JP2010529195A - Imidazopyrazine as an inhibitor of protein kinase - Google Patents

Abstract

The present invention, in its many embodiments, is a novel class of imidazopyrazine compounds as inhibitors of protein and / or Aurora kinase, methods of preparing such compounds, pharmaceuticals comprising one or more such compounds. Compositions, methods of preparing pharmaceutical formulations comprising one or more such compounds, and one or more diseases associated with protein kinases or Aurora kinases using such compounds or pharmaceutical compositions A method of treatment, prevention, inhibition or amelioration is provided.

Description

  The present invention relates to imidazo [1,2-a] pyrazine compounds useful as inhibitors, modulators or modifiers of protein kinases, pharmaceutical compositions containing the compounds, and the compounds and compositions. Relates to therapeutic methods for treating diseases such as cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases. The present invention is particularly useful as an Aurora kinase inhibitor.

  Protein kinases are a family of enzymes that catalyze the phosphorylation of proteins, particularly the hydroxyl group of certain tyrosine, serine, or threonine residues in proteins. Protein kinases are very important in the regulation of a wide variety of cellular processes including metabolism, cell proliferation, cell differentiation, and cell survival. Uncontrolled growth is a hallmark of cancer cells, and two methods—deregulating the cell division cycle in one of two ways—overactivating the stimulating gene or inactivating the inhibitory gene. Can be revealed. Protein kinase inhibitors, modulators, or modifiers include cyclin dependent kinases (CDK), mitogen activated protein kinases (MAPK / ERK), glycogen synthase kinase 3 (GSK3beta), checkpoint kinases (Chk) (eg, , CHK-1, CHK-2, etc.), AKT kinase, JNK and other kinase functions are changed. Examples of protein kinase inhibitors are described in WO 02/22610 A1 and Mettey et al. Med. Chem. (2003) 46 222-236.

  Cyclin-dependent kinases are serine / threonine-dependent protein kinases, which are the driving forces behind cell cycle and cell growth. Misregulation of CDK function occurs frequently in many important solid tumors. Individual CDKs, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, etc., play distinct roles in cell cycle progression and are either G1 phase, S phase, or G2M phase enzymes Can be classified as CDK2 and CDK4 are of particular interest. This is because these activities are frequently misregulated in a wide variety of human cancers. CDK2 activity is required for progression from the G1 phase to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint. While checkpoints serve to maintain the proper order of cell cycle events and cause cells to respond to injury or proliferation signals, loss of proper checkpoint control in cancer cells contributes to tumor development. The CDK2 pathway affects tumor development at the level of tumor suppressor function (eg, p52, RB, and p27) and oncogene activation (cyclin E). Many reports show that both CDK2 coactivator, cyclin E, and CDK2 inhibitor, p27, are breast cancer, colon cancer, non-small cell lung cancer, gastric cancer, prostate cancer, bladder cancer, non-Hodgkin lymphoma, respectively. It has been demonstrated that it is either overexpressed or underexpressed in ovarian cancer and other cancers. These changes in expression have been shown to correlate with increased CDK2 activity levels and poor overall survival. This observation makes CDK2 and its regulatory pathways a powerful target for the development of cancer therapies.

  A number of adenosine 5'-triphosphate (ATP) -competing organic small molecules as well as peptides have been reported in the literature as CDK inhibitors for potential treatment of cancer. US Pat. No. 6,413,974, column 1, line 23 to column 15, line 10 provides a good description of various CDKs and their relevance to various types of cancer. Flavopyridol (shown below) is a non-selective CDK inhibitor currently in human clinical trials. A. M.M. Senderowicz et al. Clin. Oncol. (1998) 16, 2986-2999.

他の公知のＣＤＫの阻害剤には、例えば、オロモウシン（Ｊ．Ｖｅｓｅｌｙら、Ｅｕｒ．Ｊ．Ｂｉｏｃｈｅｍ．，（１９９４）２２４，７７１−７８６）およびロスコビチン（Ｉ．Ｍｅｉｊｅｒら、Ｅｕｒ．Ｊ．Ｂｉｏｃｈｅｍ．，（１９９７）２４３，５２７−５３６）が含まれる。米国特許第６，１０７，３０５号は、ＣＤＫ阻害剤として、特定のピラゾロ［３，４−ｂ］ピリミジン化合物を記載している。’３０５特許からの例示的な化合物は

Other known CDK inhibitors include, for example, olomoucine (J. Vesely et al., Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al., Eur. J. Biochem. (1997) 243, 527-536). US Pat. No. 6,107,305 describes certain pyrazolo [3,4-b] pyrimidine compounds as CDK inhibitors. Exemplary compounds from the '305 patent are

である。

It is.

  K. S. Kim et al. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162 disclose certain aminothiazole compounds as CDK inhibitors. Imidazopyrazine is known. For example, US Pat. No. 6,919,341 (the disclosure of which is incorporated herein by reference) and US Patent Application Publication No. 2005/0009832 disclose various imidazopyrazines. The following are also referred to: International Publication No. 2005/047290; US Patent Application Publication No. 2005/095616; International Publication No. 2005/039393; International Publication No. 2005/019220; International Publication No. 2004/072081; International Publication No. 2005/014599; International Publication No. 2005/009354; International Publication No. 2005/005429; International Publication No. 2005/085252; US Patent Application Publication No. 2005/009832; US Patent Application Publication No. 2004/220189. International Publication No. 2004/074289; International Publication No. 2004/026877; International Publication No. 2004/026310; International Publication No. 2004/022562; International Publication No. 2003/088944; International Publication No. 2003/084959; Release No. 2003/051346; U.S. Patent Application Publication No. 2003/022898; WO 2002/060492; WO 2002/060386; WO 2002/028860; JP (1986) 61-057587; J. Burke et al. Biological Chem. , Vol. 278 (3), 1450-1456 (2003); Bondavali et al. Med. Chem. , Vol. 45 (22), 4875-4887 (2002).

  Patent Document 1 (published on November 4, 2004) describing a kinase inhibitor; Patent Document 2 (published on January 13, 2005); Patent Document 3 (published on April 20, 2006), and cyclin dependence Reference is also made to U.S. Pat. No. 6,057,056 (published May 18, 2006) which describes imidazopyrazines as sex kinase inhibitors. In addition, Patent Document 5 (published May 24, 2007) describes imidazopyrazine as a protein kinase inhibitor having the following structure.

  Chemical formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、エステル、もしくはプロドラッグであって、ここで：
ＲはＨ、ＣＮ、−ＮＲ^５Ｒ^６、シクロアルキル、シクロアルケニル、ヘテロシクレニル、ヘテロアリール、−Ｃ（Ｏ）ＮＲ^５Ｒ^６、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^６、ヘテロシクリル、（ＣＨ_２）_１−３ＮＲ^５Ｒ^６で置換されたヘテロアリール、非置換アルキル、または同じかもしくは異なり得る１個以上の部分で置換され、各部分が−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択されるアルキルであり；
Ｒ^１はＨ、ハロ、アリール、またはヘテロアリールであり、ここで、前記アリールおよびヘテロアリールの各々は、非置換であるか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−ＣＨ_２ＯＲ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^６、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒にヘテロシクリル環を形成する）、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、および−ＯＲ^５からなる群より独立して選択され；
Ｒ^２はＨ、ハロ、アリール、アリールアルキル、またはヘテロアリールであり、ここで、前記アリール、アリールアルキル、およびヘテロアリールの各々は、非置換であるか、または同じかもしくは異なり得る１個以上の部分で任意に独立して置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒にヘテロシクリル環を形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；
Ｒ^３はＨ、アルキル、シクロアルキル、ヘテロシクリル、アリール、またはヘテロアリールであり、ここで：
−Ｒ^３について上記に示した前記アルキルは、非置換であるか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、−ＯＲ^５、アルコキシ、ヘテロアリール、および−ＮＲ^５Ｒ^６からなる群より独立して選択され；
−Ｒ^３について上記に示した前記アリールは、非置換であるか、ハロ、ヘテロアリール、ヘテロシクリル、シクロアルキル、またはヘテロアリールアルキルで任意に置換可能であるか、または任意に縮合可能であり、ここで、前記ヘテロアリール、ヘテロシクリル、シクロアルキル、およびヘテロアリールアルキルの各々は、非置換であるか、または同じかもしくは異なり得る１個以上の部分で任意に独立して置換可能であり、各部分は、アルキル、−ＯＲ^５、−Ｎ（Ｒ^５Ｒ^６）、および−Ｓ（Ｏ_２）Ｒ^５からなる群より独立して選択され；ならびに
−Ｒ^３について上記に示した前記ヘテロアリールは、非置換であるか、同じかもしくは異なり得る１個以上の部分で任意に独立して置換可能であるか、または任意に縮合可能であり、各部分は、ハロ、アミノ、アルコキシカルボニル、−ＯＲ^５、アルキル、−ＣＨＯ、−ＮＲ^５Ｒ^６、−Ｓ（Ｏ_２）Ｎ（Ｒ^５Ｒ^６）、−Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−ＳＲ^５、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクレニル、およびヘテロシクリルからなる群より独立して選択され；
Ｒ^５はＨ、アルキル、アミノアルキル、アリール、ヘテロアリール、ヘテロシクリル、またはシクロアルキルであり；ならびに
Ｒ^６はＨ、アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロシクリル、またはシクロアルキルであり；
さらに、ここで、化学式Ｉにおける任意の−ＮＲ^５Ｒ^６において、前記Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、環を形成可能である。

Or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
R is H, CN, —NR ⁵ R ⁶ , cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C (O) NR ⁵ R ⁶ , —N (R ⁵ ) C (O) R ⁶ , heterocyclyl, (CH ₂ ) _1-3 NR ⁵ R ⁶ substituted heteroaryl, unsubstituted alkyl, or substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ^6. Alkyl independently selected from the group;
R ¹ is H, halo, aryl, or heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or can be substituted with one or more moieties that can be the same or different; each part is halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, _{^{heterocyclyl, -CH 2 OR 5, -C (}} O) NR 5 R 6, -C (O) OH, -C (O) NH ₂ , —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of the —NR ⁵ R ⁶ form a heterocyclyl ring), —S (O) R ⁵ , —S (O ₂ ^{) R 5, -CN, -CHO,} -SR 5, -C (O) oR 5, -C (O) R 5, and are independently selected from the group consisting of -OR ^5;
R ² is H, halo, aryl, arylalkyl, or heteroaryl, wherein each of said aryl, arylalkyl, and heteroaryl is unsubstituted or can be the same or different and optionally be independently substituted with moieties, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, _{aryl, -C (O) OH, -C} (O) NH 2, -NR 5 R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a heterocyclyl ring), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , Independently selected from the group consisting of —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl; Selected;
R ³ is H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where:
The alkyl shown above for —R ³ may be unsubstituted or substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , alkoxy, heteroaryl, and — Independently selected from the group consisting of NR ⁵ R ⁶ ;
The aryl for -R ³ shown above is unsubstituted, halo, heteroaryl, heterocyclyl, or can be optionally substituted with cycloalkyl or heteroarylalkyl, or optionally may be fused, where Wherein each of said heteroaryl, heterocyclyl, cycloalkyl, and heteroarylalkyl can be unsubstituted or optionally independently substituted with one or more moieties that can be the same or different, wherein each moiety is , Alkyl, —OR ⁵ , —N (R ⁵ R ⁶ ), and —S (O ₂ ) R ⁵ ; and the heteroaryl shown above for —R ³ is non- Can be substituted, optionally independently substituted with one or more moieties that can be the same or different, or optionally condensed; Moiety, halo, amino, alkoxycarbonyl, -OR ^{5, _{alkyl, -CHO, -NR 5 R 6,}} -S (O 2) N (R 5 R 6), - C (O) N (R 5 R 6 ), - SR ^5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and are independently selected from the group consisting of heterocyclyl;
R ⁵ is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl, or cycloalkyl; and R ⁶ is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, or cycloalkyl;
Further, here, in any —NR ⁵ R ⁶ in Formula I, R ⁵ and R ⁶ can be optionally bonded together with N in the —NR ⁵ R ⁶ to form a ring.

  Another set of protein kinases plays an important role as a checkpoint in cell cycle progression. Checkpoints, for example, prevent cell cycle progression at inappropriate times in response to DNA damage, maintain cell metabolic balance while stopping cells, and in some cases meet checkpoint requirements. If not, it can induce apoptosis (programmed cell death). Checkpoint control can occur in the G1 phase (before DNA synthesis) and in the G2 phase before entering mitosis.

A series of checkpoints monitors the integrity of the genome, upon sensing DNA damage, these "DNA damage checkpoints" block cell cycle progression at ₁ phase and G ₂ phases G, the progression through S phase Delay. This action allows the DNA repair process to complete their work prior to genome replication, and subsequent segregation of this genetic material into new daughter cells occurs. Inactivation of CHK1 has been shown to transduce signals from the DNA damage sensing complex and inhibit activation of cyclin B / Cdc2 kinase, which promotes entry into mitosis, and disable G ₂ phase arrest induced by DNA damage done by anticancer or endogenous DNA damage, as well as results in preferential killing of the checkpoint deficient cells resulting. For example, Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91, 865-867 (1997); Weinert, Science, 277, 1450. -1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell. 5, 147-160 (1994).

  Selective manipulation of checkpoint control in cancer cells can give widespread use in cancer chemotherapy and radiotherapy regimens, and in addition, human cancer used as a selective basis for cancer cell destruction May provide a common salient feature of “genomic instability”. A number of factors recognize CHK1 as a very important target in DNA damage checkpoint control. Inhibitors of this kinase and functionally related kinases such as CDS1 / CHK2 (Zeng et al., Nature, 395, 507), a recently discovered kinase that cooperates with CHK1 in regulating S phase progression. -510 (1998); see Matsuoka, Science, 282, 1893-1897 (1998)), elucidation of inhibitors may provide valuable new therapeutic entities for the treatment of cancer.

  Another group of kinases are tyrosine kinases. A tyrosine kinase can be a receptor type (having an extracellular domain, a transmembrane domain, and an intracellular domain) or a non-receptor type (which is entirely intracellular). Receptor tyrosine kinases are composed of a large number of transmembrane receptors with diverse biological activities. In fact, approximately 20 different subfamilies of receptor tyrosine kinases have been identified. One tyrosine kinase subfamily, called the HER subfamily, is composed of EGFR (HER1), HER2, HER3, and HER4. The ligands of this subfamily of receptors identified so far include epidermal growth factor, TGF-α, amphiregulin, HB-EGF, betacellulin, and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, IR, and IR-R. The PDGF subfamily includes PDGF-α and β receptors, CSFIR, c-kit, and FLK-II. The FLK family is composed of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4), and fms-like tyrosine kinase-1 (flt-1). The For a detailed discussion of receptor tyrosine kinases, see Plowman et al., DN & P 7 (6): 334-339, 1994.

  At least one of the non-receptor protein tyrosine kinases, LCK, is thought to mediate signal transduction in T cells from the interaction of cross-linked anti-Cd4 antibody with cell surface protein (Cd4). A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, Oncogene, 8, 2025-2031 (1993). Non-receptor tyrosine kinases are also composed of a number of subfamilies including Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is subdivided into various receptors. For example, the Src subfamily is one of the largest subfamilies, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been associated with carcinogenesis. For a detailed discussion of non-receptor tyrosine kinases, see Bolen, Oncogene, 8: 2025-2031 (1993).

  In addition to its role in cell cycle control, protein kinases also play an important role in angiogenesis, the mechanism by which new capillaries are formed from existing blood vessels. When needed, the vasculature has the potential to create new capillary networks in order to maintain the proper functioning of tissues and organs. However, in adults, angiogenesis is very limited and occurs only in the process of wound healing and neovascularization of the endometrium during menstruation. On the other hand, undesirable angiogenesis is a prominent feature of several diseases such as retinopathy, psoriasis, rheumatoid arthritis, age-related macular degeneration, and cancer (solid tumors). Protein kinases that have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family; VEGF-R2 (vascular endothelial growth factor receptor 2, KDR (kinase insert domain receptor)) And also known as FLK1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).

  VEGF-R2 expressed only on endothelial cells binds the potent angiogenic growth factor VEGF and mediates subsequent signaling through activation of its intracellular kinase activity. Thus, direct inhibition of VEGF-R2 kinase activity results in decreased angiogenesis, even in the presence of exogenous VEGF, as demonstrated using mutants of VEGF-R2 that fail to mediate signal transduction. (See Strawn et al., Cancer Research, 56, 3540-3545 (1996)). Millauer et al., Cancer Research, 56, 1615-1620 (1996). Furthermore, VEGF-R2 does not appear to have a function in adults beyond mediating the angiogenic activity of VEGF. Therefore, selective inhibitors of VEGF-R2 kinase activity are expected to show little toxicity.

  Similarly, FGFR binds angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signaling. Recently, it has been suggested that growth factors such as bFGF may play a crucial role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). However, unlike VEGF-R2, FGF-R is expressed in many different cell types throughout the body and may or may not play an important role in other normal physiological processes in the adult. . Nevertheless, systemic administration of small molecule inhibitors of FGF-R kinase activity has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904 (1998).

  TEK (also known as Tie-2) is another receptor tyrosine kinase expressed only on endothelial cells that has been shown to play a role in angiogenesis. The binding of the factor angiopoietin-1 results in autophosphorylation of the kinase domain of TEK, resulting in a signaling process that appears to mediate the interaction between periendothelial support cells and endothelial cells, thereby forming newly Facilitates maturation of damaged blood vessels. On the other hand, the factor angiopoietin-2 appears to antagonize the action of angiopoietin-1 on TEK and destroys angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997). Kinase, JNK, belongs to the mitogen activated protein kinase (MAPK) superfamily. JNK plays an important role in inflammatory responses, stress responses, cell proliferation, apoptosis, and tumorigenesis. JNK kinase activity is activated by a variety of stimuli including pro-inflammatory cytokines (TNF-α and interleukin-1), lymphocyte costimulatory receptors (CD28 and CD40), DNA damaging chemicals, radiation, and Fas signaling Is possible. Results from JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation.

  Pim-1 is a small serine / threonine kinase. Increased expression levels of Pim-1 have been detected in lymphoid and bone marrow malignancies, and recently Pim-1 has been identified as a prognostic marker in prostate cancer. K. Peltola “Signing in Cancer: Pim-1 Kinases and its Partners” Analyzes University Sites Turkuensis, Sarja-Ser. D Osa-Tom. 616, (August 30, 2005), http: // kirjasto. utu. fi / julkaisupalvelut / annaalit / 2004 / D616. html. Pim-1 acts as a cell survival factor and may interfere with apoptosis in malignant cells. K. Petersen Shay et al., Molecular Cancer Research 3: 170-181 (2005).

  Yet another kinase group is Aurora kinases. Aurora kinases (Aurora-A, Aurora-B, Aurora-C) are serine / threonine protein kinases that have been implicated in human cancers such as colon tumors, breast tumors, and other solid tumors. Aurora-A (sometimes called AIK) is thought to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-A may play a role in controlling the precise segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cell proliferation and other abnormalities. In human colon cancer tissue, Aurora-A, Aurora-B, Aurora-C have been found to be overexpressed (Bischoff et al., EMBO J., 17: 3052-3065 (1998); Schumacher et al., J. Cell Biol. 143: 1635-1646 (1998); see Kimura et al., J. Biol. Chem., 272: 13766-13771 (1997)).

US Patent Application Publication No. 2004/0220189 US Patent Application Publication No. 2005/0009832 US Patent Application Publication No. 2006/0084650 US Patent Application Publication No. 2006/0106023 US Patent Application Publication No. 2007/0117804

  There is a need for effective inhibitors of protein kinases, particularly Aurora kinases, to treat or prevent disease states associated with abnormal cell proliferation. Furthermore, it is desirable to have kinase inhibitors, especially low molecular weight compounds that can be easily synthesized.

  The present invention, in its many embodiments, comprises a novel class of imidazo [1,2-a] pyrazine compounds, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, Methods for preparing pharmaceutical formulations comprising one or more such compounds, and the treatment, prevention, inhibition, or of one or more diseases associated with protein kinases using such compounds or pharmaceutical compositions Provide a way to improve.

  In one embodiment, the present invention provides a compound of formula I:

によって表される化合物、またはその薬学的に受容可能な塩、溶媒和物、エステル、もしくはプロドラッグを提供し、ここで：
ＲはＨ、ＣＮ、−ＮＲ^５Ｒ^６、シクロアルキル、シクロアルケニル、ヘテロシクレニル、ヘテロアリール、−Ｃ（Ｏ）ＮＲ^５Ｒ^６、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^６、ヘテロシクリル、（ＣＨ_２）_１−３ＮＲ^５Ｒ^６で置換されたヘテロアリール、非置換アルキル、または同じかもしくは異なり得る１個以上の部分で置換され、各部分が−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択されるアルキルであり；
Ｒ^１はＨ、ハロ、アリール、またはヘテロアリールであり、ここで、前記アリールおよびヘテロアリールの各々は、非置換であるか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−ＣＨ_２ＯＲ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^６、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒にヘテロシクリル環を形成する）、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、および−ＯＲ^５からなる群より独立して選択され；
Ｒ^２はＨ、ハロ、アリール、アリールアルキル、またはヘテロアリールであり、ここで、前記アリール、アリールアルキル、およびヘテロアリールの各々は、非置換であるか、または同じかもしくは異なり得る１個以上の部分で任意に独立して置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒にヘテロシクリル環を形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；
Ｒ^３はヘテロシクリル−（ＣＲ^７Ｒ^８）_ｎ−Ｘ、ヘテロシクレニル−（ＣＲ^７Ｒ^８）_ｎ−Ｘ、ヘテロアリール−（ＣＲ^７Ｒ^８）_ｎ−Ｘ、またはアリール−（ＣＲ^７Ｒ^８）_ｎ−Ｘであり、ここで、前記Ｒ^３のヘテロシクリル、ヘテロシクレニル、ヘテロアリール、またはアリール−部分の各々は、非置換であるか、または−ＣＯＮＲ^５Ｒ^６、−ＯＲ^５、およびアルキルからなる群より独立して選択される１個以上の部分で置換可能であり、
ｎは１〜６であり、
Ｘは−ＮＲ^５Ｒ^６、−ＯＲ^５、−ＳＯ−Ｒ^５、−ＳＲ^５、ＳＯ_２Ｒ^５、ヘテロアリール、ヘテロシクリル、およびアリールからなる群より選択され、ここで、前記ヘテロアリールまたはアリールは、非置換であるか、または−Ｏ−アルキル、アルキル、ハロ、もしくはＮＲ^５Ｒ^６からなる群より独立して選択される１個以上の部分で置換可能であり；
Ｒ^７およびＲ^８は各々独立して、水素、アルキル、ヘテロシクリル、アリール、ヘテロアリール、またはシクロアルキルであり；
Ｒ^５は水素、アルキル、アルケニル、アルコキシアルキル、−アルキル−Ｓ−アルキル、アミノアルキル、アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクロアルキル、シクロアルキル、シクレニル、ヘテロシクリルアルコキシル、−Ｓ−アルキルヘテロシクリル、ヘテロシクリル、ヘテロシクレニル、アルキルＮ（アルキル）_２、アルキルＮＨ（アルキル）、アルキルＮ（アルケニル）_２、−アルキルＮ（アルコキシル）_２、−アルキル−ＳＨ、ヒドロキシアルキル、トリハロアルキル、ジハロアルキル、モノハロアルキルからなる群より選択され、ここで、前記アルキル、アルケニル、アルコキシアルキル、−アルキル−Ｓ−アルキル、アミノアルキル、アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクロアルキル、シクロアルキル、シクレニル、ヘテロシクリルアルコキシル、−Ｓ−アルキルヘテロシクリル、ヘテロシクリル、ヘテロシクレニル、アルキルＮ（アルキル）_２、アルキルＮＨ（アルキル）、アルキルＮ（アルケニル）_２、−アルキルＮ（アルコキシル）_２、−アルキル−ＳＨ、ヒドロキシアルキル、トリハロアルキル、ジハロアルキル、モノハロアルキルの各々は、非置換であるか、またはアルキル、アルケニル、アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、アルコキシアルキル、−アルキル−Ｓ−アルキル、−アルキルＳＨ、アルコキシル、−Ｓ−アルキル、ヒドロキシアルキル、およびアミノアルキルからなる群より独立して選択される１個以上の部分で置換可能であり；
Ｒ^６は水素、アルキル、アルケニル、アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、アルコキシアルキル、−アルキル−Ｓ−アルキル、−アルキルＳＨ、アルコキシル、−Ｓ−アルキル、ヒドロキシアルキル、アミノアルキル、−アルキルＯＣ（Ｏ）アルキル、−アルキルＯＣ（Ｏ）シクロアルキル、−アルキルＯＣ（Ｏ）アリール、−アルキルＯＣ（Ｏ）アラルキル、−アルキルＯＣ（Ｏ）ＮＲ^５アリール、−アルキルＯＣ（Ｏ）ＮＲ^５アルキル、−アルキルＯＣ（Ｏ）ＮＲ^５ヘテロシクリル、−アルキルＯＣ（Ｏ）ＮＲ^５ヘテロアリール、−アルキルＯＣ（Ｏ）ＮＲ^５シクロアルキル、−アルキルＯＣ（Ｏ）ヘテロシクリル、アルキルＣ（Ｏ）ＯＨ、アルキルＣ（Ｏ）Ｏアルキル、−アルキルＣ（Ｏ）Ｏシクロアルキル、−アルキルＣ（Ｏ）Ｏアリール、−アルキルＣ（Ｏ）Ｏアラルキル、−アルキルＣ（Ｏ）ＯＮＲ^５アリール、−アルキルＣ（Ｏ）ＯＮＲ^５アルキル、−アルキルＣ（Ｏ）ＯＮＲ^５ヘテロシクリル、−アルキルＣ（Ｏ）ＯＮＲ^５ヘテロアリール、−アルキルＣ（Ｏ）ＯＮＲ^５シクロアルキル、−アルキルＣ（Ｏ）Ｏヘテロシクリル、アルキルＣ（Ｏ）ＯＨ、およびアルキルＣ（Ｏ）Ｏアルキルからなる群より選択され、ここで、前記アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、−アルキル−ＯＣ（Ｏ）アルキル、−アルキルＯＣ（Ｏ）シクロアルキル、−アルキルＯＣ（Ｏ）アリール、−アルキルＯＣ（Ｏ）アラルキル、−アルキルＯＣ（Ｏ）ＮＲ^５アリール、−アルキルＯＣ（Ｏ）ＮＲ^５アルキル、−アルキルＯＣ（Ｏ）ＮＲ^５ヘテロシクリル、−アルキルＯＣ（Ｏ）ＮＲ^５ヘテロアリール、−アルキルＯＣ（Ｏ）ＮＲ^５シクロアルキル、−アルキルＯＣ（Ｏ）ヘテロシクリル、アルキルＣ（Ｏ）ＯＨ、アルキルＣ（Ｏ）Ｏアルキル、−アルキルＣ（Ｏ）Ｏシクロアルキル、−アルキルＣ（Ｏ）Ｏアリール、−アルキルＣ（Ｏ）Ｏアラルキル、−アルキルＣ（Ｏ）ＯＮＲ^５アリール、−アルキルＣ（Ｏ）ＯＮＲ^５アルキル、−アルキルＣ（Ｏ）ＯＮＲ^５ヘテロシクリル、−アルキルＣ（Ｏ）ＯＮＲ^５ヘテロアリール、−アルキルＣ（Ｏ）ＯＮＲ^５シクロアルキル、−アルキルＣ（Ｏ）Ｏヘテロシクリル、アルキルＣ（Ｏ）ＯＨ、およびアルキルＣ（Ｏ）Ｏアルキルの各々は、非置換であるか、またはアルキル、アルケニル、アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、アルコキシアルキル、−アルキル−Ｓ−アルキル、−アルキルＳＨ、アルコキシル、−Ｓ−アルキル、ヒドロキシアルキル、アミノアルキル、アミノ、アミノジアルキル、アミノシクロアルキル、ハロ、トリハロアルキル、ジハロアルキル、およびモノハロアルキルからなる群より独立して選択される１個以上の部分で置換可能であり；
さらに、化学式Ｉにおける任意の−ＮＲ^５Ｒ^６において、前記Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、環または架橋環を形成可能であり、ここで、前記環または架橋環の各々は、非置換であるか、または同じであるかもしくは異なり得る、ヒドロキシル、−ＳＨ、アルキル、アルケニル、ヒドロキシアルキル、−アルキル−ＳＨ、アルコキシル、−Ｓ−アルキル、−ＣＯ_２−アルキル、−ＣＯ_２−アルケニル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、ヘテロアリール、アリール、シクレニル、シクロアルキル、スピロヘテロシクリル、スピロヘテロシクレニル、スピロヘテロアリール、スピロシクリル、スピロシクレニル、スピロアリール、アルコキシアルキル、−アルキル−Ｓ−アルキル、ヘテロシクリル、ヘテロシクレニル、ハロ、トリハロアルキル、ジハロアルキル、ＣＮ、およびモノハロアルキルからなる群より独立して選択される１個以上の部分で置換可能である。

Or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, wherein:
R is H, CN, —NR ⁵ R ⁶ , cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C (O) NR ⁵ R ⁶ , —N (R ⁵ ) C (O) R ⁶ , heterocyclyl, (CH ₂ ) _1-3 NR ⁵ R ⁶ substituted heteroaryl, unsubstituted alkyl, or substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ^6. Alkyl independently selected from the group;
R ¹ is H, halo, aryl, or heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or can be substituted with one or more moieties that can be the same or different; each part is halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, _{^{heterocyclyl, -CH 2 OR 5, -C (}} O) NR 5 R 6, -C (O) OH, -C (O) NH ₂ , —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of the —NR ⁵ R ⁶ form a heterocyclyl ring), —S (O) R ⁵ , —S (O ₂ ^{) R 5, -CN, -CHO,} -SR 5, -C (O) oR 5, -C (O) R 5, and are independently selected from the group consisting of -OR ^5;
R ² is H, halo, aryl, arylalkyl, or heteroaryl, wherein each of said aryl, arylalkyl, and heteroaryl is unsubstituted or can be the same or different and optionally be independently substituted with moieties, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, _{aryl, -C (O) OH, -C} (O) NH 2, -NR 5 R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a heterocyclyl ring), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , Independently selected from the group consisting of —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl; Selected;
R ³ is heterocyclyl- (CR ⁷ R ⁸ ) _n —X, heterocyclenyl- (CR ⁷ R ⁸ ) _n —X, heteroaryl- (CR ⁷ R ⁸ ) _n —X, or aryl- (CR ⁷ R ⁸ ) _n is -X, wherein heterocyclyl wherein ^{R 3,} heterocyclenyl, heteroaryl or aryl, - each part is unsubstituted or -CONR ⁵ R ^6, from the group consisting of -OR ^5, and alkyl Can be replaced with one or more independently selected moieties;
n is 1-6,
X is selected from the group consisting of —NR ⁵ R ⁶ , —OR ⁵ , —SO—R ⁵ , —SR ⁵ , SO ₂ R ⁵ , heteroaryl, heterocyclyl, and aryl, wherein said heteroaryl or aryl is , Unsubstituted or substituted with one or more moieties independently selected from the group consisting of —O-alkyl, alkyl, halo, or NR ⁵ R ⁶ ;
R ⁷ and R ⁸ are each independently hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, or cycloalkyl;
R ⁵ is hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl , Alkyl N (alkyl) ₂ , alkyl NH (alkyl), alkyl N (alkenyl) ₂ , -alkyl N (alkoxyl) ₂ , -alkyl-SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl Wherein said alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloal Kill, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN (alkyl) ₂ , alkylNH (alkyl), alkylN (alkenyl) ₂ , -alkylN (alkoxyl) ₂ , -alkyl Each of —SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl is unsubstituted or alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, Heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -al Le SH, alkoxyl, -S- alkyl, can be substituted with one or more moieties independently selected from the group consisting of hydroxyalkyl, and aminoalkyl;
R ⁶ is hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl , -Alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl, aminoalkyl, -alkylOC (O) alkyl, -alkylOC (O) cycloalkyl, -alkylOC (O) aryl, - alkyl OC (O) aralkyl, - alkyl OC (O) NR ⁵ aryl, - alkyl OC (O) NR ⁵ alkyl, - alkyl OC (O) NR ⁵ heterocyclyl, - alkyl OC (O) NR ⁵ f Roariru, - alkyl OC (O) NR ⁵ cycloalkyl, - alkyl OC (O) heterocyclyl, alkyl C (O) OH, alkyl C (O) O-alkyl, - alkyl C (O) O cycloalkyl, - alkyl C ( O) O aryl, -alkyl C (O) O aralkyl, -alkyl C (O) ONR ⁵ aryl, -alkyl C (O) ONR ⁵ alkyl, -alkyl C (O) ONR ⁵ heterocyclyl, -alkyl C (O) Selected from the group consisting of ONR ⁵ heteroaryl, -alkyl C (O) ONR ⁵ cycloalkyl, -alkyl C (O) O heterocyclyl, alkyl C (O) OH, and alkyl C (O) O alkyl, wherein Aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, Heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, -alkyl-OC (O) alkyl, -alkylOC (O) cycloalkyl, -alkylOC (O) aryl, -alkylOC (O) aralkyl, -alkyl OC (O) NR ⁵ aryl, -alkyl OC (O) NR ⁵ alkyl, -alkyl OC (O) NR ⁵ heterocyclyl, -alkyl OC (O) NR ⁵ heteroaryl, -alkyl OC ( O) NR ⁵ cycloalkyl, -alkylOC (O) heterocyclyl, alkylC (O) OH, alkylC (O) Oalkyl, -alkylC (O) Ocycloalkyl, -alkylC (O) Oaryl,- Alkyl C (O) O aralkyl, -alkyl C (O) O R ⁵ aryl, - alkyl C (O) ONR ⁵ alkyl, - alkyl C (O) ONR ⁵ heterocyclyl, - alkyl C (O) ONR ⁵ heteroaryl, - alkyl C (O) ONR ⁵ cycloalkyl, - alkyl C ( Each of O) O heterocyclyl, alkyl C (O) OH, and alkyl C (O) O alkyl is unsubstituted or alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cyclo Alkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl, Aminoalkyl, amino, aminodialkyl, aminocycloalkyl, halo, trihaloalkyl, and can be substituted with one or more moieties independently selected from the group consisting of dihaloalkyl, and monohaloalkyl;
Furthermore, in any —NR ⁵ R ⁶ in Formula I, R ⁵ and R ⁶ can be optionally combined together with N in the —NR ⁵ R ⁶ to form a ring or a bridged ring, wherein Each of said rings or bridged rings may be unsubstituted or the same or different, hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -CO 2 _- alkyl, -CO 2 _- alkenyl, arylalkyl, Shikure alkenyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, Shikureniru, cycloalkyl, spiro-heterocyclyl, Spiroheterocyclenyl, spiroheteroaryl, One or more moieties independently selected from the group consisting of pyrocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-alkyl, heterocyclyl, heterocyclenyl, halo, trihaloalkyl, dihaloalkyl, CN, and monohaloalkyl Can be replaced.

  Compounds of formula I may be useful as protein kinase inhibitors. The compounds of formula I may also be useful as Aurora kinase inhibitors. The compounds of formula I may be useful in the treatment and prevention of proliferative diseases such as cancer, inflammation and neurodegenerative diseases such as arthritis, Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.

  In one embodiment, the present invention provides an imidazopyridine compound represented by Structural Formula I, especially an imidazo [1,2-a] pyrazine compound, or a pharmaceutically acceptable salt, solvate, ester, Alternatively, prodrugs are provided, wherein the various moieties are as described above.

  In another embodiment, the present invention provides compounds of formula I:

によって表される化合物、またはその薬学的に受容可能な塩、溶媒和物、エステル、もしくはプロドラッグを提供し、ここで：
ＲはＨ、ＣＮ、−ＮＲ^５Ｒ^６、シクロアルケニル、ヘテロシクレニル、−Ｃ（Ｏ）ＮＲ^５Ｒ^６、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^６、または同じかもしくは異なり得る１個以上の部分で置換され、各部分が−ＯＲ^５および−ＮＲ^５Ｒ^６からなる群より独立して選択されるアルキルであり；
Ｒ^１はＨ、ハロ、アリール、またはヘテロアリールであり、ここで、前記アリールおよびヘテロアリールの各々は、非置換であるか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクリル、−Ｃ（Ｏ）ＮＲ^５Ｒ^６および−ＯＲ^５からなる群より独立して選択され；
Ｒ^２はＨ、ハロ、またはヘテロアリールであり、ここで、前記ヘテロアリールは、非置換であるか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；
Ｒ^３はヘテロシクリル−（ＣＲ^７Ｒ^８）_ｎ−Ｘ、ヘテロシクレニル−（ＣＲ^７Ｒ^８）_ｎ−Ｘ、ヘテロアリール−（ＣＲ^７Ｒ^８）_ｎ−Ｘ、またはアリール−（ＣＲ^７Ｒ^８）_ｎ−Ｘであり、ここで、前記Ｒ^３のヘテロシクリル、ヘテロシクレニル、ヘテロアリール、またはアリール−部分の各々は、非置換であるか、または−ＣＯＮＲ^５Ｒ^６、−ＯＲ^５、およびアルキルからなる群より独立して選択される１個以上の部分で置換可能であり、
ｎは１であり、
Ｘは−ＮＲ^５Ｒ^６、−ＯＲ^５、−ＳＯ−Ｒ^５、および−ＳＲ^５からなる群より選択され；
Ｒ^７およびＲ^８は各々独立して水素またはアルキルであり；
Ｒ^５は水素、アルキル、アルケニル、アルコキシアルキル、−アルキル−Ｓ−アルキル、アミノアルキル、アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクロアルキル、シクロアルキル、シクレニル、ヘテロシクリルアルコキシル、−Ｓ−アルキルヘテロシクリル、ヘテロシクリル、ヘテロシクレニル、アルキルＮ（アルキル）_２、アルキルＮＨ（アルキル）、アルキルＮ（アルケニル）_２、−アルキルＮ（アルコキシル）_２、−アルキル−ＳＨ、およびヒドロキシアルキルからなる群より選択され、ここで、前記アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクロアルキル、シクロアルキル、シクレニル、ヘテロシクリルアルコキシル、−Ｓ−アルキルヘテロシクリル、ヘテロシクリル、ヘテロシクレニルの各々は、非置換であるか、またはアルキル、アルキル、アルケニル、アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、アルコキシアルキル、−アルキル−Ｓ−アルキル、−アルキルＳＨ、アルコキシル、−Ｓ−アルキル、ヒドロキシアルキル、およびアミノアルキルからなる群より独立して選択される１個以上の部分で置換可能であり；
Ｒ^６は水素、アルキル、アルケニル、アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、アルコキシアルキル、−アルキル−Ｓ−アルキル、−アルキルＳＨ、アルコキシル、−Ｓ−アルキル、ヒドロキシアルキル、およびアミノアルキルからなる群より選択され、ここで、前記アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキルの各々は、非置換であるか、またはアルキル、アルキル、アルケニル、アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、アルコキシアルキル、−アルキル−Ｓ−アルキル、−アルキルＳＨ、アルコキシル、−Ｓ−アルキル、ヒドロキシアルキル、およびアミノアルキルからなる群より独立して選択される１個以上の部分で置換可能であり；
さらに、化学式Ｉにおける任意の−ＮＲ^５Ｒ^６において、前記Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、環または架橋環を形成可能であり、ここで、前記環または架橋環の各々は、非置換であるか、または同じであるかもしくは異なり得る、ヒドロキシル、−ＳＨ、アルキル、アルケニル、ヒドロキシアルキル、−アルキル−ＳＨ、アルコキシル、−Ｓ−アルキル、−ＣＯ_２−アルキル、−ＣＯ_２−アルケニル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、ヘテロアリール、アリール、シクレニル、シクロアルキル、スピロヘテロシクリル、スピロヘテロシクレニル、スピロヘテロアリール、スピロシクリル、スピロシクレニル、スピロアリール、アルコキシアルキル、−アルキル−Ｓ−アルキル、ヘテロシクリル、およびヘテロシクレニルからなる群より独立して選択される１個以上の部分で置換可能である。

Or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, wherein:
R is H, CN, —NR ⁵ R ⁶ , cycloalkenyl, heterocyclenyl, —C (O) NR ⁵ R ⁶ , —N (R ⁵ ) C (O) R ⁶ , or one or more that may be the same or different Alkyl substituted with moieties, each moiety independently selected from the group consisting of —OR ⁵ and —NR ⁵ R ⁶ ;
R ¹ is H, halo, aryl, or heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or can be substituted with one or more moieties that can be the same or different; Each moiety is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —C (O) NR ⁵ R ⁶ and —OR ⁵ ;
R ² is H, halo, or heteroaryl, wherein the heteroaryl is unsubstituted or can be substituted with one or more moieties that may be the same or different, each moiety being halo, Independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
R ³ is heterocyclyl- (CR ⁷ R ⁸ ) _n —X, heterocyclenyl- (CR ⁷ R ⁸ ) _n —X, heteroaryl- (CR ⁷ R ⁸ ) _n —X, or aryl- (CR ⁷ R ⁸ ) _n is -X, wherein heterocyclyl wherein ^{R 3,} heterocyclenyl, heteroaryl or aryl, - each part is unsubstituted or -CONR ⁵ R ^6, from the group consisting of -OR ^5, and alkyl Can be replaced with one or more independently selected moieties;
n is 1,
X is ^-NR 5 ^{R 6,} -OR ^5, is selected from the group consisting of ^{-SO-R 5,} and -SR ^5;
R ⁷ and R ⁸ are each independently hydrogen or alkyl;
R ⁵ is hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl , Alkyl N (alkyl) ₂ , alkyl NH (alkyl), alkyl N (alkenyl) ₂ , -alkyl N (alkoxyl) ₂ , -alkyl-SH, and hydroxyalkyl, wherein the aryl, Each of heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl Is unsubstituted or alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, hetero Substitutable with one or more moieties independently selected from the group consisting of cycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl. Yes;
R ⁶ is hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl , -Alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl, wherein the aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, Each of cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl Is unsubstituted or alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, hetero Substitutable with one or more moieties independently selected from the group consisting of cycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl. Yes;
Furthermore, in any —NR ⁵ R ⁶ in Formula I, R ⁵ and R ⁶ can be optionally combined together with N in the —NR ⁵ R ⁶ to form a ring or a bridged ring, wherein Each of said rings or bridged rings may be unsubstituted or the same or different, hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -CO 2 _- alkyl, -CO 2 _- alkenyl, arylalkyl, Shikure alkenyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, Shikureniru, cycloalkyl, spiro-heterocyclyl, Spiroheterocyclenyl, spiroheteroaryl, Piroshikuriru, Supiroshikureniru, spiro aryl, alkoxyalkyl, - alkyl -S- alkyl, heterocyclyl, and can be substituted with one or more moieties independently selected from the group consisting heterocyclenyl.

