was stirred at room temperature for 2 hours. Water was added and the aqueous layer was extracted twice with ethyl acetate. The collected organic layers were washed with brine, dried with a EtOAc filter and concentrated in vacuo. The crude product was purified by flash chromatography and HPLC to give 10 mg (0.02 mmol, 8%) of the objective compound.

¹H-NMR(300MHz，氯仿-d)：δ[ppm]=0.64-0.77(m,2H),0.97-1.10(m,2H),1.66-1.81(m,1H),2.26(s,3H),3.94(s,3H),5.40(s,2H),7.03-7.15(m,2H),7.32(t,1H),7.98-8.10(m,2H),8.19(s,1H),8.26-8.36(m,2H),9.20(s,1H)。 ¹ H-NMR (300MHz, CHLOROFORM -d): δ [ppm] = 0.64-0.77 (m, 2H), 0.97-1.10 (m, 2H), 1.66-1.81 (m, 1H), 2.26 (s, 3H) , 3.94 (s, 3H), 5.40 (s, 2H), 7.03-7.15 (m, 2H), 7.32 (t, 1H), 7.98-8.10 (m, 2H), 8.19 (s, 1H), 8.26-8.36 (m, 2H), 9.20 (s, 1H).

實例2-11-1Example 2-11-1 製備4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基1-5-甲氧基嘧啶-4-基}胺基)菸鹼酸 Preparation of 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl 1 - 5-methoxypyrimidin-4-yl}amino)nicotinic acid

向722 mg 4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲酸乙酯2-6-5(1.28 mmol，1.0 eq)於13 mL THF及1.6 mL甲醇中之溶液中添加256 mg氫氧化鈉(6.39 mmol，5.0 eq)。將混合物在室溫下攪拌45分鐘。使用10%檸檬酸水溶液將混合物之pH調整至3.5。過濾所得懸浮液。以水及乙醇洗滌沈澱物且隨後乾燥以得到660 mg呈90%純目標化合物形式之所要產物(1.11 mmol，87%)。 To 722 mg 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl Add ethyl bromo -5-methoxypyrimidin-4-yl}amino)pyridine-3-carboxylate 2-6-5 (1.28 mmol, 1.0 eq) in 13 mL of THF and 1.6 mL of methanol Sodium hydroxide (6.39 mmol, 5.0 eq). The mixture was stirred at room temperature for 45 minutes. The pH of the mixture was adjusted to 3.5 using a 10% aqueous citric acid solution. The resulting suspension was filtered. The precipitate was washed with water and ethanol and then dried to give 660 mg of the desired product (1.11 mmol, 87%).

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.76(d,2 H),1.03-1.14(m,2 H),1.30(t,3 H),1.69-1.84(m,1 H),2.32(s,3 H),4.05(q,5 H),5.38(s,2 H),6.80(d,2 H),8.34(s,1 H),8.45(d,1 H),9.00(s,1 H),9.27(d,1 H),12.59(br,s,1 H)。 ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 0.77 (d, 2 H), 1.03-1.14 (m, 2 H), 1.30 (t, 3 H), 1.69-1.84 (m, 1 H), 2.32 (s, 3 H), 4.05 (q, 5 H), 5.38 (s, 2 H), 6.80 (d, 2 H), 8.34 (s, 1 H), 8.45 (d, 1 H) ), 9.00 (s, 1 H), 9.27 (d, 1 H), 12.59 (br, s, 1 H).

實例2-12-1Example 2-12-1 製備4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺 Preparation of 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]- 5-methoxy-pyrimidin-4-yl} amino) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide

向147 mg 4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸2-11-1(0.27 mmol，1.0 eq)及67.5 mg 2-胺基乙基甲基碸(0.55 mmol，2.0 eq)於2.1 mL DMF中之懸浮液中添加191 μL N,N-二異丙基乙基胺(1.10 mmol，4.0 eq)及157 mg(苯并***-1-基氧基)三吡咯啶基六氟磷酸鏻(0.30 mmol，1.1 eq)。將所得溶液在室溫下攪拌隔夜且之後以水稀釋。藉由過濾收集沈澱物，以水洗滌且乾燥。藉由製備型HPLC純化粗產物，產生40 mg分析純的目標化合物(62 μmol，22%)。 To 147 mg 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl ]-5-Methoxypyrimidin-4-yl}amino)nicotinic acid 2-11-1 (0.27 mmol, 1.0 eq) and 67.5 mg 2-aminoethylmethylhydrazine (0.55 mmol, 2.0 eq) 191 μL of N , N -diisopropylethylamine (1.10 mmol, 4.0 eq) and 157 mg (benzotriazol-1-yloxy)tripyrrolidinyl VI were added to the suspension in 2.1 mL DMF. Bismuth fluorophosphate (0.30 mmol, 1.1 eq). The resulting solution was stirred at room temperature overnight and then diluted with water. The precipitate was collected by filtration, washed with water and dried. The crude product was purified by preparative hp~~~~~~~

¹H-NMR(300MHz,DMSO-d₆)：δ[ppm]=0.71-0.80(m,2 H),1.03-1.11(m,2 H),1.31(t,3 H),1.69-1.81(m,1 H),2.32(s,3 H),3.07(s,3 H),3.43(t,2 H),3.69-3.79(m,2 H),4.00(s,3 H),4.06(q,2 H),5.38(s,2 H),6.80(d,2 H),8.30(s,1 H),8.44(d,1 H),8.85(s,1 H),9.14(d,2 H),11.65(s,1 H)。 ^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.71-0.80 (m, 2 H), 1.03-1.11 (m, 2 H), 1.31 (t, 3 H), 1.69-1.81 ( m,1 H), 2.32 (s, 3 H), 3.07 (s, 3 H), 3.43 (t, 2 H), 3.69-3.79 (m, 2 H), 4.00 (s, 3 H), 4.06 ( q, 2 H), 5.38 (s, 2 H), 6.80 (d, 2 H), 8.30 (s, 1 H), 8.44 (d, 1 H), 8.85 (s, 1 H), 9.14 (d, 2 H), 11.65 (s, 1 H).

生物研究Biological research

可使用以下分析來說明本發明化合物之商業效用。 The following analysis can be used to illustrate the commercial utility of the compounds of the invention.

在所選生物分析中測試實例一或多次。當不止一次進行測試時，數據以平均值或中值形式報導，其中˙平均值(亦稱為算術平均值)表示將所獲得之值的總和除以測試次數所得的值，且˙中值表示在以升序或降序排列時數值群組之中間數字。若數據集之數值數目為奇數，則中值為中間數值。若數據集之數值數目為偶數，則中值為兩個中間數值之算術平均值。 Test the example one or more times in the selected bioanalytical. When testing is conducted more than once, the data is reported as an average or median, where the mean (also known as the arithmetic mean) represents the sum of the values obtained. Divided by the number of tests, and ̇ median represents the middle number of the group of values when sorted in ascending or descending order. If the number of values in the data set is odd, the median is the intermediate value. If the number of values in the data set is even, the median is the arithmetic mean of the two intermediate values.

實例係經一或多次來合成。當不止一次來合成時，來自生物分析之數據表示使用由測試一或多個合成批次獲得之數據集所計算之平均值。 Examples are synthesized by one or more times. When synthesized more than once, the data from the bioanalyze represents the average calculated using the data set obtained by testing one or more synthetic batches.

生物分析1.0：Bioanalysis 1.0: Bub1激酶分析Bub1 kinase analysis

使用時差式螢光能量轉移(TR-FRET)激酶分析來定量本發明中所述之化合物之Bub1-抑制活性，該分析量測與N末端His6標籤一起表現在Hi5昆蟲細胞中且藉由親和性-(Ni-NTA)及尺寸排阻層析法純化的人類Bub1之(重組)催化結構域(胺基酸704-1085)對例如購自Biosyntan(Berlin,Germany)之合成肽生物素-Ahx-VLLPKKSFAEPG(C-末端呈醯胺形式)的磷酸化作用。 Time-division fluorescence energy transfer (TR-FRET) kinase assay was used to quantify the Bub1-inhibitory activity of the compounds described in the present invention, which was shown in Hi5 insect cells along with the N-terminal His6 tag and by affinity. -(Ni-NTA) and Size Exclusion Chromatography Purified Human (Recombinant) Catalytic Domain of Bub1 (Amino Acid 704-1085) to, for example, Synthetic Peptide Biotin-Ahx- purchased from Biosyntan (Berlin, Germany) Phosphorylation of VLLPKKSFAEPG (C-terminal in the form of a guanamine).