In one embodiment, R, R ¹ , and R ² are not all H at the same time.

In another embodiment, in Formula I, R ² is unsubstituted heteroaryl or heteroaryl substituted with alkyl.

In another embodiment, in Formula I, R ² is heteroaryl substituted with alkyl.

In another embodiment, in Formula I, R ² is pyrazolyl.

In another embodiment, in Formula I, R ² is pyrazolyl substituted with alkyl.

In another embodiment, in Formula I, R ² is 1-methyl-pyrazol-4-yl.

  In another embodiment, in Formula I, R is H.

  In another embodiment, in Formula I, R is CN.

In another embodiment, in Formula I, R is -C (O) NR < ⁵ > R < ⁶ >.

In another embodiment, in Formula I, R is -C (O) NH _2.

  In another embodiment, in Formula I, R is heterocyclenyl.

  In another embodiment, in Formula I, R is tetrahydropyridinyl.

  In another embodiment, in Formula I, R is 1,2,3,6-tetrahydropyridinyl.

In another embodiment, in Formula I, R is substituted with one or more moieties that may be the same or different, and each moiety is an alkyl independently selected from the group consisting of -OR ¹ and -NR ⁵ R ^6. is there.

In another embodiment, in Formula I, R is alkyl substituted with one or more —NR ⁵ R ⁶ .

In another embodiment, in Formula I, R is alkyl substituted with -NH _2.

  In another embodiment, in Formula I, R is alkyl substituted with -NH (methyl).

  In another embodiment, R is unsubstituted alkyl.

In certain embodiments, both R and R ¹ are not H at the same time.

In certain embodiments, in Formula I, R ³ is heteroaryl-CH ₂ —X, wherein X is —OR ⁵ , —SOR ⁵ , —NR ⁵ R ⁶ , or —SR ⁵ ; R ⁵ Is hydrogen, -alkylN (alkyl) ₂ , heterocyclylalkyl, or heterocyclenylalkyl; or R ⁵ and R ⁶ are optionally joined together with N in the —NR ⁵ R ⁶ to form a ring or bridged ring Wherein the ring or bridged ring may be unsubstituted or the same or different, hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heteros Piroshikuriru, hetero spiro Shikure alkenyl, heteroaryl spiro aryl, and -CO ₂ independently from the group consisting of alkyl It can be substituted with one or more moieties selected.

In another embodiment, in Formula I, R ³ is heteroaryl-CH ₂ —X or heteroaryl-CHmethyl-X, wherein X is —NR ⁵ R ⁶ and R ⁵ is -alkylN (Alkyl) ₂ , alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, where R ⁶ is hydrogen, alkyl, hydroxyalkyl, alkoxy Alkyl, or -alkyl N (alkyl) ₂ ; or R ⁵ and R ⁶ can be optionally joined together with N in the —NR ⁵ R ⁶ to form a ring or bridged ring, wherein The ring or bridged ring may be unsubstituted or the same or different, Hydroxyl, alkyl, alkoxyl, alkoxyl alkyl, hydroxyalkyl, arylalkyl, aryl, heteroaryl scan Piroshi heterocyclylalkyl, heteroaryl spiro Shikure alkenyl, heteroaryl spiro aryl, and -CO ₂ 1 or more independently selected from the group consisting of alkyl Can be replaced with a part.

In another embodiment, in Formula I, R ³ is heteroaryl-CH ₂ —X, wherein the heteroaryl of said heteroaryl-CH ₂ —X is substituted with alkyl or —CONR ⁵ R ⁶ , wherein X is —NR ⁵ R ⁶ , R ⁵ is alkyl, R ⁶ is alkyl, or R ⁵ and R ⁶ are optionally bonded together with N of the —NR ⁵ R ⁶ to form a ring. Form.

In another embodiment, in Formula I, R ³ is aryl-CH ₂ —X, wherein the aryl of said aryl-CH ₂ —X is substituted with alkyl, wherein X is heterocyclyl. .

In another embodiment, in Formula I, R ³ is

であり、ここで、Ｘは−ＮＲ^５Ｒ^６、−ＯＲ^５、−ＳＯ−Ｒ^５、および−ＳＲ^５からなる群より選択される。

Where X is selected from the group consisting of —NR ⁵ R ⁶ , —OR ⁵ , —SO—R ⁵ , and —SR ⁵ .

R ⁵ is hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl , Alkyl N (alkyl) ₂ , alkyl NH (alkyl), alkyl N (alkenyl) ₂ , -alkyl N (alkoxyl) ₂ , -alkyl-SH, and hydroxyalkyl, wherein the aryl, Each of heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl Is unsubstituted or alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, hetero Substitutable with one or more moieties independently selected from the group consisting of cycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl. Yes;
R ⁶ is hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl , -Alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl, wherein the aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, Each of cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl Is unsubstituted or alkyl, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, hetero Substitutable with one or more moieties independently selected from the group consisting of cycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl. Yes;
Furthermore, in any —NR ⁵ R ⁶ in Formula I, R ⁵ and R ⁶ can be optionally combined together with N in the —NR ⁵ R ⁶ to form a ring or a bridged ring, wherein Each of said rings or bridged rings may be unsubstituted or the same or different, hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -CO 2 _- alkyl, -CO 2 _- alkenyl, arylalkyl, Shikure alkenyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, Shikureniru, cycloalkyl, spiro-heterocyclyl, Spiroheterocyclenyl, spiroheteroaryl, Piroshikuriru, Supiroshikureniru, spiro aryl, alkoxyalkyl, - alkyl -S- alkyl, heterocyclyl, and can be substituted with one or more moieties independently selected from the group consisting heterocyclenyl.

In another embodiment, in Formula I, R ³ is:

で置換されたイソチアゾール、チオフェン、またはピリミジンである。

Isothiazole, thiophene, or pyrimidine substituted with

In another embodiment, in Formula I, R ³ is pyrimidinyl substituted with heterocyclylmethyl.

In another embodiment, in Formula I, R ³ is pyrimidinyl substituted with morpholinylmethyl or pyrrolidinylmethyl.

In another embodiment, in Formula I, R ³ is phenyl substituted with heterocyclylalkyl, wherein said heterocyclylalkyl is unsubstituted, or one or more moieties that can be the same or different Each of which is independently selected from the group consisting of alkyl.

In another embodiment, in Formula I, R ³ is phenyl-CHmethyl-X or phenyl-CH ₂ -X, wherein X is piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl; Wherein said piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl are unsubstituted or substitutable with one or more moieties that may be the same or different, each moiety consisting of an alkyl group More independently selected.

In another embodiment, in Formula I, R ³ is phenyl substituted with heterocyclylmethyl, wherein the phenyl group is further substituted with alkyl.

In another embodiment, in Formula I, R ³ is phenyl substituted with piperidinylmethyl, morpholinylmethyl, or thiomorpholinylmethyl, wherein the phenyl group is further substituted with methyl .

In another embodiment, in Formula I, R ³ is

であり、ここで、Ｘはヘテロシクリルであり、前記ヘテロシクリルは、非置換であるか、または同じであるかもしくは異なり得る１個以上の部分で置換可能であり、各部分はヒドロキシル、アルキル、ヒドロキシアルキル、アルコキシル、−ＣＯ_２アルキル、アリールアルキル、アリール、アルコキシアルキル、およびヘテロシクリルからなる群より独立して選択される。

Wherein X is heterocyclyl, said heterocyclyl being unsubstituted or substituting with one or more moieties that may be the same or different, each moiety being hydroxyl, alkyl, hydroxyalkyl , Alkoxyl, —CO ₂ alkyl, arylalkyl, aryl, alkoxyalkyl, and heterocyclyl.

In another embodiment, in Formula I, R ³ is

であり、ここで、Ｘはヘテロシクリルであり、ここで、前記ヘテロシクリルは、非置換であるか、または同じであるかもしくは異なり得る１個以上の部分で置換可能であり、各部分はアルキルからなる群より独立して選択される。

Wherein X is a heterocyclyl, wherein the heterocyclyl is unsubstituted or can be substituted with one or more moieties that may be the same or different, each moiety consisting of alkyl Selected independently from the group.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、エステル、もしくはプロドラッグを開示し、ここで、Ｒ^２はヘテロアリールであり、ここで、前記ヘテロアリールは、非置換であるか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであるかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘまたはヘテロアリール−ＣＨメチル−Ｘであり、ここで、Ｘは−ＮＲ^５Ｒ^６であり；Ｒ^５は−アルキルＮ（アルキル）_２、アルキル、アルコキシアルキル、ヒドロキシアルキル、アリールアルキル、ヘテロシクレニルアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、または−アルキルＳＨであり、Ｒ^６は水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、または−アルキルＮ（アルキル）_２であり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、環または架橋環を形成可能であり、ここで、前記環または架橋環は、非置換であるか、または同じであるかもしくは異なり得る、ヒドロキシル、アルキル、アルコキシル、アルコキシルアルキル、ヒドロキシアルキル、アリールアルキル、アリール、ヘテロスピロシクリル、ヘテロスピロシクレニル、ヘテロスピロアリール、および−ＣＯ_２アルキルからなる群より独立して選択される１個以上の部分で置換可能であり；ここでＲ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, wherein R ² is heteroaryl, wherein said heteroaryl is unsubstituted Or may be substituted with one or more moieties, which may be the same or different, each moiety being halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C (O) OH, —C (O) NH ₂ , —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S _{^{(O) R 5, -S (}} O 2) R 5, -CN, -CHO, -SR 5, -C (O) oR 5, -C (O) R 5, from the group consisting of heteroaryl, and heterocyclyl Independently selected R is unsubstituted alkyl or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ independently selected. R ¹ is H; R ³ is heteroaryl-CH ₂ —X or heteroaryl-CHmethyl-X, wherein X is —NR ⁵ R ⁶ ; R ⁵ is —alkylN (alkyl ) ₂ , alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, where R ⁶ is hydrogen, al Is alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN (alkyl) ₂ ; or R ⁵ and R ⁶ are optionally bonded together with N in —NR ⁵ R ⁶ to form a ring or bridged ring Where said ring or bridged ring may be unsubstituted or the same or different, hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl , Heterospirocyclenyl, heterospiroaryl, and —CO ₂ alkyl can be substituted with one or more moieties independently selected; wherein R ⁵ and R ⁶ are as defined above. is there.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２はヘテロアリールであり、ここで、前記ヘテロアリールは、非置換であるか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであるかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘであり、ここで、前記ヘテロアリール−ＣＨ_２−Ｘのヘテロアリールはアルキルまたは−ＣＯＮＲ^５Ｒ^６で置換され、ここで、Ｘは−ＮＲ^５Ｒ^６であり、あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、ヘテロシクリルを形成し；Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is heteroaryl, wherein said heteroaryl is unsubstituted or the same and it may be substituted with or different obtain one or more portions, each portion, halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, - NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) _{^{R 5, -S (O 2)}} R 5, -CN, -CHO, -SR 5, -C (O) oR 5, -C (O) R 5, independently from the group consisting of heteroaryl, and heterocyclyl Selected; R is unsubstituted Alkyl or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), — ^{N (R 5) -C (O} ) oR 6, - (CH 2) 1-3 -N (R 5 R 6) and ^-NR 5 independently from the group consisting of ^{R 6} is selected; ^{R 1} is H Yes; R ³ is heteroaryl-CH ₂ —X, wherein the heteroaryl of said heteroaryl-CH ₂ —X is substituted with alkyl or —CONR ⁵ R ⁶ , wherein X is —NR ⁵ R is ^6, or ^{R 5} and ^{R 6} are joined together to N and any of said ^-NR 5 ^{R 6,} form a heterocyclyl; ^{R 5} and ^{R 6} are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２はヘテロアリールであり、ここで、前記ヘテロアリールは、非置換であるか、または同じであるかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであるかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is heteroaryl, wherein said heteroaryl is unsubstituted or the same Can be substituted with one or more moieties that can be different or different, each moiety being halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C (O) OH, —C (O) NH ₂ , —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of the —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S ( Independently from the group consisting of O) R ⁵ , —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl. R is selected Unsubstituted alkyl or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ) , —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ ; independently selected from R ¹ ; H; R ³ is

で置換されたイソチアゾール、チオフェン、またはピリミジンであり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Isothiazole, thiophene, or pyrimidine substituted with; where R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２はヘテロアリールであり、ここで、前記ヘテロアリールは、非置換であるか、または同じであるかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであるかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はフェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘであり、ここで、前記フェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘの各々は、非置換であるかまたはアルキルで置換可能であり、ここで、さらに、Ｘはピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルであり、前記ピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルの各々は、非置換であるかまたはアルキルで置換可能であり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is heteroaryl, wherein said heteroaryl is unsubstituted or the same Can be substituted with one or more moieties that can be different or different, each moiety being halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C (O) OH, —C (O) NH ₂ , —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of the —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S ( Independently from the group consisting of O) R ⁵ , —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl. R is selected Unsubstituted alkyl or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ) , —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ ; independently selected from R ¹ ; be H; ^{R 3} is phenyl -CH methyl -X or phenyl _-CH 2 -X, wherein each of said phenyl -CH methyl -X or phenyl _-CH 2 -X is or is unsubstituted Substituted with alkyl, wherein X is piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl, said piperazinyl, piperazinyl (pipeazinyl) Adinyl), pyrrolidinyl, morpholinyl or each thiomorpholinyl is a possible unsubstituted or substituted with alkyl; wherein, R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２はヘテロアリールであり、ここで、前記ヘテロアリールは、非置換であり得るか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is heteroaryl, wherein said heteroaryl may be unsubstituted, or and may be substituted with the same or different to obtain one or more portions, each portion, halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O _{^{) R 5, -S (O 2}} ) R 5, -CN, -CHO, -SR 5, -C (O) oR 5, -C (O) R 5, heteroaryl, and independently from the group consisting of heterocyclyl R is not set Substituted alkyl or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ). , —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ ; independently selected from R ¹ ; H; R ³ is

であり、ここで、Ｘは−ＮＲ^５Ｒ^６、−ＯＲ^５−ＳＯ−Ｒ^５、および−ＳＲ^５からなる群より選択され、
Ｒ^５は水素、アルキル、アルケニル、アルコキシアルキル、−アルキル−Ｓ−アルキル、アミノアルキル、アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクロアルキル、シクロアルキル、シクレニル、ヘテロシクリルアルコキシル、−Ｓ−アルキルヘテロシクリル、ヘテロシクリル、ヘテロシクレニル、アルキルＮ（アルキル）_２、アルキルＮＨ（アルキル）、アルキルＮ（アルケニル）_２、−アルキルＮ（アルコキシル）_２、−アルキル−ＳＨ、およびヒドロキシアルキルからなる群より選択され、前記アリール、ヘテロアリール、ヘテロシクレニル、ヘテロシクロアルキル、シクロアルキル、シクレニル、ヘテロシクリルアルコキシル、−Ｓ−アルキルヘテロシクリル、ヘテロシクリル、およびヘテロシクレニルは、非置換であり得るかまたは１個以上のアルキルで置換可能であり；
Ｒ^６は水素、アルキル、アルケニル、アリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、アルコキシアルキル、−アルキル−Ｓ−アルキル、−アルキルＳＨ、アルコキシル、−Ｓ−アルキル、ヒドロキシアルキル、およびアミノアルキル
からなる群より選択され、ここで、前記のアリール、シクレニル、シクロアルキル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリール、ヘテロシクレニル、ヘテロシクリル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、およびヘテロシクロアルキルアルキルの各々は、非置換であり得るかまたは１個以上のアルキルで置換可能であり；
さらに、化学式Ｉにおける任意の−ＮＲ^５Ｒ^６において、前記Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に結合して、環または架橋環を形成可能であり、ここで、前記環または架橋環の各々は、非置換であり得るか、または同じであり得るかもしくは異なり得る、ヒドロキシル、−ＳＨ、アルキル、アルケニル、ヒドロキシアルキル、−アルキル−ＳＨ、アルコキシル、−Ｓ−アルキル、−ＣＯ_２−アルキル、−ＣＯ_２−アルケニル、アリールアルキル、シクレニルアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、ヘテロシクレニルアルキル、ヘテロシクロアルキルアルキル、ヘテロアリール、アリール、シクレニル、シクロアルキル、スピロヘテロシクリル、スピロヘテロシクレニル、スピロヘテロアリール、スピロシクリル、スピロシクレニル、スピロアリール、アルコキシアルキル、−アルキル−Ｓ−アルキル、ヘテロシクリル、およびヘテロシクレニルからなる群より独立して選択される１個以上の部分で置換可能である。

Wherein X is selected from the group consisting of —NR ⁵ R ⁶ , —OR ⁵ —SO—R ⁵ , and —SR ⁵ ;
R ⁵ is hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl , Alkyl N (alkyl) ₂ , alkyl NH (alkyl), alkyl N (alkenyl) ₂ , -alkyl N (alkoxyl) ₂ , -alkyl-SH, and hydroxyalkyl, said aryl, heteroaryl, Heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, and heterocyclenyl are non-substituted Can be substituted or can be substituted with one or more alkyls;
R ⁶ is hydrogen, alkyl, alkenyl, aryl, Shikureniru, cycloalkyl, arylalkyl, Shikure alkenyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, Heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl , -Alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl, wherein said aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl , Cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, and heterocycloalkylalkyl Each may be unsubstituted or substituted with one or more alkyl;
Further, in any —NR ⁵ R ⁶ in Formula I, the R ⁵ and R ⁶ can be bonded together with N in the —NR ⁵ R ⁶ to form a ring or a bridged ring, where Each of said rings or bridged rings may be unsubstituted or the same or different, hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -CO 2 _- alkyl, -CO 2 _- alkenyl, arylalkyl, Shikure alkenyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, Shikureniru, cycloalkyl, spiro-heterocyclyl, Spiroheterocyclenyl, spiroheteroaryl Spirocyclyl, Supiroshikureniru, spiro aryl, alkoxyalkyl, - alkyl -S- alkyl, heterocyclyl, and can be substituted with one or more moieties independently selected from the group consisting heterocyclenyl.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２はヘテロアリールであり、ここで、前記ヘテロアリールは、非置換であり得るか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルであり得るか、または同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is heteroaryl, wherein said heteroaryl may be unsubstituted, or and may be substituted with the same or different to obtain one or more portions, each portion, halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O _{^{) R 5, -S (O 2}} ) R 5, -CN, -CHO, -SR 5, -C (O) oR 5, -C (O) R 5, heteroaryl, and independently from the group consisting of heterocyclyl R is not set Alkyls substituted with one or more moieties, which may be substituted alkyls, or may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N ( Independently selected from the group consisting of: R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ^6. R ¹ is H; R ³ is

であり、ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Where R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２はピラゾリルであり、ここで、前記ピラゾリルは、非置換であり得るか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘまたはヘテロアリール−ＣＨメチル−Ｘであり、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５は−アルキルＮ（アルキル）_２、アルキル、アルコキシアルキル、ヒドロキシアルキル、アリールアルキル、ヘテロシクレニルアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、または−アルキルＳＨであり、Ｒ^６は水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、または−アルキルＮ（アルキル）_２であり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に任意に結合され、環または架橋環を形成可能であり、ここで、前記環または架橋環は、非置換または置換された１個以上の部分であり得、前記部分は、同じであるか異なり、ヒドロキシル、アルキル、アルコキシル、アルコキシルアルキル、ヒドロキシアルキル、アリールアルキル、アリール、ヘテロスピロシクリル、ヘテロスピロシクレニル、ヘテロスピロアリール、および−ＣＯ_２アルキルからなる群より独立して選択可能であり、ここで、Ｒ^５およびＲ^６は上記に定義した通りであり、ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is pyrazolyl, wherein said pyrazolyl can be unsubstituted or the same or may be substituted with one or more moieties which can be different, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, -NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl. R is unsubstituted alkyl Or alkyl substituted with one or more moieties, which may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), ^{-N (R 5) -C (O} ) oR 6, - (CH 2) is 1-3 -N ^(R 5 R ⁶⁾ and ^-NR 5 independently from the group consisting of ^{R 6} selected; ^{R 1} is H R ³ is heteroaryl-CH ₂ —X or heteroaryl-CHmethyl-X, wherein X is —NR ⁵ R ⁶ , R ⁵ is —alkylN (alkyl) ₂ , alkyl, Alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, where R ⁶ is hydrogen, alkyl, hydroxy Alkyl, alkoxyalkyl, or -alkylN (alkyl) ₂ ; or R ⁵ and R ⁶ can be optionally joined together with N in the —NR ⁵ R ⁶ to form a ring or a bridged ring, Wherein the ring or bridged ring may be one or more moieties that are unsubstituted or substituted, the moieties being the same or different, hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, Can be independently selected from the group consisting of aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl, and —CO ₂ alkyl, wherein R ⁵ and R ⁶ are as defined above; Here, R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２はピラゾリルであり、ここで、前記ピラゾリルは、非置換であり得るか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘであり、ここで、前記ヘテロアリール−ＣＨ_２−Ｘのヘテロアリールはアルキルまたは−ＣＯＮＲ^５Ｒ^６で置換され、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５はアルキルであり、Ｒ^６はアルキルであり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に任意に結合され、ヘテロシクリルを形成可能であり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is pyrazolyl, wherein said pyrazolyl can be unsubstituted or the same or may be substituted with one or more moieties which can be different, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, -NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl. R is unsubstituted alkyl Or alkyl substituted with one or more moieties, which may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), ^{-N (R 5) -C (O} ) oR 6, - (CH 2) is 1-3 -N ^(R 5 R ⁶⁾ and ^-NR 5 independently from the group consisting of ^{R 6} selected; ^{R 1} is H R ³ is heteroaryl-CH ₂ —X, wherein the heteroaryl of said heteroaryl-CH ₂ —X is substituted with alkyl or —CONR ⁵ R ⁶ , wherein X is —NR ⁵ R ⁶ , R ⁵ is alkyl, R ⁶ is alkyl; or R ⁵ and R ⁶ can be optionally joined together with N of said —NR ⁵ R ⁶ to form a heterocyclyl; wherein, ^{R 5} and ^{R 6} are as defined above It is as.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２はピラゾリルであり、ここで、前記ピラゾリルは、非置換であり得るか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is pyrazolyl, wherein said pyrazolyl can be unsubstituted or the same or may be substituted with one or more moieties which can be different, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, -NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl. R is unsubstituted alkyl Or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), ^{-N (R 5) -C (O} ) oR 6, - (CH 2) is 1-3 -N ^(R 5 R ⁶⁾ and ^-NR 5 independently from the group consisting of ^{R 6} selected; ^{R 1} is H R ³ is

で置換されたイソチアゾール、チオフェン、またはピリミジンであり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Isothiazole, thiophene, or pyrimidine substituted with; where R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２はピラゾリルであり、ここで、前記ピラゾリルは、非置換であり得るか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はフェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘであり、ここで、前記フェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘの各々の前記フェニルは非置換であり得るかまたはアルキルで置換可能であり、さらに、ここで、Ｘはピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルであり、ここで、前記ピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルの各々は非置換であり得るかまたはアルキルで置換可能であり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is pyrazolyl, wherein said pyrazolyl can be unsubstituted or the same or may be substituted with one or more moieties which can be different, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, -NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl. R is unsubstituted alkyl Or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), ^{-N (R 5) -C (O} ) oR 6, - (CH 2) is 1-3 -N ^(R 5 R ⁶⁾ and ^-NR 5 independently from the group consisting of ^{R 6} selected; ^{R 1} is H is a; ^{R 3} is phenyl -CH methyl -X or phenyl _-CH 2 -X, wherein said phenyl each of said phenyl -CH methyl -X or phenyl _-CH 2 -X may be a unsubstituted Or X is piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl, wherein said piperazinyl, pipera Sulfonyl (piperadinyl), pyrrolidinyl, morpholinyl or each thiomorpholinyl is possible or substituted with alkyl can be unsubstituted; wherein, ^{R 5} and ^{R 6} are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２はピラゾリルであり、ここで、前記ピラゾリルは、非置換であり得るか、または同じかもしくは異なり得る１個以上の部分で置換可能であり、各部分は、ハロ、アミド、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、−Ｃ（Ｏ）ＯＨ、−Ｃ（Ｏ）ＮＨ_２、−ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に環状アミンを形成する）、−ＣＮ、アリールアルキル、−ＣＨ_２ＯＲ^５、−Ｓ（Ｏ）Ｒ^５、−Ｓ（Ｏ_２）Ｒ^５、−ＣＮ、−ＣＨＯ、−ＳＲ^５、−Ｃ（Ｏ）ＯＲ^５、−Ｃ（Ｏ）Ｒ^５、ヘテロアリール、およびヘテロシクリルからなる群より独立して選択され；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is pyrazolyl, wherein said pyrazolyl can be unsubstituted or the same or may be substituted with one or more moieties which can be different, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -C (O) OH, -C (O) NH 2, -NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a cyclic amine), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl. R is unsubstituted alkyl Or alkyl substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), ^{-N (R 5) -C (O} ) oR 6, - (CH 2) is 1-3 -N ^(R 5 R ⁶⁾ and ^-NR 5 independently from the group consisting of ^{R 6} selected; ^{R 1} is H R ³ is

であり、ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Where R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘまたはヘテロアリール−ＣＨメチル−Ｘであり、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５は−アルキルＮ（アルキル）_２、アルキル、アルコキシアルキル、ヒドロキシアルキル、アリールアルキル、ヘテロシクレニルアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、または−アルキルＳＨであり、Ｒ^６は水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、または−アルキルＮ（アルキル）_２であり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、環または架橋環を形成可能であり、ここで、前記環または架橋環は、非置換であり得るか、または同じであり得るかもしくは異なり得る、ヒドロキシル、アルキル、アルコキシル、アルコキシルアルキル、ヒドロキシアルキル、アリールアルキル、アリール、ヘテロスピロシクリル、ヘテロスピロシクレニル、ヘテロスピロアリール、および−ＣＯ_２アルキルからなる群より独立して選択される１個以上の部分で置換可能であり；Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl or the same Alkyl substituted with one or more moieties that can be obtained or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ^{5 _{) -C (O) oR 6,}} - (CH 2) is 1-3 -N ^(R 5 R ⁶⁾ and ^-NR 5 independently from the group consisting of ^{R 6} selected; ^{R 1} is an H; ^{R 3} is heteroaryl _-CH 2 -X or heteroaryl -CH methyl -X, wherein, X is ^{-NR 5 R 6, R} 5 is - alkyl N _{(alkyl) 2,} alkyl, alkoxyalkyl, hydroxyalkyl , Arylalkyl, hetero Kure cycloalkenyl alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl or - alkyl SH, R ⁶ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or - an alkyl N (alkyl) _2; or R ⁵ and R ⁶ can be optionally joined together with N of the —NR ⁵ R ⁶ to form a ring or a bridged ring, wherein the ring or bridged ring can be unsubstituted or the same It is obtained to or may differ in, hydroxyl, alkyl, alkoxyl, alkoxyl alkyl, hydroxyalkyl, arylalkyl, aryl, heteroaryl scan Piroshi heterocyclylalkyl, heteroaryl spiro Shikure alkenyl, heteroaryl spiro aryl, and -CO ₂ independently from the group consisting of alkyl Can be replaced with one or more selected parts There; ^{R 5} and ^{R 6} are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘであり、ここで、前記ヘテロアリール−ＣＨ_２−Ｘのヘテロアリールはアルキルまたは−ＣＯＮＲ^５Ｒ^６で置換され、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５はアルキルであり、Ｒ^６はアルキルであり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、ヘテロシクリルを形成可能であり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl or the same Alkyl substituted with one or more moieties that may be obtained or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ ; independently selected; R ¹ is H; R ³ is heteroaryl _-CH 2 -X, wherein said heteroaryl heteroaryl _-CH 2 -X is substituted with alkyl or -CONR ⁵ R ^6, wherein, X is ^-NR 5 ^{R 6,} R ⁵ is alkyl, ^{R 6} is alkyl; Rui ^{R 5} and ^{R 6} are joined together to N and any of said ^-NR 5 ^{R 6,} is capable of forming a heterocyclyl; wherein, ^{R 5} and ^{R 6} is as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl or the same Alkyl substituted with one or more moieties that may be obtained or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ ; independently selected; R ¹ is H; R ³ Is

で置換されたイソチアゾール、チオフェン、またはピリミジンであり：ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Isothiazole, thiophene, or pyrimidine substituted with: wherein R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３はフェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘであり、ここで、前記フェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘの各々の前記フェニルは、非置換であり得るかまたはアルキルで置換可能であり、ここで、さらに、Ｘはピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルであり、前記ピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルの各々は、非置換であり得るかまたはアルキルで置換可能であり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl or the same Alkyl substituted with one or more moieties that can be obtained or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ ; independently selected; R ¹ is H; R ³ is phenyl -CH methyl -X or phenyl _-CH 2 -X, wherein said phenyl each of said phenyl -CH methyl -X or phenyl _-CH 2 -X is a possible or alkyl unsubstituted Where X is Perazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl, each of said piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl can be unsubstituted or substituted with alkyl; , R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、またはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルまたは同じであり得るかもしくは異なり得る１個以上の部分で置換されたアルキルであり、各部分は−ＯＲ^５、ヘテロシクリル、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｎ（Ｒ^５Ｒ^６）、−Ｎ（Ｒ^５）−Ｃ（Ｏ）ＯＲ^６、−（ＣＨ_２）_１−３−Ｎ（Ｒ^５Ｒ^６）および−ＮＲ^５Ｒ^６からなる群より独立して選択され；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl or the same Alkyl substituted with one or more moieties that may be obtained or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ⁶ ; independently selected; R ¹ is H; R ³ Is

であり、ここで、Ｒ^５およびＲ^６は前記に定義した通りである。

, And the wherein, R ⁵ and R ⁶ are as previously defined.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルであり；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘまたはヘテロアリール−ＣＨメチル−Ｘであり、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５は−アルキルＮ（アルキル）_２、アルキル、アルコキシアルキル、ヒドロキシアルキル、アリールアルキル、ヘテロシクレニルアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、または−アルキルＳＨであり、Ｒ^６は水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、または−アルキルＮ（アルキル）_２であり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、環または架橋環を形成可能であり、ここで、前記環または架橋環は、非置換であるか、または同じであるかもしくは異なり得る、ヒドロキシル、アルキル、アルコキシル、アルコキシルアルキル、ヒドロキシアルキル、アリールアルキル、アリール、ヘテロスピロシクリル、ヘテロスピロシクレニル、ヘテロスピロアリール、および−ＣＯ_２アルキルからなる群より独立して選択される１個以上の部分で置換可能であり；Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl; ¹ is H; R ³ is heteroaryl-CH ₂ —X or heteroaryl-CHmethyl-X, where X is —NR ⁵ R ⁶ and R ⁵ is —alkylN (alkyl) ₂ , alkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, Heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl or - alkyl SH, R ⁶ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or - an alkyl N _{(alkyl) 2;} or ^{R 5} and ^{R 6} N and any of said ^-NR 5 ^{R 6} Can be linked together to form a ring or bridged ring, wherein said ring or bridged ring can be unsubstituted or the same or different, hydroxyl, alkyl, alkoxyl, alkoxylalkyl, R ⁵ may be substituted with one or more moieties independently selected from the group consisting of hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl, and —CO ₂ alkyl; And R ⁶ is as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルであり；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘであり、ここで、前記ヘテロアリール−ＣＨ_２−Ｘのヘテロアリールはアルキルまたは−ＣＯＮＲ^５Ｒ^６で置換され、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５はアルキルであり、Ｒ^６はアルキルであり；あるいはＲ^５およびＲ^６は、上記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、ヘテロシクリルを形成し；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl; ¹ is H; R ³ is heteroaryl-CH ₂ —X, wherein the heteroaryl of said heteroaryl-CH ₂ —X is substituted with alkyl or —CONR ⁵ R ⁶ , wherein X is a -NR ⁵ R ^{6, R 5} is alkyl, ^{R 6} is alkyl; or ^{R 5} and ^{R 6} may bind together to N and any of the above ^-NR 5 ^{R 6,} form a heterocyclyl Where R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルであり；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl; ¹ is H; R ³ is

で置換されたイソチアゾール、チオフェン、またはピリミジンであり；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Isothiazole, thiophene, or pyrimidine substituted with; where R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルであり；Ｒ^１はＨであり；Ｒ^３はフェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘであり、ここで、前記フェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘの各々の前記フェニルは、非置換であるかまたはアルキルで置換可能であり、ここで、さらに、Ｘはピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルであり、前記ピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルの各々は、非置換であるかまたはアルキルで置換可能であり；
ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl; ¹ is an H; ^{R 3} is phenyl -CH methyl -X or phenyl _-CH 2 -X, wherein said phenyl each of said phenyl -CH methyl -X or phenyl _-CH 2 -X are non Substituted or alkylable, wherein X is piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl, said piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl Each may be unsubstituted or substituted with alkyl;
Here, R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒは非置換アルキルであり；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is unsubstituted alkyl; ¹ is H; R ³ is

である。

It is.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒはメチルであり；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘまたはヘテロアリール−ＣＨメチル−Ｘであり、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５は−アルキルＮ（アルキル）_２、アルキル、アルコキシアルキル、ヒドロキシアルキル、アリールアルキル、ヘテロシクレニルアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、または−アルキルＳＨであり、Ｒ^６は水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、または−アルキルＮ（アルキル）_２であり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、環または架橋環を形成可能であり、ここで、前記環または架橋環は、非置換であるか、または同じであるかもしくは異なり得る、ヒドロキシル、アルキル、アルコキシル、アルコキシルアルキル、ヒドロキシアルキル、アリールアルキル、アリール、ヘテロスピロシクリル、ヘテロスピロシクレニル、ヘテロスピロアリール、および−ＣＯ_２アルキルからなる群より独立して選択される１個以上の部分で置換可能であり；Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is methyl; R ¹ is H; R ³ is heteroaryl-CH ₂ —X or heteroaryl-CHmethyl-X, wherein X is —NR ⁵ R ⁶ , R ⁵ is —alkylN (alkyl) ₂ , alkyl , Alkoxyalkyl, hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, where R ⁶ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN _{(alkyl) 2;} or ^{R 5} and ^{R 6} are forming together N and any of said ^-NR 5 ^{R 6} Can form a ring or a bridged ring, wherein said ring or bridged ring can be unsubstituted or the same or different, hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, R ⁵ and R ⁶ may be substituted with one or more moieties independently selected from the group consisting of arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl, and —CO ₂ alkyl; Is as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒはメチルであり；Ｒ^１はＨであり；Ｒ^３はヘテロアリール−ＣＨ_２−Ｘであり、ここで、前記ヘテロアリール−ＣＨ_２−Ｘの上記ヘテロアリールは、アルキルもしくは−ＣＯＮＲ^５Ｒ^６で置換され、ここで、Ｘは−ＮＲ^５Ｒ^６であり、Ｒ^５はアルキルであり、Ｒ^６はアルキルであり；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して、ヘテロシクリルを形成し；ここで、Ｒ^５およびＲ^６は上記に定義した通りである。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is methyl; R ¹ is H; R ³ is heteroaryl-CH ₂ —X, wherein said heteroaryl of said heteroaryl-CH ₂ —X is substituted with alkyl or —CONR ⁵ R ⁶ , wherein X is a -NR ⁵ R ^{6, R 5} is alkyl, ^{R 6} is alkyl; or ^{R 5} and ^{R 6} are joined together to N and any of said ^-NR 5 ^{R 6,} form a heterocyclyl Where R ⁵ and R ⁶ are as defined above.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒはメチルであり；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is methyl; R ¹ is H; R ³ is

で置換されたイソチアゾール、チオフェン、またはピリミジンである。

Isothiazole, thiophene, or pyrimidine substituted with

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒはメチルであり；Ｒ^１はＨであり；Ｒ^３はフェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘであり、ここで、前記フェニル−ＣＨメチル−Ｘまたはフェニル−ＣＨ_２−Ｘの各々の前記フェニルは、非置換であるかまたはアルキルで置換可能であり、ここで、さらに、Ｘはピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルであり、前記ピペラジニル、ピペラジニル（ｐｉｐｅｒａｄｉｎｙｌ）、ピロリジニル、モルホリニル、またはチオモルホリニルの各々は、非置換であるかまたはアルキルで置換可能である。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is methyl; R ¹ is It is H; ^{R 3} is phenyl -CH methyl -X or phenyl _-CH 2 -X, wherein said phenyl each of said phenyl -CH methyl -X or phenyl _-CH 2 -X is unsubstituted Or X is piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl, each of said piperazinyl, piperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl. Can be unsubstituted or substituted with alkyl.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^２は１−Ｈ−ピラゾール−４−イルであり；Ｒはメチルであり；Ｒ^１はＨであり；Ｒ^３は

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ² is 1-H-pyrazol-4-yl; R is methyl; R ¹ is H; R ³ is

である。

It is.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^５はアルキルであり、Ｒ^６はアルコキシアルキル、ヒドロキシアルキル、シクロアルキルからなる群より選択され、ここで前記シクロアルキルはヒドロキシアルキルによって置換され；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと任意に一緒に結合して環を形成し、ここで前記環は、アルコキシアルキル、ヒドロキシアルキル、およびアルキルからなる群より独立して選択される１個以上の部分によって置換される。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ⁵ is alkyl and R ⁶ is selected from the group consisting of alkoxyalkyl, hydroxyalkyl, cycloalkyl Wherein said cycloalkyl is substituted by hydroxyalkyl; or R ⁵ and R ⁶ are optionally joined together with N of said —NR ⁵ R ⁶ to form a ring, wherein said ring is an alkoxyalkyl Substituted by one or more moieties independently selected from the group consisting of, hydroxyalkyl, and alkyl.

  In another embodiment, the present invention provides compounds of the formula:

の化合物、またはその薬学的に受容可能な塩、溶媒和物、もしくはエステルを開示し、ここで、Ｒ^５はメチル、エチル、またはプロピルであり；Ｒ^６は、エトキシエチル、１，１−ジメチルヒドロキシエチル、シクロペンチル、シクロヘキシルからなる群より選択され、ここで、前記シクロペンチルおよびシクロヘキシルの各々はヒドロキシメチルによって置換され；あるいはＲ^５およびＲ^６は、前記−ＮＲ^５Ｒ^６のＮと一緒に任意に結合されて環を形成し；ここで、前記環は、エトキシメチル、メトキシメチル、ヒドロキシメチル、およびメチルからなる群より独立して選択される１個以上の部分によって置換される。

Or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R ⁵ is methyl, ethyl, or propyl; R ⁶ is ethoxyethyl, 1,1-dimethyl Selected from the group consisting of hydroxyethyl, cyclopentyl, cyclohexyl, wherein each of said cyclopentyl and cyclohexyl is substituted by hydroxymethyl; or R ⁵ and R ⁶ are optionally together with N of said —NR ⁵ R ⁶ Bonded to form a ring; wherein said ring is substituted by one or more moieties independently selected from the group consisting of ethoxymethyl, methoxymethyl, hydroxymethyl, and methyl.

  Non-limiting examples of compounds of formula I include the following:

またはその薬学的に受容可能な塩、溶媒和物、エステル、もしくはプロドラッグ。

Or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

  As used above and throughout this disclosure, the following terms are to be understood to have the following meanings, including any possible substitution of the referenced groups or moieties, unless otherwise indicated.

  “Patient” includes both humans and animals.

  “Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. “Alkyl” may be unsubstituted or optionally substituted with one or more substituents, which may be the same or different, each substituent being halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, Alkoxy, alkylthio, amino, oxime (e.g., = N-OH), -NH (alkyl), -NH (cycloalkyl), -N (alkyl) ₂ , -O-C (O) -alkyl, -O-C It is independently selected from the group consisting of (O) -aryl, —O—C (O) -cycloalkyl, carboxy, and —C (O) O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and t-butyl.

  “Alkenyl” is an aliphatic carbonization containing at least one carbon-carbon double bond, which may be straight or branched and containing from about 2 to about 15 carbon atoms in the chain. It means a hydrogen group. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. “Alkenyl” may be unsubstituted or optionally substituted with one or more substituents, which may be the same or different, each substituent being halo, alkyl, aryl, cycloalkyl, cyano, alkoxy, And independently selected from the group consisting of —S (alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

  “Alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene, and propylene.

  “Alkynyl” is an aliphatic carbonization containing at least one carbon-carbon triple bond, which may be straight or branched, and containing from about 2 to about 15 carbon atoms in the chain. It means a hydrogen group. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, and 3-methylbutynyl. “Alkynyl” may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, each substituent independently from the group consisting of alkyl, aryl, and cycloalkyl. Selected.

  “Aryl” means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Aryl groups can be optionally substituted with one or more “ring system substituents” as defined herein, which can be the same or different. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

  A “bridged ring” is a hydrocarbon ring, such as cycloalkyl, cyclenyl, or aryl, or a valence bond that connects two different parts of the ring or a bridge that is an atom or an unbranched chain of atoms, or Or a heteroatom-containing ring such as heterocyclyl, heterocyclenyl, or heteroaryl. Two tertiary carbon atoms connected through a bridge are called “bridgeheads”.

  “Heteroaryl” refers to about 5 to about 14 ring atoms, preferably one or more ring atoms, alone or in combination, other than carbon, such as nitrogen, oxygen, or sulfur, preferably By aromatic monocyclic or polycyclic ring system containing about 5 to about 10 ring atoms. Preferred heteroaryls contain about 5 to about 6 ring atoms. “Heteroaryl” may be optionally substituted by one or more “ring system substituents” as defined herein, which may be the same or different. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen atom of the heteroaryl can be optionally oxidized to the corresponding N oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, Pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benz Imidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2, - triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

  “Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred aralkyl groups include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

  “Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls contain a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

  “Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl groups contain about 5 to about 7 ring atoms. Cycloalkyls can be optionally substituted by one or more “ring system substituents” as defined herein, which may be the same or different. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

  “Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyl include cyclohexylmethyl, adamantylmethyl and the like.

  “Cycloalkenyl” is a non-aromatic group containing from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, containing at least one carbon-carbon double bond. Means monocyclic or polycyclic. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted by one or more “ring system substituents” as defined above, which can be the same or different. Non-limiting examples of suitable monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

  “Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyl include cyclopentenylmethyl, cyclohexenylmethyl and the like.

  “Halogen” means fluorine, chlorine, bromine, or iodine. Preference is given to fluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. The ring system substituents may be the same or different and each is alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, Hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroary Ruthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, amide, -CHO, -O-C (O) -alkyl, -O- (O) - aryl, -O-C (O) - _{cycloalkyl, -C (= N-CN)} -NH 2, -C (= NH) -NH 2, -C (= NH) -NH ( alkyl) , oximes _{(e.g., = N-OH), Y} 1 Y 2 N-, Y 1 Y 2 N- alkyl _{-, Y 1 Y 2 NC (} O) -, Y 1 Y 2 NSO 2 - and _-SO 2 NY ₁ Y ₂ is independently selected from the group consisting of Y ₁ and Y ₂ can be the same or different and is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. “Ring system substituent” also refers to a single moiety that simultaneously replaces two available hydrogens on two adjacent carbon atoms of a ring system (one H on each carbon). Examples of such moiety are methylene dioxy, ethylenedioxy, -C _{(CH 3) 2} - and the like, it is, for example,

などの部分を形成する。

And so on.

  “Heteroarylalkyl” means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryl include 2-pyridinylmethyl, quinolinylmethyl and the like.

  “Heterocyclyl” means about 3 to about 10 ring atoms, preferably one or more atoms of the ring system, alone or in combination, other than carbon, such as nitrogen, oxygen, or sulfur, Means a non-aromatic saturated monocyclic or polycyclic ring system containing about 5 to about 10 ring atoms. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any —NH in the heterocyclyl ring may be present protected, eg, as a —N (Boc), —N (CBz), —N (Tos) group, etc .; Considered part of the invention. A heterocyclyl can be optionally substituted by one or more “ring system substituents” as defined herein, which can be the same or different. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” also refers to a single moiety (eg, carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom of a ring system. Examples of such parts are pyrrolidone:

である。

It is.

  “Heterocyclylalkyl” means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyl include piperidinylmethyl, piperazinylmethyl and the like.

  “Heterocyclenyl” is an element other than carbon, such as nitrogen, oxygen, or sulfur, in which one or more atoms of the ring system, alone or in combination, and at least one carbon-carbon double bond or carbon- By non-aromatic monocyclic or polycyclic ring system containing from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms, containing a nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3, 6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl , 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo [2.2.1] heptenyl, dihydrothiophenyl, dihydrothiopyranyl and the like. “Heterocyclenyl” also refers to a single moiety (eg, carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom of a ring system. Examples of such moieties are pyrrolidinone:

である。

It is.

  “Heterocyclenylalkyl” means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.

  In a heteroatom comprising a ring system of the present invention, there is no hydroxyl group on the carbon atom adjacent to N, O, or S, and there is no N or S group on the carbon adjacent to another heteroatom. Should be noted. Thus, for example, the ring:

において、２および５とマークした炭素に直接結合する−ＯＨは存在しない。

There is no —OH attached directly to the carbons marked 2 and 5.

  Also tautomeric forms such as moieties:

は、本発明の特定の実施形態において、等価であると見なされることが注目されるべきである。

It should be noted that are considered equivalent in certain embodiments of the invention.

  “Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls include lower alkynyl and lower alkyl groups. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

  “Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

  A “spiro ring system” has two or more rings connected by one common atom. Preferred spiro ring systems include spiroheteroaryl, spiroheterocyclenyl, spiroheterocyclyl, spirocycloalkyl, spirocyclenyl, and spiroaryl. Spiro ring systems can be optionally substituted with one or more ring system substituents, wherein “ring system substituent” is as defined above. Non-limiting examples of suitable spiro ring systems include

スピロ［４．５］デカン、

Spiro [4.5] decane,

８−アザスピロ［４．５］デサ−２−エン、および

8-azaspiro [4.5] des-2-ene, and

スピロ［４．４］ノナ−２，７−ジエンが含まれる。

Spiro [4.4] nona-2,7-diene is included.

  “Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previously defined. Preferred hydroxyalkyl include lower alkyl. Non-limiting examples of suitable hydroxyalkyl include hydroxymethyl and 2-hydroxyethyl.

  “Acyl” means HC (O) —, alkyl-C (O) —, or cycloalkyl-C (O) —, wherein the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls include lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, and propanoyl.

  “Aroyl” means an aryl-C (O) — group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups are benzoyl and 1-naphthoyl.

  “Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. The bond to the parent moiety is through ether oxygen.

  “Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through ether oxygen.

  “Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through ether oxygen.

  “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through sulfur.

  “Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through sulfur.

  “Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkylthio groups include benzylthio. The bond to the parent moiety is through sulfur.

  “Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

  “Aryloxycarbonyl” means an aryl-O—C (O) — group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

  “Aralkoxycarbonyl” means an aralkyl-O—C (O) — group. Non-limiting example of a suitable aralkoxycarbonyl group includes benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S (O ₂ ) — group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

“Arylsulfonyl” means an aryl-S (O ₂ ) — group. The bond to the parent moiety is through the sulfonyl.

  The term “substituted” means that one or more hydrogens on a specified atom are removed from the indicated group, provided that the normal valence in the existing environment of the specified atom is not exceeded. Means that this substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

  The term “optionally substituted” means optional substitution with a particular group, radical, or moiety.

  The term “purified”, “purified form”, or “isolated and purified form” for a compound was isolated from a synthetic process (eg, from a reaction mixture) or from a natural source or combination thereof. Later, it refers to the physical state of the compound. Thus, the term “purified”, “purified form”, or “isolated and purified form” for a compound is characterized by standard analytical techniques as described herein or well known to those of skill in the art. Physics of the compound after it has been obtained from a purification process described herein or well known to those skilled in the art (eg, chromatography, recrystallization, etc.) with sufficient purity to be attachable State.

  In the text, schemes, examples and tables herein, any carbon and heteroatom having an unsaturated valence is assumed to have a sufficient number of hydrogen atoms to saturate the valence. It should also be noted.

  When a functional group in a compound is referred to as “protected”, this means that the group is in a modified form to eliminate unwanted side reactions at the protected site when the compound is subjected to reaction. means. Suitable protecting groups are known by those skilled in the art as well as, for example, W. Recognized by reference to standard textbooks such as Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

When any variable (eg, aryl, heterocycle, R ^2, etc.) occurs more than once in any configuration of Formula I, its definition for each occurrence is independent of its definition in all other occurrences. ing.

  As used herein, the term “composition” refers to a product that contains a specific amount of a specific component, as well as any product that results directly or indirectly from a combination from a specific amount of a specific component. Intended to include objects.

Prodrugs and solvates of the compounds of the invention are also contemplated by the invention. The discussion of prodrugs is discussed in T.W. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 theA. C. S. Symposium Series and Bioreversible Carriers in Drug Design (1987) Edward B. Supplied in the Roche edition, American Pharmaceutical Association and Pergamon Press. The term “prodrug” refers to a compound that is converted in vivo to yield a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate of the compound (eg, a drug precursor). Body). This conversion can occur by various mechanisms (eg, by metabolic or chemical processes), for example through hydrolysis in the blood. A discussion of the use of prodrugs is found in T.W. Higuchi and W.H. Stella “Pro-drugs as Novel Delivery Systems” Vol. 14 the A.E. C. S. Symposium Series and Bioreversible Carriers in Drug Design, Edward B. Supplied by Roche Ed, American Pharmaceutical Association and Pergamon Press, 1987.

For example, when a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, a prodrug is, for example, (C ₁ -C ₈ ) _alkyl, (C 2 _{-C 12)} alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 5 to 10 pieces of 1-methyl-1- (alkanoyl having carbon atoms Oxy) -ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1 having 5 to 8 carbon atoms -Methyl-1- (alkoxycarbonyloxy) ethyl, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 4 to 10 carbon atoms Having 1- (N- (alkoxycarbonyl) amino) ethyl, 3-phthalidyl, 4-crotonolactonyl, gamma - butyrolactone-4-yl, di _{-N, N- (C 1 -C 2} ) alkylamino (C ₂ -C ₃ ) alkyl (eg, β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C1-C2) alkyl, and piperidino -, pyrrolidino -, or morpholino (C 2 _{-C 3)} may comprise an ester formed by the replacement of the hydrogen atom of the acid group by groups such as alkyl.

Similarly, when the compound of formula (I) contains an alcohol functional group, the prodrug is, for example, (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆ ) alkanoyloxy) ethyl, 1 - methyl _{-1 - ((C 1 -C 6} ) alkanoyloxy) _{ethyl, (C} 1 -C ₆₎ alkoxycarbonyloxymethyl, N- _(C 1 -C ₆₎ alkoxycarbonylamino-methyl, succinoyl, _{(C 1} - C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanyl, arylacyl, and α-aminoacyl, or α-aminoacyl-α-aminoacyl, can be formed by replacement of a hydrogen atom of an alcohol group, Here, each α-aminoacyl group is a naturally occurring L-amino acid, P (O) (OH) ₂ , —P (O) ( O (C ₁ -C ₆ ) alkyl) ₂ or glycosyl (group resulting from removal of the hydroxyl group of a hemiacetal-type carbohydrate) or the like.

If the compound of formula (I) contains an amine function, a prodrug can be formed, for example, by replacement of the hydrogen atom of the amine group with a group such as: R-carbonyl, RO-carbonyl, NRR′-carbonyl Where R and R ′ are each independently (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or Natural α-aminoacyl, —C (OH) C (O) OY ¹ , where Y ¹ is H, (C ₁ -C ₆ ) alkyl, or benzyl, —C (OY ² ) Y ³ Where Y ² is (C ₁ -C ₄ ) alkyl and Y ³ is (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl or Mono- -N- or di -N, a N- _(C 1 -C ₆₎ ^{alkylaminoalkyl, -C (Y 4) Y 5} , wherein, ^{Y 4} is H or methyl and ^{Y 5} is mono - N- or di _{-N, N- (C 1 -C 6} ) alkylamino, morpholino, piperidin-1-yl, or pyrrolidin-1-yl, and the like.

One or more compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Includes both solvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvated molecules are incorporated into the crystalline lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate and the like. “Hydrate” is a solvate wherein the solvent molecule is H ₂ O.

One or more compounds of the invention may optionally be converted to a solvate. The preparation of solvates is generally known. Thus, for example, M.I. Caira et al. Pharmaceutical Sci. , 93 (3) . 601-611 (2004) describes the preparation of a solvate of the antifungal agent fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in E. C. van Tonder et al., AAPS PharmSciTech. , 5 (1) , article 12 (2004); L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting process involves dissolving the compound of the invention in a desired amount of the desired solvent (organic solvent or water or mixtures thereof) at a temperature above ambient and forming crystals. Cooling the solution at a rate sufficient to allow the crystals to be isolated by standard methods. For example, analytical techniques such as infrared spectroscopy show the presence of the solvent (or water) in the crystal as a solvate (or hydrate).

  An “effective amount” or “therapeutically effective amount” is an effective amount of the present invention that is effective in inhibiting the above-mentioned diseases and thus producing the desired medical, ameliorative, inhibitory, or prophylactic effect. It is meant to describe the amount of the compound or composition.

  Compounds of formula I are capable of forming salts, which are also within the scope of the invention. References to compounds of formula I of the present invention are understood to include references to salts thereof, unless otherwise indicated. The term “salt” as used herein refers to acidic salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula I contains both a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety such as, but not limited to, a carboxylic acid, Salt), which is included within the term “salt” as used herein. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful. A salt of a compound of formula I is, for example, in a medium in which the salt precipitates, or in a medium in which subsequent lyophilization is carried out, with a certain amount, for example an equivalent amount of an acid or base, of formula I It may be formed by reacting a compound.

Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate Acid salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylic acid Salts, succinates, sulfates, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In addition, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are, for example, P.I. Stahl et al., Camille G. et al. (Eds) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. et al. of Pharmaceuticals (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Doo. Is discussed. These disclosures are incorporated herein by reference thereto.

  Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, dicyclohexylamine, t-butylamine, and the like. Salts with organic bases (eg, organic amines) and salts with amino acids such as arginine and lysine are included. Basic nitrogen-containing groups include lower alkyl halides (eg, methyl, ethyl, and butyl chloride, bromide, and iodide), dialkyl sulfates (eg, dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long chains It may be quaternized with halides (eg, decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (eg, benzyl bromide and phenethyl bromide), and other agents.

  All such acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acidic and basic salts are intended for the purposes of the present invention. Is considered equivalent to the free form of the corresponding compound.

The pharmaceutically acceptable esters of the compounds of the present invention include the following groups: (1) Carboxylic acid esters obtained by esterification of hydroxy groups, wherein the non-carbonyl part of the ester group part of the carboxylic acid is Linear or branched alkyl (eg acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg Carboxylic acid esters selected from phenoxymethyl), aryl (eg, halogen, C _1-4 alkyl, or optionally substituted with C _1-4 alkoxy or amino, eg, phenyl); (2) alkyl- or aralkyl Sulfonic esters such as sulfonyl (eg methanesulfonyl) (3) amino acid esters (e.g., L- valyl or L- isoleucyl); (4) phosphonate esters and (5) mono-, - di - or triphosphate esters. The phosphate ester may be further esterified, for example, with a C _1-20 alcohol or a reactive derivative thereof, or with a 2,3-di (C _6-24 ) acylglycerol.

  Compounds of formula I and their salts, solvates, esters, and prodrugs may exist as their tautomeric forms (eg, amides or imino ethers). All such tautomeric forms are contemplated by the present invention as part of the present invention.

  The compounds of formula (I) may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of formula (I), as well as their mixtures, including racemic mixtures, form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers. For example, where a compound of formula (I) incorporates a double bond or fused ring, both cis and trans forms, as well as mixtures, are included within the scope of the present invention.

  Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their individual chemical differences by methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization. is there. Enantiomers convert an enantiomer mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or an acid chloride of Mosher), separating the diastereomers, and Individual diastereomers can be separated by conversion (eg, hydrolysis) to the corresponding pure enantiomers. Also, some of the compounds of formula (I) may be atropisomers (eg, substituted biaryls) and are considered part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

  The compounds of formula (I) may exist in different tautomeric forms and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine type compounds are included in the present invention.

  All stereoisomers (eg, geometric isomers, optical isomers) of the compounds of the present invention (including salts, solvates, esters, and prodrugs of the compound, and salts, solvates, and esters of the prodrug) Asymmetric on various substituents, including, for example, enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotamer forms, atropisomers, and diastereomeric forms What may exist due to carbon is intended within the scope of the present invention (eg, two compounds of formula (I), as well as positional isomers (eg, 4-pyridyl, 3-pyridyl, etc.)). When incorporating a heavy bond or fused ring, both cis and trans forms, as well as mixtures, are encompassed within the scope of the invention, eg, all keto-enol forms and compounds of the compound. Down - enamine type are included in the present invention). Individual stereoisomers of the compounds of the invention may be substantially free of other isomers, for example, or may be, for example, as a racemic mixture, or all other or other selected stereoisomers. May be mixed with the body. The chiral centers of the present invention can have the S and R configurations as defined by the IUPAC 1974 Recommendations. The use of terms such as “salts”, “solvates”, “esters”, “prodrugs”, enantiomers, stereoisomers, rotational isomers, tautomers, regioisomers, racemates of the compounds of the invention. It is intended to apply equally to mixtures, or salts, solvates, esters, and prodrugs of prodrugs.

The present invention also encompasses isotope-labeled compounds of the present invention, in which one or more atoms have an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Except for the fact that it is replaced by the same as those listed herein. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, nitrogen, phosphorus, fluorine, and chlorine isotopes, eg, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ , respectively. N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl are included.

Compounds labeled with certain isotopes of formula (I) (eg, compounds labeled with ³ H and ¹⁴ C) are useful in compound and / or substrate tissue distribution assays. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (ie ² H) has certain therapeutic benefits resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements). May therefore be preferred in certain situations. Isotopically labeled compounds of formula (I) are generally not labeled with an isotope by following procedures similar to those disclosed in the schemes and / or examples herein below. It can be prepared by replacing the reagent with a reagent labeled with the appropriate isotope.

  Polymorphic forms of the compound of formula I, as well as polymorphic forms of the salts, solvates, esters, and prodrugs of the compound of formula I are intended to be included in the present invention.

  The compounds according to the invention have pharmacological properties; in particular, the compounds of formula I may be protein kinase inhibitors, modulators or modifiers. Non-limiting examples of protein kinases that can be inhibited, regulated, or modified include: cyclin dependent kinases (CDKs), eg, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, and CDK7, CDK8, mitogen activated protein kinase (MAPK / ERK), glycogen synthase kinase 3 (GSK3beta), Pim-1 kinase, Chk kinase (eg Chk1 and Chk2), tyrosine kinase, eg HER subfamily (eg EGFR (eg EGFR ( HER1), HER2, HER3, and HER4), insulin subfamily (eg, including INS-R, IGF-IR, IR, and IR-R), PDGF subfamily (eg, PDGF-alpha and Including beta receptor, CSFIR, c-kit, and FLK-II), FLK family (eg, kinase insert domain receptor (KDR), fetal liver kinase-1 (including FLK-1), fetal liver kinase-4) (Including FLK-4), and fms-like tyrosine kinase-1 (flt-1)), non-receptor protein tyrosine kinases such as LCK, Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak , Jak, Ack, and LIMK, growth factor receptor tyrosine kinases such as VEGF-R2, FGF-R, TEK, Akt kinase, Aurora kinase (Aurora A, Aurora B, Aurora C) and the like.

The compound of formula I may be an inhibitor of a protein kinase, for example an inhibitor of a checkpoint kinase such as Chk1, Chk2, etc. Preferred compounds may exhibit IC ₅₀ values of less than about 5 μm, preferably from about 0.001 to about 1.0 μm, more preferably from about 0.001 to about 0.1 μm. The assay method is described in the examples given below.

Compounds of formula I may be used in cancer, autoimmune diseases, viral diseases, fungal diseases, neurological / neurodegenerative disorders, arthritis, inflammation, antiproliferative diseases (eg ocular retinopathy), neuronal cell diseases, alopecia And in the treatment of proliferative diseases such as cardiovascular disease. Many of these diseases and disorders are listed in US Pat. No. 6,413,974, cited earlier, which is incorporated herein by reference.

More specifically, compounds of formula I may be useful in the treatment of various cancers including (but not limited to):
Bladder tumor, breast tumor (including BRCA mutant breast cancer), colorectal tumor, colon tumor, kidney tumor, liver tumor, lung tumor, small cell lung cancer, non-small cell lung cancer, head and neck tumor, esophageal tumor, bladder tumor, gallbladder tumor Skin tumors, including ovarian tumors, pancreatic tumors, gastric tumors, cervical tumors, thyroid tumors, prostate tumors, and squamous cell carcinomas;
Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkitt lymphoma;
Chronic lymphocytic leukemia ("CLL");
Acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
Fibrosarcoma, rhabdomyosarcoma;
Head and neck cancer, mantle cell lymphoma, myeloma;
Astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glioma, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor (“GIST”), and schwannoma;
Melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xeroderoma pigmentosum, keratocantoma, thyroid follicular carcinoma, and Kaposi's sarcoma.

  In general, due to the key role of kinases in the regulation of cell proliferation, inhibitors are reversible cytostatics that may be useful in the treatment of any disease process characterized by abnormal cell proliferation Can act as This disease process is for example: benign prostatic hypertrophy, familial adenomatous polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, angioplasty or Restenosis after vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxic shock, and fungal infection.

Compounds of formula I are also useful in the treatment of Alzheimer's disease, as suggested by recent findings that CDK5 is involved in tau protein phosphorylation (J. Biochem (1995) 117 , 741-749). possible.

  The compound of formula I may induce or inhibit apoptosis. Apoptotic responses are abnormal in various human diseases. Compounds of formula I as modulators of apoptosis are useful in the following therapies: cancer (including but not limited to the types referred to herein above), viral infections (herpesviruses, poxviruses) , Including but not limited to, Epstein-Barr virus, Sindbis virus, and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (systemic lupus, lupus erythematosus, autoimmune mediated glomerulonephritis, joints) Including, but not limited to, rheumatism, psoriasis, inflammatory bowel disease, and autoimmune diabetes, neurodegenerative diseases (Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa) , Including spinal muscular atrophy, and cerebellar degeneration Not defined), myelodysplastic syndrome, aplastic anemia, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, blood disease (chronic) Including but not limited to anemia and aplastic anemia), musculoskeletal degenerative diseases (including but not limited to osteoporosis and arthritis), aspirin-sensitive sinusitis, cystic fibrosis, multiple sclerosis Disease, kidney disease, and cancer pain.

  The compounds of formula I can modulate the level of cellular RNA and DNA synthesis as inhibitors of kinases. Therefore, these agents are useful in the treatment of viral infections, including but not limited to HIV, human papillomavirus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus, and adenovirus.

  The compounds of formula I may also be useful in the chemoprevention of cancer. Chemoprophylaxis is the prevention of invasive cancers by either blocking mutagenic events, blocking the progression of premalignant cells already suffering from damage, or inhibiting tumor recurrence. Defined as inhibiting development.

  The compounds of formula I may also be useful in inhibiting tumor angiogenesis and metastasis.

  Compounds of formula I are cyclin dependent kinases and other protein kinases such as protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, It can also act as an inhibitor of Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.

  Another aspect of the invention comprises administering to a mammal a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug of said compound. A method of treating a mammal (eg, a human) having a disease or condition associated with a kinase (eg, CDK, CHK, and Aurora kinase).

  A preferred dosage is about 0.001 to 1000 mg / kg body weight / day of a compound of formula I. An especially preferred dosage is about 0.01 to 25 mg / kg body weight / day of a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound.

  The compounds of the present invention may also be combined (administered together or sequentially) with one or more anticancer therapies, eg, radiation therapy, and / or one or more anticancer agents different from the compound of formula I. Can be useful. The compounds of the invention can be present in the same dosage unit as the anticancer agent or in separate dosage units.

  Another aspect of the present invention is a compound of Formula I, or an amount of a first compound that is a pharmaceutically acceptable salt, solvate, ester, or prodrug of the above compound; and Comprises administering to a mammal in need of such treatment at least one fixed amount of a second compound that is a different anticancer agent, wherein said first compound and second compound of said An amount is a method of treating one or more diseases associated with kinases (eg, CDK, CHK, and Aurora) that produce a therapeutic effect.

  Non-limiting examples of suitable anticancer agents are selected from the group consisting of: cytostatic, cisplatin, doxorubicin, liposomal doxorubicin (eg, Caelix®, Myocet ( Registered trademark), Doxil (registered trademark)), taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methoxytrexate, temozolomide, cyclophosphamide, SCH 66336, R115777 (registered trademark), L778, 123 (registered trademark), BMS 214662 (registered trademark), Iressa (registered trademark), Tarceva (registered trademark), Antibodies against EGFR, antibodies against IGFR (including, for example, those published in US Patent Application Publication No. 2005/0136063 published on June 23, 2005), KSP inhibitors (eg, International Publication No. Such as those published in 099962 and WO 2006/098961; ispinesive, such as SB-743921 from Cytokinetics), centrosome-associated protein E (“CENP-E”) inhibitors (eg, GSK-923295), Gleevec®, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipbloman, triethylene melami , Triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucobilin, ELOXATIN (trademark), pentostatin, vinblastine , Vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, Fluoxymesterone, drmostanolone propionate, test lactone Megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea , Amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, nabelben, anastrazole, letrazol, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexer, bortezomib ("Velcade"), zevaline, trisenox , Xeloda, vinorelbine, porfimer, erbitux, liposomal, thio Pa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfamide, Rituximab, C225 (registered trademark), Satriplatin, Milotag, Avastin, Rituxan, Panitubimab, Stent, Sorafinib, Spliceb (Dastinib) , Nilotinib, Tie curve (Lapatinib), and Campus.

When formulated in a fixed dose, such combination products may produce a dosage range of a compound herein, as described herein, and other pharmaceutically active agents, or treatment of that dosage range. Is used. For example, the CDC2 inhibitor oromsin has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897). Compounds of formula I may also be administered continuously with known anticancer or cytotoxic agents if a combination formulation is inappropriate. The present invention is not limited in the order of administration; the compound of formula I may be administered either before or after administration of a known anti-cancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the order of administration of anticancer agents. Cancer Research, (1997) 57 , 3375. Such techniques are within the scope of those skilled in the art as well as attending physicians.

  Accordingly, in one aspect, the invention provides an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and an amount of one or more. Anti-cancer treatments and combination treatments comprising the anti-cancer agents listed above, wherein the amount of compound / therapeutic produces the desired therapeutic effect.

  Another aspect of the invention is the step of administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of inhibiting one or more Aurora kinases in the patient.

  Another aspect of the invention includes the step of administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of treating or delaying the progression of a disease associated with one or more aurora kinases in a patient.

  Yet another aspect of the invention is an amount of a first compound that is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and at least one that is an anticancer agent. Administering an amount of a second compound to a mammal in need of such treatment, wherein the amounts of the first compound and the second compound produce a therapeutic effect, A method of treating one or more diseases associated with the disease.

  Another aspect of the present invention combines at least one pharmaceutically acceptable carrier and at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. Administering a therapeutically effective amount of a pharmaceutical composition comprising treating a disease associated with one or more aurora kinases in a patient in need thereof, or delaying its progression.

  In the above method, the Aurora kinase that is inhibited can be Aurora A, Aurora B, and / or Aurora C.

  Another aspect of the invention is the step of administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of inhibiting one or more checkpoint kinases in the patient.

  Another aspect of the invention includes the step of administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of treating or delaying the progression of a disease associated with one or more checkpoint kinases in a patient.

  Yet another aspect of the invention is an amount of a first compound that is a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and at least one anticancer agent. Administering a quantity of a second compound to a mammal in need of such treatment, wherein the amounts of the first compound and the second compound produce a therapeutic effect. A method of treating one or more diseases associated with a kinase.

  Another aspect of the present invention combines at least one pharmaceutically acceptable carrier and at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. Administering a therapeutically effective amount of a pharmaceutical composition comprising treating a disease associated with one or more checkpoint kinases in a patient in need thereof, or delaying its progression.

  In the above method, the checkpoint kinase to be inhibited can be Chk1 and / or Chk2.

  Another aspect of the invention is the step of administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of inhibiting one or more cyclin dependent kinases in the patient.

  Another aspect of the invention includes the step of administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of treating or delaying the progression of a disease associated with one or more cyclin dependent kinases in a patient.

  Yet another aspect of the invention is an amount of a first compound that is a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and at least one anticancer agent. Administering a quantity of a second compound to a mammal in need of such treatment, wherein the amount of the first compound and the second compound is cyclin-dependent, producing a therapeutic effect. A method of treating one or more diseases associated with sex kinases.

  Another aspect of the present invention combines at least one pharmaceutically acceptable carrier and at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. Administering a therapeutically effective amount of a pharmaceutical composition comprising treating a disease associated with one or more cyclin dependent kinases in a patient in need thereof, or delaying its progression.

  In the above method, the cyclin dependent kinase to be inhibited can be CDK1 and / or CDK2.

  Another aspect of the invention is the step of administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of inhibiting one or more tyrosine kinases in the patient.

  Yet another aspect of the invention includes administering a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, A method of treating or delaying progression of a disease associated with one or more tyrosine kinases in a patient in need.

  Another aspect of the invention is an amount of a first compound that is a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and at least one anticancer agent. Administering a quantity of a second compound to a mammal in need of such treatment, wherein the amount of the first compound and the second compound is a tyrosine kinase that produces a therapeutic effect; A method of treating one or more related diseases.

  Another aspect of the present invention combines at least one pharmaceutically acceptable carrier and at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. Administering a therapeutically effective amount of a pharmaceutical composition comprising treating a disease associated with one or more tyrosine kinases in a patient in need thereof, or delaying its progression.

  In the above method, the tyrosine kinase can be VEGFR (VEGF-R2), EGFR, HER2, SRC, JAK, and / or TEK.

  Another aspect of the invention is the step of administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. A method of inhibiting one or more Pim-1 kinases in the patient.

  Yet another aspect of the invention includes administering a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, A method of treating or delaying the progression of one or more Pim-1 kinase associated diseases in a patient in need thereof.

  Another aspect of the invention is an amount of a first compound that is a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and at least one anticancer agent. Administering a quantity of a second compound to a mammal in need of such treatment, wherein the amounts of the first compound and the second compound produce a therapeutic effect, Pim-1 A method of treating one or more diseases associated with a kinase.

  Another aspect of the present invention combines at least one pharmaceutically acceptable carrier and at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. Administering a therapeutically effective amount of a pharmaceutical composition comprising treating a disease associated with one or more Pim-1 kinases in a patient in need thereof, or delaying its progression.

  The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays described herein below have been carried out using the compounds of the invention and their salts, solvates, esters, or prodrugs.

  The present invention also relates to pharmaceutical compositions comprising at least one compound, or a salt, solvate, ester, or prodrug of the above compound, and at least one pharmaceutically acceptable carrier.

  For preparing pharmaceutical compositions from the compounds described by this invention, inert pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may be comprised of from about 5 to about 95% active ingredient. Suitable solid carriers are known in the art, eg, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Pharmaceutically acceptable carriers and methods for preparing various compositions are described in A. Gennaro (eds.), Remington's Pharmaceutical Sciences, 18th Edition, (1990) Mack Publishing Co. , Easton, Pennsylvania.

  Liquid form preparations include solutions, suspensions, and emulsions. By way of example, mention may be made of water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

  Aerosol preparations suitable for inhalation may include liquid and powder type solids, which may be combined with a pharmaceutically acceptable carrier such as an inert compressed gas, for example nitrogen. .

  Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

  The compounds of the invention may also be deliverable transdermally. Transdermal compositions can take the form of creams, lotions, aerosols, and / or emulsions and can be included in the matrix or reservoir form of transdermal patches, as is conventional in the art for this purpose.

  The compounds of the present invention may also be delivered subcutaneously.

  Preferably the compound is administered orally or intravenously.

  A delivery method that is a combination of the delivery methods described above is also contemplated. Such methods are typically determined by those skilled in the art.

  Preferably, the pharmaceutical preparation is in unit dosage form. In such dosage forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, eg, an effective amount to achieve the desired purpose.

  The amount of active compound in a unit dose preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. .

  The actual dose utilized may vary depending on the requirements of the patient and the severity of the condition being treated. Determination of an appropriate dosing regimen for a particular situation is within the skill of the art. For convenience, the entire daily dosage may be divided and administered in portions during the day as needed.

  The amount and frequency of administration of the compounds of the invention and / or pharmaceutically acceptable salts thereof will depend on such factors as the patient's age, condition, and size, and the severity of the symptoms being treated, It is adjusted according to the judgment of the attending physician. A typical recommended daily dosage regimen for oral administration is in the range of about 1 mg / day to about 500 mg / day, preferably 1 mg / day to 200 mg / day, in 2 to 4 divided doses. obtain.

  Another aspect of the invention is a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester, or prodrug of the above compound, and a pharmaceutically acceptable A kit containing a carrier, vehicle, or diluent.

  Yet another aspect of the present invention is a fixed amount of at least one compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, and at least one quantifiable amount. Anti-cancer treatments and / or kits comprising the anti-cancer agents listed above, wherein the amount of two or more components produces the desired therapeutic effect.

  The invention disclosed herein is exemplified by the following preparations and examples, which should not be considered as limiting the scope of the disclosure. Alternative mechanistic pathways and similar structures will be apparent to those skilled in the art.

When NMR data is presented, ¹ H spectra are obtained on either Varian VXR-200 (200 MHz, ¹ H), Varian Gemini-300 (300 MHz), or XL-400 (400 MHz) and from Me ₄ Si. Ppm in the downstream region, with the number of protons in brackets, multiplicity, and coupling constant in hertz. When LC / MS data is presented, the analysis was performed on an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33 mm × 7 mm ID; gradient flow: 0 min-10% CH ₃ CN, 5 min _-95% CH 3 CN, 7 min _-95% CH 3 CN, 7.5 min _-10% CH 3 CN, 9 min - were performed using a stop. The retention time and observed parent ion are given.

The following solvents and reagents may be cited by their abbreviations in parentheses:
Thin layer chromatography: TLC
Dichloromethane: CH ₂ Cl ₂
Ethyl acetate: AcOEt or EtOAc
Methanol: MeOH
Trifluoroacetic acid: TFA
Triethylamine: Et ₃ N or TEA
Butoxycarbonyl: n-Boc or Boc
Nuclear magnetic resonance spectrum analysis: NMR
Liquid chromatography mass spectrometry: LCMS
High resolution mass spectrometry: HRMS
Milliliters: mL
Mmol: mmol
Microliter: μl
Gram: g
Milligrams: mg
Room temperature or rt (atmosphere): about 25 ° C
Dimethoxyethane: DME
The synthesis of the compounds of the present invention is illustrated below. It should also be noted that the disclosures of commonly owned US Pat. No. 6,919,341 and US patent application Ser. No. 11 / 598,186 are incorporated herein by reference.

( Example 1 )

パートＡ：米国特許出願公開第２００６０１０６０２３（Ａ１）号に従って調製した。

Part A: Prepared according to US Patent Application Publication No. 20060106023 (A1).

Part B: To a solution of the compound from Example 1, Part A (2.00 g, 8.19 mmol) in DMF (50 mL) was added N-iodosuccinimide (1.84 g, 8.19 mmol). The reaction mixture was stirred at 60 ° C. for 16 hours. The mixture was cooled to 25 ° C. and concentrated. The residue was dissolved in DCM with a small amount of methanol and then loaded onto the column. Purification by column chromatography _(SiO 2, 40% ethyl acetate / hexane) gave 2.30 g (76%) of compound 4 as a white solid.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．８７分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ７Ｈ５ＢｒＩＮ３Ｓの質量計算値３７０．０１、実測値ＬＣ／ＭＳ ｍ／ｚ ３７０．９（Ｍ＋Ｈ）。

_HPLC-MS t R = 1.87 min _{(UV 254nm).} Mass calculated for chemical formula C7H5BrIN3S 370.01, found LC / MS m / z 370.9 (M + H).

Part C: Suspension of bromide from Part B in DMF (410 mL) (45.6 g), Pd (PPh ₃ ) ₄ (10.8 g), potassium carbonate (77.4 g), trimethylboroxine (46 .9 g), and potassium carbonate (77.4 g) were heated at 105 ° C. overnight under nitrogen. After cooling, the mixture was diluted with ethyl acetate (1 L), washed with brine (2 × 500 mL), dried (magnesium sulfate), filtered, concentrated and purified by chromatography on silica gel. The title compound was obtained as a pale yellow solid (21.4 g, 64%).

  Part D: To a solution of the compound from Example 1, Part C (21.8 g) in DMF (400 mL) was added N-iodosuccinimide (26.9 g) and the resulting mixture was heated at 60 ° C. overnight. did. The mixture was concentrated and water (400 mL) was added. After stirring for 1 hour at room temperature, saturated sodium carbonate was added (250 mL) followed by another 30 minutes of stirring at room temperature. The mixture was filtered and washed with water, methanol (100 mL) and the filter cake was dried overnight under vacuum. A brown solid was obtained (31.4 g, 87%).

Part E: In a flask, the iodide from Part D (1.00 eq), Bpin-compound 5a (1.3 eq), PdCl ₂ (dppf) (0.1 eq), and potassium phosphate monohydrate (3.0 equivalents) was charged. After purging the flask with argon, 1,4-dioxane (50 mL) and water (5) were added and the resulting mixture was heated at 80 ° C. overnight (23 h). The reaction was cooled to room temperature. EtOAc was added to the reaction mixture and filtered through celite. After concentration, the residue was purified by column chromatography (silica gel, 25% EtOAc / hexanes) to give the title compound.

Part F: To a solution of the compound from Example 1, Part E (1.0 eq) in DCM (10 mL) was added m-CPBA (2.05 eq) in one portion. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated and then partitioned between EtOAc and water. The organic phase was washed with NaHCO ₃ (saturated aqueous solution, twice), brine and dried (Na ₂ SO ₄ ). After concentration, the title compound was obtained and used directly in the next step without further purification.

( Example 2 )

２０ｍＬのＤＭＦ中の１^１（１．０４ｇ、５．９８ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（２．４８ｇ、１７．９ｍｍｏｌ）およびＭｅＩ（１．２７ｇ、８．９６ｍｍｏｌ）を加えた。反応物を室温で一晩攪拌した。これを２００ｍＬの５０％ ＥｔＯＡｃ／ヘキサンで希釈し、水（２００ｍＬ）およびブライン（１００ｍＬ）で洗浄した。有機相を濃縮した。残渣に２０ｍＬのヘキサンを加えた。濾過により固形物を収集し、２を得た。濾液を濃縮し、２５％ ＥｔＯＡｃ／ヘキサンで溶出するカラムによって精製し、追加量の２を得た。２の合わせた収量は１．０５ｇである。

To a solution of 1 ¹ (1.04 g, 5.98 mmol) in 20 mL of DMF was added K ₂ CO ₃ (2.48 g, 17.9 mmol) and MeI (1.27 g, 8.96 mmol). The reaction was stirred at room temperature overnight. This was diluted with 200 mL of 50% EtOAc / hexanes and washed with water (200 mL) and brine (100 mL). The organic phase was concentrated. 20 mL of hexane was added to the residue. The solid was collected by filtration to give 2. The filtrate was concentrated and purified by column eluting with 25% EtOAc / hexanes to give an additional amount of 2. The combined yield of 2 is 1.05 g.

（実施例３）

( Example 3 )

６ｍＬのＡｃＯＨ中の２（２６０ｍｇ、１．３８ｍｍｏｌ）の溶液に、鉄粉（７７４ｍｇ、１３．８ｍｍｏｌ）を加えた。この反応混合物を７０〜７５℃で１２分間加熱した。この混合物を室温まで冷却し、次いで、２０ｍＬのＭｅＯＨを加えた。得られた混合物をセライトで濾過した（セライトは追加量のＭｅＯＨですすいだ）。濾液を濃縮して、ＡｃＯＨの大部分を除去した。残渣に、１５ｍＬの２０％ ＭｅＯＨ／ＣＨ_２Ｃｌ_２、続いて、２０ｍＬの飽和ＮａＨＣＯ_３水溶液を加えた。発泡がなくなるまで、この混合物を攪拌した。この混合物をＥｔＯＡｃ（６０ｍＬ×２）によって抽出し、Ｎａ_２ＳＯ_４で乾燥させ、次いで濃縮した。この残渣に５ｍＬのエーテル、そして５ｍＬのヘキサンを加えた。濾過により固形物を収集して、１６０ｍｇの粗３を得た。これは、わずかなアクリル化アミンを含むが、スルホン置換反応のために十分な純度であった。濾液は２０％のＡｃＯＥｔ／ＣＨ_２Ｃｌ_２を用いるカラムによって精製し、さらに３０ｍｇの３を得た。

To a solution of 2 (260 mg, 1.38 mmol) in 6 mL of AcOH was added iron powder (774 mg, 13.8 mmol). The reaction mixture was heated at 70-75 ° C. for 12 minutes. The mixture was cooled to room temperature and then 20 mL of MeOH was added. The resulting mixture was filtered through celite (celite rinsed with additional amount of MeOH). The filtrate was concentrated to remove most of AcOH. To the residue was added 15 mL of 20% MeOH / CH ₂ Cl ₂ followed by 20 mL of saturated aqueous NaHCO ₃ solution. The mixture was stirred until there was no foaming. The mixture was extracted with EtOAc (60 mL × 2), dried over Na ₂ SO ₄ and then concentrated. To this residue was added 5 mL of ether and 5 mL of hexane. The solid was collected by filtration to give 160 mg of crude 3. This contained a small amount of acrylated amine but was pure enough for the sulfone substitution reaction. The filtrate was purified by column with 20% AcOEt / CH ₂ Cl ₂ to give an additional 30 mg of 3.

（実施例４）

( Example 4 )

２ｍＬ ＤＭＦ中の化合物３（８９ｍｇ、０．５６ｍｍｏｌ）および６−ブロモ−８−メタンスルホニル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジン（２５８ｍｇ、０．５５ｍｍｏｌ）に、ＮａＨ（油中６０％分散液、４４ｍｇ、１．１ｍｍｏｌ）を加えた。反応物を室温で１５分間攪拌した。これは、５ｍＬの飽和ＮＨ_４Ｃｌ水溶液でクエンチし、３０ｍＬの水で希釈した。濾過により固形物を収集し、水およびＭｅＯＨで洗浄した。これを真空下で乾燥させ、２５５ｍｇの化合物４を得た。

Compound 3 (89 mg, 0.56 mmol) and 6-bromo-8-methanesulfonyl-3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [2] in 2 mL DMF To 1,2-a] pyrazine (258 mg, 0.55 mmol) was added NaH (60% dispersion in oil, 44 mg, 1.1 mmol). The reaction was stirred at room temperature for 15 minutes. This was quenched with 5 mL of saturated aqueous NH ₄ Cl and diluted with 30 mL of water. The solid was collected by filtration and washed with water and MeOH. This was dried under vacuum to obtain 255 mg of compound 4.