在典型分析中，在同一微量滴定盤中重複測試11種不同濃度之每種化合物(0.1 nM、0.33 nM、1.1 nM、3.8 nM、13 nM、44 nM、0.15 μM、0.51 μM、1.7 μM、5.9 μM及20 μM)。為此目的，藉由在透明低容積384孔源微量滴定盤(Greiner Bio-One,Frickenhausen,Germany)中連續稀釋(1：3.4)2 mM儲備液來預先製備100倍濃縮之化合物溶液(於DMSO中)，自其將50 nl化合物轉移至來自相同供應商之黑色低容積測試微量滴定盤中。隨後，向測試盤中之化合物中添加2 μl於含水分析緩衝液[50 mM Tris/HCl pH 7.5、10 mM氯化鎂(MgCl₂)、200 mM氯化鉀(KCl)、1.0 mM二硫蘇糖醇(DTT)、0.1 mM正釩酸鈉、1%(v/v)甘油、0.01%(w/v)牛血清白蛋白(BSA)、0.005%(v/v)Trition X-100(Sigma)、1×完全不含EDTA之蛋白酶抑制劑混合物(Roche)]中之Bub1(視酶批次之活性而定調整Bub1之最終濃度以在分析之線性動態範圍內：一般使用約200 μg/ml)，且將混合物在22℃下培育15 min以使得假定酶-抑制劑複合物在激酶反應開始之前達到預平衡，而該激酶反應係藉由添加3 μl三磷酸腺苷(ATP，10 μM最終濃度)與肽受質(1 μM最終濃度)之1.67倍濃縮溶液(在分析緩衝液中)來起始。將所得混合物(5 μl最終體積)在22℃下培育60 min，且藉由添加5 μl EDTA水溶液(50 mM EDTA，於100 mM HEPES(pH 7.5)及0.2%(w/v)牛血清白蛋白中)來終止反應，該溶液亦含有TR-FRET偵測試劑(0.2 μM抗生蛋白鏈菌素-XL665[Cisbio Bioassays,Codolet,France]及1 nM抗磷酸絲胺酸抗體[Merck Millipore，目錄號# 35-001]及0.4 nM LANCE EU-W1024標記之抗小鼠IgG抗體[Perkin-Elmer，產品號AD0077，或者可使用來自Cisbio Bioassays之經鋱-穴狀化合物標記之抗小鼠IgG抗體])。將經終止之反應混合物在22℃下進一步培育1 h以使得可在肽與偵測試劑之間形成複合物。隨後，藉由量測自識別磷酸絲胺酸殘基之Eu螯合抗體複合物至與肽之生物素部分結合之抗生蛋白鏈菌素-XL665的共振能量轉移來評估產物之量。為此目的，在TR-FRET培養盤閱讀器(例如Rubystar或Pherastar(兩者均來自BMG Labtechnologies,Offenburg,Germany)或Viewlux(Perkin-Elmer))中量測在330-350 nm下激發之後在620 nm及665 nm下之螢光發射，且將發射比率(665 nm/622 nm)視作對磷酸化受質之量的指示。使用兩組對照孔(各組一般為32個孔)來校正高-(=無抑制劑之酶反應=0%=最小抑制)及低-(=無酶之所有分析組分=100%=最大抑制)Bub1活性之數據。藉由使經校正之抑制數據與4參數邏輯方程式(最小值、最大值、IC₅₀、希爾值(Hill)；Y=Max+(Min-Max)/(1+(X/IC₅₀)希爾值))擬合來計算IC₅₀值。 In a typical assay, 11 different concentrations of each compound (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 μM, 0.51 μM, 1.7 μM, 5.9) were repeated in the same microtiter plate. μM and 20 μM). For this purpose, a 100-fold concentrated solution of the compound (in DMSO) was prepared in advance by serial dilution (1:3.4) of 2 mM stock in a transparent low volume 384-well source microtiter plate (Greiner Bio-One, Frickenhausen, Germany). Medium), from which 50 nl of the compound was transferred to a black low volume test microtiter plate from the same supplier. Subsequently, 2 μl of the assay solution was added to the aqueous assay buffer [50 mM Tris/HCl pH 7.5, 10 mM magnesium chloride (MgCl ₂ ), 200 mM potassium chloride (KCl), 1.0 mM dithiothreitol). (DTT), 0.1 mM sodium orthovanadate, 1% (v/v) glycerol, 0.01% (w/v) bovine serum albumin (BSA), 0.005% (v/v) Trition X-100 (Sigma), Bub1 in 1× completely free of EDTA protease inhibitor cocktail (Roche)] (adjust the final concentration of Bub1 depending on the activity of the enzyme batch to be within the linear dynamic range of the assay: generally about 200 μg/ml) And the mixture was incubated at 22 ° C for 15 min to allow the putative enzyme-inhibitor complex to reach pre-equilibration before the start of the kinase reaction by adding 3 μl of adenosine triphosphate (ATP, 10 μM final concentration) to the peptide. Start with a 1.67 times concentrated solution (in assay buffer) of the mass (1 μM final concentration). The resulting mixture (5 μl final volume) was incubated at 22 °C for 60 min, and by adding 5 μl of EDTA aqueous solution (50 mM EDTA, 100 mM HEPES (pH 7.5) and 0.2% (w/v) bovine serum albumin In order to terminate the reaction, the solution also contains TR-FRET detection reagent (0.2 μM streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM anti-phosphoric acid antibody [Merck Millipore, Catalog # 35-001] and 0.4 nM LANCE EU-W1024-labeled anti-mouse IgG antibody [Perkin-Elmer, product number AD0077, or anti-mouse IgG antibody labeled with sputum-cryptate compound from Cisbio Bioassays]). The terminated reaction mixture was further incubated at 22 °C for 1 h to allow complex formation between the peptide and the detection reagent. Subsequently, the amount of the product was evaluated by measuring the resonance energy transfer from the Eu chelate antibody complex recognizing the phosphoserine residue to the streptavidin-XL665 bound to the biotin moiety of the peptide. For this purpose, measurements were taken at 620 after excitation at 330-350 nm in a TR-FRET plate reader (eg Rubystar or Pherastar (both from BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). Fluorescence emission at nm and 665 nm, and the emission ratio (665 nm / 622 nm) is taken as an indication of the amount of phosphorylation. Two sets of control wells (typically 32 wells in each group) were used to correct for high- (= no inhibitory enzyme response = 0% = minimal inhibition) and low - (= no enzymes for all analytical components = 100% = maximum Inhibition of data for Bub1 activity. By making the corrected suppression data and the 4-parameter logic equation (minimum, maximum, IC ₅₀ , Hill (Hill); Y=Max+(Min-Max)/(1+(X/IC ₅₀ ) Hill Value)) Fit to calculate the IC ₅₀ value.