（実施例５）

( Example 5 )

工程Ａ：６ｍＬ ＴＨＦ中の４（７６ｍｇ、０．１４ｍｍｏｌ）の溶液に、Ｐｄ（ＰＰｈ_３）_４（１６ｍｇ、０．０１４ｍｍｏｌ）および０．３５ｍＬ ＭｅＺｎＣｌ（ＴＨＦ中２Ｍ溶液、０．６９ｍｍｏｌ）を加えた。この反応物を８０℃で２０分間攪拌した。これを室温まで冷却し、０．５ｍＬ ＭｅＯＨを加えることによってクエンチした。これを３０ｍＬ ＣＨ_２Ｃｌ_２で希釈し、そして２０ｍＬの０．５Ｎ ＨＣｌ水溶液で洗浄した。溶媒を真空下で除去した。残渣を、５％ ＭｅＯＨ／ＣＨ_２Ｃｌ_２で溶出するフラッシュクロマトグラフィーによって精製し、少量のトリフェニルホスフィンオキシドが夾雑している５０ｍｇの５−｛６−メチル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ− ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジン−８−イルアミノ｝−イソチアゾール−３−カルボン酸メチルエステルを得た。

Step A: To a solution of 4 (76 mg, 0.14 mmol) in 6 mL THF was added Pd (PPh ₃ ) ₄ (16 mg, 0.014 mmol) and 0.35 mL MeZnCl (2M solution in THF, 0.69 mmol). . The reaction was stirred at 80 ° C. for 20 minutes. It was cooled to room temperature and quenched by adding 0.5 mL MeOH. This was diluted with 30 mL CH ₂ Cl ₂ and washed with 20 mL 0.5 N aqueous HCl. The solvent was removed under vacuum. The residue was purified by flash chromatography eluting with 5% MeOH / CH ₂ Cl ₂ and 50 mg 5- {6-methyl-3- [1- (2-trimethyl) contaminated with a small amount of triphenylphosphine oxide. Silanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazin-8-ylamino} -isothiazole-3-carboxylic acid methyl ester was obtained.

Step B: The above crude material was dissolved in 5 mL THF. To this solution was added 0.5 mL LiBHEt ₃ (1M solution in THF). The reaction was stirred at room temperature for 30 minutes. This was quenched by adding 5 mL of saturated aqueous NH ₄ Cl. This mixture was extracted with 30 mL CH ₂ Cl ₂ . The organic phase was concentrated and purified by flash chromatography eluting with 5% MeOH / CH ₂ Cl ₂ to give 25 mg of compound 5.

（実施例６）

( Example 6 )

２０ｍＬ ＴＨＦ中の化合物５（２００ｍｇ、０．４３８ｍｍｏｌ）の溶液に、トリエチルアミン（０．２１ｍＬ、１．５ｍｍｏｌ）およびメタンスルホニルクロリド（０．１０ｍＬ、１．３ｍｍｏｌ）を加えた。この反応物を室温で３０分間攪拌した。これは、１ｍＬ ＭｅＯＨを加えることによってクエンチした。この溶液を３０ｍＬのＣＨ_２Ｃｌ_２によって希釈し、１５ｍＬの２Ｎ ＨＣｌ水溶液、水、およびブラインで連続的に洗浄した。溶媒を真空下で除去して、２３０ｍｇの粗化合物６を得た。これを、さらなる精製なしで、さらなる転換において使用した。

To a solution of compound 5 (200 mg, 0.438 mmol) in 20 mL THF was added triethylamine (0.21 mL, 1.5 mmol) and methanesulfonyl chloride (0.10 mL, 1.3 mmol). The reaction was stirred at room temperature for 30 minutes. This was quenched by adding 1 mL MeOH. The solution was diluted with 30 mL CH ₂ Cl ₂ and washed sequentially with 15 mL 2N aqueous HCl, water, and brine. The solvent was removed under vacuum to give 230 mg of crude compound 6. This was used in further transformations without further purification.

( Example 7 )

工程Ａ：１ｍＬ ＤＭＦ中の化合物６（１７ｍｇ、０．０３２ｍｍｏｌ）およびアジ化ナトリウム（１５ｍｇ、０．２３ｍｍｏｌ）の混合物を、７０℃で３時間加熱した。これを室温まで冷却し、１０ｍＬの水を加えた。得られた固形物を濾過によって収集し、５％ ＭｅＯＨ／ＣＨ_２Ｃｌ_２を用いて溶出するフラッシュクロマトグラフィーによって精製して、１２ｍｇの（３−アジドメチル−イソチアゾール−５−イル）−｛６−メチル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジン−８−イル｝−アミンを得た。

Step A: A mixture of compound 6 (17 mg, 0.032 mmol) and sodium azide (15 mg, 0.23 mmol) in 1 mL DMF was heated at 70 ° C. for 3 hours. This was cooled to room temperature and 10 mL of water was added. The resulting solid was collected by filtration and purified by flash chromatography eluting with 5% MeOH / CH ₂ Cl ₂ to yield 12 mg (3-azidomethyl-isothiazol-5-yl)-{6- Methyl-3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazin-8-yl} -amine was obtained.

Step B: The above material was dissolved in 3 mL MeOH. To this solution was added 15 mg of 10 wt% Pd / C. The mixture was stirred for 1 h under H ₂ (1 atm). This was filtered through celite. The filtrate was concentrated in vacuo to give 12 mg of compound 7.

（実施例８）

( Example 8 )

７０℃に加熱した２ｍＬ ＴＨＦ中の化合物７（１２ｍｇ、０．０２６ｍｍｏｌ）の溶液に、ジオキサン中０．５ｍＬの４Ｎ ＨＣｌを加えた。得られた混合物に、混合物が均質になるまでＭｅＯＨを加えた。反応物を７０℃で１時間攪拌し、次いで、室温まで冷却した。固形物を濾過により収集し、エーテルで洗浄して、９ｍｇの化合物８をＨＣｌ塩形態として得た。

To a solution of compound 7 (12 mg, 0.026 mmol) in 2 mL THF heated to 70 ° C. was added 0.5 mL 4N HCl in dioxane. To the resulting mixture was added MeOH until the mixture was homogeneous. The reaction was stirred at 70 ° C. for 1 hour and then cooled to room temperature. The solid was collected by filtration and washed with ether to give 9 mg of compound 8 as the HCl salt form.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．８２分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１４Ｈ_１４Ｎ_８Ｓの質量計算値３２６．１；実測値ＭＨ^＋（ＬＣＭＳ）３２７．２（ｍ／ｚ）。

_HPLC-MS t R = 1.82 min _{(UV 254nm).} Chemical formula _C 14 _H 14 _{N 8} S mass calcd 326.1; Found ^{MH + (LCMS) 327.2 (m} / z).

( Example 9 )

工程Ａ：１ｍＬのＭｅＯＨ／ＣＨ_２Ｃｌ_２（１：１）中の化合物７（９ｍｇ、０．０２ｍｍｏｌ）の溶液に、ホルムアルデヒド（４０重量％、水中、６ｍｇ、０．２ｍｍｏｌ）を加えた。これを室温で１５分間攪拌し、その時点でＮａＢＨ_４（１６ｍｇ、０．４ｍｍｏｌ）を２回に分けて加えた。この混合物をＮＨ_４Ｃｌ（水溶液）／ＭｅＯＨ／ＣＨ_２Ｃｌ_２（１：５：１９０）を用いて溶出するフラッシュクロマトグラフィーによって精製し、５ｍｇの（３−ジメチルアミノメチル−イソチアゾール−５−イル）−｛６−メチル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジン−８−イル｝−アミンを得た。

Step A: To a solution of compound 7 (9 mg, 0.02 mmol) in 1 mL of MeOH / CH ₂ Cl ₂ (1: 1) was added formaldehyde (40 wt%, 6 mg, 0.2 mmol in water). This was stirred at room temperature for 15 minutes, at which point NaBH ₄ (16 mg, 0.4 mmol) was added in two portions. The mixture was purified by flash chromatography eluting with NH ₄ Cl (aq) / MeOH / CH ₂ Cl ₂ (1: 5: 190) and purified with 5 mg of (3-dimethylaminomethyl-isothiazol-5-yl). )-{6-Methyl-3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazin-8-yl} -amine is obtained. It was.

  Step B: The above material was then dissolved in 2 mL of THF. The resulting solution was heated at 70 ° C. at which time 0.5 mL of 4N HCl in dioxane was added. To the resulting mixture was added 1 mL of MeOH. The reaction was stirred at 70 ° C. for 1 hour and then cooled to room temperature. Most of the solvent was removed under vacuum. To the residue was added 5 mL of ether. The solid was collected by filtration and washed with ether to give 5 mg of compound 9 as its HCl salt form.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．０４分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１６Ｈ_１８Ｎ_８Ｓの質量計算値３５４．１；実測値ＭＨ^＋（ＬＣＭＳ）３５５．２（ｍ／ｚ）。

_HPLC-MS t R = 2.04 min _{(UV 254nm).} Formula _C 16 _H 18 _{N 8} S mass calcd 354.1; Found ^{MH + (LCMS) 355.2 (m} / z).

( Example 10 )

１００ｍＬ ＴＨＦ中の化合物５（２．５０ｇ、５．４７ｍｍｏｌ）の溶液に、０．３ｍＬの水、続いてＤｅｓｓ−Ｍａｒｔｉｎペルヨウ化物（６．９６ｇ、１６．４ｍｍｏｌ）を加えた。この反応物を室温で３０分間攪拌した。固形物を濾過して除いた。濾液を２００ｍＬのＣＨ_２Ｃｌ_２で希釈し、１００ｍＬの飽和ＮＨ_４Ｃｌ水溶液で洗浄した。有機相を無水Ｎａ_２ＳＯ_４で乾燥させ、次いで濃縮した。この残渣に３０ｍＬのアセトニトリルを加えた。濾過により固形物を収集し、２．０５ｇの化合物１０を得た。

To a solution of compound 5 (2.50 g, 5.47 mmol) in 100 mL THF was added 0.3 mL water followed by Dess-Martin periodide (6.96 g, 16.4 mmol). The reaction was stirred at room temperature for 30 minutes. The solid was filtered off. The filtrate was diluted with 200 mL CH ₂ Cl ₂ and washed with 100 mL saturated aqueous NH ₄ Cl. The organic phase was dried over anhydrous Na ₂ SO ₄ and then concentrated. To this residue was added 30 mL of acetonitrile. The solid was collected by filtration to give 2.05 g of compound 10.

（実施例１１）

(Example 11)

工程Ａ：１４ｍＬのＣＨ_２Ｃｌ_２中の化合物１０（１００ｍｇ、０．２２０ｍｍｏｌ）およびピロリジン（１５６ｍｇ、２．２０ｍｍｏｌ）の溶液を室温で２０分間攪拌した。この溶液に、２滴の酢酸を加え、続いてＮａＢＨ_４（６７ｍｇ、１．８ｍｍｏｌ）を加えた。得られた混合物を室温で５分間攪拌し、その時点で３ｍＬのＭｅＯＨを加えた。攪拌をさらに２０分間継続した。反応物は１５ｍＬの飽和ＮａＨＣＯ_３水溶液の添加によってクエンチした。２０ｍＬのＣＨ_２Ｃｌ_２で希釈後、有機相を単離した。溶媒を真空下で除去した。残渣は、ＮＨ_４Ｃｌ（水溶液）／ＭｅＯＨ／ＣＨ_２Ｃｌ_２（１：１０：１９０）を用いて溶出するフラッシュクロマトグラフィーによって精製し、９８ｍｇの｛６−メチル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジン−８−イル｝−（３−ピロリジン−１−イルメチル−イソチアゾール−５−イル）−アミンを得た。

Step A: A solution of compound 10 (100 mg, 0.220 mmol) and pyrrolidine (156 mg, 2.20 mmol) in 14 mL of CH ₂ Cl ₂ was stirred at room temperature for 20 minutes. To this solution was added 2 drops of acetic acid followed by NaBH ₄ (67 mg, 1.8 mmol). The resulting mixture was stirred at room temperature for 5 minutes, at which time 3 mL of MeOH was added. Stirring was continued for an additional 20 minutes. The reaction was quenched by the addition of 15 mL saturated aqueous NaHCO ₃ solution. After dilution with 20 mL CH ₂ Cl ₂ , the organic phase was isolated. The solvent was removed under vacuum. The residue was purified by flash chromatography eluting with NH ₄ Cl (aq) / MeOH / CH ₂ Cl ₂ (1: 10: 190) and 98 mg of {6-methyl-3- [1- (2- Trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazin-8-yl}-(3-pyrrolidin-1-ylmethyl-isothiazol-5-yl) -amine Got.

工程Ｂ：７０℃で加熱した８ｍＬのＴＨＦ中の｛６−メチル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４イル］−イミダゾ［１，２−ａ］ピラジン−８−イル｝−（３−ピロリジン−１−イルメチル−イソチアゾール−５−イル）−アミン（９８ｍｇ、０．１９ｍｍｏｌ）の溶液に、２ｍＬのジオキサン中４Ｎ ＨＣｌを加えた。得られた混合物に、混合物が均質になるまで、ＭｅＯＨを加えた。反応物を、７０℃で１時間攪拌し、次いで室温まで冷却した。この混合物に３ｍＬのエーテルを加えた。濾過により固形物を収集し、エーテルで洗浄して、７９ｍｇの化合物１１をそのＨＣｌ塩形態として得た。

Step B: {6-Methyl-3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] in 8 mL THF heated at 70 ° C. To a solution of pyrazin-8-yl}-(3-pyrrolidin-1-ylmethyl-isothiazol-5-yl) -amine (98 mg, 0.19 mmol) was added 2 mL of 4N HCl in dioxane. To the resulting mixture was added MeOH until the mixture was homogeneous. The reaction was stirred at 70 ° C. for 1 hour and then cooled to room temperature. To this mixture was added 3 mL of ether. The solid was collected by filtration and washed with ether to give 79 mg of compound 11 as its HCl salt form.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．０３分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１８Ｈ_２０Ｎ_８Ｓの質量計算値３８０．２；実測値ＭＨ^＋（ＬＣＭＳ）３８１．２（ｍ／ｚ）。

_HPLC-MS t R = 2.03 min _{(UV 254nm).} Chemical formula _C 18 _H 20 _{N 8} S mass calcd 380.2; Found ^{MH + (LCMS) 381.2 (m} / z).

( Example 12 )
The compounds shown in column 2 of Table 1 were prepared by essentially the same procedure as shown in Example 11 except that pyrrolidine was replaced with each other aliphatic amine in Step A.

（実施例１３）

( Example 13 )

８−メタンスルホニル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジンで、６−ブロモ−８−メタンスルホニル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジンを置き換えるのみで、実施例４に示したのと本質的に同じ手順によって、化合物１３を調製した。

8-Methanesulfonyl-3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazine with 6-bromo-8-methanesulfonyl- Essentially as shown in Example 4 only replacing 3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazine. Compound 13 was prepared by the same procedure.

（実施例１４）

( Example 14 )

０℃で攪拌した５０ｍＬのＣＨ_２Ｃｌ_２中の化合物１３（８３０ｍｇ、１．７６ｍｍｏｌ）の溶液に、７．０５ｍＬのＬｉＢＨＥｔ_３（ＴＨＦ中１Ｍ溶液）を加えた。この反応物を室温で１０分間攪拌した。これは飽和ＮＨ_４Ｃｌ水溶液を加えることによってクエンチした。有機相を分離し、飽和ＮａＨＣＯ_３水溶液で洗浄した。溶媒は真空下で除去した。残渣に１０ｍＬのＭｅＯＨを加えた。濾過により固形物を収集し、５３０ｍｇの化合物１４を得た。

To a solution of compound 13 (830 mg, 1.76 mmol) in 50 mL CH ₂ Cl ₂ stirred at 0 ° C., 7.05 mL LiBHEt ₃ (1M solution in THF) was added. The reaction was stirred at room temperature for 10 minutes. This was quenched by the addition of saturated aqueous NH ₄ Cl. The organic phase was separated and washed with saturated aqueous NaHCO ₃ solution. The solvent was removed under vacuum. To the residue was added 10 mL MeOH. The solid was collected by filtration to give 530 mg of compound 14.

（実施例１５）

( Example 15 )

２０ｍＬのＴＨＦ中の化合物１４（２５８ｍｇ、０．５８２ｍｍｏｌ）の溶液に、０．０５ｍｌの水、そしてＤｅｓｓ−Ｍａｒｔｉｎペルヨウ化物（７４０ｍｇ、１．７５ｍｍｏｌ）を加えた。この反応物を室温で１．５時間攪拌した。固形物を濾過して除いた。濾液を１００ｍＬのＣＨ_２Ｃｌ_２で希釈し、水およびブラインで洗浄した。溶媒を真空下で除去し、残渣を、５％のＭｅＯＨ／ＣＨ_２Ｃｌ_２で溶出するフラッシュクロマトグラフィーによって精製して、２３０ｍｇの化合物１５を得た。

To a solution of compound 14 (258 mg, 0.582 mmol) in 20 mL THF was added 0.05 ml water and Dess-Martin periodide (740 mg, 1.75 mmol). The reaction was stirred at room temperature for 1.5 hours. The solid was filtered off. The filtrate was diluted with 100 mL CH ₂ Cl ₂ and washed with water and brine. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with 5% MeOH / CH ₂ Cl ₂ to give 230 mg of compound 15.

( Example 16 )

化合物１５で化合物１０を置き換えること、および工程Ａにおける他のそれぞれの脂肪族アミンでピロリジンを置き換えることにより、実施例１１に示したのと本質的に同じ手順によって、表２のカラム２に示す化合物を調製した。

The compound shown in column 2 of Table 2 by essentially replacing the pyrrolidine with compound 15 and pyrrolidine with the other respective aliphatic amine in step A Was prepared.

１）Ｗａｌｓｈ Ｒ．Ｊ．Ａ．；Ｗｏｏｌｄｒｉｄｇｅ，Ｋ．Ｒ．Ｈ．Ｊ．Ｃｈｅｍ．Ｓｏｃ．Ｐｅｒｋｉｎ Ｔｒａｎｓ．１９７２，１２４７．
（実施例１７）

1) Walsh R.M. J. et al. A. Woodridge, K .; R. H. J. et al. Chem. Soc. Perkin Trans. 1972, 1247.
( Example 17 )

パートＡ：ＤＭＦ（４０ｍＬ）中のエステル（２．３８ｇ、４．９１ｍｍｏｌ、１当量）の溶液をＮａＨ（油中６０％分散液、１．５当量）で２０分間、室温にて処理し、その時点で、反応混合物を−１０℃に冷却し、そしてこの反応混合物に２−（トリメチルシリル）エトキシメチルクロリド（０．８７ｍＬ、１当量）を加えた。得られた溶液は室温までゆっくりと温めさせ、さらに１時間、室温にて攪拌を継続した。ＬＣ−ＭＳ分析は、反応が完了したことを示した。反応物をメタノール（１５ｍＬ）でクエンチし、酢酸エチル（３００ｍＬ）で希釈し、そして飽和炭酸水素ナトリウム、水、ブラインで洗浄し、乾燥させ（硫酸ナトリウム）、そして濃縮した。カラムクロマトグラフィー（ＳｉＯ_２ ４０％ 酢酸エチル／ヘキサン）による精製は、所望の生成物を１．２ｇ（４０％）の黄色固形物として与えた。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．７９分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ２７Ｈ４１Ｎ７Ｏ４ＳＳｉ２の質量計算値６１５．２５、実測値ＬＣ／ＭＳ ｍ／ｚ６１６．２（Ｍ＋Ｈ）。

Part A: A solution of the ester (2.38 g, 4.91 mmol, 1 eq) in DMF (40 mL) was treated with NaH (60% dispersion in oil, 1.5 eq) for 20 minutes at room temperature. At that time, the reaction mixture was cooled to −10 ° C. and 2- (trimethylsilyl) ethoxymethyl chloride (0.87 mL, 1 eq) was added to the reaction mixture. The resulting solution was allowed to warm slowly to room temperature and continued to stir at room temperature for an additional hour. LC-MS analysis indicated that the reaction was complete. The reaction was quenched with methanol (15 mL), diluted with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate, water, brine, dried (sodium sulfate) and concentrated. Purification by column chromatography (SiO ₂ 40% ethyl acetate / hexane) gave the desired product as 1.2 g (40%) of a yellow solid.
_HPLC-MS t R = 2.79 min _{(UV 254nm).} Mass calculated for formula C27H41N7O4SSi2, 615.25, found LC / MS m / z 616.2 (M + H).

Part B: To a solution of the compound from Part A (1.2 g, 1.90 mmol, 1 eq) in THF (100 mL) was added super hydride solution (4 eq) at room temperature. The resulting solution was stirred at room temperature for 30 minutes, at which time LC-MS analysis indicated that the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride and then extracted with dichloromethane (twice). The combined organic layers were dried (sodium sulfate) and concentrated. Purification by column chromatography (SiO ₂ 60% ethyl acetate / hexane) gave the alcohol as a clear oil (47%).
_HPLC-MS t R = 2.49 min _{(UV 254nm).} Mass calculated for formula C26H41N7O3SSi2, 587.25, found LC / MS m / z 588.3 (M + H).

Part C: A solution of the alcohol from Part B (0.52 g, 0.88 mmol, 1 eq) in DCM (15 mL) with triethylamine (1.5 eq) for 15 min at 0 ° C. (ice bath). At that time, methanesulfonyl chloride (1.2 eq) was added to the reaction at 0 ° C. The resulting solution was allowed to warm slowly to room temperature and continued to stir for an additional 3 hours at room temperature. LC-MS analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, dried (anhydrous sodium sulfate) and concentrated to give the mesylate as a red / brown oil 0.59 g (100%), This was used without further purification.
_HPLC-MS t R = 2.66 min _{(UV 254nm).} Mass calculated for formula C27H43N7O5S2Si2, 665.23, found LC / MS m / z 666.1 (M + H).

  Part D: A solution of each alcohol (3 eq) in THF (1.5 mL) was treated with NaH (60% dispersion in oil, 2 eq) for 15 min at room temperature, at which point from Part C Of mesylate (40 mg, 0.06 mmol, 1 eq) was added to the reaction mixture. After stirring for 1 hour at room temperature, LC-MS analysis indicated that the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate (twice). The combined organic layers were dried (sodium sulfate) and concentrated to give the crude ether, which was used without further purification.

  Part E: A solution of the compound from Part D in 1,4-dioxane (1 mL) was treated with 4N HCl in 1,4-dioxane solution (1 mL) at 60 ° C. for 10 minutes, at which point HPLC-MS showed that the reaction was complete. The solvent was removed and the residue was purified by preparative (Prep-) LC. Conversion to the hydrochloride salt gave the compounds listed in Table 3.

（実施例１８）

( Example 18 )

調製実施例１７に示されるのと本質的に同じ手順によって、表４に示される化合物が調製可能である。

The compounds shown in Table 4 can be prepared by essentially the same procedure as shown in Preparative Example 17.

（実施例１９）

( Example 19 )

実施例１９は、実施例４と同様の様式で調製した。

Example 19 was prepared in a similar manner as Example 4.

（実施例２０）

( Example 20 )

実施例２０は、実施例１７、パートＡと同様の様式で調製した。

Example 20 was prepared in a similar manner as Example 17, Part A.

（実施例２１）

( Example 21 )

テトラヒドロフラン（９６ｍＬ）中のエステル（２．４０ｇ、４．４０ｍｍｏｌ）の−７８℃の攪拌溶液に、ＤＩＢＡＬ−Ｈ（ジクロロメタン中１Ｍ、１１．０ｍＬ、１１．０ｍｍｏｌ）を滴下して加えた。この混合物を−７８℃で３時間攪拌し、その時点で、薄層クロマトグラフィー（３０％ 酢酸エチル／ヘキサン）は、反応が完了したことを示した。この混合物を攪拌飽和酒石酸ナトリウムカリウム水溶液に迅速に注ぎ、室温で１４時間攪拌した。この混合物を酢酸エチルで抽出し（２×２５０ｍｌ）、有機層を合わせ、ブライン（１００ｍＬ）で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、そして減圧下で濃縮して、化合物２１を２．２０ｇ（９７％）の黄色固形物として得た。

To a stirred solution of ester (2.40 g, 4.40 mmol) in tetrahydrofuran (96 mL) at −78 ° C., DIBAL-H (1 M in dichloromethane, 11.0 mL, 11.0 mmol) was added dropwise. The mixture was stirred at −78 ° C. for 3 hours, at which time thin layer chromatography (30% ethyl acetate / hexanes) indicated that the reaction was complete. The mixture was quickly poured into a stirred saturated aqueous potassium potassium tartrate solution and stirred at room temperature for 14 hours. The mixture was extracted with ethyl acetate (2 × 250 ml) and the organic layers were combined, washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 2.20 g of compound 21. Obtained as a (97%) yellow solid.

（実施例２２）

( Example 22 )

１，２−ジクロロエタン（１７ｍＬ）中のアルデヒド（１．３０ｇ、２．５２ｍｍｏｌ）、ピペリジン（２５７ｍｇ、３．０２ｍｍｏｌ）、および酢酸（１５０μＬ、２．５２ｍｍｏｌ）の室温の攪拌溶液に、トリアセトキシ水素化ホウ素ナトリウム（８０１ｍｇ、３．７８ｍｍｏｌ）を一度に加えた。この混合物を室温で２時間攪拌し、その時点で、薄層クロマトグラフィー（４０％ 酢酸エチル／ヘキサン）は反応が完了したことを示した。反応物を１Ｎ 水酸化ナトリウム（２５ｍＬ）でクエンチし、２０分間攪拌した。この混合物をクロロホルムで抽出し（３×２０ｍＬ）、有機層を合わせ、硫酸ナトリウムで乾燥させ、濾過し、そして減圧下で濃縮した。化合物２２が黄色固形物として１．３５ｇ（９２％）得られた。

To a stirred solution of aldehyde (1.30 g, 2.52 mmol), piperidine (257 mg, 3.02 mmol), and acetic acid (150 μL, 2.52 mmol) in 1,2-dichloroethane (17 mL) at room temperature was triacetoxyhydrogenated. Sodium boron (801 mg, 3.78 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, at which time thin layer chromatography (40% ethyl acetate / hexanes) indicated that the reaction was complete. The reaction was quenched with 1N sodium hydroxide (25 mL) and stirred for 20 minutes. The mixture was extracted with chloroform (3 × 20 mL) and the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. 1.35 g (92%) of compound 22 was obtained as a yellow solid.

（実施例２３）

( Example 23 )

実施例２３は、ピペリジンを３−メチルピペリジンで置き換えることを用いて、実施例２２と同様の様式で調製した。

Example 23 was prepared in a similar manner as Example 22 using the replacement of piperidine with 3-methylpiperidine.

（実施例２４）

( Example 24 )

実施例２４は、ピペリジンをピロリジンで置き換えることを用いて、実施例２３と同様の様式で調製した。

Example 24 was prepared in a similar manner as Example 23 using the replacement of piperidine with pyrrolidine.

（実施例２５）

( Example 25 )

１，４−ジオキサン（１ｍＬ）中の実施例２４からのヨウ化物（２０ｍｇ、０．０３５ｍｍｏｌ）の溶液を１，４−ジオキサン（１ｍＬ）中の４Ｎ ＨＣｌで処理した。この混合物を、室温で２．５時間、超音波処理し、その時点でＨＰＬＣは反応が完了したことを示した。この混合物を減圧下で濃縮し、得られた残渣を調製用ＨＰＬＣによって精製し、そして塩酸塩への変換は、化合物２５を白色固形物１５ｍｇ（８３％）として与えた。

A solution of the iodide from Example 24 (20 mg, 0.035 mmol) in 1,4-dioxane (1 mL) was treated with 4N HCl in 1,4-dioxane (1 mL). The mixture was sonicated for 2.5 hours at room temperature, at which point HPLC showed the reaction was complete. The mixture was concentrated under reduced pressure, the resulting residue was purified by preparative HPLC, and conversion to the hydrochloride salt gave compound 25 as a white solid 15 mg (83%).

ＨＰＬＣ ｔ_Ｒ＝４．８３分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１５Ｈ_１７ＩＮ_６Ｓの質量計算値４４０．０３；実測値ＭＨ^＋（ＭＳ）４４１．５（ｍ／ｚ）。

HPLC t _R = 4.83 min _{(UV 254nm).} Chemical formula _C 15 _H 17 IN ₆ S mass calcd 440.03; found ^{MH + (MS) 441.5 (m} / z).

( Example 26 )

実施例２６は実施例２５と同様の様式で調製した。

Example 26 was prepared in a similar manner as Example 25.

ＨＰＬＣ ｔ_Ｒ＝５．０６分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１７Ｈ_２１ＩＮ_６Ｓの質量計算値４６８．３；実測値ＭＨ^＋（ＭＳ）４６９．７（ｍ／ｚ）。

HPLC t _R = 5.06 min _{(UV 254nm).} Chemical formula _C 17 _H 21 IN ₆ S mass calcd 468.3; Found ^{MH + (MS) 469.7 (m} / z).

( Example 27 )
The compounds shown in column 2 of Table 5 were prepared as follows:

調製したヨウ化アリール骨格（実施例２２、２３、または２４からの化合物、１当量）、市販のまたは１〜３工程で容易に調製されるアリール／ヘテロアリール／アルキルボロン酸／エステル／ボロキシンまたはアリール／ヘテロアリール／アルキルマグネシウムブロミドまたはアリール／ヘテロアリール／アルキル塩化亜鉛（１．５〜３当量）、リン酸カリウムまたは炭酸カリウム（２〜３当量）、およびＰｄ（ＰＰｈ_３）_４またはＰｄＣｌ_２ｄｐｐｆ（０．０５〜０．１０当量）を含むフラスコの空気を抜き、窒素を再充填し、そして反復した。１，４−ジオキサンまたはＮ，Ｎ−ジメチルホルムアミドまたは１，２−ジメトキシエタン（１〜３ｍＬ）を加え、薄層クロマトグラフィー（酢酸エチル／ヘキサン）またはＨＰＬＣによって判断されるように、反応が完了するまでこの混合物を５０〜１３０℃で攪拌した。この混合物を水（３〜１０ｍＬ）で希釈し、酢酸エチルで抽出した（２〜３回、１０〜３０ｍＬ）。有機層を合わせ、ブラインで洗浄し（１５〜３０ｍＬ）、硫酸マグネシウムで乾燥させ、濾過し、濃縮し、そしてカラムクロマトグラフィーによって精製した（ＳｉＯ_２、酢酸エチル／ヘキサン）。得られた生成物を１，４−ジオキサン（１ｍＬ）に溶解し、１，４−ジオキサン中の４Ｎ ＨＣｌ（１ｍＬ）で処理し、室温で１〜５時間超音波処理し、この時点で、ＨＰＬＣは反応が完了したことを示した。この混合物を減圧下で濃縮し、得られた残渣を調製用ＨＰＬＣによって精製し、そして塩酸塩への変換は化合物２７−１〜２７−７を与えた。

Prepared aryl iodide backbone (compound from Examples 22, 23, or 24, 1 equivalent), commercially available or easily prepared in 1-3 steps aryl / heteroaryl / alkylboronic acid / ester / boroxine or aryl / Heteroaryl / alkyl magnesium bromide or aryl / heteroaryl / alkyl zinc chloride (1.5-3 eq), potassium phosphate or potassium carbonate (2-3 eq), and Pd (PPh ₃ ) ₄ or PdCl ₂ dppf ( The flask containing 0.05-0.10 equivalent) was evacuated, refilled with nitrogen and repeated. Add 1,4-dioxane or N, N-dimethylformamide or 1,2-dimethoxyethane (1-3 mL) and complete the reaction as judged by thin layer chromatography (ethyl acetate / hexane) or HPLC. The mixture was stirred at 50-130 ° C until. The mixture was diluted with water (3-10 mL) and extracted with ethyl acetate (2-3 times, 10-30 mL). The organic layers were combined, washed with brine (15～30ML), dried over magnesium sulfate, filtered, concentrated, and purified by column chromatography (SiO _2, ethyl acetate / hexane). The resulting product was dissolved in 1,4-dioxane (1 mL), treated with 4N HCl in 1,4-dioxane (1 mL) and sonicated at room temperature for 1-5 hours, at which point HPLC Indicated that the reaction was complete. The mixture was concentrated under reduced pressure, the resulting residue was purified by preparative HPLC, and conversion to the hydrochloride salt provided compounds 27-1 to 27-7.

（実施例２８）

( Example 28 )

ヨウ化物（６０ｍｇ、０．１０３ｍｍｏｌ）、トリメチル（トリフルオロメチル）シラン（４４ｍｇ、０．３０８ｍｍｏｌ）、ヨウ化銅（７３ｍｇ、０．３８５ｍｍｏｌ）、フッ化カリウム（１５ｍｇ、０．２５７ｍｍｏｌ）、および無水ＤＭＦ（１．０ｍＬ）の混合物を窒素で脱気し、次いで、密封したチューブ中で、８０℃にて一晩加熱した。この混合物を室温まで冷却し、水（３０ｍＬ）で希釈し、そして酢酸エチル（１００ｍＬ）で抽出した。有機層を硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮し、そしてカラムクロマトグラフィー（ＳｉＯ_２、９０：１０：０．２５ 塩化メチレン／メタノール／濃水酸化アンモニウム）によって精製した。得られた残渣を無水１，４−ジオキサン（１ｍＬ）に溶解し、ジオキサン（１ｍＬ）中４Ｍ ＨＣｌを加えた。得られた溶液を室温で２時間超音波処理し、そして乾燥するまで減圧下で濃縮した。調製用ＨＰＬＣによる精製および塩酸塩への変換は標題の化合物を３．１ｍｇ（６％）オフホワイト固形物として与えた。

Iodide (60 mg, 0.103 mmol), trimethyl (trifluoromethyl) silane (44 mg, 0.308 mmol), copper iodide (73 mg, 0.385 mmol), potassium fluoride (15 mg, 0.257 mmol), and anhydrous DMF (1.0 mL) of the mixture was degassed with nitrogen and then heated at 80 ° C. overnight in a sealed tube. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure and column chromatography was purified by _{(SiO 2, 90:: 10} 0.25 methylene chloride / methanol / concentrated ammonium hydroxide chloride). The resulting residue was dissolved in anhydrous 1,4-dioxane (1 mL) and 4M HCl in dioxane (1 mL) was added. The resulting solution was sonicated for 2 hours at room temperature and concentrated under reduced pressure until dry. Purification by preparative HPLC and conversion to the hydrochloride salt provided the title compound as a 3.1 mg (6%) off-white solid.

ＨＰＬＣ ｔ_Ｒ＝７．１９分。化学式Ｃ_１７Ｈ_１９Ｆ_３Ｎ_６Ｓの質量計算値３９６．１３；実測値ＭＨ^＋ ３９７．２（ｍ／ｚ）。

HPLC t _R = 7.19 min. Mass calculated formula _{C 17 H 19 F 3 N 6} S 396.13; Found ^{MH + 397.2 (m / z)} .

( Example 29 )

無水ＴＨＦ（２．０ｍＬ）中のヨウ化物（１００ｍｇ、０．１７１ｍｍｏｌ）の混合物を−７８℃まで冷却し、ｎ−ブチルリチウム（ヘキサン中２．５Ｍ溶液、８９μＬ、０．２２２ｍｍｏｌ）を滴下して加えた。１５分間の攪拌後、ＴＨＦ（１．０ｍＬ）中のヘキサクロロエタン（４５ｍｇ、０．１８８ｍｍｏｌ）の溶液を滴下して加えた。−７８℃で３０分間の反応物の攪拌後、溶液を塩化アンモニウムの飽和水溶液（３．０ｍＬ）でクエンチし、室温まで温めた。反応物を減圧下で濃縮し、酢酸エチル（５０ｍＬ）で抽出し、有機層を硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮し、そしてカラムクロマトグラフィーによって精製した（ＳｉＯ_２、９０：１０：０．２５ 塩化メチレン／メタノール／濃水酸化アンモニウム）。得られた残渣を無水１，４−ジオキサン（１ｍＬ）に溶解し、そしてジオキサン中４Ｍ ＨＣｌ（１ｍＬ）を加えた。得られた溶液を室温で２時間超音波処理し、そして乾燥するまで減圧下で濃縮した。調製用ＨＰＬＣによる精製および塩酸塩への変換は、標題の化合物を３０ｍｇ（４０％）のオフホワイト固形物として与えた。

A mixture of iodide (100 mg, 0.171 mmol) in anhydrous THF (2.0 mL) was cooled to −78 ° C. and n-butyllithium (2.5 M solution in hexane, 89 μL, 0.222 mmol) was added dropwise. added. After stirring for 15 minutes, a solution of hexachloroethane (45 mg, 0.188 mmol) in THF (1.0 mL) was added dropwise. After stirring the reaction at −78 ° C. for 30 minutes, the solution was quenched with a saturated aqueous solution of ammonium chloride (3.0 mL) and allowed to warm to room temperature. The reaction is concentrated under reduced pressure and extracted with ethyl acetate (50 mL), the organic layer is dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (SiO ₂ , 90:10). : 0.25 methylene chloride / methanol / concentrated ammonium hydroxide). The resulting residue was dissolved in anhydrous 1,4-dioxane (1 mL) and 4M HCl in dioxane (1 mL) was added. The resulting solution was sonicated for 2 hours at room temperature and concentrated under reduced pressure until dry. Purification by preparative HPLC and conversion to the hydrochloride salt gave the title compound as 30 mg (40%) off-white solid.

ＨＰＬＣ ｔ_Ｒ＝４．７９分。化学式Ｃ_１６Ｈ_１９ＣｌＮ_６Ｓの質量計算値３６２．１１；実測値ＭＨ^＋ ３６３．７（ｍ／ｚ）。

HPLC t _R = 4.79 min. Calculated mass for chemical formula C ₁₆ H ₁₉ ClN ₆ S 362.11; found MH ⁺ 363.7 (m / z).

( Example 30 )

実施例３０は、実施例２９と同様の様式で調製した。

Example 30 was prepared in a similar manner as Example 29.

ＨＰＬＣ ｔ_Ｒ＝４．９８分。化学式Ｃ_１７Ｈ_２１ＣｌＮ_６Ｓの質量計算値３７６．１２；実測値ＭＨ^＋ ３７７．６（ｍ／ｚ）。

HPLC t _R = 4.98 min. Calculated mass for chemical formula C ₁₇ H ₂₁ ClN ₆ S 376.12; found MH ⁺ 377.6 (m / z).

( Example 31 )

実施例３１は、ヘキサクロロエタンをテトラクロロジブロモエタンで置き換えて、化合物２９と同様の様式で調製した。

Example 31 was prepared in a similar manner as compound 29, replacing hexachloroethane with tetrachlorodibromoethane.

ＨＰＬＣ ｔ_Ｒ＝５．１９分。化学式Ｃ_１６Ｈ_１９ＢｒＮ_６Ｓの質量計算値４０６．０６；実測値ＭＨ^＋ ４０７．４（ｍ／ｚ）。

HPLC t _R = 5.19 min. Chemical mass calculated of Formula _{C 16 H 19 BrN 6 S 406.06} ; Found ^{MH + 407.4 (m / z)} .

( Example 32 )

無水ピリジン（２．０ｍＬ）中のアミノピリミジン（１００ｍｇ、０．４５２ｍｍｏｌ）の溶液に、３−フルオロベンゾイルクロリド（７２ｍｇ、０．４５２ｍｍｏｌ）を加えた。室温で一晩の攪拌後、反応物を減圧下で濃縮し、水（３０ｍＬ）で希釈し、そして塩化メチレン（１００ｍＬ）で抽出した。有機層を硫酸ナトリウムで乾燥させ、濾過し、そして濃縮して、標題の化合物を１２４ｍｇ（８０％）のオフホワイト固形物として得た。

To a solution of aminopyrimidine (100 mg, 0.452 mmol) in anhydrous pyridine (2.0 mL) was added 3-fluorobenzoyl chloride (72 mg, 0.452 mmol). After stirring at room temperature overnight, the reaction was concentrated under reduced pressure, diluted with water (30 mL), and extracted with methylene chloride (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as 124 mg (80%) of an off-white solid.

（実施例３３）

( Example 33 )

化合物３１と同様の様式で調製して、標題の化合物を１３１ｍｇ（８０％）のオフホワイト固形物として得た。

Prepared in a similar manner as compound 31 to give the title compound as 131 mg (80%) of an off-white solid.

（実施例３４）

( Example 34 )

無水１，４−ジオキサン（１．０ｍＬ）中のヨウ化物（６０ｍｇ、０．１０３ｍｍｏｌ）、トリ−ｎ−ブチル（ピリジル）スズ（５７ｍｇ、０．１５４ｍｍｏｌ）、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロロメタン付加物（８ｍｇ、０．０１０３ｍｍｏｌ）、およびフッ化カリウム（１８ｍｇ、０．３０９ｍｍｏｌ）の混合物を窒素で脱気し、次いで密封チューブ中で８５℃で一晩加熱した。この混合物を室温まで冷却し、水（３０ｍＬ）で希釈し、そして酢酸エチルで抽出した（２×１００ｍＬ）。次いで有機層を分離し、硫酸ナトリウムで乾燥させ、濾過し、減圧下で残渣まで濃縮し、そしてカラムクロマトグラフィー（ＳｉＯ_２、９０：１０：０．２５ 塩化メチレン／メタノール／濃水酸化アンモニウム）によって精製した。次いで、得られた残渣を無水１，４−ジオキサン（１ｍＬ）に溶解し、ジオキサン中４Ｍ ＨＣｌ（１ｍＬ）を加えた。得られた溶液を室温で２時間超音波処理し、次いで、乾燥するまで減圧下で濃縮した。調製用ＨＰＬＣによる精製および塩酸塩への変換は、脱ハロゲン生成物を３．２ｍｇ（１０％）のオフホワイト固形物として与えた。

Iodide (60 mg, 0.103 mmol), tri-n-butyl (pyridyl) tin (57 mg, 0.154 mmol), dichloro [1,1′-bis (diphenyl) in anhydrous 1,4-dioxane (1.0 mL). A mixture of phosphino) ferrocene] palladium (II) dichloromethane adduct (8 mg, 0.0103 mmol) and potassium fluoride (18 mg, 0.309 mmol) was degassed with nitrogen and then in a sealed tube at 85 ° C. overnight. Heated. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (2 × 100 mL). Then the organic layer was separated, dried over sodium sulfate, filtered, and concentrated to a residue under reduced pressure and column chromatography by _{(SiO 2, 90:: 10} 0.25 methylene chloride / methanol / concentrated ammonium hydroxide chloride) Purified. The resulting residue was then dissolved in anhydrous 1,4-dioxane (1 mL) and 4M HCl in dioxane (1 mL) was added. The resulting solution was sonicated at room temperature for 2 hours and then concentrated under reduced pressure until dry. Purification by preparative HPLC and conversion to the hydrochloride salt gave the dehalogenated product as 3.2 mg (10%) of an off-white solid.

ＨＰＬＣ ｔ_Ｒ＝３．４９分。化学式Ｃ_１５Ｈ_１６Ｎ_６Ｓの質量計算値３１４．１３；実測値ＭＨ^＋ ３１５．２（ｍ／ｚ）。

HPLC t _R = 3.49 min. Calculated mass of C ₁₅ H ₁₆ N ₆ S 314.13; found MH ⁺ 315.2 (m / z).

  The coupled product was also provided as 5.0 mg (10%) of an off-white solid.

ＨＰＬＣ ｔ_Ｒ＝４．８０分。化学式Ｃ_２０Ｈ_２１Ｎ_７Ｓの質量計算値３９１．１６；実測値ＭＨ^＋ ３９２．５（ｍ／ｚ）。

HPLC t _R = 4.80 min. Mass calculated for chemical formula C ₂₀ H ₂₁ N ₇ S 391.16; found MH ⁺ 392.5 (m / z).

( Example 35 )

水素化ホウ素ナトリウム（３ｍｇ、０．０７３ｍｍｏｌ）を、メタノール（１ｍＬ）中のヨウ化物（１５ｍｇ、０．０３７）の室温懸濁液に加えた。反応物を３０分間攪拌させ、次いで、水（２０ｍＬ）でクエンチした。この混合物をジエチルエーテル（２０ｍＬ）で希釈し、相を分離させた。有機層を乾燥させ（硫酸ナトリウム）、濾過し、そして濃縮して、保護化脱ハロゲン中間体を得た。還元生成物（７ｍｇ、０．０１７ｍｍｏｌ）を、以前に概説した酸性条件に供して、標題の化合物を２ｍｇ（１７％）の黄色固形物として得た。

Sodium borohydride (3 mg, 0.073 mmol) was added to a room temperature suspension of iodide (15 mg, 0.037) in methanol (1 mL). The reaction was allowed to stir for 30 minutes and then quenched with water (20 mL). The mixture was diluted with diethyl ether (20 mL) and the phases were separated. The organic layer was dried (sodium sulfate), filtered and concentrated to give the protected dehalogenated intermediate. The reduction product (7 mg, 0.017 mmol) was subjected to the acidic conditions outlined previously to give the title compound as 2 mg (17%) of a yellow solid.

ＨＰＬＣ ｔ_Ｒ＝４．６７分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１２Ｈ_１１Ｎ_５Ｏ_２Ｓの質量計算値２８９．０６；実測値ＭＨ^ー（ＥＳＩ ＭＳ） ２８８．０（ｍ／ｚ）。

HPLC t _R = 4.67 min _{(UV 254nm).} Formula _{C 12 H 11 N 5 O 2} S mass calcd 289.06; found MH ^{chromatography} (ESI MS) 288.0 (m / z).

( Example 36 )

実施例３６は実施例３１と同様の様式で調製した。

Example 36 was prepared in a similar manner as Example 31.

ＨＰＬＣ ｔ_Ｒ＝５．００分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１６Ｈ_１９ＩＮ_６Ｓの質量計算値４５４．０４；実測値ＭＨ^＋（ＥＳＩ ＭＳ） ４５５．０（ｍ／ｚ）。

HPLC t _R = 5.00 min _{(UV 254nm).} Mass calculated formula _{C 16 H 19 IN 6 S 454.04} ; Found ^{MH + (ESI MS) 455.0 (} m / z).

( Example 37 )

Ｐｄ_２（ｄｂａ）_３（５ｍｇ、０．００５ｍｍｏｌ）を、 Ｎ，Ｎ’−ジメチルホルムアミド（１ｍＬ）中のＤＰＰＦ（６ｍｇ、０．１０３ｍｍｏｌ）の室温溶液中に加え、１０分間攪拌した。次いで、この混合物をＮ，Ｎ’ジメチルホルムアミド（４ｍＬ）中のヨウ化物（６０ｍｇ、０．１０３ｍｍｏｌ）、Ｚｎ（ＣＮ）_２（１２ｍｇ、０．１０３ｍｍｏｌ）の溶液に加えた。この反応物を、３０分間、マイクロ波によって１５０℃に加熱し、室温まで冷却し、次いで、乾燥するまで濃縮した。得られた残渣のフラッシュクロマトグラフィー（ＳｉＯ_２；１２ｇ；塩化メチレン中１０％ メタノール）による精製は、不純物を含むニトリルを黄色固形物として与えた。不純物を含むニトリル（２２ｍｇ、０．０４５ｍｍｏｌ）を、さらなる精製なしで２Ｎ ＨＣｌ（４ｍＬ）に溶解した。得られた溶液は４５℃で２時間、超音波処理した。完了の際に、反応物は乾燥するまで濃縮した。調製用ＨＰＬＣによる得られた残渣の精製は、標題の化合物を８ｍｇ（１８％）の白色固形物として与えた。

Pd ₂ (dba) ₃ (5 mg, 0.005 mmol) was added to a room temperature solution of DPPF (6 mg, 0.103 mmol) in N, N′-dimethylformamide (1 mL) and stirred for 10 minutes. This mixture was then added to a solution of iodide (60 mg, 0.103 mmol), Zn (CN) ₂ (12 mg, 0.103 mmol) in N, N ′ dimethylformamide (4 mL). The reaction was heated to 150 ° C. by microwave for 30 minutes, cooled to room temperature, and then concentrated to dryness. Purification of the resulting residue by flash chromatography (SiO ₂ ; 12 g; 10% methanol in methylene chloride) gave the impure nitrile as a yellow solid. Impure nitrile (22 mg, 0.045 mmol) was dissolved in 2N HCl (4 mL) without further purification. The resulting solution was sonicated at 45 ° C. for 2 hours. Upon completion, the reaction was concentrated to dryness. Purification of the resulting residue by preparative HPLC gave the title compound as 8 mg (18%) of a white solid.

ＨＰＬＣ ｔ_Ｒ＝４．５０分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１７Ｈ_１９Ｎ_７Ｓの質量計算値３５３．１４；実測値ＭＨ^＋（ＥＳＩ ＭＳ） ３５４．３（ｍ／ｚ）。

HPLC t _R = 4.50 min _{(UV 254nm).} Mass calculated formula _{C 17 H 19 N 7 S 353.14} ; Found ^{MH + (ESI MS) 354.3 (} m / z).

( Example 38 )

ヨウ化物（７０ｍｇ、０．１２ｍｍｏｌ）、Ｐｄ（ｄｐｐｆ）Ｃｌ_２（９ｍｇ、０．０１２ｍｍｏｌ）、ｔｅｒｔ−ブトキシドナトリウム（３５ｍｇ、０．３６ｍｍｏｌ）、およびチオメトキシドナトリウム（１７ｍｇ、０．２４ｍｍｏｌ）の混合物に窒素をフラッシュし、次いで、１，４−ジオキサン（５ｍＬ）に溶解した。この溶液は、９０分間、マイクロ波によって９５℃に加熱した。この反応物を室温まで冷却し、酢酸エチル（１００ｍＬ）で希釈し、そしてセライトを通して濾過した。有機層を水（５０ｍＬ）およびブライン（５０ｍＬ）で洗浄し、次いで乾燥させ（硫酸ナトリウム）、濾過し、そして乾燥するまで濃縮した。得られた残渣の調製用ＨＰＬＣによる精製は、保護化チオメチルエーテルを与えた。このチオメチルエーテル（３５ｍｇ、０．０７ｍｍｏｌ）は、実施例１１０に概説される反応条件に供されて、標題の化合物を６ｍｇ（１１％）の白色固形物として得た。

Mixture of iodide (70 mg, 0.12 mmol), Pd (dppf) Cl ₂ (9 mg, 0.012 mmol), sodium tert-butoxide (35 mg, 0.36 mmol), and sodium thiomethoxide (17 mg, 0.24 mmol) Was flushed with nitrogen and then dissolved in 1,4-dioxane (5 mL). This solution was heated to 95 ° C. by microwave for 90 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered through celite. The organic layer was washed with water (50 mL) and brine (50 mL), then dried (sodium sulfate), filtered and concentrated to dryness. Purification of the resulting residue by preparative HPLC gave the protected thiomethyl ether. This thiomethyl ether (35 mg, 0.07 mmol) was subjected to the reaction conditions outlined in Example 110 to give the title compound as 6 mg (11%) of a white solid.

ＨＰＬＣ ｔ_Ｒ＝４．７４分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１７Ｈ_２２Ｎ_６Ｓ_２の質量計算値３７４．１３；実測値ＭＨ^＋（ＥＳＩ ＭＳ） ３７５．３（ｍ／ｚ）。

HPLC t _R = 4.74 min _{(UV 254nm).} Formula _C 17 _H 22 _N 6 _{S 2} mass calcd 374.13; found ^{MH + (ESI MS) 375.3 (} m / z).

( Example 39 )

ヨウ化物（７０ｍｇ、０．１２ｍｍｏｌ）、チオエトキシドナトリウム（２０ｍｇ、０．２４ｍｍｏｌ）、Ｐｄ（ｄｐｐｆ）Ｃｌ_２（９ｍｇ、０．０１２ｍｍｏｌ）、およびｔｅｒｔ−ブトキシドナトリウム（３５ｍｇ、０．３６ｍｍｏｌ）の合わせた混合物に窒素ガスをフラッシュし、次いで、１，４−ジオキサン（５ｍＬ）に溶解した。反応物を９５℃に加熱し、７２時間攪拌した。次いで、この反応物を室温まで冷却し、酢酸エチル（１００ｍＬ）で希釈し、そしてセライトを通して濾過した。濾液を水（５０ｍＬ）およびブライン（５０ｍＬ）で洗浄し、次いで乾燥させ（硫酸ナトリウム）、濾過し、そして乾燥するまで濃縮した。得られた残渣のフラッシュクロマトグラフィーによる精製（ＳｉＯ_２；１２ｇ；塩化メチレン中０％〜１０％ メタノール）は、黄色固形物としてチオエチルエーテル中間体を与えた。このチオエチルエーテル（１０ｍｇ、０．０１９ｍｍｏｌ）は、実施例１１０に概説される反応条件に供されて、標題の化合物を２ｍｇ（４％）の白色固形物として得た。

Combined iodide (70 mg, 0.12 mmol), sodium thioethoxide (20 mg, 0.24 mmol), Pd (dppf) Cl ₂ (9 mg, 0.012 mmol), and sodium tert-butoxide (35 mg, 0.36 mmol) The mixture was flushed with nitrogen gas and then dissolved in 1,4-dioxane (5 mL). The reaction was heated to 95 ° C. and stirred for 72 hours. The reaction was then cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was washed with water (50 mL) and brine (50 mL), then dried (sodium sulfate), filtered and concentrated to dryness. Purification of the resulting residue by flash chromatography (SiO ₂ ; 12 g; 0% to 10% methanol in methylene chloride) gave the thioethyl ether intermediate as a yellow solid. This thioethyl ether (10 mg, 0.019 mmol) was subjected to the reaction conditions outlined in Example 110 to give the title compound as 2 mg (4%) of a white solid.

ＨＰＬＣ ｔ_Ｒ＝５．２７分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１８Ｈ_２４Ｎ_６Ｓ_２の質量計算値３８８．１５；実測値ＭＨ^＋（ＥＳＩ ＭＳ） ３８９．７（ｍ／ｚ）。

HPLC t _R = 5.27 min _{(UV 254nm).} Formula _C 18 _H 24 _N 6 _{S 2} mass calcd 388.15; found ^{MH + (ESI MS) 389.7 (} m / z).

( Example 40 )

パートＡ：ｔ−ブタノール（３０ｍＬ）およびトリエチルアミン（１．５ｍＬ、１０．５７ｍｍｏｌ）中の２−ブロモ−チアゾール−５−カルボン酸（２．０ｇ、９．６１５ｍｍｏｌ）の攪拌溶液にアジ化ジフェニルホスホリル（２．９ｇ、１０．５７ｍｍｏｌ）を加え、この反応混合物を８０℃に加熱し、１２時間攪拌した。ＬＣＭＳは出発物質の完全な消失を示した。反応混合物を室温まで冷却し、真空下で溶媒を除去し、水（１００ｍＬ）を加え、そして酢酸エチルで抽出した（３×１００ｍＬ）。有機層を水、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、そして濃縮して、粗物質を小さなシリカゲルのパッドを通過させ、得られる（２−ブロモ−チアゾール−５−イル）カルバミン酸ｔｅｒｔ−ブチルエステル（固形物）をそれ自体次の工程において使用し、２．５ｇ（９０％）を得た。

Part A: To a stirred solution of 2-bromo-thiazole-5-carboxylic acid (2.0 g, 9.615 mmol) in t-butanol (30 mL) and triethylamine (1.5 mL, 10.57 mmol) was added diphenylphosphoryl azide (2.0 g, 9.615 mmol). 2.9 g, 10.57 mmol) was added and the reaction mixture was heated to 80 ° C. and stirred for 12 hours. LCMS showed complete disappearance of starting material. The reaction mixture was cooled to room temperature, the solvent was removed under vacuum, water (100 mL) was added and extracted with ethyl acetate (3 × 100 mL). The organic layer is washed with water, brine, dried over sodium sulfate and concentrated to pass the crude material through a small pad of silica gel and the resulting tert-butyl (2-bromo-thiazol-5-yl) carbamate. The ester (solid) was used as such in the next step, yielding 2.5 g (90%).

化学式Ｃ_８Ｈ_１１ＢｒＮ_２Ｏ_２Ｓの質量計算値２７７．９７；実測値ＭＨ^＋（ＬＣＭＳ） ２７９．０（ｍ／ｚ）。

Formula _{C 8 H 11 BrN 2 O 2} S of mass calculated 277.97; found ^{MH + (LCMS) 279.0 (m} / z).

  Part B: To a stirred solution of (2-bromo-thiazol-5-yl) -carbamic acid tert-butyl ester (2.5 g, 8.9828 mmol) in 1,4-dioxane (20.0 mL) was added tributyl. ) (Vinyl) tin (2.9 mL, 9.892 mmol), 2,6-di-tert-butyl-4-methylphenol (catalytic amount), and tetrakis (triphenylphosphine) palladium (0) (506.0 mg, 0.4496 mmol) was added. The reaction mixture was heated to 100 ° C. and stirred for 12 hours. LCMS showed complete disappearance of starting material. The reaction mixture is cooled to room temperature, filtered, the solid is washed with ethyl acetate, the combined filtrate (organic solvent) is removed in vacuo, and a biotage HPLC using a hexane / ethyl acetate gradient 0.0-100% is performed. The crude material was used to purify to give 1.1 g (54%) of (2-vinyl-thiazol-5-yl) -carbamic acid tert-butyl ester (solid).

化学式Ｃ_１０Ｈ_１４Ｎ_２Ｏ_２Ｓの質量計算値２２６．０８；実測値ＭＨ^＋（ＬＣＭＳ） ２２７．１（ｍ／ｚ）。

Calculated mass for chemical formula C ₁₀ H ₁₄ N ₂ O ₂ S 226.008; found MH ⁺ (LCMS) 227.1 (m / z).

  Part C: To a stirred solution of (2-vinyl-thiazol-5-yl) -carbamic acid tert-butyl ester (0.76 g, 2.857 mmol) in 1,4-dioxane: water (30: 9 mL) was added. Add sodium iodate (2.5 g, 11.43 mmol), osmium tetroxide (2.5% solution in 2-propanol) (0.5 mL), and 2,6-lutidine (0.663 mL, 5.714 mmol) The reaction mixture was stirred for 4 hours. LCMS showed almost complete disappearance of starting material. The reaction mixture is diluted with water (100 mL) and extracted with ethyl acetate, the organic layer is washed with water, brine, dried over sodium sulfate and concentrated under high vacuum to give 710 mg (92%) of the aldehyde. It was. The crude product was used as such for the next reaction.

化学式Ｃ_９Ｈ_１２Ｎ_２Ｏ_３Ｓの質量計算値２２８．０６；実測値ＭＨ^＋（ＬＣＭＳ） ２２９．１（ｍ／ｚ）。

Formula _{C 9 H 12 N 2 O 3} S mass calcd 228.06; found ^{MH + (LCMS) 229.1 (m} / z).

Part D: To a stirred solution of (2-formyl-thiazol-5-yl) -carbamic acid tert-butyl ester (0.76 g, 2.857 mmol) in 1,2-dichloroethane (10 mL) was added morpholine (250 mg, 1 1135 mmol), sodium triacetoxyborohydride (472 mg, 2.227 mmol), and a catalytic amount of acetic acid (3 drops) and stirred at room temperature for 2 hours. To this reaction mixture, sodium borohydride (126 mg, 3.3405 mmol) was added and stirred for 1 hour. LCMS showed the disappearance of starting material. The reaction mixture is diluted with water (100 mL) and extracted with dichloromethane, the organic layer is washed with water, brine, dried over sodium sulfate and concentrated under high vacuum to (2-morpholin-4-ylmethyl- 298 mg (91%) of thiazol-5-yl) -carbamic acid tert-butyl ester were obtained. The crude product was used as such for the next reaction.
Mass calculated for formula C14H25N3O3S 315.43; found MH ⁺ (LCMS) 300.3 (m / z).

Part E: To a stirred solution of (2-morpholin-4-ylmethyl-thiazol-5-yl) -carbamic acid tert-butyl ester (80.0 mg, 0.268 mmol) in dichloromethane (5 mL) was added iodotrimethylsilane (44 μL, 0.321 mmol) was added and stirred for 10 minutes. LCMS showed the disappearance of starting material. The reaction mixture is diluted with water (10 mL), 1N aqueous NaOH (5 mL), extracted with 10% 2-propanol in DCM (3 × 25 mL), the organic layer is dried over sodium sulfate and concentrated under high vacuum. As a result, 30.0 mg (56%) of 2-morpholin-4-ylmethyl-thiazol-5-ylamine was obtained. The crude product was used as such for the next reaction.
Calculated mass for chemical formula C8H13N3OS 199.27; Found MH ⁺ (LCMS) 200.1 (m / z).

Part F: To a stirred solution of 2-morpholin-4-ylmethyl-thiazol-5-ylamine (30.0 mg, 0.151 mmol) in DMSO (2.5 mL) was added 8-methanesulfonyl-6-methyl-3- ( 1H-pyrazol-4-yl) -imidazo [1,2-a] pyrazine (25.0 mg, 0.09045 mmol) was added followed by 60% NaH in mineral oil (48 mg, 1.206 mmol) and stirred for 30 minutes. . LCMS showed the disappearance of starting material. The reaction mixture is quenched with a 1: 1 mixture of acetonitrile and saturated ammonium chloride (10 mL), extracted with 10% 2-propanol in DCM (3 × 25 mL), and the organic layer is concentrated under high vacuum, Crude [6-methyl-3- (1H-pyrazol-4-yl) -imidazo [1,2-a] pyrazin-8-yl]-(2-morpholin-4-ylmethyl-thiazol-5-yl) -amine This was subsequently purified by Agilent reverse phase HPLC using the formic acid method to give 10 mg (28%).
HPLC-MS (10 min method) _t R = 2.06 min _{(UV 254nm).} Calculated mass for chemical formula C18H20N8OS 396.47; Found MH ⁺ (LCMS) 397.5 (m / z).

  The compounds described in Table 6 were prepared using the procedure described in Example 40.

（実施例４１）

( Example 41 )

ジメチルホルムアミド（４０ｍＬ）中の５−ニトロチオフェン−３−カルボン酸（５．００ｇ、２８．８８ｍｍｏｌ）の溶液に、炭酸カリウム（１１．９８ｇ、８６．７１ｍｍｏｌ）およびヨードメタン（２．７０ｍＬ、４３．３７ｍｍｏｌ）を加えた。この反応混合物を室温で１６時間攪拌した。出発物質が完全に消費された後、反応物を５０％ 酢酸エチル／ヘキサン（３５０ｍＬ）で希釈し、Ｈ_２Ｏ（３５０ｍＬ）で抽出した。有機層をブラインで洗浄し（１５０ｍＬ）、そして濃縮した。ヘキサン（５０ｍＬ）を固形物に加え、そして再度濃縮して、５．４５６ｇ（９９％）の生成物を得た。

To a solution of 5-nitrothiophene-3-carboxylic acid (5.00 g, 28.88 mmol) in dimethylformamide (40 mL) was added potassium carbonate (11.98 g, 86.71 mmol) and iodomethane (2.70 mL, 43.37 mmol). ) Was added. The reaction mixture was stirred at room temperature for 16 hours. After complete consumption of the starting material, the reaction was diluted with 50% ethyl acetate / hexane (350 mL) and extracted with H ₂ O (350 mL). The organic layer was washed with brine (150 mL) and concentrated. Hexane (50 mL) was added to the solid and concentrated again to give 5.456 g (99%) of product.

化学式Ｃ_６Ｈ_５ＮＯ_４Ｓの質量計算値１８７．１７；実測値Ｍ４Ｈ^＋（ＭＳ） １９１．１５（ｍ／ｚ）。

Formula _C 6 _H 5 NO ₄ S mass calcd 187.17; found ^{M4H + (MS) 191.15 (m} / z).

( Example 42 )

ＴＦＡ（１５ｍＬ）中のニトロ−エステル（１．００６ｇ、５．３７５ｍｍｏｌ）の溶液に、丸底フラスコ中でＦｅ粉（１．５１３５ｇ、２７．１０ｍｍｏｌ）をゆっくりと加えた。反応物を６０℃まで４５分間加熱し、その時点で、ＴＬＣ（１：１、酢酸エチル対ヘキサン）は出発物質の消費を示した。反応物を酢酸エチルで希釈し、Ｆｅを濾過して除いた。濾液をＮａ_２ＣＯ_３水溶液で中和し、１時間攪拌させた。水層をＥｔＯＡｃで抽出した。有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して、０．７０１ｇ（８３％）の黄色固形物を得た。

To a solution of the nitro-ester (1.006 g, 5.375 mmol) in TFA (15 mL) was slowly added Fe powder (1.5135 g, 27.10 mmol) in a round bottom flask. The reaction was heated to 60 ° C. for 45 min, at which time TLC (1: 1, ethyl acetate vs. hexane) showed consumption of starting material. The reaction was diluted with ethyl acetate and Fe was filtered off. The filtrate was neutralized with an aqueous Na ₂ CO ₃ solution and allowed to stir for 1 hour. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give 0.701 g (83%) of a yellow solid.

化学式Ｃ_６Ｈ_７ＮＯ_２Ｓの質量計算値１５７．１９；実測値ＭＨ^＋（ＬＣＭＳ） １５８．１（ｍ／ｚ）。

Formula _C 6 _H 7 NO ₂ S mass calcd 157.19; found ^{MH + (LCMS) 158.1 (m} / z).

( Example 43 )

質量スペクトル分析および薄層クロマトグラフィー（５０％ 酢酸エチル／ヘキサン）が反応が完了したことを示すまで、ＤＭＦ（３５ｍＬ）中のスルホン（１．２７ｇ、３．１１ｍｍｏｌ）および２−アミノチオフェン−４−カルボキシレートメチルエステル（０．７０１ｇ、４．４６ｍｍｏｌ）の溶液を、室温にてＮａＨ（６０％ 油中分散液、０．４０２ｇ、１０．０５ｍｍｏｌ）で処理した。飽和塩化アンモニウム（１５ｍＬ）および水（５０ｍＬ）を反応物に加えた。反応物を１０分間攪拌した。沈殿した固形物を濾過して収集し、所望の生成物を得た。

Sulfone (1.27 g, 3.11 mmol) and 2-aminothiophene-4-in DMF (35 mL) until mass spectral analysis and thin layer chromatography (50% ethyl acetate / hexanes) indicated the reaction was complete. A solution of carboxylate methyl ester (0.701 g, 4.46 mmol) was treated with NaH (60% dispersion in oil, 0.402 g, 10.05 mmol) at room temperature. Saturated ammonium chloride (15 mL) and water (50 mL) were added to the reaction. The reaction was stirred for 10 minutes. The precipitated solid was collected by filtration to give the desired product.

化学式Ｃ_２２Ｈ_２８Ｎ_６Ｏ_３ＳＳｉの質量計算値４８４．６５；実測値ＭＨ^＋（ＭＳ） ４８５．１（ｍ／ｚ）。

Chemical formula _{C 22 H 28 N 6 O 3} SSi mass calcd 484.65; found ^{MH + (MS) 485.1 (m} / z).

( Example 44 )

ＴＨＦ（１０ｍＬ）およびＭｅＯＨ（３ｍＬ）中の実施例４３において調製したエステル（０．５６５ｇ、１．１７ｍｍｏｌ）の溶液を、固体ＮａＯＨ（９ペレット）、続いてＨ_２Ｏ（５ｍＬ）で処理した。反応物を室温で１６時間、激しく攪拌した。ＴＨＦおよびＭｅＯＨを真空中で除去し、残渣をＥｔＯＡｃ（３×２０ｍＬ）で抽出した。ＨＣｌ水溶液を用いて水相をｐＨ ３〜４にした。酸性化された水相をＥｔＯＡｃ（５×２０ｍＬ）で抽出し、そして真空中で濃縮して、０．３９３ｇ（７１％）の所望のカルボン酸を得た。

A solution of the ester prepared in Example 43 (0.565 g, 1.17 mmol) in THF (10 mL) and MeOH (3 mL) was treated with solid NaOH (9 pellets) followed by H ₂ O (5 mL). The reaction was stirred vigorously at room temperature for 16 hours. THF and MeOH were removed in vacuo and the residue was extracted with EtOAc (3 × 20 mL). The aqueous phase was brought to pH 3-4 using aqueous HCl. The acidified aqueous phase was extracted with EtOAc (5 × 20 mL) and concentrated in vacuo to give 0.393 g (71%) of the desired carboxylic acid.

( Example 45 )

ＤＭＦ（３ｍＬ）中のカルボン酸（実施例４において調製）（０．０５４ｇ、０．１１５ｍｍｏｌ）の溶液を、アミン（０．０３ｍＬ、０．２６２ｍｍｏｌ）、ＮＭＭ（０．０７ｍＬ、０．６３７ｍｍｏｌ）で、次いでＨＡＴＵ（０．１４１ｇ、０．３７２ｍｍｏｌ）で処理した。反応物を室温で１６時間攪拌した。水（１５ｍＬ）を加え、反応物を１０分間攪拌した。沈殿した固形物を濾過して収集し、０．０３８ｇ（６０％）の所望のアミドを得た。

A solution of the carboxylic acid (prepared in Example 4) (0.054 g, 0.115 mmol) in DMF (3 mL) was added with amine (0.03 mL, 0.262 mmol), NMM (0.07 mL, 0.637 mmol). And then treated with HATU (0.141 g, 0.372 mmol). The reaction was stirred at room temperature for 16 hours. Water (15 mL) was added and the reaction was stirred for 10 minutes. The precipitated solid was collected by filtration to give 0.038 g (60%) of the desired amide.

化学式Ｃ_２７Ｈ_３７Ｎ_７Ｏ_２ＳＳｉの質量計算値５５１．７８；実測値ＭＨ^＋（ＭＳ） ５５２．１（ｍ／ｚ）。

Calculated mass for C ₂₇ H ₃₇ N ₇ O ₂ SSi 551.78; found MH ⁺ (MS) 552.1 (m / z).

  The compound in column 3 was prepared by essentially the same procedure as shown in Example 45, only replacing the amine shown in column 2 of Table 7.

（実施例４６）

( Example 46 )

ジクロロメタン（４ｍＬ）中のアミド（０．０３８ｇ、０．０６９ｍｍｏｌ）の溶液に、水素化アルミニウムリチウム（０．０２９ｇ、０．７７５ｍｍｏｌ）およびエチルエーテル（０．８ｍＬ）を加えた。反応混合物を室温で１０分間攪拌し、次いで、４０℃で５時間還流した。反応は質量スペクトル測定によってモニターした。出発物質であるアミドの消費の際に、反応物を室温まで冷却し、Ｈ_２Ｏ（２ｍＬ）でクエンチした。反応物をＤＣＭで希釈し、濾過した。濾液をＨ_２Ｏ（≦８ｍＬ）で洗浄した。有機層を濃縮して、０．０１９ｇ（５２％）のアミンを得た。ＴＨＦ中の上記のアミンを、６０℃にて１時間、４Ｎ ＨＣｌ／ジオキサンでさらに処理した。室温に冷却した際に、Ｅｔ_２Ｏを加え、そしてこの混合物を１０分間攪拌した。沈殿した固形物を収集して、１３．９ｍｇ（９６％収率）の所望のアミンを得た。

To a solution of the amide (0.038 g, 0.069 mmol) in dichloromethane (4 mL) was added lithium aluminum hydride (0.029 g, 0.775 mmol) and ethyl ether (0.8 mL). The reaction mixture was stirred at room temperature for 10 minutes and then refluxed at 40 ° C. for 5 hours. The reaction was monitored by mass spectral measurement. Upon consumption of the starting amide, the reaction was cooled to room temperature and quenched with H ₂ O (2 mL). The reaction was diluted with DCM and filtered. The filtrate was washed with H ₂ O (≦ 8 mL). The organic layer was concentrated to give 0.019 g (52%) of amine. The above amine in THF was further treated with 4N HCl / dioxane at 60 ° C. for 1 h. Upon cooling to room temperature, Et ₂ O was added and the mixture was stirred for 10 minutes. The precipitated solid was collected to give 13.9 mg (96% yield) of the desired amine.

  The following compounds shown in column 2 of Table 8 were prepared by essentially the same procedure as shown in Example 46.

（実施例４７）

( Example 47 )

エチル ４−クロロ−３−オキソブタノエート（１４．１５ｇ、８６ｍｍｏｌ）、シアノ酢酸（８．００ｇ、８６ｍｍｏｌ）、ＮＨ_４ＯＡｃ（１．３２ｇ、１７．２ｍｍｏｌ）、ＡｃＯＨ（２．４６ｍＬ、４３ｍｍｏｌ）、およびベンゼン（４０ｍＬ）を、Ｄｅａｎ−Ｓｔａｒｋトラップを用いる還流で一晩攪拌した。この混合物を室温まで冷却し、ＥｔＯＡｃで希釈し、飽和ＮａＨＣＯ_３、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して、粗生成物１（９．２９ｇ、５８％）を得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．６７分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値１８７．０、実測値ＬＣ／ＭＳ ｍ／ｚ １８８．１（Ｍ＋Ｈ）。

Ethyl 4-chloro-3-oxobutanoate (14.15 g, 86 mmol), cyanoacetic acid (8.00 g, 86 mmol), NH ₄ OAc (1.32 g, 17.2 mmol), AcOH (2.46 mL, 43 mmol) , And benzene (40 mL) were stirred overnight at reflux using a Dean-Stark trap. The mixture was cooled to room temperature, diluted with EtOAc, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated to give crude product 1 (9.29 g, 58%). .
_HPLC-MS t R = 1.67 min _{(UV 254nm).} Calculated mass for M + 187.0, found LC / MS m / z 188.1 (M + H).

( Example 48 )

モルホリン（５８０μＬ、６．６５ｍｍｏｌ）を、ＥｔＯＨ（５ｍＬ）中のエチル ３−（クロロメチル）−４−シアノブタ−３−エノエート（６２２ｍｇ、３．３３ｍｍｏｌ）およびＳ−フレーク（ｆｌａｋｅｓ）（１１６ｍｇ、３．６３ｍｍｏｌ）の混合液に滴下して加えた。反応物を室温で一晩攪拌した。この混合物を濃縮した。この混合物をＥｔＯＡｃで希釈し、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して、粗生成物を得た。調製用ＬＣによる精製は標題の化合物を与えた（１８２ｍｇ、２０％）。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝０．８０分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値２７０．１、実測値ＬＣ／ＭＳ ｍ／ｚ ２７１．１（Ｍ＋Ｈ）。

Morpholine (580 μL, 6.65 mmol) was added to ethyl 3- (chloromethyl) -4-cyanobut-3-enoate (622 mg, 3.33 mmol) and S-flakes (116 mg, 3.65 mmol) in EtOH (5 mL). 63 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The mixture was concentrated. The mixture was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and concentrated to give the crude product. Purification by preparative LC gave the title compound (182 mg, 20%).
_HPLC-MS t R = 0.80 min _{(UV 254nm).} Calculated mass for M + 270.1, found LC / MS m / z 271.1 (M + H).

( Example 49 )

ＤＭＦ（２ｍＬ）中のエチル ５−アミノ−３−（モルホリノメチル）チオフェン−２−カルボキシレート（６１．０ｍｇ、０．２２５ｍｍｏｌ）およびスルホン（７１．０ｍｇ、０．１７３ｍｍｏｌ）の溶液を、室温にてＮａＨ（油中６０％分散液、２０．９ｍｇ、０．５２１ｍｍｏｌ）で処理した。反応が完了したことをＬＣＭＳが示すまで、この混合物を室温で攪拌した。この反応混合物をＥｔＯＡｃで希釈し、飽和ＮＨ_４Ｃｌで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して標題の化合物を得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．７９分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値５９７．２、実測値ＬＣ／ＭＳ ｍ／ｚ ５９８．３（Ｍ＋Ｈ）。

A solution of ethyl 5-amino-3- (morpholinomethyl) thiophene-2-carboxylate (61.0 mg, 0.225 mmol) and sulfone (71.0 mg, 0.173 mmol) in DMF (2 mL) at room temperature. Treated with NaH (60% dispersion in oil, 20.9 mg, 0.521 mmol). The mixture was stirred at room temperature until LCMS indicated that the reaction was complete. The reaction mixture was diluted with EtOAc, washed with saturated NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated to give the title compound.
_HPLC-MS t R = 1.79 min _{(UV 254nm).} Calculated mass for M + 597.2, found LC / MS m / z 598.3 (M + H).

( Example 50 )

ＴＨＦ（０．７８μＬ、１．５６ｍｍｏｌ）中のｉ−ＰｒＭｇＣｌの溶液を、実施例４９からの粗化合物（１０４．２ｍｇ、０．１７３ｍｍｏｌ）およびＴＨＦ（３ｍＬ）中のジエチルアミン（９１μＬ、０．７８２ｍｍｏｌ）の−２０℃溶液に滴下して加えた。この混合物を室温までゆっくりと温め、そして反応が完了したことをＬＣＭＳが示すまで、この温度で攪拌した。この反応混合物を０℃まで冷却し、飽和ＮＨ_４Ｃｌでクエンチした。この反応混合物をＥｔＯＡｃで抽出し、有機層をＮａ_２ＳＯ_４で乾燥させ、そして濃縮して、粗生成物４を得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．８１分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値６２４．３、実測値ＬＣ／ＭＳ ｍ／ｚ ６２５．３（Ｍ＋Ｈ）。

A solution of i-PrMgCl in THF (0.78 μL, 1.56 mmol) was added to the crude compound from Example 49 (104.2 mg, 0.173 mmol) and diethylamine (91 μL, 0.782 mmol) in THF (3 mL). Was added dropwise to a −20 ° C. solution. The mixture was slowly warmed to room temperature and stirred at this temperature until LCMS indicated that the reaction was complete. The reaction mixture was cooled to 0 ° C. and quenched with saturated NH ₄ Cl. The reaction mixture was extracted with EtOAc, the organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude product 4.
_HPLC-MS t R = 1.81 min _{(UV 254nm).} Calculated mass for M + 624.3, found LC / MS m / z 625.3 (M + H).

( Example 51 )

ジオキサン（１ｍＬ）中の４Ｎ ＨＣｌを、０℃で粗化合物４（１７ｍｇ、０．０２７ｍｍｏｌ）に加えた。この混合物を室温まで温め、反応が完了したことをＬＣＭＳが示すまで、この温度で攪拌した。濃縮および調製用ＬＣによる精製および塩酸塩への変換は、標題の化合物を与えた。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．１４分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値４９４．２、実測値ＬＣ／ＭＳ ｍ／ｚ ４９５．２（Ｍ＋Ｈ）。

4N HCl in dioxane (1 mL) was added to crude compound 4 (17 mg, 0.027 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred at this temperature until LCMS indicated that the reaction was complete. Concentration and purification by preparative LC and conversion to the hydrochloride salt gave the title compound.
_HPLC-MS t R = 1.14 min _{(UV 254nm).} Calculated mass for M + 494.2, found LC / MS m / z 495.2 (M + H).

  By essentially the same procedure, the compound shown in column 2 of Table 9 can be prepared.

（実施例５２）

( Example 52 )

ｔｅｒｔ−ブタノール（８０ｍＬ）中のチオフェン−２，５−ジカルボン酸（２．７３ｇ、１５．８４ｍｍｏｌ）、ジフェニルホスホリルアジド（３．４１ｍＬｇ、１５．８４ｍｍｏｌ）、およびトリエチルアミン（４．４ｍＬ、３１．６８ｍｍｏｌ）の溶液を、還流にて５時間加熱した。この反応混合物を室温まで冷却し、次いで濃縮して、粗標題化合物を得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．５２分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値２４３．０、実測値ＬＣ／ＭＳ ｍ／ｚ ２４４．１（Ｍ＋Ｈ）。

Thiophene-2,5-dicarboxylic acid (2.73 g, 15.84 mmol), diphenylphosphoryl azide (3.41 mLg, 15.84 mmol), and triethylamine (4.4 mL, 31.68 mmol) in tert-butanol (80 mL) The solution of was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and then concentrated to give the crude title compound.
_HPLC-MS t R = 1.52 min _{(UV 254nm).} Calculated mass for M + 243.0, found LC / MS m / z 244.1 (M + H).

( Example 53 )

Ｅｔ_３Ｎ（１２６１．６μＬ、９．０５ｍｍｏｌ）を、０℃にて、ＤＭＦ（６ｍｌ）中の５−ｔｅｒｔ−ブトキシカルボニルアミノ−チオフェン−２−カルボン酸（５５０ｍｇ、２．２６ｍｍｏｌ）、ＥＤＣＩ（１０８６ｍｇ、５．６５ｍｍｏｌ）、およびピペリジン（４４７μＬ、４．５２ｍｍｏｌ）の混合物に加えた。この反応混合物を室温まで温め、この温度で一晩攪拌した。この混合物をＥｔＯＡｃで希釈し、ブラインで洗浄し（２×）、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して粗残渣を得た。Ｂｉｏｔａｇｅによる精製は化合物２（３６８ｍｇ、５３％）を与えた。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．８９分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値３１０．１、実測値ＬＣ／ＭＳ ｍ／ｚ ３１１．２（Ｍ＋Ｈ）。ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．４分（ＵＶ_{２５４ｎｍ}）。

Et ₃ N (1261.6 μL, 9.05 mmol) was added at 0 ° C. to 5-tert-butoxycarbonylamino-thiophene-2-carboxylic acid (550 mg, 2.26 mmol), EDCI (1086 mg) in DMF (6 ml). 5.65 mmol), and piperidine (447 μL, 4.52 mmol). The reaction mixture was warmed to room temperature and stirred at this temperature overnight. The mixture was diluted with EtOAc, washed with brine (2 ×), dried over Na ₂ SO ₄ and concentrated to give a crude residue. Purification by Biotage gave compound 2 (368 mg, 53%).
_HPLC-MS t R = 1.89 min _{(UV 254nm).} Calculated mass for M + 310.1, found LC / MS m / z 311.2 (M + H). _HPLC-MS t R = 2.4 min _{(UV 254nm).}

( Example 54 )

実施例５３からの化合物（９０ｍｇ、０．２９ｍｍｏｌ）を、２０％ ＴＦＡ／ＣＨ_２Ｃｌ_２溶液（５ｍＬ）中で、室温にて１．５時間攪拌した。この反応混合物を濃縮して化合物３を得た。この粗生成物をさらなる精製なしで使用した。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．１６分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値２１０．０、実測値ＬＣ／ＭＳ ｍ／ｚ ２１１．１（Ｍ＋Ｈ）。

The compound from Example 53 (90 mg, 0.29 mmol) was stirred in 20% TFA / CH ₂ Cl ₂ solution (5 mL) at room temperature for 1.5 hours. The reaction mixture was concentrated to give compound 3. This crude product was used without further purification.
_HPLC-MS t R = 1.16 min _{(UV 254nm).} Calculated mass of M + 210.0, found LC / MS m / z 211.1 (M + H).