生物分析2.0：Bioanalysis 2.0: 增殖分析：Proliferation analysis:

視各自的細胞株之生長速率而定，在96孔多滴定盤中將經培養之腫瘤細胞(細胞係自ATCC定購，但HeLa-MaTu及HeLa-MaTu-ADR除外，其係自EPO-GmbH,Berlin定購)以每孔1000至5000個細胞之密度接種於200 μL其各自補充有10%胎牛血清之生長培養基中。24小時之後，將一個培養盤(零點培養盤)之細胞用晶體紫(參見下文)染色，同時將其他培養盤之培養基以新鮮培養基(200 μL)置換，向其中添加各種濃度(0 μM，以及0.001 μM至10 μM範圍內；溶劑二甲亞碸之最終濃度為0.5%)之測試物質。在測試物質存在下將細胞培育4天。藉由用晶體紫染色細胞來測定細胞增殖：藉由在室溫下每個量測點添加20 μL 11%之戊二酸醛溶液來將細胞固定15分鐘。將固定細胞用水洗滌三個循環之後，在室溫下乾燥培養盤。藉由每個量測點添加100 μL 0.1%晶體紫溶液(pH 3.0)來使細胞染色。將染色細胞用水洗滌三個循環之後，在室溫下乾燥培養盤。藉由每個量測點添加100 μL 10%乙酸溶液來溶解染料。藉由在595 nm波長下之測光法來測定吸收。藉由針對零點培養盤之吸收值(=0%)與未處理(0 μm)細胞之吸收值(=100%)來校正量測值而計算細胞數目之變化(以百分比計)。藉助於4參數擬合來測定IC₅₀值。 Depending on the growth rate of the respective cell lines, cultured tumor cells are plated in 96-well multi-titration plates (cell lines are ordered from ATCC, except HeLa-MaTu and HeLa-MaTu-ADR, which are from EPO-GmbH, Berlin ordered) at a density of 1000 to 5000 cells per well in 200 μL of growth medium supplemented with 10% fetal calf serum. After 24 hours, cells of one plate (zero plate) were stained with crystal violet (see below) while the medium of the other plates was replaced with fresh medium (200 μL), and various concentrations (0 μM, and Test substance in the range of 0.001 μM to 10 μM; the final concentration of the solvent dimethyl sulfoxide is 0.5%). The cells were incubated for 4 days in the presence of the test substance. Cell proliferation was determined by staining cells with crystal violet: cells were fixed for 15 minutes by adding 20 μL of 11% glutaraldehyde solution at each measurement point at room temperature. After the fixed cells were washed with water for three cycles, the plates were dried at room temperature. Cells were stained by adding 100 μL of 0.1% crystal violet solution (pH 3.0) to each measurement point. After the stained cells were washed with water for three cycles, the plates were dried at room temperature. The dye was dissolved by adding 100 μL of 10% acetic acid solution to each measurement point. Absorption was measured by photometry at 595 nm. The change in cell number (in percentage) was calculated by correcting the measured value for the absorption value of the zero-point culture plate (=0%) and the absorption value of the untreated (0 μm) cell (=100%). IC ₅₀ values were determined by means of a 4 parameter fit.

下表給出本發明實例在生物分析1及2中之數據： The table below gives the data for the examples of the invention in bioassays 1 and 2:

如在生物分析2.0下所述測定本發明化合物對HeLa-MaTu-ADR、MCF7、NCI-H460、DU145、Caco-2及B16F10細胞增殖之抑制作用。所有IC₅₀(在50%最大作用下之抑制濃度)值均以[mol/L]指示。 The inhibitory effects of the compounds of the invention on the proliferation of HeLa-MaTu-ADR, MCF7, NCI-H460, DU145, Caco-2 and B16F10 cells were determined as described under Bioassay 2.0. All IC ₅₀ (inhibitory concentrations at 50% maximal effect) values are indicated in [mol/L].

因此，本發明之另一態樣為如技術方案第1項至第5項之化合物且尤其為如上表指定之化合物用於治療子宮頸癌、NSCLC、***癌、結腸癌及黑素瘤之用途。 Thus, another aspect of the invention is the use of a compound according to items 1 to 5 of the technical means and in particular for the treatment of cervical cancer, NSCLC, prostate cancer, colon cancer and melanoma, as specified in the above table. .

Claims

一種式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³彼此獨立地為氫、1-6C-烷氧基、鹵素、2-6C-烯基、3-6C-環烷基、1-6C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-6C-烷氧基，視情況經以下取代：(c1)1至2個OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)-S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為(a)氫；(b)2-6C-羥烷基； (c)，其中*為連接點； (d)-C(O)-(1-6C-烷基)；(e)-C(O)-(1-6C-伸烷基)-O-(1-6C-烷基)；(f)-C(O)-(1-6C-伸烷基)-O-(1-6C-伸烷基)-O-(1-6C-烷基)，R⁶為氫、鹵素、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為氫、1-6C-烷基、2-6C-烯基、1-6C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-6C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-6C-烷基，R¹¹、R¹²彼此獨立地為氫、1-6C-烷基、2-6C-羥烷基或(1-4C-烷基)-SO₂-(1-4C-烷基)， R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 a compound of formula (I), Wherein R ¹ /R ² are independently of each other hydrogen, halogen or phenyl-S-, and R ^{3 is} independently of each other hydrogen, 1-6C-alkoxy, halogen, 2-6C-alkenyl, 3-6C-ring Alkyl, 1-6C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxy; (c) 1-6C-alkoxy, optionally Substituted by: (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; (c4) 1-4C-alkyl-S(O)-; (c5) 1-4C-alkyl-S(O) ₂ -; (c6)-S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is (a) hydrogen; (b) 2-6C-hydroxyalkyl; c) Where * is the point of attachment; (d) -C(O)-(1-6C-alkyl); (e)-C(O)-(1-6C-alkylene)-O-(1-6C -alkyl); (f)-C(O)-(1-6C-alkylene)-O-(1-6C-alkylene)-O-(1-6C-alkyl), R ⁶ is Hydrogen, halogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is hydrogen, 1-6C-alkyl, 2-6C-alkenyl, 1- 6C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen or 1-6C-alkyl, m is 1-4, and R ⁹ and R ¹⁰ are independently hydrogen or 1- 6C-alkyl, R ¹¹ and R ¹² are each independently hydrogen, 1-6C-alkyl, 2-6C-hydroxyalkyl or (1-4C-alkyl)-SO ₂ -(1-4C-alkyl R ¹³ is hydrogen or 1-4C-alkyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N-oxide, tautomer or stereoisomer Salt.

如請求項1之式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³獨立地為氫、鹵素、1-4C-烷氧基、3-6C-環烷基、1-4C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-4C-烷氧基，視情況經以下取代：(c1)1至2個OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)S(O)₂NR⁹R¹⁰； (d)，其中*為連接點； (e)，其中*為連接點； (f)氰基； (g)1-4C-烷基-S(O)₂-，R⁵為氫，R⁶為氫、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為2-4C-烯基、1-4C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-4C-烷基，m為1-4，R⁹、R¹⁰彼此獨立地為氫或1-4C-烷基，R¹¹、R¹²彼此獨立地為氫、1-4C-烷基、2-6C-羥烷基或(1-4C-烷基)-SO₂-(1-4C-烷基)，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 A compound of the formula (I) according to claim 1, wherein R ¹ /R ² are independently of each other hydrogen, halogen or phenyl-S-, and R ^{3 is} independently hydrogen, halogen, 1-4C-alkoxy, 3- 6C-cycloalkyl, 1-4C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxy; (c) 1-4C-alkoxy , as the case may be substituted by: (c1) 1 to 2 OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; (c4) 1-4C-alkyl-S (O --(c5)1-4C-alkyl-S(O) ₂ -; (c6)S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is hydrogen, R ⁶ is hydrogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is 2-4C-alkenyl, 1-4C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen Or 1-4C-alkyl, m is 1-4, R ⁹ and R ¹⁰ are each independently hydrogen or 1-4C-alkyl, and R ¹¹ and R ¹² are each independently hydrogen, 1-4C-alkyl, 2-6C-hydroxyalkyl or (1-4C-alkyl)-SO ₂ -(1-4C-alkyl), R ¹³ is hydrogen or 1-4C-alkyl, or an N-oxide of the compound, a salt, tautomer or stereoisomer or a salt of the N-oxide, tautomer or stereoisomer.

如請求項1之式(I)化合物，其中R¹/R²彼此獨立地為氫、鹵素或苯基-S-，R³獨立地為氫、鹵素、1-4C-烷氧基、3-6C-環烷基、1-4C-鹵烷氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)1-4C-烷氧基，視情況經以下取代： (c1)OH；(c2)NR⁹R¹⁰；(c3)1-4C-烷基-S-；(c4)1-4C-烷基-S(O)-；(c5)1-4C-烷基-S(O)₂-；(c6)S(O)₂NR⁹R¹⁰；(d)，其中*為連接點； (e)，其中*為連接點； (f)氰基；(g)1-4C-烷基-S(O)₂-，R⁵為氫，R⁶為氫、氰基、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH，R⁷為2-4C-烯基、1-4C-烷氧基、3-6C-環烷基或NR⁹R¹⁰，R⁸為氫或1-4C-烷基，m為1，R⁹、R¹⁰彼此獨立地為氫或1-4C-烷基，R¹¹、R¹²彼此獨立地為氫、1-4C-烷基、2-4C-羥烷基或(1-4C-烷基)-SO₂-(1-4C-烷基)，R¹³為氫或1-4C-烷基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 A compound of the formula (I) according to claim 1, wherein R ¹ /R ² are independently of each other hydrogen, halogen or phenyl-S-, and R ^{3 is} independently hydrogen, halogen, 1-4C-alkoxy, 3- 6C-cycloalkyl, 1-4C-haloalkoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxy; (c) 1-4C-alkoxy , as the case may be substituted by: (c1) OH; (c2) NR ⁹ R ¹⁰ ; (c3) 1-4C-alkyl-S-; (c4) 1-4C-alkyl-S(O)-; C5) 1-4C-alkyl-S(O) ₂ -; (c6) S(O) ₂ NR ⁹ R ¹⁰ ; (d) Where * is the connection point; (e) Wherein * is the point of attachment; (f) cyano; (g) 1-4C-alkyl-S(O) ₂ -, R ⁵ is hydrogen, R ⁶ is hydrogen, cyano, C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is 2-4C-alkenyl, 1-4C-alkoxy, 3-6C-cycloalkyl or NR ⁹ R ¹⁰ , R ⁸ is hydrogen Or 1-4C-alkyl, m is 1, R ⁹ and R ¹⁰ are each independently hydrogen or 1-4C-alkyl, and R ¹¹ and R ¹² are independently of each other hydrogen, 1-4C-alkyl, 2- 4C-hydroxyalkyl or (1-4C-alkyl)-SO ₂ -(1-4C-alkyl), R ¹³ is hydrogen or 1-4C-alkyl, or the N-oxide, salt of the compound, A tautomer or a stereoisomer or a salt of the N-oxide, tautomer or stereoisomer.