( Example 55 )

ＤＭＦ（２ｍＬ）中の実施例５４からの粗物質およびスルホン（９８．０ｍｇ、０．２４１ｍｍｏｌ）の溶液を、室温にてＮａＨ（油中６０％分散液、２９．０ｍｇ、０．７２５ｍｍｏｌ）で処理した。反応が完了したことをＬＣＭＳが示すまで、この混合物を攪拌した。この反応混合物をＥｔＯＡｃで希釈し、飽和ＮＨ_４Ｃｌで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して、粗生成物４を得た。Ｂｉｏｔａｇｅによる精製は標題の化合物を与えた（８２ｍｇ、６３％）。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．３０分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値５３７．２、実測値ＬＣ／ＭＳ ｍ／ｚ ５３８．２（Ｍ＋Ｈ）。

Treatment of the crude material from Example 54 and sulfone (98.0 mg, 0.241 mmol) in DMF (2 mL) with NaH (60% dispersion in oil, 29.0 mg, 0.725 mmol) at room temperature. did. The mixture was stirred until LCMS indicated that the reaction was complete. The reaction mixture was diluted with EtOAc, washed with saturated NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated to give crude product 4. Purification by Biotage gave the title compound (82 mg, 63%).
_HPLC-MS t R = 2.30 min _{(UV 254nm).} Calculated mass for M + 537.2, found LC / MS m / z 538.2 (M + H).

( Example 56 )

ジクロロメタン（５ｍＬ）中のアミド（４７．６ｍｇ、０．０８９ｍｍｏｌ）の溶液に、水素化アルミニウムリチウム（３９．９ｍｇ、１．０ｍｍｏｌ）およびエチルエーテル（１ｍＬ）を加えた。この反応混合物を室温で１０分間攪拌し、次いで、反応が完了したことをＬＣＭＳが示すまで、４０℃で還流した。この反応物を室温まで冷却し、Ｈ_２Ｏ（０．５ｍＬ）でクエンチした。この反応物をジクロロメタンで希釈し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して、標題化合物を得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．５２分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値５２３．２、実測値ＬＣ／ＭＳ ｍ／ｚ ５２４．２（Ｍ＋Ｈ）。

To a solution of the amide (47.6 mg, 0.089 mmol) in dichloromethane (5 mL) was added lithium aluminum hydride (39.9 mg, 1.0 mmol) and ethyl ether (1 mL). The reaction mixture was stirred at room temperature for 10 minutes and then refluxed at 40 ° C. until LCMS indicated that the reaction was complete. The reaction was cooled to room temperature and quenched with H ₂ O (0.5 mL). The reaction was diluted with dichloromethane, dried over Na ₂ SO ₄ and concentrated to give the title compound.
_HPLC-MS t R = 1.52 min _{(UV 254nm).} Calculated mass for M + 523.2, found LC / MS m / z 524.2 (M + H).

( Example 57 )

ジオキサン（２ｍＬ）中の４Ｎ ＨＣｌを、実施例５６からの粗化合物に０℃で加えた。この混合物を室温まで温め、そして反応が完了したことをＬＣＭＳが示すまで、この温度で攪拌した。濃縮により粗標題化合物を得た。調製用ＬＣによる精製および塩酸塩への変換は標題化合物を与えた。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝０．９１分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値３９３．１、実測値ＬＣ／ＭＳ ｍ／ｚ ３９４．１（Ｍ＋Ｈ）。

4N HCl in dioxane (2 mL) was added to the crude compound from Example 56 at 0 ° C. The mixture was warmed to room temperature and stirred at this temperature until LCMS indicated that the reaction was complete. Concentration gave the crude title compound. Purification by preparative LC and conversion to the hydrochloride salt gave the title compound.
_HPLC-MS t R = 0.91 min _{(UV 254nm).} Calculated mass for M + 393.1, found LC / MS m / z 394.1 (M + H).

  The compounds in Table 10 were prepared by essentially the same procedure.

（実施例５８）

( Example 58 )

ジメチルホルムアミド（ＤＭＦ；０．８ｍＬ）中の８−メタンスルホニル−６−メチル−３−チアゾール−２−イル−イミダゾ［１，２−ａ］ピラジン（０．０７０ｇ；０．２４ｍｍｏｌ）および５−アミノ−３−カルボメトキシ−イソチアゾール（０．０３９ｇ；０．２５ｍｍｏｌ）の溶液に、水素化ナトリウム（油中ＮａＨ；６０％；０．０２４ｇ）を加えた。この反応混合物を室温で０．５時間攪拌し、次いで、塩化アンモニウム（ＮＨ_４Ｃｌ）の飽和水溶液でクエンチした。さらに水で希釈し、濾過した。濾過ケーキを水およびヘキサンで洗浄した。この濾過ケーキを真空中で洗浄し、標題化合物を黄色固形物として得た（０．０７８ｇ；８７％）。

8-Methanesulfonyl-6-methyl-3-thiazol-2-yl-imidazo [1,2-a] pyrazine (0.070 g; 0.24 mmol) and 5-amino in dimethylformamide (DMF; 0.8 mL) To a solution of -3-carbomethoxy-isothiazole (0.039 g; 0.25 mmol) was added sodium hydride (NaH in oil; 60%; 0.024 g). The reaction mixture was stirred at room temperature for 0.5 h and then quenched with a saturated aqueous solution of ammonium chloride (NH ₄ Cl). Further diluted with water and filtered. The filter cake was washed with water and hexane. The filter cake was washed in vacuo to give the title compound as a yellow solid (0.078 g; 87%).

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝４．３５分（ＵＶ_{２５４ｎｍ}）。Ｃ_１５Ｈ_１２Ｎ_６Ｏ_２Ｓ_２の質量計算値３７２．０４、実測値ＭＨ^＋（ＬＣＭＳ）３７３．２（ｍ／ｚ）。

_HPLC-MS t R = 4.35 min _{(UV 254nm).} Mass calculated for C ₁₅ H ₁₂ N ₆ O ₂ S ₂ 372.04, found MH ⁺ (LCMS) 373.2 (m / z).

( Example 59 )

リチウムトリエチルボロハイドライド（Ｓｕｐｅｒ Ｈｙｄｒｉｄｅ；ＴＨＦ中１Ｍ；０．３２ｍＬ）の溶液を、乾燥ＴＨＦ（０．８ｍＬ）中のメチルエステル（０．０３ｇ；０．０８ｍｍｏｌ）の溶液に滴下して加えた。室温で１．５時間の攪拌後、この反応混合物を飽和ＮＨ_４Ｃｌ水溶液（８ｍＬ）でクエンチし、そして水で希釈した。少量の沈殿黄色固形物を濾過し、水およびエーテルで洗浄した。固形物を真空中で乾燥させて、約１０ｍｇ（３６％）のアルコールを得た。

A solution of lithium triethylborohydride (Super Hydride; 1M in THF; 0.32 mL) was added dropwise to a solution of the methyl ester (0.03 g; 0.08 mmol) in dry THF (0.8 mL). After stirring for 1.5 hours at room temperature, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (8 mL) and diluted with water. A small amount of precipitated yellow solid was filtered and washed with water and ether. The solid was dried in vacuo to give about 10 mg (36%) of alcohol.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．９８分（ＵＶ_{２５４ｎｍ}）。Ｃ_１４Ｈ_１２Ｎ_６ＯＳ_２の質量計算値３４４．０５、実測値ＭＨ^＋（ＬＣＭＳ）３４５．２（ｍ／ｚ）。

_HPLC-MS t R = 2.98 min _{(UV 254nm).} C ₁₄ H ₁₂ N ₆ OS ₂ mass calcd 344.05, found ^{MH + (LCMS) 345.2 (m} / z).

( Example 60 )

ＤＭＦ（１．５ｍＬ）中のエステル（０．１１３ｇ；０．３ｍｍｏｌ）の溶液を、ＮａＨ（油中６０％；０．０３ｇ；０．７６ｍｍｏｌ）、続いて２−（トリメチルシリル）エトキシメチルクロリド（ＳＥＭ−Ｃｌ；０．１ｍＬ；０．６１ｍｍｏｌ）で処理した。この反応混合物を室温で３時間攪拌し、そして飽和ＮＨ_４Ｃｌ水溶液および水でクエンチした。沈殿黄色固形物を濾過によって収集し、水で洗浄し、そして乾燥させた。標題化合物を黄色固形物として得た（０．１４２ｇ；９２％）。

A solution of the ester (0.113 g; 0.3 mmol) in DMF (1.5 mL) was added NaH (60% in oil; 0.03 g; 0.76 mmol) followed by 2- (trimethylsilyl) ethoxymethyl chloride (SEM -Cl; 0.1 mL; 0.61 mmol). The reaction mixture was stirred at room temperature for 3 hours and quenched with saturated aqueous NH ₄ Cl and water. The precipitated yellow solid was collected by filtration, washed with water and dried. The title compound was obtained as a yellow solid (0.142 g; 92%).

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝５．９８分（ＵＶ_{２５４ｎｍ}）。Ｃ_２１Ｈ_２６Ｎ_６Ｏ_３Ｓ_２Ｓｉの質量計算値５０２．１３、実測値ＭＨ^＋（ＬＣＭＳ）５０３．３（ｍ／ｚ）。

_HPLC-MS t R = 5.98 min _{(UV 254nm).} Calculated mass for C ₂₁ H ₂₆ N ₆ O ₃ S ₂ Si 502.13, found MH ⁺ (LCMS) 503.3 (m / z).

( Example 61 )

リチウムトリエチルボロハイドライド（Ｓｕｐｅｒ Ｈｙｄｒｉｄｅ；ＴＨＦ中１Ｍ；１ｍＬ）の溶液を、乾燥ＴＨＦ中のメチルエステル２の溶液に滴下して加えた。室温で１時間の攪拌後、反応混合物を飽和ＮＨ_４Ｃｌ水溶液（８ｍＬ）およびＲｏｃｈｅｌｌｅ塩の飽和水溶液でクエンチした。有機生成物をジクロロメタン（ＣＨ_２Ｃｌ_２）で抽出し、水およびブラインで洗浄した。真空中での濃縮により、約１２０ｍｇ（１００％）のアルコールを得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝４．２２分（ＵＶ_{２５４ｎｍ}）。Ｃ_２０Ｈ_２６Ｎ_６Ｏ_２Ｓ_２Ｓｉの質量計算値４７４．１３、実測値ＭＨ^＋（ＬＣＭＳ）４７５．３（ｍ／ｚ）。

A solution of lithium triethylborohydride (Super Hydride; 1M in THF; 1 mL) was added dropwise to a solution of methyl ester 2 in dry THF. After stirring for 1 hour at room temperature, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (8 mL) and a saturated aqueous solution of Rochelle salt. The organic product was extracted with dichloromethane (CH ₂ Cl ₂ ) and washed with water and brine. Concentration in vacuo yielded approximately 120 mg (100%) of alcohol.
_HPLC-MS t R = 4.22 min _{(UV 254nm).} Calculated mass of C ₂₀ H ₂₆ N ₆ O ₂ S ₂ Si 474.13, found MH ⁺ (LCMS) 475.3 (m / z).

( Example 62 )

Ｄｅｓｓ−Ｍａｒｔｉｎペルヨウ化物（０．１４７ｇ；０．３５ｍｍｏｌ）を、乾燥ＴＨＦ中のアルコール（０．１１ｇ；０．２３ｍｍｏｌ）の溶液に加え、そして室温で４０分間攪拌した。この反応混合物を３０ｍＬのＣＨ_２Ｃｌ_２で希釈し、飽和炭酸水素ナトリウム（ＮａＨＣＯ_３）溶液および水で洗浄し、そして乾燥させた。濃縮は黄色固形物を与え、これをＣＨ_２Ｃｌ_２に再溶解し、濾過した。濾液を濃縮して、１２０ｍｇの粗標題化合物を黄色固形物として得て、これをそのままで次の工程で使用した。

Dess-Martin periodide (0.147 g; 0.35 mmol) was added to a solution of alcohol (0.11 g; 0.23 mmol) in dry THF and stirred at room temperature for 40 minutes. The reaction mixture was diluted with 30 mL of CH ₂ Cl ₂ , washed with saturated sodium bicarbonate (NaHCO ₃ ) solution and water and dried. Concentration gave a yellow solid, which was redissolved in CH ₂ Cl ₂ and filtered. The filtrate was concentrated to give 120 mg of the crude title compound as a yellow solid that was used as such in the next step.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝６．１４分（ＵＶ_{２５４ｎｍ}）。Ｃ_２０Ｈ_２４Ｎ_６Ｏ_２Ｓ_２Ｓｉの質量計算値４７２．１２、実測値ＭＨ^＋（ＬＣＭＳ）４７３．３（ｍ／ｚ）。

_HPLC-MS t R = 6.14 min _{(UV 254nm).} Calculated mass for C ₂₀ H ₂₄ N ₆ O ₂ S ₂ Si 472.12, found MH ⁺ (LCMS) 473.3 (m / z).

( Example 63 )

ＣＨ_２Ｃｌ_２（１ｍＬ）中のアルデヒド（０．０５ｇ；０．１ｍｍｏｌ）およびピペリジン（０．０５ｍＬ；０．５ｍｍｏｌ）の溶液を、氷酢酸（ＡｃＯＨ；１滴）で処理し、そして室温（ＲＴ）で３時間攪拌した。固体水素化ホウ素ナトリウム（ＮａＢＨ_４；０．０１６ｇ；０．４２ｍｍｏｌ）を加え、この反応混合物を氷／ブラインバス（−５℃）中で冷却し、そしてメタノール（０．２ｍＬ）を滴下して加えた。低温で３０分間の攪拌後、反応物を飽和ＮＨ_４Ｃｌでクエンチし、ＣＨ_２Ｃｌ_２中に抽出した。この有機抽出物を、飽和ＮＨ_４Ｃｌ、水、およびブラインで洗浄した。溶媒の除去は粗生成物を与え、これを、４％ ＣＨ_３ＯＨおよび１％ 水酸化アンモニウムを含むＣＨ_２Ｃｌ_２を使用する調製用薄層クロマトグラフィー（Ｐｒｅｐ ＴＬＣ）によって精製した。標題化合物が黄色フィルムとして単離された（２５ｍｇ；４５％）。

A solution of aldehyde (0.05 g; 0.1 mmol) and piperidine (0.05 mL; 0.5 mmol) in CH ₂ Cl ₂ (1 mL) was treated with glacial acetic acid (AcOH; 1 drop) and at room temperature (RT ) For 3 hours. Solid sodium borohydride (NaBH ₄ ; 0.016 g; 0.42 mmol) is added, the reaction mixture is cooled in an ice / brine bath (−5 ° C.), and methanol (0.2 mL) is added dropwise. It was. After stirring at low temperature for 30 minutes, the reaction was quenched with saturated NH ₄ Cl and extracted into CH ₂ Cl ₂ . The organic extract was washed with saturated NH ₄ Cl, water, and brine. Removal of the solvent gave the crude product, which was purified by preparative thin layer chromatography (Prep TLC) using CH ₂ Cl ₂ containing 4% CH ₃ OH and 1% ammonium hydroxide. The title compound was isolated as a yellow film (25 mg; 45%).

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝３．８２分（ＵＶ_{２５４ｎｍ}）。Ｃ_２５Ｈ_３５Ｎ_７ＯＳ_２Ｓｉの質量計算値５４１．２１、実測値ＭＨ^＋（ＬＣＭＳ）５４２．３（ｍ／ｚ）。

_HPLC-MS t R = 3.82 min _{(UV 254nm).} Mass calculated for C ₂₅ H ₃₅ N ₇ OS ₂ Si 541.21, found MH ⁺ (LCMS) 542.3 (m / z).

( Example 64 )

０．５ｍＬのＴＨＦ中の実施例６３（０．０１３ｇ；０．０２ｍｍｏｌ）からの化合物の溶液を、ジオキサン中のＨＣｌ（４Ｍ；０．５ｍＬ）で処理し、７０℃のオイルバス中に配置した。３０分間の加熱後、形成した沈殿を、０．５ｍＬのメタノールを加えて溶解した。この反応混合物を７０℃のバス温度で、さらに１時間加熱した。反応の内容物を室温まで冷却し、すべての揮発性物質をロータリーエバポレーターで除去した。残渣をＴＨＦ中に懸濁し、エーテルで粉砕した。沈殿物を濾過によって収集し、約１０ｍＬのエーテルで洗浄し、そして空気中（０．５時間）および真空中（１６時間）で乾燥させ、１０ｍｇ（９３％）の標題化合物を黄色固形物として得た。

A solution of the compound from Example 63 (0.013 g; 0.02 mmol) in 0.5 mL THF was treated with HCl in dioxane (4M; 0.5 mL) and placed in an oil bath at 70 ° C. . After heating for 30 minutes, the precipitate formed was dissolved by adding 0.5 mL of methanol. The reaction mixture was heated at a bath temperature of 70 ° C. for an additional hour. The reaction contents were cooled to room temperature and all volatiles were removed on a rotary evaporator. The residue was suspended in THF and triturated with ether. The precipitate is collected by filtration, washed with about 10 mL of ether, and dried in air (0.5 hours) and in vacuo (16 hours) to give 10 mg (93%) of the title compound as a yellow solid. It was.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．９６分（ＵＶ_{２５４ｎｍ}）。Ｃ_１９Ｈ_２１Ｎ_７Ｓ_２の質量計算値４１１．１３、実測値ＭＨ^＋（ＬＣＭＳ）４１２．２（ｍ／ｚ）。

_HPLC-MS t R = 2.96 min _{(UV 254nm).} Mass calculated for C ₁₉ H ₂₁ N ₇ S ₂ 411.13, found MH ⁺ (LCMS) 412.2 (m / z).

  The compounds in Table 11 were prepared according to the above examples.

（実施例６５）

( Example 65 )

パートＡ：リチウム ヘキサメチルジシラジド（ＴＨＦ中１Ｍ；０．１８ｍＬ）を、室温で、２ｍＬのＴＨＦ中の４−モルホリン−４−イルメチル フェニルアミン（０．０１３ｇ；０．０６８ｍｍｏｌ）および８−メタンスルホニル−６−メチル−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジン（０．０２５ｇ；０．０６１ｍｍｏｌ）の琥珀色溶液に加え、ワイン色の溶液を生じた。室温で２０分間の攪拌後、この反応混合物を飽和ＮＨ_４Ｃｌ水溶液でクエンチした。内容物を酢酸エチルで希釈し、そして水およびブラインで洗浄した。有機抽出物からの粗物質を調製用ＴＬＣ（５％ メタノール−ＣＨ_２Ｃｌ_２）によって精製し、標題化合物を淡黄色油状物として得た（０．０２５ｇ；８０％）。

Part A: Lithium hexamethyldisilazide (1M in THF; 0.18 mL) was added 4-morpholin-4-ylmethylphenylamine (0.013 g; 0.068 mmol) and 8-methane in 2 mL of THF at room temperature. Of sulfonyl-6-methyl-3- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazine (0.025 g; 0.061 mmol) In addition to the amber solution, a wine-colored solution was produced. After stirring for 20 minutes at room temperature, the reaction mixture was quenched with saturated aqueous NH ₄ Cl. The contents were diluted with ethyl acetate and washed with water and brine. The crude material from the organic extract was purified by preparative TLC (5% methanol-CH ₂ Cl ₂ ) to give the title compound as a pale yellow oil (0.025 g; 80%).

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝３．０５分（ＵＶ_{２５４ｎｍ}）。Ｃ_２７Ｈ_３７Ｎ_７Ｏ_２Ｓｉの質量計算値５１９．２７、実測値ＭＨ^＋（ＬＣＭＳ）５２０．３（ｍ／ｚ）。

_HPLC-MS t R = 3.05 min _{(UV 254nm).} Mass calculated for C ₂₇ H ₃₇ N ₇ O ₂ Si 519.27, found MH ⁺ (LCMS) 520.3 (m / z).

  Part B: Compound from Part A (0.025 g; 0.048 mmol) was suspended in dry THF, treated with HCl in dioxane (4M; 1 mL) and in an oil bath set at 70 ° C. for 15 minutes. Upon heating, a white precipitate formed at that point. Methanol was added to dissolve some solids and the reaction mixture was heated continuously for 45 minutes. After cooling to room temperature, volatile materials were removed on a rotary evaporator. The residue was suspended in THF and the precipitated solid was collected by filtration, washed with ether and dried in vacuo overnight. The title compound was isolated as a beige solid (14 mg; 78%). All analogs in Table 12 were prepared similarly.

（実施例６６）

( Example 66 )

パートＡ：４−アミノ−２−メチル−安息香酸メチルエステル（０．３３ｇ；２ｍｍｏｌ；市販の４−ニトロ−２−メチル−安息香酸より調製）および８−メタンスルホニル−６−ブロモ−３−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ピラゾール−４−イル］−イミダゾ［１，２−ａ］ピラジン（０．４７２ｇ；１．０ｍｍｏｌ）の溶液を、室温で、ＬｉＨＭＤＳ（ＴＨＦ中１Ｍ；２ｍＬ）で処理した。得られたワイン色の溶液を室温で２０分間攪拌し、次いで、飽和ＮＨ_４Ｃｌ水溶液でクエンチした。実施例６５に記載されたような標準の手順およびフラッシュシリカゲルクロマトグラフィー（ＣＨ_２Ｃｌ_２中２５％ ＥｔＯＡｃ）は、標題化合物を淡黄色泡状物として与えた（０．４８ｇ；８６％）。

Part A: 4-Amino-2-methyl-benzoic acid methyl ester (0.33 g; 2 mmol; prepared from commercially available 4-nitro-2-methyl-benzoic acid) and 8-methanesulfonyl-6-bromo-3- [ A solution of 1- (2-trimethylsilanyl-ethoxymethyl) -1H-pyrazol-4-yl] -imidazo [1,2-a] pyrazine (0.472 g; 1.0 mmol) was added at room temperature to LiHMDS (THF 1M; 2 mL). The resulting wine-colored solution was stirred at room temperature for 20 minutes and then quenched with saturated aqueous NH ₄ Cl. Standard procedures as described in Example 65 and flash silica gel chromatography (25% EtOAc in CH ₂ Cl ₂ ) gave the title compound as a pale yellow foam (0.48 g; 86%).

Ｃ_２４Ｈ_２９ＢｒＮ_６Ｏ_３Ｓｉの質量計算値５５６．１３、実測値ＭＨ^＋（Ｃｌ−ＭＳ）５５７／５５９（ｍ／ｚ）。

Calculated mass of C ₂₄ H ₂₉ BrN ₆ O ₃ Si 556.13, found MH ⁺ (Cl-MS) 557/559 (m / z).

Part B: A solution of the compound from Part A (0.48 g; 0.86 mmol) in 2 mL dry THF was treated dropwise with a solution of dimethylzinc (2M; 4 mL). After effervescence ceased, solid Pd (PPh ₃ ) ₄ was added, the reaction was flushed with nitrogen, fitted with a reflux condenser, and heated to 65-70 ° C. in an oil bath. After 0.5 hours, the reaction mixture turned from yellowish orange to deep red, and after 4 hours it became an opaque black. _{TLC (25% EtOAc- CH 2 Cl} 2) indicated the formation of polar spot slightly. The reaction was cooled to room temperature, quenched with saturated aqueous NH ₄ Cl, and extracted with EtOAc. Flash silica gel chromatography of the crude material gave 6-methyl title compound as a yellow solid (0.38 g; 90%).

Ｃ_２５Ｈ_３２Ｎ_６Ｏ_３Ｓｉの質量計算値４９２．２３、実測値ＭＨ^＋（Ｃｌ−ＭＳ）４９３．１１（ｍ／ｚ）。

Mass calculated for C ₂₅ H ₃₂ N ₆ O ₃ Si 492.23, found MH ⁺ (Cl-MS) 493.11 (m / z).

( Example 67 )

パートＡ：エステルは、最初に、ＴＨＦ中のＬｉＢＥｔ_３Ｈを使用して室温でアルコールに還元し、続いて、Ｄｅｓｓ−Ｍａｒｉｎペルヨウ化物を使用して、以前に記載されたようにアルデヒドに酸化した。種々の二級アミンを用いるアルデヒドの還元的アミノ化を実行して、ＳＥＭ保護された標題化合物を提供した。ＳＥＭ保護基の除去は、以前に記載した条件下で実行した。同様の様式で、表１３に列挙された他の三級アミンもまた、対応する二級アミン、続いてＳＥＭ保護基の除去を用いる同様の反応スキームによって調製した。

Part A: The ester was first reduced to the alcohol at room temperature using LiBEt ₃ H in THF, followed by oxidation to the aldehyde as described previously using Dess-Marin periodide. . Reductive amination of the aldehyde with various secondary amines was performed to provide the SEM protected title compound. Removal of the SEM protecting group was performed under previously described conditions. In a similar manner, the other tertiary amines listed in Table 13 were also prepared by a similar reaction scheme using the corresponding secondary amine followed by removal of the SEM protecting group.

（実施例６８）

( Example 68 )

基質（１ｇ、５．０７ｍｍｏｌ）をＴＨＦ：Ｈ_２Ｏ（１２ｍＬ、１：１、ｖ／ｖ）に溶解し、室温でＫ_２ＣＯ_３（１．４ｇ、１０．１５ｍｍｏｌ）で処理した。次いで、ＴＨＦ（２ｍＬ）中のベンジルクロロホルメート（０．７９ｍＬ、５．５８ｍｍｏｌ）をゆっくりと加えた。この混合物を１６時間攪拌した。これを酢酸エチル（２５ｍＬ）で攪拌した。２つの層が分離し、水層を酢酸エチル（２×２５ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し（１×３０ｍＬ）、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下でエバポレートして粗生成物を得、これを、酢酸エチル−ヘキサンで溶出するカラムクロマトグラフィー（ＳｉＯ_２）によって精製した。

The substrate (1 g, 5.07 mmol) was dissolved in THF: H ₂ O (12 mL, 1: 1, v / v) and treated with K ₂ CO ₃ (1.4 g, 10.15 mmol) at room temperature. Then benzyl chloroformate (0.79 mL, 5.58 mmol) in THF (2 mL) was added slowly. The mixture was stirred for 16 hours. This was stirred with ethyl acetate (25 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 25 mL). The combined organic layers are washed with brine (1 × 30 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product, which is eluted with ethyl acetate-hexane. Purified by column chromatography (SiO ₂ ).

( Example 69 )

基質アセタール（１．２ｇ、３．６４ｇ）をアセトン（２０ｍＬ）に溶解し、そして室温にて１Ｎ ＨＣｌ水溶液（２ｍＬ）で処理し、この混合物を７時間攪拌した。次いで、アセトンをエバポレートして除き、残渣を飽和ＮａＨＣＯ_３水溶液（３０ｍＬ）で希釈した。水相を酢酸エチル（２×３０ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し（１×３０ｍＬ）、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下でエバポレートして、粗生成物を固形物をして得、これをさらなる精製なしで次の工程において使用した。

Substrate acetal (1.2 g, 3.64 g) was dissolved in acetone (20 mL) and treated with 1N aqueous HCl (2 mL) at room temperature and the mixture was stirred for 7 h. The acetone was then evaporated off and the residue was diluted with saturated aqueous NaHCO ₃ (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL), dried (Na ₂ SO ₄ ), filtered, and evaporated under reduced pressure to give the crude product as a solid that was further purified. Used in the next step without.

( Example 70 )

１，２−ジクロロエタン中の基質（１当量）、アミン（４当量）、触媒ＡｃＯＨ、ＮａＢ（ＯＡｃ）_３Ｈ（２当量）を、室温で２時間攪拌した。次いで、水素化ホウ素ナトリウム（３当量）を加え、そしてこの混合物を３０分間攪拌し、この時点で、ＬＣ−ＭＳ分析は、出発物質の生成物への完全な消費を示す。次いで、反応物を２Ｎ ＮａＯＨ水溶液でクエンチし、そしてこの混合物は、２つの明確な層が分離するまで、激しく攪拌した。有機層を水、ブラインで洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下で濃縮して、生成物を得た。

Substrate (1 eq), amine (4 eq), catalyst AcOH, NaB (OAc) ₃ H (2 eq) in 1,2-dichloroethane was stirred at room temperature for 2 h. Sodium borohydride (3 eq) is then added and the mixture is stirred for 30 minutes, at which point LC-MS analysis indicates complete consumption of starting material to product. The reaction was then quenched with 2N aqueous NaOH and the mixture was stirred vigorously until two distinct layers were separated. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the product.

  The crude product was hydrogenated in ethyl acetate using 10% Pd / C at a hydrogen pressure of 1 atmosphere. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure to give the crude product.

( Example 71 )

パートＡ：１，２−ジクロロエタン中の基質（１当量）、アミン（４当量）、触媒ＡｃＯＨ、ＮａＢ（ＯＡｃ）_３Ｈを室温で２時間攪拌した。次いで、水素化ホウ素ナトリウム（３当量）を加え、そしてこの混合物を３０分間攪拌し、この時点で、ＬＣ−ＭＳ分析は、出発物質の生成物への完全な消費を示す。次いで、反応物を２Ｎ ＮａＯＨ水溶液でクエンチし、そしてこの混合物は、２つの明確な層が分離するまで、激しく攪拌した。有機層を水、ブラインで洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下で濃縮して、生成物を得た。

Part A: Substrate (1 eq), amine (4 eq), catalyst AcOH, NaB (OAc) ₃ H in 1,2-dichloroethane was stirred at room temperature for 2 h. Sodium borohydride (3 eq) is then added and the mixture is stirred for 30 minutes, at which point LC-MS analysis indicates complete consumption of starting material to product. The reaction was then quenched with 2N aqueous NaOH and the mixture was stirred vigorously until two distinct layers were separated. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the product.

  Part B: The crude product was hydrogenated in ethyl acetate using 10% Pd / C at a hydrogen pressure of 1 atmosphere. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure to give the crude product.

( Example 72 )

パートＡ：１，２−ジクロロエタン中の基質（１当量）、アミン（４当量）、触媒ＡｃＯＨ、ＮａＢ（ＯＡｃ）_３Ｈを室温で２時間攪拌した。次いで、水素化ホウ素ナトリウム（３当量）を加え、そしてこの混合物を３０分間攪拌し、この時点で、ＬＣ−ＭＳ分析は、出発物質の生成物への完全な消費を示す。次いで、反応物を２Ｎ ＮａＯＨ水溶液でクエンチし、そしてこの混合物は、２つの明確な層が分離するまで、激しく攪拌した。有機層を水、ブラインで洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下で濃縮して、生成物を得た。

Part A: Substrate (1 eq), amine (4 eq), catalyst AcOH, NaB (OAc) ₃ H in 1,2-dichloroethane was stirred at room temperature for 2 h. Sodium borohydride (3 eq) is then added and the mixture is stirred for 30 minutes, at which point LC-MS analysis indicates complete consumption of starting material to product. The reaction was then quenched with 2N aqueous NaOH and the mixture was stirred vigorously until two distinct layers were separated. The organic layer was washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the product.

  Part B: The crude product was hydrogenated in ethyl acetate using 10% Pd / C at a hydrogen pressure of 1 atmosphere. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure to give the crude product.

( Example 73 )

パートＡ：基質（１当量）およびアミン（１．５〜２当量）をアルゴン下でＤＭＳＯに溶解し、ＮａＨ（５当量、油中６０％分散液）で処理した。３０分後、ＬＣ−ＭＳ分析は、出発物質の生成物への完全な消費を示した。反応物は、飽和ＮＨ_４Ｃｌ水溶液−アセトニトリル（１：１、ｖ／ｖ）の添加によってクエンチした。２つの層が分離し、水層を酢酸エチルで抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下で濃縮して、生成物を得た。

Part A: Substrate (1 eq) and amine (1.5-2 eq) were dissolved in DMSO under argon and treated with NaH (5 eq, 60% dispersion in oil). After 30 minutes, LC-MS analysis indicated complete consumption of starting material to product. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl-acetonitrile (1: 1, v / v). The two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the product.

  Part B: The substrate was dissolved in 4N HCl in dioxane and stirred at room temperature for 30 minutes. The solvent was then evaporated and the residue was purified by preparative LC. Conversion to the hydrochloride salt gave the product as a solid.

（実施例７４）

( Example 74 )

パートＡ：実施例１および１３のために記載されたのと本質的に同じ手順による。

Part A: By essentially the same procedure as described for Examples 1 and 13.

Part B: To a solution of the compound from Example 74, Part A (0.16 g, 0.57 mmol) in THF (20 mL) and water (0.025 mL) was added Dess-Martin periodide (3 eq). . The resulting solution was stirred at room temperature for 1.5 hours, at which point LC-MS analysis indicated that the reaction was complete. The reaction mixture was diluted with dichloromethane (75 mL), washed with water, dried (sodium sulfate) and concentrated. Purification by column chromatography (SiO ₂ 10% methanol / DCM) gave the title compound as 0.08 g (49%) of a yellow solid. _HPLC-MS t R = 1.59 min _{(UV 254nm).} Mass calculated for chemical formula C13H11N5OS 285.07, found LC / MS m / z 286.1 (M + H).

Part C: Acetic acid (1 drop) was added to a solution (3 mL) of the compound from Part B (30 mg, 0.105 mmol, 1 eq), 3-methylpiperidine (10 eq) in dichloromethane: methanol (5: 1). It was. The resulting solution was stirred at room temperature for 30 minutes and then sodium borohydride (8 eq) was added to the reaction. The reaction mixture was stirred at room temperature for 1 hour, at which point LC-MS analysis indicated that the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate and then extracted with dichloromethane (twice). The combined organic layers were dried (sodium sulfate) and concentrated. Purification by preparative LC and conversion to the hydrochloride salt gave the title compound.
_HPLC-MS t R = 3.73 min _{(UV 254nm).} Mass calculated for formula C19H24N6S 368.18, found LC / MS m / z 369.2 (M + H).

( Example 75 )

パートＡ：ジクロロメタン：メタノール（５：１）中の化合物１（３０ｍｇ、０．１０５ｍｍｏｌ、１当量）、ピペリジン（１０当量）の溶液（３ｍＬ）に酢酸（１滴）を加えた。得られた溶液を室温で３０分間攪拌し、次いで、水素化ホウ素ナトリウム（８当量）を反応物に加えた。この反応混合物を室温で１時間攪拌し、この時点で、ＬＣ−ＭＳ分析は、反応が完了したことを示した。反応物を飽和炭酸水素ナトリウム水溶液でクエンチし、次いで、ジクロロメタンで抽出した（２回）。合わせた有機層を乾燥させ（硫酸ナトリウム）そして濃縮した。調製用ＬＣによる精製および塩酸塩への変換は標題化合物２を与えた。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝３．４７分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１８Ｈ_２２Ｎ_６Ｓの質量計算値３５４．１６、実測値ＬＣ／ＭＳ ｍ／ｚ３５５．１（Ｍ＋Ｈ）。

Part A: Acetic acid (1 drop) was added to a solution (3 mL) of compound 1 (30 mg, 0.105 mmol, 1 eq), piperidine (10 eq) in dichloromethane: methanol (5: 1). The resulting solution was stirred at room temperature for 30 minutes and then sodium borohydride (8 eq) was added to the reaction. The reaction mixture was stirred at room temperature for 1 hour, at which point LC-MS analysis indicated that the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate and then extracted with dichloromethane (twice). The combined organic layers were dried (sodium sulfate) and concentrated. Purification by preparative LC and conversion to the hydrochloride salt gave the title compound 2.
_HPLC-MS t R = 3.47 min _{(UV 254nm).} Chemical formula _C 18 _H 22 _{N 6} S mass calcd 354.16, found LC / MS m / z355.1 (M + H).

( Example 76 )

工程Ａ：水素化ナトリウム（鉱油中６０％分散液、６．６８ｇ、３．４０当量）を、ＤＭＦ（４９０ｍＬ）中の化合物スルホン（２０．０ｇ、１．００当量）およびアミノイソチアゾール（１１．５ｇ、１．２０当量、ＨＣｌ塩として）の攪拌溶液に室温で一度にゆっくりと加えた（室温のウォーターバスで補助する）。反応物を１時間攪拌させ、この時点で、ＨＰＬＣ分析は、反応が完了したことを示した。反応物を飽和炭酸水素ナトリウム水溶液（２００ｍＬ）で注意深くクエンチし、次いで、水（１Ｌ）で希釈した。この混合物を室温で２０分間攪拌し、次いで、得られた沈殿を濾過によって収集し、水（２００ｍＬ）で洗浄し、そして高真空下で１６時間乾燥させた。得られたワックス状固形物を１．８Ｌの１：１ クロロホルム：メタノールに溶解し、硫酸ナトリウムで乾燥させ、濾過し、そして減圧下で濃縮して、標題化合物を暗黄色固形物として得た（２２．３ｇ、９３％）。

Step A: Sodium hydride (60% dispersion in mineral oil, 6.68 g, 3.40 equiv) was added to compound sulfone (20.0 g, 1.00 equiv) and aminoisothiazole (11. 5 g, 1.20 eq, as HCl salt) was slowly added at once at room temperature (assisted by room temperature water bath). The reaction was allowed to stir for 1 hour, at which point HPLC analysis indicated that the reaction was complete. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (200 mL) and then diluted with water (1 L). The mixture was stirred at room temperature for 20 minutes, then the resulting precipitate was collected by filtration, washed with water (200 mL) and dried under high vacuum for 16 hours. The resulting waxy solid was dissolved in 1.8 L of 1: 1 chloroform: methanol, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a dark yellow solid ( 22.3 g, 93%).

化学式Ｃ_２１Ｈ_２７Ｎ_７Ｏ_３ＳＳｉの質量計算値４８５．６３、実測値ＭＨ^＋（ＭＳ）４８６．６（ｍ／ｚ）。

Calculated mass of C ₂₁ H ₂₇ N ₇ O ₃ SSi 485.63, found MH ⁺ (MS) 486.6 (m / z).

Step B: A mixture of the compound from Step A (4.27 g, 3.73 mmol) was dissolved in 180 mL THF. The resulting solution was cooled to 0 ° C. and LiAlH ₄ powder (2.6 g, 68.5 mmol) was carefully added. The cooling bath was removed and the reaction was stirred at room temperature under N ₂ atmosphere for 1.5 hours. The reaction was cooled to 0 ° C. and quenched by sequential addition of 2.6 mL H ₂ O; 2.6 mL 15% NaOH (aq); 7.8 mL H ₂ O. After 10 minutes of stirring, the reaction was filtered through a very thin pad of celite (rinsing with THF, EtOAc, and DCM). Concentration of the filtrate resulted in a light yellow solid. High purity alcohol (2.66 g, 66% yield) was obtained via trituration with MeOH and used directly in Step C.

Step B (alternative procedure; eg, Examples 76-39): NaH (60% dispersion in mineral oil) in a solution of 4,4-difluoropiperidine hydrochloride (25.1 mg, 0.16 mmol) in THF (2.0 mL). Solution, 12 mg, 0.30 mmol). The mixture was stirred at room temperature for 10 minutes under N ₂ atmosphere, then mesylate (31.4 mg, 0.06 mmol) and NaI (4 mg, 0.03 mmol) were added to the reaction flask. The reaction was heated at 80 ° C. for 8 hours under N ₂ atmosphere. The reaction was cooled to room temperature and 15 mL of saturated NH ₄ Cl (water) solution was added. The reaction was diluted with dichloromethane (20 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 20 mL). The organic phase was washed with 15 mL saturated NaHCO ₃ (aq) then brine (15 mL). The organic phase was dried over NaSO ₄ and concentrated in vacuo. Purification via preparative TLC (10% MeOH / CH ₂ Cl ₂ ) gave 19.7 mg (60% yield) of the title compound.

Step C: Compound from Step B (2.40 g, 4.49 mmol), amine (1.57 g, 13.46 mmol), and NaI (63.0 mg, 0.449 mmol) in 45 mL of THF at 80 ° C. Heated for hours. This was diluted with 200 mL CH ₂ Cl ₂ and washed with 100 mL saturated aqueous NaHCO ₃ then brine (100 mL). The solvent was removed under vacuum. The residue was purified by flash chromatography eluting with 5% to 10% MeOH / CH ₂ Cl ₂ to give 1.68 g of the title compound.

８０℃で攪拌した３６ｍＬのＭｅＯＨ／ＣＨ_２Ｃｌ_２（１：１）中のＳｅｍ保護化化合物（２．０ｇ、３．６ｍｍｏｌ）の溶液に、３６ｍＬのジオキサン中４Ｎ ＨＣｌを加えた。この反応物を８０℃で３０分間攪拌した。これを室温まで冷却した後、１２０ｍＬのエーテルを加えた。固形物を濾過によって収集し、エーテルで洗浄し、そして真空下で乾燥させて、２．０ｇの標題化合物をそのＨＣｌ型で得た。
化学式Ｃ_２０Ｈ_２６Ｎ_８ＯＳの質量計算値４２６．２、実測値ＭＨ^＋（ＬＣＭＳ）４２７．２（ｍ／ｚ）。

To a solution of Sem protected compound (2.0 g, 3.6 mmol) in 36 mL MeOH / CH ₂ Cl ₂ (1: 1) stirred at 80 ° C. was added 36 mL 4N HCl in dioxane. The reaction was stirred at 80 ° C. for 30 minutes. After cooling to room temperature, 120 mL of ether was added. The solid was collected by filtration, washed with ether and dried under vacuum to give 2.0 g of the title compound in its HCl form.
Chemical formula _C 20 _H 26 _N 8 OS mass calcd 426.2, found ^{MH + (LCMS) 427.2 (m} / z).

  The following compounds were prepared using essentially the same procedure as described for Example 76.

実施例７６−１：

Example 76-1:

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．２８分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_２０Ｈ_２６Ｎ_８ＯＳの質量計算値４２６．２、実測値ＭＨ^＋（ＬＣＭＳ）４２７．２（ｍ／ｚ）。

_HPLC-MS t R = 2.28 min _{(UV 254nm).} Chemical formula _C 20 _H 26 _N 8 OS mass calcd 426.2, found ^{MH + (LCMS) 427.2 (m} / z).