如請求項1之式(I)化合物，其中R¹/R²彼此獨立地為氫、氟、氯或苯基-S-，R³為氫、氟、甲氧基、乙氧基、環丙基、二氟甲氧基、2,2,2-三氟乙氧基或C(O)OH，n為1-3，R⁴為(a)氫；(b)羥基；(c)視情況經S(O)₂NH₂取代之甲氧基；(d)視情況經羥基或-N(CH₃)₂、-SCH₃、-S(O)CH₃或-S(O)₂CH₃取代之乙氧基；(e)經-SCH₃、-S(O)CH₃或-S(O)₂CH₃取代之丙氧基； (f)，其中*為連接點； (g)，其中*為連接點； (h)氰基；(i)-S(O)₂CH₃；(k)-S(O)₂CH(CH₃)₂，R⁵為氫，R⁶為氫、氰基、C(O)NH₂、C(O)NR¹¹R¹²、C(O)OR¹³或C(O)NHOH， R⁷為乙烯基、甲氧基、乙氧基、環丙基或-N(CH₃)₂，R⁸為氫、甲基或乙基，m為1，R⁹、R¹⁰為氫或甲基，R¹¹為氫，R¹²為甲基、-CH₂-CH₂-OH、-CH₂-CH₂-SO₂-CH₃，R¹³為氫或乙基，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 A compound of the formula (I) according to claim 1, wherein R ¹ /R ² are independently of each other hydrogen, fluorine, chlorine or phenyl-S-, and R ³ is hydrogen, fluorine, methoxy, ethoxy, cyclopropane Base, difluoromethoxy, 2,2,2-trifluoroethoxy or C(O)OH, n is 1-3, R ⁴ is (a) hydrogen; (b) hydroxyl; (c) optionally a methoxy group substituted with S(O) ₂ NH ₂ ; (d) optionally via a hydroxy group or -N(CH ₃ ) ₂ , -SCH ₃ , -S(O)CH ₃ or -S(O) ₂ CH ₃ a substituted ethoxy group; (e) a propoxy group substituted with -SCH ₃ , -S(O)CH ₃ or -S(O) ₂ CH ₃ ; (f) Where * is the connection point; (g) Where * is the point of attachment; (h) cyano; (i)-S(O) ₂ CH ₃ ; (k)-S(O) ₂ CH(CH ₃ ) ₂ , R ⁵ is hydrogen and R ⁶ is hydrogen , cyano, C(O)NH ₂ , C(O)NR ¹¹ R ¹² , C(O)OR ¹³ or C(O)NHOH, R ⁷ is vinyl, methoxy, ethoxy, cyclopropyl Or -N(CH ₃ ) ₂ , R ⁸ is hydrogen, methyl or ethyl, m is 1, R ⁹ , R ¹⁰ are hydrogen or methyl, R ¹¹ is hydrogen, R ¹² is methyl, -CH ₂ - CH ₂ -OH, -CH ₂ -CH ₂ -SO ₂ -CH ₃ , R ¹³ is hydrogen or ethyl, or an N-oxide, a salt, a tautomer or a stereoisomer of the compound or the N- a salt of an oxide, a tautomer or a stereoisomer.

如請求項1之式(I)化合物，其係選自由以下各物組成之群：2-[1-(4-乙氧基-2,6-二氟苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-乙氧基-1-(2-氟苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-環丙基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-(1-苯甲基-5-乙烯基-1H-吡唑-3-基)-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲腈；2-[5-環丙基-1-(4-甲氧基苯甲基)-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2,6-二氯苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(2-氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[1-(2,6-二氯苯甲基)-5-甲氧基-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(二甲胺基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；{3-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]氧雜環丁烷-3-基}甲醇；2-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)乙醇；4-({2-[1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)吡啶-3-甲醯胺；2,4-二氯-3-({5-環丙基-3-[5-甲氧基-4-(吡啶-4-基胺基) 嘧啶-2-基]-4-甲基-1H-吡唑-1-基}甲基)苯甲酸；2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基硫基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；1-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲磺醯胺；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體1；5-[({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-基}氧基)甲基]吡咯啶-2-酮對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲基硫基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；[3-({[2-{5-環丙基-1-[4-乙氧基-2-氟-6-(苯基硫基)苯甲基]-4-甲基-1H-吡唑-3-基}-4-(吡啶-4-基胺基)嘧啶-5-基]氧基}甲基)氧雜環丁烷-3-基]甲醇；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺； 4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼醯胺；2-[5-環丙基-1-(4-甲氧基苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-(二甲胺基)-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-4-(吡啶-4-基胺基)嘧啶-5-甲腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼腈；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼腈；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-(甲磺醯基)-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-(異丙磺醯基)-N-(吡啶-4-基)嘧啶-4-胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸乙酯；2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺； 4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸乙酯；2-[5-環丙基-1-(4-環丙基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺對映異構體1；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲基亞磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺對映異構體2；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[3-(甲基亞磺醯基)丙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-[2-(甲磺醯基)乙氧基]-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-1-[4-(二氟甲氧基)-2,6-二氟苯甲基]-4-甲基-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺；2-{5-環丙基-4-甲基-1-[2,3,5,6-四氟-4-(2,2,2-三氟乙氧基)苯甲基]-1H-吡唑-3-基}-5-甲氧基-N-(吡啶-4-基)嘧啶-4-胺； 4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)菸鹼酸；4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼酸；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-甲基菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-(2-羥乙基)菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]嘧啶-4-基}胺基)-N-[2-(甲磺醯基)乙基]菸鹼醯胺；4-({2-[5-環丙基-1-(4-乙氧基-2,6-二氟苯甲基)-4-甲基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)-N-羥基菸鹼醯胺；4-({2-[4-乙基-1-(2-氟苯甲基)-5-甲氧基-1H-吡唑-3-基]-5-甲氧基嘧啶-4-基}胺基)菸鹼醯胺，或該化合物之N-氧化物、鹽、互變異構體或立體異構體或該N-氧化物、互變異構體或立體異構體之鹽。 A compound of the formula (I) according to claim 1 which is selected from the group consisting of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy 4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino)- 1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[1-(2 -fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5- Ethoxy-1-(2-fluorobenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-( 1-Benzyl-5-cyclopropyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-(1-benzene Methyl-5-vinyl-1 H -pyrazol-3-yl)-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-({2-[1-( 2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile; 2-[5 -cyclopropyl-1-(4-methoxybenzyl)-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(2,6-dichlorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridine- 4-yl)pyrimidine-4-amine ;2-[5-cyclopropyl-1-(2-fluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridine-4- Pyrimidine-4-amine; 2-[1-(2,6-dichlorobenzyl)-5-methoxy-4-methyl-1 H -pyrazol-3-yl]-5- Oxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl -1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxyl) -2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5 -cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-(dimethylamino) Ethoxy]-N-(pyridin-4-yl)pyrimidine-4-amine; {3-[({2-[5-cyclopropyl-1-(4-ethoxy-2,6-di) Fluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl]oxetane -3-yl}methanol; 2-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole -3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)ethanol; 4-({2-[1-(2-fluorobenzyl)-5-methoxy yl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) pyridine-3- Amine; 2,4-dichloro-3-({5-cyclopropyl-3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-4-methyl -1 H -pyrazol-1-yl}methyl)benzoic acid; 2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenylthio)benzyl ]-4-methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidine-5-ol; 2-[5-cyclopropyl-1-(4-ethyl) methyl-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- [2- (methylthio) ethoxy] - N - (pyridin- 4-yl)pyrimidine-4-amine; 1-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methanesulfonamide; 5-[({2-[5-cyclopropyl-1 -(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5- })oxy)methyl]pyrrolidin-2-one enantiomer 1;5-[({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluoro) Benzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl}oxy)methyl]pyrrolidin-2-one Enantiomer 2; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl ] -5- [3- (methylthio) propoxy] - N - (pyridin-4 Pyrimidine-4-amine; [3-({[2-{5-cyclopropyl-1-[4-ethoxy-2-fluoro-6-(phenylthio))benzyl]-4 -methyl-1 H -pyrazol-3-yl}-4-(pyridin-4-ylamino)pyrimidin-5-yl]oxy}methyl)oxetan-3-yl]methanol; 2-[5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[3- (methanesulfonamide acyl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({2- [5-cyclopropyl-1- (4-ethoxy -2, 6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinium amide; 4-({2- [5-Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino Nicotine decylamine; 2-[5-cyclopropyl-1-(4-methoxybenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-(dimethylamino)-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl -1 H -pyrazol-3-yl]-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxyl) -2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidine-5-carbonitrile; 4-( {2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl) 4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic nitrile; 4-({2-[5-cyclopropyl-1- (4-Ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotine Ethyl acetate; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3- Benzopyrimidin-4-yl}amino)nicotinic nitrile; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H - pyrazol-3-yl] -5- (methanesulfonamide acyl) - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5-cyclopropyl-1- (4-ethoxyphenyl methyl-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- (isopropyl sulfonylurea yl) - N - (pyridin-4-yl) pyrimidin - 4-amine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3- Ethyl pyrimidin-4-yl}amino) nicotinic acid ethyl ester; 2-[4-ethyl-1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazole-3- 5-yloxy- N- (pyridin-4-yl)pyrimidine-4-amine; 4-({2-[4-ethyl-1-(2-fluorobenzyl)-5-) Oxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) nicotinic acid ethyl ester; 2-[5-cyclopropyl-1-(4-cyclopropane) Base-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl] -5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl) -4-methyl -1 H - pyrazol-3-yl] -5- [2- (methylsulfinyl acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2- (methylsulfinyl acyl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine enantiomer 1; 2- [5-cyclopropyl-1- (4-ethoxyphenyl methyl-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5- [2- (methylsulfinyl acyl) ethoxy] - N - ( Pyridin-4-yl)pyrimidine-4-amine enantiomer 2; 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl yl -1 H - pyrazol-3-yl] -5- [3- (methylsulfinyl acyl) propoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- [5 -cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-[2-(methylsulfonate) yl) ethoxy] - N - (pyridin-4-yl) pyrimidin-4-amine; 2- {5-cyclopropyl-1- [4- (difluoromethoxy) -2,6-difluoro Benzyl]-4-methyl-1 H -pyrazol-3-yl}-5-methoxy- N- (pyridin-4-yl)pyrimidine-4-amine; 2-{5-cyclopropyl -4-methyl-1-[2,3,5,6-tetrafluoro-4-(2,2,2-three Ethoxy) benzyl] -1 H - pyrazol-5-methoxy-3-yl} - N - (pyridin-4-yl) pyrimidin-4-amine; 4 - ({2- [5- Cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl }amino)nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyridyl Zin-3-yl]pyrimidin-4-yl}amino)nicotinic acid; 4-({2-[4-ethyl-1-(2-fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinic acid; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2) , 6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - [2- (methyl sulfonylurea Ethyl]nicotine decylamine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]pyrimidin-4-yl}amino) -N -methylnicotinium amide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2) , 6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] -5-methoxy-pyrimidin-4-yl} amino) - N - (2- hydroxyethyl) Nicotinamide; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazole-3 - yl] amino} pyrimidin-4-yl) - N - (2- hydroxyethyl) nicotinic XI ; 4 - ({2- [5-cyclopropyl-1- (4-ethoxy-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] - 5-methoxy-pyrimidin-4-yl} amino) - N - [2- (acyl methanesulfonamide) ethyl] niacinamide; 4 - ({2- [5-cyclopropyl-1- ( 4-ethoxy-2,6-difluorophenyl) -4-methyl -1 H - pyrazol-3-yl] amino} pyrimidin-4-yl) - N - [2- (methanesulfonamide Mercapto)ethyl]nicotine decylamine; 4-({2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino) -N -hydroxynicotinium amide; 4-({2-[4-ethyl-1-(2-) Fluorobenzyl)-5-methoxy-1 H -pyrazol-3-yl]-5-methoxypyrimidin-4-yl}amino)nicotinium amide, or N-oxide of the compound a salt, a tautomer or a stereoisomer or a salt of the N-oxide, tautomer or stereoisomer.