  Example 76-2:

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．２６分（ＵＶ_{２５４ｎｍ}）。

_HPLC-MS t R = 2.26 min _{(UV 254nm).}

  Example 76-3:

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．２６分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_２０Ｈ_２６Ｎ_８ＯＳの質量計算値４５２．２、実測値ＭＨ^＋（ＬＣＭＳ）４５３．２（ｍ／ｚ）。

_HPLC-MS t R = 2.26 min _{(UV 254nm).} Chemical formula _C 20 _H 26 _N 8 OS mass calcd 452.2, found ^{MH + (LCMS) 453.2 (m} / z).

  Example 76-4:

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．４８分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_２０Ｈ_２６Ｎ_８ＯＳの質量計算値４６６．３、実測値ＭＨ^＋（ＬＣＭＳ）４６７．３（ｍ／ｚ）。

_HPLC-MS t R = 2.48 min _{(UV 254nm).} Calculated mass of C ₂₀ H ₂₆ N ₈ OS 466.3, found MH ⁺ (LCMS) 467.3 (m / z).

  Example 76-5:

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．３５分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_２０Ｈ_２６Ｎ_８ＯＳの質量計算値４５２．２、実測値ＭＨ^＋（ＬＣＭＳ）４５３．２（ｍ／ｚ）。

_HPLC-MS t R = 2.35 min _{(UV 254nm).} Chemical formula _C 20 _H 26 _N 8 OS mass calcd 452.2, found ^{MH + (LCMS) 453.2 (m} / z).

  Example 76-6:

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．３９分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_２０Ｈ_２６Ｎ_８ＯＳの質量計算値４４０．２、実測値ＭＨ^＋（ＬＣＭＳ）４４１．２（ｍ／ｚ）。

_HPLC-MS t R = 2.39 min _{(UV 254nm).} Chemical formula _C 20 _H 26 _N 8 OS mass calcd 440.2, found ^{MH + (LCMS) 441.2 (m} / z).

  Example 76-7:

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．８０分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ２１Ｈ２６Ｎ８ＯＳの質量計算値４３８．５５、実測値ＬＣ／ＭＳ ｍ／ｚ ４３９．１（Ｍ＋Ｈ）。

_HPLC-MS t R = 1.80 min _{(UV 254nm).} Mass calculated for formula C21H26N8OS, 438.55, found LC / MS m / z 439.1 (M + H).

  Example 76-8:

実施例７６−９：

Example 76-9:

実施例７６−１０：

Example 76-10:

実施例７６−１１：

Example 76-11:

実施例７６−１２：

Example 76-12:

実施例７６−４０：

Example 76-40:

実施例７６−４２：

Examples 76-42:

（実施例７７）

( Example 77 )

ヨードエタン（５２．５ｇ、３３６．５ｍｍｏｌ）および２−アミノ−２−メチル−１−プロパノール（３０．０ｇ、３３６．５ｍｍｏｌ）の混合物を６０℃で１５分間攪拌した。これを５００ｍＬのエーテルで希釈し、ｐＨ＝１０に達するまで、５Ｎ ＮａＯＨ水溶液を加えることによって塩基性化した。有機層を分離した。水層をエーテルで抽出した（５００ｍＬ×３）。合わせた有機層を、１００ｍＬの水および１００ｍＬのブラインで連続的に洗浄し、次いで、無水Ｎａ_２ＳＯ_４で乾燥させた。溶媒を除去し、２０ｇの粗生成物を得て、これを１５０ｍＬのヘキサン中での再結晶によって精製し、１３ｇの白色固形物を得た。この固形物を、減圧下での昇華によってさらに精製し、１２ｇの標題化合物を得た。

A mixture of iodoethane (52.5 g, 336.5 mmol) and 2-amino-2-methyl-1-propanol (30.0 g, 336.5 mmol) was stirred at 60 ° C. for 15 minutes. This was diluted with 500 mL of ether and basified by adding 5N aqueous NaOH until pH = 10 was reached. The organic layer was separated. The aqueous layer was extracted with ether (500 mL × 3). The combined organic layers were washed successively with 100 mL water and 100 mL brine and then dried over anhydrous Na ₂ SO ₄ . Solvent was removed to give 20 g of crude product, which was purified by recrystallization in 150 mL of hexane to give 13 g of white solid. This solid was further purified by sublimation under reduced pressure to give 12 g of the title compound.

（実施例７８）

( Example 78 )

工程Ａ：基質（１０ｇ）をＴＨＦ（２００ｍＬ）に懸濁した。次いで、水素化アルミニウムリチウム溶液（１１０ｍＬ、ＴＨＦ中２Ｍ）をゆっくりと加えた。この混合物を室温で１２時間攪拌した。この溶液を０℃に冷却し、飽和Ｎａ_２ＳＯ_４水溶液（２００ｍＬ）をゆっくりと加えた。この混合物をセライトを通して濾過し、そしてフィルターケーキを酢酸エチル（４００ｍＬ）で洗浄した。有機層を水（２００ｍＬ）およびブライン（２００ｍＬ）で洗浄した。有機層を乾燥させ（無水Ｎａ_２ＳＯ_４）、濾過し、そしてエバポレートしてアミノアルコール（６．９ｇ）を得た。このアミノアルコール（６．９ｇ）を、室温で ＴＨＦ（８０ｍＬ）および水（８０ｍＬ）に溶解した。炭酸カリウム（１４．７６ ｇ）を加えた。次いで、ＴＨＦ（４０ｍＬ）中のベンジルクロロホルメート（８．２８ｍＬ）を滴下して加えた。この混合物を室温で３０分間攪拌した。溶媒を減圧下でエバポレートして除き、そして酢酸エチル（１００ｍＬ）を加えた。２つの層が分離し、水層を酢酸エチル（２×１００ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し（２００ｍＬ）、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下でエバポレートして粗生成物を得、これをカラムクロマトグラフィーによって精製した。ラセミ体アミノアルコールはＳＦＣ ＨＰＣＬ法によってラセミ分離した。次いで、ピーク１およびピーク２に対応するエナンチオマーを、対応するビルディングブロックを調製するために、別々に進めた。

Step A: Substrate (10 g) was suspended in THF (200 mL). Then lithium aluminum hydride solution (110 mL, 2M in THF) was added slowly. The mixture was stirred at room temperature for 12 hours. The solution was cooled to 0 ° C. and saturated aqueous Na ₂ SO ₄ (200 mL) was added slowly. The mixture was filtered through celite and the filter cake was washed with ethyl acetate (400 mL). The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried (anhydrous Na ₂ SO ₄ ), filtered and evaporated to give the amino alcohol (6.9 g). This amino alcohol (6.9 g) was dissolved in THF (80 mL) and water (80 mL) at room temperature. Potassium carbonate (14.76 g) was added. Benzyl chloroformate (8.28 mL) in THF (40 mL) was then added dropwise. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure and ethyl acetate (100 mL) was added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (200 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography. Racemic amino alcohol was racemic separated by SFC HPCL method. The enantiomers corresponding to peak 1 and peak 2 were then advanced separately to prepare the corresponding building blocks.

Step B: The alcohol from Step A (1.936 g) was dissolved in dichloromethane (80 mL) and treated with proton sponge (8.32 g) at room temperature. Then trimethyloxonium tetrafluoroborate (5.69 g) was added. The mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (100 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with hydrochloric acid (200 mL, 1N), saturated aqueous sodium bicarbonate (200 mL), brine (200 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give crude. The product was obtained and purified by column chromatography.

Step C: Enantiomerically pure ether from Step B in EtOH is treated with Pd (OH) ₂ on carbon (20 wt%) and at atmospheric pressure for 2 hours at room temperature under a hydrogen atmosphere. Stir. The mixture was filtered off and the filtrate was evaporated under reduced pressure to give the amine.

( Example 79 )

工程Ａ：−７８℃において、ＴＨＦ（５０ｍｌ）中のエステル（６３５９ｍｇ、２４．７ｍｍｏｌ）を、ＴＨＦ（２００ｍｌ）中のＬＤＡ（ＴＨＦ中１．８Ｍ、２７．５ｍＬ、４９．４ｍｍｏｌ）に滴下して加えた。この反応混合物をゆっくりと室温まで温め、この温度で一晩攪拌した。反応物を０℃に冷却し、飽和ＮＨ_４Ｃｌ溶液でクエンチした。この混合物をＨ_２Ｏで希釈し、ＥｔＯＡｃで抽出した（２回）。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮した。カラムクロマトグラフィーによる精製は標題化合物を与えた（６２２１ｍｇ、９３％）。
ＬＣＭＳ ｔ_Ｒ＝２．２７分。Ｍ＋の質量計算値２７１．１、実測値ＬＣ／ＭＳ ｍ／ｚ ２１６．１（Ｍ＋Ｈ−Ｃ_４Ｈ_８）。
ＴＨＦ（３００ｍＬ）中のエステル（４６５９ｍｇ、１７．２ｍｍｏｌ）の溶液にＬｉＢＨＥｔ_３（６９ｍＬ、ＴＨＦ中１Ｍ）を加えた。この反応物は室温で３０分間攪拌した。これは、飽和ＮＨ_４Ｃｌを加えることによってクエンチした。この混合物はＣＨ_２Ｃｌ_２で抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮した。カラムクロマトグラフィーによる精製は標題化合物を与えた（３０３２ｍｇ、７７％）。
ＬＣＭＳ ｔ_Ｒ＝１．８２分。Ｍ＋の質量計算値２２９．１、実測値ＬＣ／ＭＳ ｍ／ｚ １７４．１（Ｍ＋Ｈ−Ｃ_４Ｈ_８）。

Step A: At −78 ° C., ester (6359 mg, 24.7 mmol) in THF (50 ml) was added dropwise to LDA (1.8 M in THF, 27.5 mL, 49.4 mmol) in THF (200 ml). added. The reaction mixture was slowly warmed to room temperature and stirred at this temperature overnight. The reaction was cooled to 0 ° C. and quenched with saturated NH ₄ Cl solution. The mixture was diluted with H ₂ O and extracted with EtOAc (2 times). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by column chromatography gave the title compound (6221 mg, 93%).
LCMS t _R = 2.27 min. M + mass calcd 271.1, found LC / MS m / z 216.1 ( M + H-C 4 H 8).
To a solution of the ester (4659 mg, 17.2 mmol) in THF (300 mL) was added LiBHEt ₃ (69 mL, 1M in THF). The reaction was stirred at room temperature for 30 minutes. This was quenched by adding saturated NH ₄ Cl. This mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by column chromatography gave the title compound (3032 mg, 77%).
LCMS t _R = 1.82 min. M + mass calcd 229.1, found LC / MS m / z 174.1 ( M + H-C 4 H 8).

Step B: NaH (1324 mg, 60% dispersion in mineral oil, 33.1 mmol) was added slightly to a mixture of the compound from Step A and MeI (3.3 mL, 52.9 mmol) in DMF (66 mL) at 0 ° C. Added one by one. The reaction mixture was slowly warmed to room temperature and stirred at this temperature overnight. The reaction was cooled to 0 ° C. and quenched with saturated NH ₄ Cl solution. The mixture was diluted with H ₂ O and extracted with EtOAc (2 times). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by column chromatography gave the title compound (2633 mg, 82%).
LCMS t _R = 2.32 min. M + mass calcd 243.1, found LC / MS m / z 188.1 ( M + H-C 4 H 8).
A solution of compound 4 (901 mg, 3.71 mmol) was stirred in 20% TFA in CH ₂ Cl ₂ (20 mL) at 0 ° C. for 30 minutes and then at room temperature for 15 minutes. The reaction mixture was concentrated. The crude residue was used without further purification, for example.
LCMS t _R = 0.26 min. Calculated mass for M + 143.1, found LC / MS m / z 144.1 (M + H).

Step C: CbzCl (604 μl, 4.08 mmol) in THF (1 mL) was added to the compound from Step B and K ₂ CO ₃ (1125 mg, 8.08 mmol) in THF (20 mL) and H ₂ O (20 mL) at 0 ° C. 15 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was extracted with EtOAc (twice). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. Purification by column chromatography gave the title compound (965 mg, 94%).
LCMS t _R = 2.28 min _{(UV 254nm).} Calculated mass for M + 277.1, found LC / MS m / z 278.1 (M + H).
The title amine was chirally separated utilizing a Gilson GX-281 liquid handling system with HPLC performance. Separation was achieved under the following conditions: Chiral Technologies Chiral PAK AD column (5 × 50 cm; 20 μ); flow rate = 50 mL / min; 7.5% isopropanol in hexane (same composition); detection at 210 nm.

Step D: The enantiomerically pure isomer from Step C (1 mmol, 277 mg) is dissolved in EtOH (6 mL), mixed with 20% Pd (OH) ₂ (51 mg) and H ₂ balloon. Filtration through celite and concentration under stirring at room temperature for 2 hours afforded the title compound, which was used for the next step without further purification.
LCMS t _R = 0.26 min. Calculated mass for M + 143.1, found LC / MS m / z 144.1 (M + H).

  (Example 80)

工程Ａ：親の化合物は、標準的な反応条件を用いて、酸塩化物、酸、尿素、およびイソシアネートを使用して、実施例７６−２から調製した。

Step A: The parent compound was prepared from Example 76-2 using acid chloride, acid, urea, and isocyanate using standard reaction conditions.

  Step B: The Sem protected material from Step A was dissolved in 1,4-dioxane (1 mL) and treated with 4N HCl in 1,4-dioxane (1 mL) then heated at 60 ° C. for 1 hour. . The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC, and conversion to the hydrochloride salt gave the title compound as a colorless solid.

  The following compounds were prepared using essentially the same procedure as described for Example 80.

（実施例８１）

( Example 81 )

工程Ａ：出発物質のスルホンは、エチルボロン酸またはシクロプロピルボロン酸を使用したこと以外は、実施例６に記載されたのと本質的に同じ手順によって調製した。表１７に列挙された最終生成物は、実施例７６のために記載された手順を使用して得た。

Step A: The starting sulfone was prepared by essentially the same procedure as described in Example 6 except that ethylboronic acid or cyclopropylboronic acid was used. The final product listed in Table 17 was obtained using the procedure described for Example 76.

（実施例８２）

( Example 82 )

工程Ａ：標題化合物は、ｔ−ブチルアミンを使用した以外は、実施例７のために記載されたのと同様の手順を使用して調製した。

Step A: The title compound was prepared using a procedure similar to that described for Example 7 except that t-butylamine was used.

Step B: To a solution of the product of Step A (1 eq) in THF (3 mL) was added DIEA (3 eq) and the respective trifilate (1.2 eq) at room temperature. The reaction was heated at reflux until consumption of starting material was observed by LC-MS. The solution was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography _(SiO 2, 30% ethyl acetate / dichloromethane) gave the intermediates desired coupling. This material was dissolved in 1,4-dioxane, HCl (4N in dioxane) was added, and the mixture was sonicated to the point where HPLC showed no starting material left. The mixture was concentrated under reduced pressure, purified by preparative HPLC, and conversion to the hydrochloride salt gave the title compound in Table 18 as an off-white solid.

（実施例８３）

( Example 83 )

工程Ａ：チオメトキシドナトリウム（３９ｍｇ、３．００当量）を、室温で、ＤＭＦ（６ｍＬ）中の実施例７において調製したメシレート（１００ｍｇ、１．００当量）およびヨウ化ナトリウム（１４ｍｇ、０．５０当量）の攪拌混合物に加えた。得られた混合物を２．５時間攪拌させ、この時点で、ＬＣ−ＭＳ分析は、反応が完了したことを示した。反応物は、飽和炭酸水素ナトリウム水溶液（３０ｍＬ）でクエンチし、次いでジクロロメタンで抽出した（２×７０ｍＬ）。合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、そして減圧下で濃縮して、標題化合物を黄色固形物、１００ｍｇ（＞９９％）として得た。

Step A: Sodium thiomethoxide (39 mg, 3.00 equiv) was prepared at room temperature with mesylate (100 mg, 1.00 equiv) prepared in Example 7 in DMF (6 mL) and sodium iodide (14 mg, .0 equiv.). 50 equivalents) of the stirred mixture. The resulting mixture was allowed to stir for 2.5 hours, at which point LC-MS analysis indicated that the reaction was complete. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and then extracted with dichloromethane (2 × 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid, 100 mg (> 99%).

  Step B: m-Chloroperbenzoic acid (66 mg, 2.05 eq) was added to a stirred solution of the compound from Step A (91 mg, 1.00 eq) in dichloromethane (3 mL) at room temperature. The mixture was allowed to stir for 2 hours, at which point thin layer chromatography indicated that the reaction was complete. The mixture was diluted with ethyl acetate (40 mL) and then washed with saturated aqueous sodium bicarbonate (15 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. This material was dissolved in 1,4-dioxane, HCl (4N in dioxane) was added, and the mixture was sonicated until HPLC showed that no starting material remained. The mixture was concentrated under reduced pressure, purified by preparative HPLC, and conversion to the hydrochloride salt gave the title compound as an off-white solid, 18 mg (27%).

ＨＰＬＣ ｔ_ｒ＝４．０４分（ＵＶ_{２５４ｎｍ}）。Ｃ_１５Ｈ_１５Ｎ_７Ｏ_２Ｓ_２の質量計算値３８９．１、実測値ＭＨ^＋（ＭＳ）３９０．７（ｍ／ｚ）。

HPLC t _r = 4.04 minutes _{(UV 254nm).} Calculated mass for C ₁₅ H ₁₅ N ₇ O ₂ S ₂ 389.1, found MH ⁺ (MS) 390.7 (m / z).

( Example 84 )

工程Ａ：ＥｔＮ（ｉＰｒ）_２（１０．５５ｍＬ、６０．６９ｍｍｏｌ）を、０℃にて、ＤＭＦ（１００ｍＬ）中の酸（２９５３ｍｇ、２０．２３ｍｍｏｌ、Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，１１（２０），４３３３−４３４０；２００３に従って調製）、ＥＤＣＩ（５８１７ｍｇ、３０．３４ｍｍｏｌ）、ＨＯＢＴ（４１００ｍｇ、３０．３４ｍｍｏｌ）およびピペリジン（２３９８μＬ、２４．２８ｍｍｏｌ）に加えた。室温で一晩の攪拌後、粗反応物質をＥｔＯＡｃで希釈し、そしてブラインで洗浄した（２回）。有機層をＮａ_２ＳＯ_４で乾燥させ、濾過し、そして濃縮して粗生成物を得て、これにクロマトグラフィーを行って生成物アミドを得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．５７分（ＵＶ_{２５４ｎｍ}）。化学式Ｍ＋の質量計算値２１３．０、実測値ＬＣ／ＭＳ ｍ／ｚ ２１４．１（Ｍ＋Ｈ）。

Step A: EtN (iPr) ₂ (10.55 mL, 60.69 mmol) was added acid (2953 mg, 20.23 mmol, Bioorganic & Medicinal Chemistry, 11 (20), 4333-) in DMF (100 mL) at 0 ° C. 4340; prepared according to 2003), EDCI (5817 mg, 30.34 mmol), HOBT (4100 mg, 30.34 mmol) and piperidine (2398 μL, 24.28 mmol). After stirring at room temperature overnight, the crude reaction material was diluted with EtOAc and washed with brine (twice). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was chromatographed to give the product amide.
_HPLC-MS t R = 1.57 min _{(UV 254nm).} Calculated mass of formula M + 213.0, found LC / MS m / z 214.1 (M + H).

Step B: Powdered KNO ₃ (1100.8 mg, 10.89 mmol) was added in portions to a stirred solution of the amide (927.6 mg, 4.356 mmol) in concentrated H ₂ SO ₄ (20 mL) at 0 ° C. After stirring for 30 minutes at 0 ° C., the reaction mixture was poured onto ice. Extracted with CH ₂ Cl ₂ and the combined organic layers were washed with H ₂ O, dried over Na ₂ SO ₄ and concentrated. Purification by column chromatography initially gave 545.5 mg (48.5%) of the undesired nitrated product.
_HPLC-MS t R = 1.79 min _{(UV 254nm).} Calculated mass for M + 258.0, found LC / MS m / z 259.1 (M + H).

を生じ、次いで、所望のニトロ化生成物４３５．６ｍｇ（３８．８％）、
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．６８分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値２５８．０、実測値ＬＣ／ＭＳ ｍ／ｚ ２５９．１（Ｍ＋Ｈ）。

Followed by 435.6 mg (38.8%) of the desired nitrated product,
_HPLC-MS t R = 1.68 min _{(UV 254nm).} Calculated mass for M + 258.0, found LC / MS m / z 259.1 (M + H).

を生じた。

Produced.

Step C: Iron powder (471.5 mg, 8.44 mmol) was added to a solution of nitroamide (435.6 mg, 1.69 mmol) in HOAc (20 mL). The reaction mixture was heated at 70 ° C. for 30 minutes. The mixture was cooled to room temperature and concentrated to dryness. To the residue was added 30 mL of 20% MeOH / CH ₂ Cl ₂ followed by 20 mL of saturated aqueous NaHCO ₃ solution. The mixture was stirred until effervescence ceased. The mixture was extracted with EtOAc (2 times), dried over Na ₂ SO ₄ and then concentrated. The crude amine was used for the substitution reaction without further purification.
_HPLC-MS t R = 1.32 min _{(UV 254nm).} Calculated mass for M + 228.0, found LC / MS m / z 229.1 (M + H).

Step D: The crude amine from Step C (491.5 mg, 2.156 mmol) and sulfone (292 mg, 0.719 mmol) in DMSO (10 mL) was added NaH (60% dispersion in oil, 172.5 mg) at room temperature. 4.312 mmol). The mixture was stirred until LCMS indicated that the reaction was complete. The reaction mixture was diluted with EtOAc, washed with saturated NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated to give crude product 4. Purification gave compound 4.
_HPLC-MS t R = 2.503 min _{(UV 254nm).} Calculated mass for M + 555.2, found LC / MS m / z 556.3 (M + H).

Step E: To a solution of the amide from Step D (120 mg, 0.216 mmol) in dichloromethane (12 mL) at 0 ° C. was added lithium aluminum hydride (86.4 mg, 2.162 mmol) and ethyl ether (3 mL). It was. The reaction mixture was stirred at room temperature until LCMS indicated that the reaction was complete. The reaction was quenched with H ₂ O (86 μL), 3N NaOH (86 μL), and H ₂ O (264 μL). The reaction was filtered and concentrated to give crude compound 5.
_HPLC-MS t R = 1.738 min _{(UV 254nm).} Calculated mass for M + 541.2, found LC / MS m / z 542.2 (M + H).

Step F: 4N HCl in dioxane (3 mL) was added to the crude product from Step E at 0 ° C. The mixture was stirred at room temperature until LCMS indicated that the reaction was complete. Concentration gave a crude product. Purification by preparative LC and conversion to the hydrochloride salt gave the title compound.
_HPLC-MS t R = 0.923 min _{(UV 254nm).} Calculated mass for M + 411.1, found LC / MS m / z 412.2 (M + H).

( Example 85 )

実施例８４に示されたのと本質的に同じ手順によって、標題化合物を調製可能である。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．００５分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値４２５．１、実測値ＬＣ／ＭＳ ｍ／ｚ ４２６．２（Ｍ＋Ｈ）。

The title compound can be prepared by essentially the same procedure as shown in Example 84.
_HPLC-MS t R = 1.005 min _{(UV 254nm).} Calculated mass for M + 425.1, found LC / MS m / z 426.2 (M + H).

( Example 86 )

工程Ａ：ＨＯＡｃ（５５ｍＬ）中のニトロエステル（２２８５ｍｇ、１２．２２ｍｍｏｌ）の溶液に、鉄粉（６８２５ｍｇ、１２２．２０ｍｍｏｌ）を加えた。この反応混合物を７５℃で１０分間加熱した。この混合物を室温まで冷却し、次いで、２００ｍＬのＭｅＯＨを加えた。得られた混合物はセライトを通して濾過した（セライトは追加量のＭｅＯＨですすいだ）。濾液を濃縮して、大部分のＡｃＯＨを除いた。この残渣に、５０ｍＬの２０％ ＭｅＯＨ／ＣＨ_２Ｃｌ_２を加え、続いて飽和ＮａＨＣＯ３水溶液を、発泡が停止するまで加えた。この混合物をＥｔＯＡｃで抽出し（２回）、Ｎａ_２ＳＯ_４で乾燥させ、次いで濃縮した。粗アミンはさらなる精製なしで使用した。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．０７分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値１５７．０．０、実測値ＬＣ／ＭＳ ｍ／ｚ １５８．１（Ｍ＋Ｈ）。

Step A: To a solution of the nitroester (2285 mg, 12.22 mmol) in HOAc (55 mL) was added iron powder (6825 mg, 122.20 mmol). The reaction mixture was heated at 75 ° C. for 10 minutes. The mixture was cooled to room temperature and then 200 mL of MeOH was added. The resulting mixture was filtered through celite (celite rinsed with additional amount of MeOH). The filtrate was concentrated to remove most of the AcOH. To this residue was added 50 mL of 20% MeOH / CH ₂ Cl ₂ followed by saturated aqueous NaHCO 3 until foaming stopped. The mixture was extracted with EtOAc (2 times), dried over Na ₂ SO ₄ and then concentrated. The crude amine was used without further purification.
_HPLC-MS t R = 1.07 min _{(UV 254nm).} Calculated mass for M + 157.0.0, found LC / MS m / z 158.1 (M + H).

Step B: A solution of the amino ester (850 mg, 5.414 mmol)) in DMSO (36 mL) and the sulfone from Example 1 (1 eq, 1469 mg, 3.609 mmol) was added to NaH (60% dispersion in oil, 14 .43 mmol, 777 mg) at room temperature. After 10 minutes, LC-MS analysis of the reaction indicated that the reaction was complete. While cooling with a water bath, the reaction was quenched dropwise with saturated NH 4 Cl (5 mL), then H ₂ O (160 mL) was added and extracted with ethyl acetate (2 ×). The combined organic layers were washed with brine and dried (sodium sulfate). Purification by evaporation and column chromatography (0-100% EtOAc / hexanes) gave the title compound (1492 mg, 85%).
_HPLC-MS t R = 2.41 min _{(UV 254nm).} Calculated mass for M + 484.1, Found LC / MS m / z 485.2 (M + H).

Step C: To a solution of the product of Step B (206 mg, 0.4271 mmol) in THF (8 mL) at −78 ° C., add DIBAL (1.0 M in CH ₂ Cl ₂ , 2.56 mL) dropwise. did. After stirring at −78 ° C. for 4.5 hours, LCMS showed the presence of a small amount of starting material. Two more equivalent DIBALs (0.85 mL) were added. After stirring at −78 ° C. for an additional 0.5 h, brine (6 mL) was added in portions at −78 ° C. to quench excess reagent. The reaction mixture was extracted with CH ₂ Cl ₂ (3 times). Evaporation of the solvent and purification by column chromatography (EtOAc / hexane in 0-> 100% 2% MeOH) gave the alcohol (153 mg, 79%).
_HPLC-MS t R = 2.01 min _{(UV 254nm).} Calculated mass for M + 456.1, found LC / MS m / z 457.1 (M + H).

Step D: To a solution of the alcohol from Step C (537 mg, 1.17 mmol) in THF (26 mL) was added H ₂ O (0.078 mL) followed by Dess-Martin periodide (599 mg, 1.41 mmol). Added at ° C. The reaction was stirred until LCMS indicated that the reaction was complete. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NH ₄ Cl solution. The organic layer was dried over anhydrous Na ₂ SO ₄ and then concentrated. Purification by column chromatography gave the aldehyde (237.1 mg, 44%).
_HPLC-MS t R = 2.15 min _{(UV 254nm).} Calculated mass for M + 454.1, found LC / MS m / z 455.1 (M + H).

Step E: To a mixture of aldehyde (94 mg, 0.21 mmol) and 4-fluoropiperidine hydrochloride (58 mg, 0.41 mmol) in DCE (10 mL) was added DIEA (144 μL, 0.828 mmol) followed by NaBH (OAc). ₃ (139 mg, 0.62 mmol) was added. The reaction mixture was stirred at room temperature overnight, then diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ solution. The organic layer was dried over anhydrous Na ₂ SO ₄ and then concentrated. The crude product was used for the next step without further purification.
_HPLC-MS t R = 1.57 min _{(UV 254nm).} Calculated mass for M + 541.2, found LC / MS m / z 542.2 (M + H).

Step F: 4N HCl in dioxane (5 mL) was added to the crude amine at 0 ° C. The mixture was stirred at room temperature until LCMS indicated that the reaction was complete. Concentration and purification by preparative LC gave the title compound.
_HPLC-MS t R = 0.89 min _{(UV 254nm).} Calculated mass for M + 411.1, found LC / MS m / z 412.1 (M + H).

( Example 87 )

実施例８６と本質的に同じ手順によって、標題化合物を調製可能である。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝０．９７分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値４２９．１、実測値ＬＣ／ＭＳ ｍ／ｚ ４３０．１（Ｍ＋Ｈ）。

The title compound can be prepared by essentially the same procedure as Example 86.
_HPLC-MS t R = 0.97 min _{(UV 254nm).} Calculated mass for M + 429.1, found LC / MS m / z 430.1 (M + H).

( Example 88 )

実施例８６と本質的に同じ手順によって、標題化合物を調製可能である。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝０．９９分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値４４３．１、実測値ＬＣ／ＭＳ ｍ／ｚ ４４４．１（Ｍ＋Ｈ）。

The title compound can be prepared by essentially the same procedure as Example 86.
_HPLC-MS t R = 0.99 min _{(UV 254nm).} Calculated mass for M + 443.1, found LC / MS m / z 444.1 (M + H).

( Example 89 )

パートＡ：ＣＨ３ＣＮ（１００ｍＬ）中の６−ブロモ化合物（４５６２ｍｇ、１０．３９ｍｍｏｌ）、ＰｄＣｌ２ｄｐｐｆ（４２４．３ｍｇ、０．５１９ｍｍｏｌ）、ＣｕＩ（２９６．９ｍｇ、１．５６ｍｍｏｌ）およびトリブチル（１−エトキシビニル）スズ（５６１７μＬ、１６．６２７ｍｍｏｌ）の混合物を、反応が完了したことをＬＣＭＳが示すまで還流した。１Ｎ ＨＣｌ（１５ｍＬ）を加え、この混合物を、ケトンへの変換をＬＣＭＳが示すまで攪拌した。この反応混合物をＥｔＯＡｃで希釈し、飽和ＮＨ_４Ｃｌで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮した。精製によりケトンを得た（３２００ｍｇ、７６％）。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．３２分（ＵＶ_{２５４ｎｍ}）。Ｍ＋の質量計算値４０３．１、実測値ＬＣ／ＭＳ ｍ／ｚ ４０４．２（Ｍ＋Ｈ）。

Part A: 6-bromo compound (4562 mg, 10.39 mmol), PdCl2dppf (424.3 mg, 0.519 mmol), CuI (296.9 mg, 1.56 mmol) and tributyl (1-ethoxyvinyl) in CH3CN (100 mL) A mixture of tin (5617 μL, 16.627 mmol) was refluxed until LCMS indicated that the reaction was complete. 1N HCl (15 mL) was added and the mixture was stirred until conversion to the ketone was indicated by LCMS. The reaction mixture was diluted with EtOAc, washed with saturated NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated. Purification gave the ketone (3200 mg, 76%).
_HPLC-MS t R = 2.32 min _{(UV 254nm).} Calculated mass for M + 403.1, found LC / MS m / z 404.2 (M + H).

Part B: Bis (2-methoxyethyl) aminosulfur trifluoride (2745 μL, 14.89 mmol) was added to the ketone from Part A (600 mg, 1.490 mmol) in CH ₂ Cl ₂ (1 mL) at 0 ° C. Added dropwise. The mixture was stirred at room temperature for 1 week and then saturated NaHCO ₃ solution was carefully added dropwise. The mixture was extracted with CH ₂ Cl ₂ and the organic layer was dried over Na ₂ SO ₄ and concentrated. The di-fluoro compound was obtained by purification.
_HPLC-MS t R = 2.52 min _{(UV 254nm).} Calculated mass for M + 425.1, found LC / MS m / z 426.2 (M + H).

Part C: m-CPBA (1515.7mg, 6.76mmol) _was added to a solution of CH ₂ Cl ₂ (31mL) product from Part B in (1307mg, 3.07mmol). After stirring for 2 hours at room temperature, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The sulfone (5-A) was used directly without further purification.
_HPLC-MS t R = 2.17 min _{(UV 254nm).} Calculated mass for M + 457.1, found LC / MS m / z 458.0 (M + H).

Part D: A solution of aminoisothiazole (400 mg, 2.53 mmol) and sulfone (964 mg, 2.11 mmol) from Part C in DMF (13 mL) was added to NaH (60% dispersion in oil, 4.64 mmol, 186 mg). ). The mixture was stirred until LCMS indicated that the reaction was complete. The reaction mixture was diluted with EtOAc, washed with saturated NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated. Purification gave the substituted product (438.5 mg, 39%).
_HPLC-MS t R = 2.22 min _{(UV 254nm).} Calculated mass for M + 535.1, found LC / MS m / z 536.1 (M + H).

Part E: To a solution of the ester (406.5 mg, 0.759 mmol) in THF (39 mL) was added LiBHEt ₃ (3.79 mL, 1M solution in THF). The reaction was stirred at room temperature for 30 minutes. This was quenched by adding saturated aqueous NH ₄ Cl (15 mL). This mixture was extracted with 30 mL of CH ₂ Cl ₂ . The organic layer was concentrated and the crude alcohol was used for the next step without further purification.
_HPLC-MS t R = 1.99 minutes _{(UV 254nm).} Calculated mass for M + 507.1, found LC / MS m / z 508.1 (M + H).

Part F: To a solution of the crude alcohol from Part E in THF (40 mL) was added triethylamine (365 μL, 2.62 mmol) and methanesulfonyl chloride (173 μL, 2.23 mmol). The reaction was stirred at room temperature for 30 minutes. This was quenched by adding MeOH. The solution was diluted with 30 mL of CH ₂ Cl ₂ and washed sequentially with 15 mL of 2N aqueous HCl, water, and brine. The solvent was removed under vacuum to give the crude mesylate, which was used in the next conversion without further purification.
_HPLC-MS t R = 2.35 min _{(UV 254nm).} Calculated mass for M + 585.1, found LC / MS m / z 586.1 (M + H).

Part G: of crude compound (30 mg, 0.051 mmol), 3-methylpiperidine (24 μL, 0.205 mmol), EtN (iPr) ₂ (54 μL, 0.307 mmol), and NaI (1 mg) in THF (2 ml). The solution was heated at 80 ° C. for 1 hour and 10 minutes. The mixture was cooled to room temperature and then concentrated. 4N HCl in dioxane (3 mL) was added to the crude replacement product at 0 ° C. The mixture was stirred at room temperature until LCMS indicated that the reaction was complete. Concentration and purification gave compound 5-1.
_HPLC-MS t R = 1.27 min _{(UV 254nm).} Calculated mass for M + 458.1, found LC / MS m / z 459.1 (M + H).

  The compounds listed in Table 19 can be prepared by essentially the same procedure as shown in Example 89.

（実施例９０）

( Example 90 )

工程Ａ：０℃のＤＭＳＯ（２０ｍＬ）中のメシレート（１．１ｇ、１．６５ｍｍｏｌ）の溶液に、室温で、ＮａＩ（２８０ｍｇ、１．８８ｍｍｏｌ）およびＮａＣＮ（３００ｍｇ、６．１２ｍｍｏｌ）を加えた。この混合物を６０℃で１時間攪拌した。これを２００ｍＬのＥｔＯＡｃで希釈し、そして水（２００ｍＬ×２）で洗浄した。溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、６０％ ＥｔＯＡｃ／ヘキサン）によって精製して、９８０ｍｇの標題化合物を得た。

Step A: To a solution of mesylate (1.1 g, 1.65 mmol) in DMSO (20 mL) at 0 ° C. was added NaI (280 mg, 1.88 mmol) and NaCN (300 mg, 6.12 mmol) at room temperature. The mixture was stirred at 60 ° C. for 1 hour. This was diluted with 200 mL EtOAc and washed with water (200 mL × 2). The solvent was removed under vacuum. The residue was purified by column chromatography _(SiO 2, 60% EtOAc / hexanes) to afford the title compound 980 mg.

工程Ｂ：３０ｍＬのＣＨ_２Ｃｌ_２中の工程Ａからの化合物（５３０ｍｇ、０．８８９ｍｍｏｌ）の溶液を０℃まで冷却した。これに、ＤＩＢＡＬ−Ｈ溶液（ＣＨ_２Ｃｌ_２中１Ｍ、３．５６ｍＬ、３．５６ｍｍｏｌ）をゆっくりと加えた。この反応物を０℃で２０分間攪拌した。これを１ｍＬのＭｅＯＨでクエンチし、得られた溶液を、５０ｍＬの飽和Ｒｏｃｈｅｌｌｅ塩溶液とともに室温で２時間攪拌した。有機層を単離し、溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、ＭｅＯＨ／ ＣＨ_２Ｃｌ_２中１０％ ７Ｎ ＮＨ_３）によって精製して、４５０ｍｇの標題化合物を得た。

Step B: A solution of the compound from Step A (530 mg, 0.889 mmol) in 30 mL of CH ₂ Cl ₂ was cooled to 0 ° C. Thereto, DIBAL-H solution _(CH 2 Cl ₂ in 1M, 3.56mL, 3.56mmol) was added slowly. The reaction was stirred at 0 ° C. for 20 minutes. This was quenched with 1 mL of MeOH and the resulting solution was stirred with 50 mL of saturated Rochelle salt solution for 2 hours at room temperature. The organic layer was isolated and the solvent removed in vacuo. The residue was purified by column chromatography (SiO ₂ , 10% 7N NH ₃ in MeOH / CH ₂ Cl ₂ ) to give 450 mg of the title compound.

工程Ｃ：２０ｍＬのＡｃＯＨ中の工程Ｂからの化合物（４００ｍｇ、０．６６７ｍｍｏｌ）およびＮａＯＡｃ（４００ｍｇ、４．８８ｍｍｏｌ）の溶液を６０℃で攪拌した、これに、ｔ−ブチルニトライト（１．４０ｍＬ、１１．８ｍｍｏｌ）をゆっくりと加えた。この反応物を６０℃で２０分間攪拌した。これを室温まで冷却し、２０ｍＬのＣＨ_２Ｃｌ_２を加えた。固形物を濾過して除き、濾液中の溶媒を真空下で除去した。残渣を１００ｍＬのＣＨ_２Ｃｌ_２で希釈し、５０ｍＬの飽和ＮａＨＣＯ_３水溶液で洗浄した。有機層部分を濃縮した。残渣を１０ｍＬのＭｅＯＨに溶解した。この溶液に、１ｍＬ水中のＮａＯＨ（２００ｍｇ）の溶液を加えた。室温で３０分間の攪拌後、これを１００ｍＬのＣＨ_２Ｃｌ_２で希釈し、１００ｍＬのブラインで洗浄した。溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、７５％ ＥｔＯＡｃ／ヘキサン）によって精製して、２４０ｍｇの標題化合物を得た。

Step C: A solution of the compound from Step B (400 mg, 0.667 mmol) and NaOAc (400 mg, 4.88 mmol) in 20 mL AcOH was stirred at 60 ° C., to which was added t-butylnitrite (1.40 mL, 11.8 mmol) was added slowly. The reaction was stirred at 60 ° C. for 20 minutes. This was cooled to room temperature and 20 mL of CH ₂ Cl ₂ was added. The solid was filtered off and the solvent in the filtrate was removed under vacuum. The residue was diluted with 100 mL CH ₂ Cl ₂ and washed with 50 mL saturated aqueous NaHCO ₃ . The organic layer portion was concentrated. The residue was dissolved in 10 mL MeOH. To this solution was added a solution of NaOH (200 mg) in 1 mL water. After stirring for 30 minutes at room temperature, it was diluted with 100 mL CH ₂ Cl ₂ and washed with 100 mL brine. The solvent was removed under vacuum. The residue was purified by column chromatography _(SiO 2, 75% EtOAc / hexanes) to afford the title compound 240 mg.

（実施例９１）

( Example 91 )

工程Ａ：１０ｍＬのＴＨＦ中の実施例９０（２００ｍｇ、０．３３３ｍｏｌ）の溶液にＮＥｔ_３（８４ｍｇ、０．８３０ｍｍｏｌ）、続いてメタンスルホニルクロリド（７６．４ｍｇ、０．６６７ｍｍｏｌ）を加えた。この反応物を室温で２０分間攪拌した。これを１０ｍＬの水を加えることによってクエンチし、５０ｍＬのＣＨ_２Ｃｌ_２で希釈した。この混合物を２０ｍＬの０．５Ｎ ＨＣｌ水溶液で洗浄した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させた。溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、７０％ ＥｔＯＡｃ／ヘキサン）によって精製して、１８０ｍｇの標題化合物を得た。

Step A: To a solution of Example 90 (200 mg, 0.333 mol) in 10 mL of THF was added NEt ₃ (84 mg, 0.830 mmol) followed by methanesulfonyl chloride (76.4 mg, 0.667 mmol). The reaction was stirred at room temperature for 20 minutes. This was quenched by adding 10 mL of water and diluted with 50 mL of CH ₂ Cl ₂ . The mixture was washed with 20 mL of 0.5N aqueous HCl. The organic layer was dried over anhydrous Na ₂ SO ₄ . The solvent was removed under vacuum. The residue was purified by column chromatography _(SiO 2, 70% EtOAc / hexanes) to afford the title compound 180 mg.

Step B: Mesylate from Step A (42 mg, 0.062 mmol), thiomorpholine (16 mg, 0.16 mmol), K ₂ CO ₃ (8.5 mg, 0.062 mmol), and trace amounts in 1.5 mL of THF. Of NaI was stirred at 80 ° C. for 24 hours. This was cooled to room temperature. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO ₂ , 5% 7N NH ₃ in MeOH / CH ₂ Cl ₂ ) to give 37 mg of the title compound.