一種如請求項1至5中任一項之通式(I)之化合物的用途，其係用於製造用以治療或預防疾病之藥物。 A use of a compound of the formula (I) according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment or prevention of a disease.

如請求項6之通式(I)之化合物的用途，其中該等疾病為對誘導細胞凋亡起反應之過度增殖性疾病及/或病症。 The use of a compound of the formula (I) according to claim 6, wherein the diseases are hyperproliferative diseases and/or conditions which are responsive to induction of apoptosis.

如請求項7之通式(I)之化合物的用途，其中該等對誘導細胞凋亡起反應之過度增殖性疾病及/或病症為血液腫瘤、實體腫瘤及/或其轉移。 The use of a compound of the formula (I) according to claim 7, wherein the hyperproliferative diseases and/or conditions which are responsive to induction of apoptosis are hematological tumors, solid tumors and/or metastasis thereof.

如請求項8之通式(I)之化合物的用途，其中該過度增殖性疾病為子宮頸癌、NSCLC、***癌、結腸癌及黑素瘤。 The use of a compound of the formula (I) according to claim 8, wherein the hyperproliferative diseases are cervical cancer, NSCLC, prostate cancer, colon cancer and melanoma.

一種醫藥組合物，其包含至少一種如請求項1至5中任一項之通式(I)之化合物以及至少一種醫藥學上可接受之助劑。 A pharmaceutical composition comprising at least one compound of the formula (I) according to any one of claims 1 to 5 and at least one pharmaceutically acceptable adjuvant.

如請求項10之組合物，其係用於治療血液腫瘤、實體腫瘤及/或其轉移。 The composition of claim 10 for use in the treatment of hematological tumors, solid tumors and/or metastases thereof.

一種組合，其包含一或多種選自如請求項1至5中任一項之通式(I)之化合物的第一活性成分及一或多種選自化學療法抗癌劑及標靶特異性抗癌劑之第二活性成分。 A combination comprising one or more first active ingredients selected from the compounds of formula (I) according to any one of claims 1 to 5 and one or more selected from the group consisting of chemotherapeutic anticancer agents and target-specific anticancer The second active ingredient of the agent.