工程Ｃ：８０℃で攪拌した、２ｍＬのＴＨＦ／ＭｅＯＨ（１：１）中の工程Ｂ（３７ｍｇ、０．０５４ｍｍｏｌ）からの生成物の溶液に、０．５ｍＬのジオキサン溶液中４Ｎ ＨＣｌを加えた。この反応物を８０℃で３０分間攪拌した。これを室温まで冷却し、２ｍＬのＴＨＦおよび１ｍＬのエーテルで希釈した。固形物を濾過によって収集し、そしてエーテルで洗浄して、２６ｍｇの標題化合物をそのＨＣｌ塩形態として得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．２１分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１９Ｈ_２０Ｎ_８ＯＳの質量計算値４２６．１、実測値ＭＨ^＋（ＬＣＭＳ）４２７．２（ｍ／ｚ）。

Step C: To a solution of the product from Step B (37 mg, 0.054 mmol) in 2 mL THF / MeOH (1: 1) stirred at 80 ° C., 0.5 mL 4N HCl in dioxane solution was added. . The reaction was stirred at 80 ° C. for 30 minutes. This was cooled to room temperature and diluted with 2 mL of THF and 1 mL of ether. The solid was collected by filtration and washed with ether to give 26 mg of the title compound as its HCl salt form.
_HPLC-MS t R = 2.21 min _{(UV 254nm).} Mass calculated for chemical formula C ₁₉ H ₂₀ N ₈ OS 426.1, found MH ⁺ (LCMS) 427.2 (m / z).

  The compound shown in column 2 of Table 20 was prepared by essentially the same procedure as shown in Example 91, but only replacing thiomorpholine with each other aliphatic amine in Step B.

（実施例９２）

( Example 92 )

工程Ａ：０℃で攪拌した４ｍＬのＣＨ_２Ｃｌ_２中の四臭化炭素（１７０ｍｇ、０．５１２ｍｍｏｌ）の溶液にＰＰｈ_３（２６７ｍｇ、１．０２ｍｍｏｌ）を加えた。この反応物を０℃で１５分間攪拌し、その時点でアルデヒド（２００ｍｇ、０．３４１ｍｍｏｌ）を加えた。得られた溶液をさらに０℃で１５分間攪拌した。これを、１０ｍＬの飽和ＮａＨＣＯ_３水溶液でクエンチした。この混合物を２０ｍＬのＣＨ_２Ｃｌ_２によって抽出した。水相をさらにＣＨ_２Ｃｌ_２（１０ｍＬ×２）によって抽出した。合わせた有機相を濃縮し、さらにカラムクロマトグラフィー（ＳｉＯ_２、５０％ ＥｔＯＡｃ／ヘキサン）によって精製して、１５０ｍｇの標題化合物を得た。

Step A: To a stirred solution of carbon tetrabromide (170 mg, 0.512 mmol) in 4 mL of CH ₂ Cl ₂ at 0 ° C. was added PPh ₃ (267 mg, 1.02 mmol). The reaction was stirred at 0 ° C. for 15 minutes, at which point aldehyde (200 mg, 0.341 mmol) was added. The resulting solution was further stirred at 0 ° C. for 15 minutes. This was quenched with 10 mL of saturated aqueous NaHCO ₃ solution. This mixture was extracted with 20 mL of CH ₂ Cl ₂ . The aqueous phase was further extracted with CH ₂ Cl ₂ (10 mL × 2). The combined organic phases were concentrated and further purified by column chromatography _(SiO 2, 50% EtOAc / hexanes) to afford the title compound 150 mg.

Step B: A stirred solution of the compound from Step A (40 mg, 0.054 mmol) and pyrrolidine (30 mg, 0.43 mmol) in 0.6 mL DMSO and 0.15 mL water was stirred at 100 ° C. for 3 hours. This was cooled to room temperature and diluted with 15 mL of CH ₂ Cl ₂ . The contents were washed successively with water, saturated aqueous NaHCO ₃ solution, and brine. The organic phase was concentrated and purified by column chromatography (SiO ₂ , 3.5% 7N NH ₃ in MeOH / CH ₂ Cl ₂ ) to give 20 mg of the title compound.

工程Ｃ：１ｍＬのＴＨＦおよび２ｍＬのＴＦＡ中のパートＢからの化合物（２０ｍｇ、０．０２９ｍｍｏｌ）の溶液を６０℃で２時間攪拌した。溶媒を真空下で除去した。残渣を２ｍＬのＴＨＦに溶解した。この攪拌溶液に１ｍＬのエーテル中１Ｍ ＨＣｌを加えた。固形物を濾過により収集し、エーテルで洗浄して、１０ｍｇの標題化合物をそのＨＣｌ塩形態として得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．５５分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１９Ｈ_２０Ｎ_８ＯＳの質量計算値４０８．２、実測値ＭＨ^＋（ＬＣＭＳ）４０９．２（ｍ／ｚ）。

Step C: A solution of the compound from Part B (20 mg, 0.029 mmol) in 1 mL THF and 2 mL TFA was stirred at 60 ° C. for 2 h. The solvent was removed under vacuum. The residue was dissolved in 2 mL THF. To this stirred solution was added 1 mL of 1M HCl in ether. The solid was collected by filtration and washed with ether to give 10 mg of the title compound as its HCl salt form.
_HPLC-MS t R = 2.55 min _{(UV 254nm).} Mass calculated for formula C ₁₉ H ₂₀ N ₈ OS 408.2, found MH ⁺ (LCMS) 409.2 (m / z).

  The compound shown in column 2 of Table 21 was prepared by essentially the same procedure as shown in Example 92, but only replacing the pyrrolidine with each other aliphatic amine in Step B.

（実施例９３）

( Example 93 )

工程Ａ：１６ｍＬのアセトン中のメシレート（５６０ｍｇ、０．８４１ｍｍｏｌ）の溶液に、ＬｉＢｒ（７３０ｍｇ、８．４１ｍｍｏｌ）を加えた。この混合物を室温で１．５時間攪拌した。これを１００ｍＬのＣＨ_２Ｃｌ_２で希釈し、ブライン（１００ｍＬ）で洗浄した。溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、４０％ ＥｔＯＡｃ／ヘキサン）によって精製して、５０６ｍｇの標題化合物を得た。

Step A: To a solution of mesylate (560 mg, 0.841 mmol) in 16 mL of acetone, LiBr (730 mg, 8.41 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. This was diluted with 100 mL of CH ₂ Cl ₂ and washed with brine (100 mL). The solvent was removed under vacuum. The residue was purified by column chromatography _(SiO 2, 40% EtOAc / hexanes) to afford the title compound 506 mg.

工程Ｂ：１．５ｍＬのＴＨＦ中の工程Ａからの化合物（４０ｍｇ、０．０６１ｍｍｏｌ）の溶液に、２−トリ−ｎ−ブチルスタニルピリジン（４５ｍｇ、０．１２ｍｍｏｌ）およびＰｄ（ＰＰｈ_３）_４（１７ｍｇ、０．０１５ｍｍｏｌ）を加えた。この反応物を、密封バイアル中で、８０℃にて１６時間攪拌した。溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、ＭｅＯＨ／ＣＨ_２Ｃｌ_２中３％ ７Ｎ ＮＨ_３）によって精製して、トリフェニルホスフィンオキシドが夾雑している３２ｍｇの粗標題化合物を得た。この材料をさらなる精製なしで工程Ｃにおいて使用した。

Step B: To a solution of the compound from Step A (40 mg, 0.061 mmol) in 1.5 mL THF was added 2-tri-n-butylstannylpyridine (45 mg, 0.12 mmol) and Pd (PPh ₃ ) _4. (17 mg, 0.015 mmol) was added. The reaction was stirred in a sealed vial at 80 ° C. for 16 hours. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO ₂ , 3% 7N NH ₃ in MeOH / CH ₂ Cl ₂ ) to give 32 mg of the crude title compound contaminated with triphenylphosphine oxide. This material was used in Step C without further purification.

  Step C: The product of Step B was dissolved in 2 mL of MeOH / THF (1: 1) at 80 ° C. To this solution was added 0.5 mL of 4N HCl in dioxane. The reaction was stirred at 80 ° C. for 30 minutes. This was cooled to room temperature and diluted with 1 mL of THF. The solid was collected by filtration and washed with THF and ether to give 15 mg of the title compound as its HCl salt form.

ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．００分（ＵＶ_{２５４ｎｍ}）。化学式Ｃ_１９Ｈ_１６Ｎ_８Ｓの質量計算値３８８．１、実測値ＭＨ^＋（ＬＣＭＳ）３８９．２（ｍ／ｚ）。

_HPLC-MS t R = 2.00 min _{(UV 254nm).} Mass calculated for chemical formula C ₁₉ H ₁₆ N ₈ S 388.1, found MH ⁺ (LCMS) 389.2 (m / z).

  It was shown in column 2 of Table 22 by essentially the same procedure as shown in Example 93, only replacing 2-tri-n-butylstannylpyridine with each other tin reagent in Step B. The compound was prepared.

（実施例９４）

( Example 94 )

工程Ａ：１０ｍＬのＴＨＦ／ＤＭＦ（１：１）の混合物に、ＮａＨ（３９．３ｍｇ、１．６４ｍｍｏｌ）を加えた。これを−１０℃まで冷却し、次いで、５ｍＬのＤＭＳＯ中のトリメチルスルホニウムヨーダイド（３３４ｍｇ、１．６４ｍｍｏｌ）の溶液をゆっくりと加えた。得られた混合物にアルデヒドを加えた。この反応物を室温で４０分間攪拌した。これを氷水でクエンチし、５０ｍＬのＣＨ_２Ｃｌ_２で希釈した。この混合物を水およびブラインで洗浄した。溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、４０％ ＥｔＯＡｃ／ヘキサン）によって精製して、３９０ｍｇの標題化合物を得た。

Step A: To a mixture of 10 mL THF / DMF (1: 1), NaH (39.3 mg, 1.64 mmol) was added. This was cooled to −10 ° C. and then a solution of trimethylsulfonium iodide (334 mg, 1.64 mmol) in 5 mL DMSO was added slowly. Aldehyde was added to the resulting mixture. The reaction was stirred at room temperature for 40 minutes. This was quenched with ice water and diluted with 50 mL of CH ₂ Cl ₂ . This mixture was washed with water and brine. The solvent was removed under vacuum. The residue was purified by column chromatography _(SiO 2, 40% EtOAc / hexanes) to afford the title compound 390 mg.

工程Ｂ：４ｍＬのＤＭＦ中の工程Ａからの化合物（２７０ｍｇ、０．４５０ｍｍｏｌ）の溶液を、メタンチオレートナトリウム（１００ｍｇ、１．４３ｍｍｏｌ）で処理した。この反応物を室温で３０分間攪拌した。これを１５ｍＬの水で希釈した。この混合物をＥｔＯＡｃ（２０ｍＬ×３）で抽出した。合わせた有機相をブライン（２０ｍＬ）で洗浄し、次いで濃縮した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、７０％ ＥｔＯＡｃ／ヘキサン）によって精製して、２２０ｍｇの標題化合物を得た。

Step B: A solution of the compound from Step A (270 mg, 0.450 mmol) in 4 mL of DMF was treated with sodium methanethiolate (100 mg, 1.43 mmol). The reaction was stirred at room temperature for 30 minutes. This was diluted with 15 mL of water. This mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL) and then concentrated. The residue was purified by column chromatography _(SiO 2, 70% EtOAc / hexanes) to afford the title compound 220 mg.

工程Ｃ：１ｍＬのＴＨＦ中の工程Ｂからの化合物（３０ｍｇ、０．０４６ｍｏｌ）の溶液に、ＮＥｔ_３（１４ｍｇ、０．１４ｍｍｏｌ）、続いてメタンスルホニルクロリド（１６ｍｇ、０．１４ｍｍｏｌ）を加えた。この反応物を室温で１５分間攪拌した。これは２ｍＬの水を加えることによってクエンチし、１５ｍＬのＣＨ_２Ｃｌ_２で希釈した。この混合物を１０ｍＬの０．２Ｎ ＨＣｌ水溶液で洗浄した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、次いで濃縮した。残渣を１ｍＬ ＴＨＦ中のＮａＩ（１０ｍｇ、０．０７１ｍｍｏｌ）およびピペリジン（１３ｍｇ、０．１５ｍｍｏｌ）で処理した。得られた混合物を８０℃で１２時間攪拌した。これを１５ｍＬのＣＨ_２Ｃｌ_２で希釈し、そして１５ｍＬの飽和ＮａＨＣＯ_３水溶液で洗浄した。溶媒を減圧下で除去し、残渣をカラムクロマトグラフィー（ＳｉＯ_２、ＭｅＯＨ／ＣＨ_２Ｃｌ_２中３％ ７Ｎ ＮＨ_３）によって精製して、１２ｍｇの標題化合物を得た。

Step C: To a solution of the compound from Step B (30 mg, 0.046 mol) in 1 mL of THF was added NEt ₃ (14 mg, 0.14 mmol) followed by methanesulfonyl chloride (16 mg, 0.14 mmol). The reaction was stirred at room temperature for 15 minutes. This was quenched by the addition of 2 mL water and diluted with 15 mL CH ₂ Cl ₂ . The mixture was washed with 10 mL of 0.2N aqueous HCl. The organic layer was dried over anhydrous Na ₂ SO ₄ and then concentrated. The residue was treated with NaI (10 mg, 0.071 mmol) and piperidine (13 mg, 0.15 mmol) in 1 mL THF. The resulting mixture was stirred at 80 ° C. for 12 hours. This was diluted with 15 mL CH ₂ Cl ₂ and washed with 15 mL saturated aqueous NaHCO ₃ . The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO ₂ , 3% 7N NH ₃ in MeOH / CH ₂ Cl ₂ ) to give 12 mg of the title compound.

Step D: To a solution of the compound from Step C (12 mg, 0.017 mmol) in 1 mL THF / MeOH (1: 1) was added 0.5 mL 4N HCl in dioxane. The reaction was stirred at 80 ° C. for 1 hour. This was cooled to room temperature and diluted with 10 mL of ether. The solid was collected by filtration and washed with ether to give 8 mg of the title compound as its HCl salt form.
_HPLC-MS t R = 2.88 min _{(UV 254nm).} Chemical formula _C 21 _H 26 _N 8 _{S 2} mass calcd 454.2, found ^{MH + (LCMS) 455.3 (m} / z).

  The compound shown in column 2 of Table 23 was prepared by essentially the same procedure as shown in Example 94, but only replacing the piperidine with each other aliphatic amine in Step B.

（実施例９５）
工程Ａにおいてメタンチオレートナトリウムをベンゼンチオレートナトリウムで置き換えること、および工程Ｂにおいてピペリジンを置き換えるためにそれぞれの脂肪族アミンを利用するのみで、実施例９４に示されたのと本質的に同じ手順によって、表２４のカラム２に示された化合物を調製した。

( Example 95 )
Essentially the same procedure as shown in Example 94, just replacing sodium methanethiolate with sodium benzenethiolate in step A and utilizing the respective aliphatic amine to replace piperidine in step B. To prepare the compounds shown in column 2 of Table 24.

（実施例９６）

( Example 96 )

５ｍＬのＤＭＦ中のジメチルスルホン（２８１ｍｇ、２．９９ｍｍｏｌ）の攪拌溶液を、ｔ−ブトキシドナトリウム（２８７ｍｇ、２．９９ｍｍｏｌ）で、室温で５分間処理した。次いで、アルデヒドを加えた。この反応物は室温で１５分間攪拌した。これは飽和ＮＨ_４Ｃｌ水溶液（５ｍＬ）でクエンチした。この混合物を５０ｍＬの水で希釈し、５０ｍＬのＥｔＯＡｃ／ヘキサン（１：１）で、続いて２５ｍＬのＥｔＯＡｃで抽出した。合わせた有機相をブラインで洗浄し、次いで濃縮した。残渣をカラムクロマトグラフィー（ＳｉＯ_２、５０％ ＥｔＯＡｃ／ヘキサン）によって精製して、２７０ｍｇの標題化合物を得た。

A stirred solution of dimethylsulfone (281 mg, 2.99 mmol) in 5 mL of DMF was treated with sodium t-butoxide (287 mg, 2.99 mmol) for 5 minutes at room temperature. The aldehyde was then added. The reaction was stirred at room temperature for 15 minutes. This was quenched with saturated aqueous NH ₄ Cl (5 mL). The mixture was diluted with 50 mL water and extracted with 50 mL EtOAc / hexane (1: 1) followed by 25 mL EtOAc. The combined organic phases were washed with brine and then concentrated. The residue was purified by column chromatography _(SiO 2, 50% EtOAc / hexanes) to afford the title compound 270 mg.

実施例９６における工程Ｂおよび工程Ｃに示されるのと本質的に同じ手順によって、表２５のカラム２に示された化合物を調製した。

The compound shown in column 2 of Table 25 was prepared by essentially the same procedure as shown in Step B and Step C in Example 96.

（実施例９７）

( Example 97 )

表２４のカラム２に示される化合物は、上記の反応スキームに従って、および一般的な手順を利用して調製した。

The compounds shown in column 2 of Table 24 were prepared according to the above reaction scheme and using general procedures.

Step A: To a stirred solution of compound alcohol (1.00 g, 1.70 mmol) in 20 mL of THF was added Dess-Martin periodide (1.84 g, 4.26 mmol) and a trace amount of water. The reaction was stirred at room temperature for 40 minutes, which was diluted with 200 mL of CH ₂ Cl ₂ and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was removed under vacuum. The residue was purified by column chromatography _(SiO 2, 40% EtOAc / hexane) gave the title compound in 250 mg.

Step B: To a solution of the compound from Step A (0.05 mmol) in 1 mL of CH ₂ Cl ₂ / MeOH (1: 1) was added the respective amine (5 eq) and a trace amount of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes, at which point NaBH ₄ (10 eq) was added. Stirring was continued for an additional 10 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl. This mixture was extracted with CH ₂ Cl ₂ . The organic phase was concentrated and the residue was purified by column chromatography (SiO ₂ , 5% 7N NH ₃ in MeOH / CH ₂ Cl ₂ ) to give the title compound.

  Step C: To a solution of the compound from Step B (0.05 mmol) in 1 mL THF / MeOH (1: 1) was added 1 mL 4N HCl in dioxane. The reaction was stirred at 80 ° C. for 30 minutes. This was cooled to room temperature and diluted with 10 mL of ether. The solid was collected by filtration to give compounds 97-1 and 97-2, respectively.

（実施例９８）

( Example 98 )

パートＡ：無水ＴＨＦ（９ｍＬ）中のイソチアゾール−アルデヒド（５３４ｍｇ；０．９ｍｍｏｌ）の溶液にメチルマグネシウムブロミド（３Ｍ；１．８ｍＬ）を室温で加えた。２０分間の攪拌後、反応混合物を５ｍＬの飽和ＮＨ_４Ｃｌ水溶液でクエンチし、ＣＨ_２Ｃｌ_２で希釈した。有機層を水およびブラインで洗浄した。水相をＣＨ_２Ｃｌ_２で逆抽出した。合わせた有機層を硫酸ナトリウムで乾燥させ、そして濃縮して粗生成物を得た。フラッシュシリカゲルクロマトグラフィー（ＥｔＯＡｃ：ＣＨ_２Ｃｌ_２＝２：１）は、所望のカルビノールを白色固形物として与え（４６０ｍｇ；８４％）これには未反応アルデヒド（５０ｍｇ）が付随した。

Part A: To a solution of isothiazole-aldehyde (534 mg; 0.9 mmol) in anhydrous THF (9 mL) was added methylmagnesium bromide (3 M; 1.8 mL) at room temperature. After stirring for 20 minutes, the reaction mixture was quenched with 5 mL of saturated aqueous NH ₄ Cl and diluted with CH ₂ Cl ₂ . The organic layer was washed with water and brine. The aqueous phase was back extracted with CH ₂ Cl ₂ . The combined organic layers were dried over sodium sulfate and concentrated to give the crude product. Flash silica gel chromatography (EtOAc: CH ₂ Cl ₂ = 2: 1) gave the desired carbinol as a white solid (460 mg; 84%) which was accompanied by unreacted aldehyde (50 mg).

パートＢ：トリエチルアミン（１３６ｍｇ；１．３５ｍｍｏｌ）およびメタンスルホニルクロリド（８８ｍｇ；０．７７ｍｍｏｌ）を、室温で、１２ｍＬのＴＨＦ中のパートＡからのカルビノール（２３２ｍｇ；０．３９ｍｍｏｌ）の溶液に加えた。１０分後、反応物を水でクエンチし、ＣＨ_２Ｃｌ_２で希釈した。有機層を水およびブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して、粗生成物を得た。フラッシュシリカゲルカラムからのＣＨ_２Ｃｌ_２：ＥｔＯＡｃ（２：１）を用いる迅速な溶出は、所望のメシレートを白色固形物として与えた（２６８ｍｇ；１００％）。

Part B: Triethylamine (136 mg; 1.35 mmol) and methanesulfonyl chloride (88 mg; 0.77 mmol) were added to a solution of carbinol (232 mg; 0.39 mmol) from Part A in 12 mL of THF at room temperature. . After 10 minutes, the reaction was quenched with water and diluted with CH ₂ Cl ₂ . The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give the crude product. Rapid elution with CH ₂ Cl ₂ : EtOAc (2: 1) from a flash silica gel column gave the desired mesylate as a white solid (268 mg; 100%).

パートＣ：２ｍＬの無水ＴＨＦ中のメシレート（４０ｍｇ；０．０６ｍｍｏｌ）の溶液を、ヘキサメチレンイミン（１５ｍｇ；０．１５ｍｍｏｌ）と触媒量のＮａＩで処理し、そしてこの混合物はオイルバス中で還流して加熱した（８０℃；２０時間）。この反応混合物を室温まで冷却し、水およびＣＨ_２Ｃｌ_２で希釈した。有機層を水、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させた。真空中での濃縮は粗生成物を与えた。精製をフラッシュシリカゲルカラム上で実施し、２〜４％のメタノール中７Ｎ−アンモニアを含むＣＨ_２Ｃｌ_２で生成物を溶出した。所望のジ−ＳＥＭ保護化アミン生成物を無色フィルム状物として得た（３１ｍｇ；７５％）。

Part C: A solution of mesylate (40 mg; 0.06 mmol) in 2 mL of anhydrous THF was treated with hexamethyleneimine (15 mg; 0.15 mmol) and a catalytic amount of NaI, and the mixture was refluxed in an oil bath. And heated (80 ° C .; 20 hours). The reaction mixture was cooled to room temperature and diluted with water and CH ₂ Cl ₂ . The organic layer was washed with water, brine and dried over Na ₂ SO ₄ . Concentration in vacuo gave the crude product. Purification was performed on flash silica gel column and eluted the product with _CH 2 Cl ₂ containing 2-4% of methanol 7N- ammonia. The desired di-SEM protected amine product was obtained as a colorless film (31 mg; 75%).

パートＤ：０．２ｍＬのＴＨＦおよび０．２ｍＬのＣＨ_３ＯＨ中のパートＣからの上記のジ−ＳＥＭ保護化アミン（３１ｍｇ；０．０４５ｍｍｏｌ）の溶液に、ジオキサン中４Ｎ−ＨＣｌ（０．２ｍＬ）を加えた。得られた混合物をオイルバス中で８０℃で３０分間加熱し、次いで、室温まで冷却させた。ＴＨＦ（２ｍＬ）を反応混合物に加え、沈殿生成物を濾過によって収集した。フィルターケーキをＴＨＦおよびエーテルで洗浄し、真空下で乾燥させて、標題化合物を白色固形物として得た（２３ｍｇ）。

Part D: The above di -SEM protected amine from Part C in _CH 3 OH in THF and 0.2mL of 0.2mL; To a solution of (31 mg 0.045 mmol), dioxane 4N-HCl (0.2mL ) Was added. The resulting mixture was heated in an oil bath at 80 ° C. for 30 minutes and then allowed to cool to room temperature. THF (2 mL) was added to the reaction mixture and the precipitated product was collected by filtration. The filter cake was washed with THF and ether and dried under vacuum to give the title compound as a white solid (23 mg).

  In the above procedure, all target compounds listed in Table 1 were prepared and characterized by using the appropriate Grignard reagent in the first step and the appropriate amine in the third step.

（実施例９９）

( Example 99 )

基質（５００ｍｇ）をｔ−ＢｕＯＨ（３０ｍＬ）に懸濁し、Ｅｔ_３Ｎ（０．４５ｍＬ）およびＤＰＰＡ（０．７３ｍＬ）を、室温で連続的に加えた。次いで、この混合物を８５℃で一晩加熱した。この反応混合物を室温まで冷却し、溶媒を減圧下でエバポレートした。残渣を酢酸エチル（５０ｍＬ）にとり、水（５０ｍＬ）を加えた。２層混合物を１５分間攪拌した。次いで、２つの層を分離させ、水層を酢酸エチル（２×５０ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し（５０ｍＬ）、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下でエバポレートして粗生成物を得、これをカラムクロマトグラフィー（ＳｉＯ_２）によって精製した。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．７０分。Ｃ_１１Ｈ_１５ＮＯ_３Ｓの質量計算値２４１．０８、実測値ＭＨ^＋（ＬＣＭＳ）２４２．２（ｍ／ｚ）（ＵＶ_{２５４ｎｍ}）。

Substrate (500 mg) was suspended in t-BuOH (30 mL) and Et ₃ N (0.45 mL) and DPPA (0.73 mL) were added sequentially at room temperature. The mixture was then heated at 85 ° C. overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and water (50 mL) was added. The bilayer mixture was stirred for 15 minutes. The two layers were then separated and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography (SiO ₂ ). .
_HPLC-MS t R = 1.70 min. Mass calculated for C ₁₁ H ₁₅ NO ₃ S 241.08, found MH ⁺ (LCMS) 242.2 (m / z) (UV _{254 nm} ).

( Example 100 )

パートＡ：二酸（３ｇ）をＣＨ_２Ｃｌ_２（５０ｍＬ）中に懸濁し、そしてＮ，Ｏ−ジメチルヒドロキシルアミン塩酸塩（１．６９ｇ）、ＨＡＴＵ（６．６ｇ）、およびジイソプロピルエチルアミン（１２．１２ｍＬ）を、室温で連続的に加えた。この反応混合物を一晩攪拌し、水（１００ｍＬ）の添加によりクエンチした。２つの層を分離させた。水層はｐＨ ４．０に酸性化し、ＣＨＣｌ_３（５×１００ｍＬ）で抽出した。有機層を合わせ、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、そして減圧下でエバポレートして、生成物を得た。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝１．１４。Ｃ_８Ｈ_９ＮＯ_４Ｓの質量計算値２１５．０３、実測値ＭＨ^＋（ＬＣＭＳ）２１６．１（ｍ／ｚ）（ＵＶ_{２５４ｎｍ}）。

Part A: Diacid (3 g) was suspended in CH ₂ Cl ₂ (50 mL) and N, O-dimethylhydroxylamine hydrochloride (1.69 g), HATU (6.6 g), and diisopropylethylamine (12. 12 mL) was added continuously at room temperature. The reaction mixture was stirred overnight and quenched by the addition of water (100 mL). The two layers were separated. The aqueous layer was acidified to pH 4.0 and extracted with CHCl ₃ (5 × 100 mL). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the product.
_HPLC-MS t R = 1.14. Calculated mass for C ₈ H ₉ NO ₄ S 215.03, found MH ⁺ (LCMS) 216.1 (m / z) (UV _{254 nm} ).

Part B: Substrate from Part A (3.2 g) was suspended in t-BuOH (100 mL) and Et ₃ N (2.27 mL) and DPPA (3.64 mL) were added sequentially at room temperature. The mixture was then heated at 85 ° C. overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and water (100 mL) was added. The bilayer mixture was stirred for 15 minutes. The two layers were then separated and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (150 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography (SiO ₂ ). .
_HPLC-MS t R = 1.55. _{C 12 H 18 N 2 O 4} S Mass calcd 286.1, found ^{MH + (LCMS) 287.2 (m} / z) (UV 254nm).

Part C: The substrate from Part B (191 mg) was dissolved in THF / Et ₂ O (3 mL / 6 mL) and cooled to 0 ° C. Methyl magnesium bromide (0.83 mL, 2.0 M solution) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 12 hours, and quenched by the addition of saturated ammonium chloride (10 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (30 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography (SiO ₂ ). did.

Part D: The substrate from Part C (10 mg) was dissolved in 30% TFA in CH ₂ Cl ₂ (2 mL) and the mixture was stirred for 30 minutes. The solvent was then evaporated under reduced pressure and the residue was dried in vacuo. The crude product was used in the next step without further purification.

Part E: Sulfone (574.19 mg) and amine trifluoroacetate (514 mg) were dissolved in DMF (15 mL) under argon and treated with NaH (432 mg, 60% dispersion in oil). After LCMS showed complete conversion of starting material to product, the reaction mixture was quenched with saturated ammonium chloride solution (15 mL). Ethyl acetate (25 mL) was added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layers were washed with brine (30 mL), dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography (SiO ₂ ). did.
_HPLC-MS t R = 2.31. Calculated mass for C ₂₂ H ₂₈ N ₆ O ₂ SSi 468.2, found MH ⁺ (LCMS) 469.1 (m / z) (UV _{254 nm} ).

Part F: Ketone (25 mg) was suspended in Ti (Oi-Pr) ₄ (1 mL) and treated with piperidine (0.2 mL) under argon. The mixture was stirred overnight at room temperature. Methanol (2 mL) was then added followed by NaBH ₄ (10 mg). The reaction mixture was stirred for an additional 30 minutes and quenched by the addition of 2M aqueous NaOH (5 mL). This was filtered and ethyl acetate (5 mL) was added to the filtrate. The two layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure to give the crude product, which was taken to the next step without further purification.

Part G: The substrate was dissolved in 4N HCl in dioxane and stirred for 30 minutes. LCMS showed complete conversion of starting material to product. The solvent was then evaporated under reduced pressure and the crude material was purified by reverse phase HPLC.
_HPLC-MS t R = 1.28. Calculated mass for C ₂₁ H ₂₅ N ₇ S 407.2, found (M-84) ⁺ (LCMS) 323 (m / z) (UV _{254 nm} ).

  The compounds in Table 28 were prepared according to the following similar procedure.

（実施例１０１）

( Example 101 )

工程Ａ：ジエチルエーテル（４０ｍＬ）中の２−エトキシエチルアミン（２．０ｇ、２２．４ｍｍｏｌ）の溶液に、０℃で、トリフルオロ酢酸無水物（４．７ｇ、２２．４ｍｍｏｌ）を滴下して加えた。この反応物を室温で１時間攪拌した。炭酸カリウム（１０ｇ）を反応溶液に加えた。この反応物を室温で１時間攪拌した。この混合物はセライトを通して濾過し、有機濾液を濃縮して、１．５ｇ（３６％収率）の標題化合物を得た。

Step A: To a solution of 2-ethoxyethylamine (2.0 g, 22.4 mmol) in diethyl ether (40 mL) at 0 ° C., trifluoroacetic anhydride (4.7 g, 22.4 mmol) was added dropwise. It was. The reaction was stirred at room temperature for 1 hour. Potassium carbonate (10 g) was added to the reaction solution. The reaction was stirred at room temperature for 1 hour. The mixture was filtered through celite and the organic filtrate was concentrated to give 1.5 g (36% yield) of the title compound.

Step _B: Et 2 O (20mL) solution of from Step A (trifluoromethyl) acetamide (1.5 g, 8.1 mmol) _solution, Et 2 O (20mL) solution of lithium aluminum hydride (0.92 g , 24.3 mmol) was added to the flask charged. The reaction was stirred at room temperature for 30 minutes and then refluxed for 12 hours. The reaction was cooled to room temperature and quenched with MeOH until bubbling ceased. The reaction was diluted with Et ₂ O (30 mL) and filtered through a pad of celite. The filtrate was concentrated by distillation to give 0.5 g (36% yield) of the title compound as a colorless liquid. This amine was used without further purification.

( Example 102 )

工程Ａ：ジクロロメタン（５０ｍＬ）中の２−エトキシエチルアミン（１．０ｇ、１１．２ｍｍｏｌ）の溶液に、０℃で、ピリジン（２．２ｇ、２８．１ｍｍｏｌ）を加えた。次いで、ジフルオロ酢酸無水物（２．３ｇ、１３．５ｍｍｏｌ）を反応溶液にゆっくりと加えた。この反応物はさらに、０℃で１５分間、次いで、室温で２．５時間攪拌した。この反応物をジクロロメタン（５０ｍＬ）およびＨ_２Ｏ（２０ｍＬ）で希釈した。この反応物は、１Ｎ ＨＣｌ（水溶液）；飽和ＮａＨＣＯ_３（水溶液）；ブラインで連続的に洗浄した。有機相をＮａＳＯ_４で乾燥させ、真空中で濃縮して、１．０３ｇ（５５％収率）の（ジフルオロメチル）アセトアミドを無色液体として得た。

Step A: To a solution of 2-ethoxyethylamine (1.0 g, 11.2 mmol) in dichloromethane (50 mL) at 0 ° C. was added pyridine (2.2 g, 28.1 mmol). Difluoroacetic anhydride (2.3 g, 13.5 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 ° C. for 15 minutes and then at room temperature for 2.5 hours. The reaction was diluted with dichloromethane (50 mL) and H ₂ O (20 mL). The reaction was washed successively with 1N HCl (aq); saturated NaHCO ₃ (aq); brine. The organic phase was dried over NaSO ₄ and concentrated in vacuo to give 1.03 g (55% yield) of (difluoromethyl) acetamide as a colorless liquid.

Step B: A solution of (difluoromethyl) acetamide (1.04 g, 6.20 mmol) from Step A in Et ₂ O (21 mL) in Et ₂ O (25 mL) at 0 ° C. under N ₂ atmosphere. Of lithium aluminum hydride (0.47 g, 12.39 mmol) was added to the flask. The reaction was stirred at room temperature for 2 hours under N ₂ atmosphere. The reaction was quenched by sequential addition of 0.47 mL H ₂ O; 0.47 mL 15% NaOH (water) solution; 1.4 mL H ₂ O. The reaction was stirred at room temperature for 15 minutes and then filtered through a pad of celite. The filtrate was concentrated by distillation to give 0.79 g (83% yield) of the title compound as a colorless liquid. This amine was used without further purification.

( Example 103 )

工程Ａ：ジクロロメタン（３５ｍＬ）中の１−アミノ−１−シクロペンタンメタノール（１．０ｇ、８．６８ｍｍｏｌ）の溶液にピリジン（２．４ｇ、３０．４ｍｍｏｌ）を加えた。次いで、トリフルオロ酢酸無水物（４．６ｇ、２１．７ｍｍｏｌ）を反応溶液にゆっくりと加えた。反応物はさらに０℃で１５分間攪拌し、次いで、室温で１６時間攪拌した。反応物は、１Ｎ ＨＣｌ（水溶液）；飽和ＮａＨＣＯ_３（水溶液）；ブラインで連続的に洗浄した。有機相はＮａＳＯ_４で乾燥させ、そして真空中で濃縮して、１．０７ｇ（６０％収率）の標題化合物を明茶色液体として得た。標題化合物は、さらなる精製なしで次の反応（工程Ｂ）で直接的に使用した。

Step A: To a solution of 1-amino-1-cyclopentanemethanol (1.0 g, 8.68 mmol) in dichloromethane (35 mL) was added pyridine (2.4 g, 30.4 mmol). Then trifluoroacetic anhydride (4.6 g, 21.7 mmol) was slowly added to the reaction solution. The reaction was further stirred at 0 ° C. for 15 minutes and then at room temperature for 16 hours. The reaction was washed successively with 1N HCl (aq); saturated NaHCO ₃ (aq); brine. The organic phase was dried over NaSO ₄ and concentrated in vacuo to give 1.07 g (60% yield) of the title compound as a light brown liquid. The title compound was used directly in the next reaction (Step B) without further purification.

Step B: A solution of (trifluoromethyl) acetamide from Step A (0.64 g, 3.06 mmol) in Et ₂ O (10 mL) at 0 ° C. under N ₂ atmosphere, Et ₂ O (30 mL). Was added to a flask charged with lithium aluminum hydride (0.35 g, 9.1 mmol). The reaction was stirred at 0 ° C. for 30 minutes under N ₂ atmosphere, then at room temperature for 19 hours. The reaction was cooled to room temperature and stirred for 3 days. Then, the reaction was cooled to 0 ° C., _H 2 O of 0.35 mL; was quenched by the sequential addition of _{1.05mL H 2 O; 15% NaOH} ( aq) solution of 0.35 mL. The reaction was stirred at room temperature for 20 minutes and then filtered through a pad of celite. The filter cake was washed with Et ₂ O and concentrated in vacuo to give 0.39 g (65% yield) of the title compound as a white solid. This amine was used without further purification.

( Example 104 )

工程Ａ：ジクロロメタン（１００ｍＬ）中の２−アミノ−２−メチル−１−プロパノール（１．０ｇ、１１．２ｍｍｏｌ）の溶液に、０℃で、ピリジン（３．１ｇ、３９．６ｍｍｏｌ）を加えた。次いで、トリフルオロ酢酸無水物（５．９ｇ、２８．１ｍｍｏｌ）を反応溶液にゆっくりと加えた。この反応物は、さらに０℃で１５分間攪拌し、次いで、室温で１６時間攪拌した。反応物は、１Ｎ ＨＣｌ（水溶液）；飽和ＮａＨＣＯ_３（水溶液）；ブラインで連続的に洗浄した。有機相をＮａＳＯ４で乾燥させ、真空中で濃縮して、０．７９ｇ（３８％収率）の標題化合物を白色固形物として得た。

Step A: To a solution of 2-amino-2-methyl-1-propanol (1.0 g, 11.2 mmol) in dichloromethane (100 mL) at 0 ° C. was added pyridine (3.1 g, 39.6 mmol). . Then trifluoroacetic anhydride (5.9 g, 28.1 mmol) was slowly added to the reaction solution. The reaction was further stirred at 0 ° C. for 15 minutes and then at room temperature for 16 hours. The reaction was washed successively with 1N HCl (aq); saturated NaHCO ₃ (aq); brine. The organic phase was dried over NaSO4 and concentrated in vacuo to give 0.79 g (38% yield) of the title compound as a white solid.

Step B: A solution of (trifluoromethyl) acetamide (0.79 g, 4.29 mmol) from Step A in Et ₂ O (43 mL) at 0 ° C. under N ₂ atmosphere, Et ₂ O (13 mL). In a flask charged with lithium aluminum hydride (0.49 g, 12.91 mmol). The reaction was stirred at 0 ° C. for 30 minutes under N ₂ atmosphere and then refluxed for 4 hours. The reaction was then cooled to room temperature and stirred for 3 days. Then, the reaction was cooled to 0 ° C., _H 2 O of 0.49 mL; was quenched by the sequential addition of _{1.47mL H 2 O; 15% NaOH} ( aq) solution of 0.49 mL. The reaction was stirred at room temperature for 20 minutes and then filtered through a pad of celite. The filter cake was washed with Et ₂ O and concentrated in vacuo to give 0.67 g (92% yield) of the title compound as a white solid. This amine was used without further purification.

( Example 105 )

工程Ａ：ジクロロメタン（５０ｍＬ）中の２−アミノ−２−メチル−１−プロパノール（１．０ｇ、１１．２ｍｍｏｌ）の溶液に、０℃で、ピリジン（２．７ｇ、３３．７ｍｍｏｌ）を加えた。次いで、ジフルオロ酢酸無水物（３．９ｇ、２２．４ｍｍｏｌ）をゆっくりと反応溶液に加えた。この反応物は、さらに０℃で１５分間攪拌し、次いで、室温で２時間攪拌した。この反応物は、ジクロロメタン（５０ｍＬ）およびＨ_２Ｏ（２０ｍＬ）で希釈した。この反応物は、１Ｎ ＨＣｌ（水溶液）；飽和ＮａＨＣＯ_３（水溶液）；ブラインで連続的に洗浄した。有機相をＮａＳＯ_４で乾燥させ、真空中で濃縮して、２．０４ｇ（７４％収率）の標題化合物を無色液体として得た。

Step A: To a solution of 2-amino-2-methyl-1-propanol (1.0 g, 11.2 mmol) in dichloromethane (50 mL) at 0 ° C. was added pyridine (2.7 g, 33.7 mmol). . Difluoroacetic anhydride (3.9 g, 22.4 mmol) was then slowly added to the reaction solution. The reaction was further stirred at 0 ° C. for 15 minutes and then at room temperature for 2 hours. The reaction was diluted with dichloromethane (50 mL) and H ₂ O (20 mL). The reaction was washed successively with 1N HCl (aq); saturated NaHCO ₃ (aq); brine. The organic phase was dried over NaSO ₄ and concentrated in vacuo to give 2.04 g (74% yield) of the title compound as a colorless liquid.

Step B: A solution of (difluoromethyl) acetamide (2.04 g, 8.31 mmol) from Step A in Et ₂ O (17 mL) in Et ₂ O (50 mL) at 0 ° C. under N ₂ atmosphere. Of lithium aluminum hydride (0.95 g, 24.92 mmol) was added to the flask. The reaction was stirred at room temperature for 2 hours under N ₂ atmosphere. The reaction was quenched by continuous addition of 0.95 mL H ₂ O; 0.95 mL 15% NaOH (water) solution; 2.85 mL H ₂ O. The reaction was stirred at room temperature for 15 minutes and then filtered through a pad of celite. The filter cake was washed with Et ₂ O and concentrated in vacuo to give 1.23 g (97% yield) of the title compound as white needles. This amine was used without further purification.

( Example 106 )

工程Ａ：Ｄｅｓｓ−Ｍａｒｔｉｎペルヨウ化物（１．３ｇ、３．１ｍｍｏｌ）を、０．０６ｍＬの水を含む３０ｍＬのＴＨＦ中のイソチアゾールアルコール（４５０ｍｇ；１ｍｍｏｌ）の溶液に加え、この反応混合物を室温で４５分間攪拌した。この反応物をエーテルで希釈し、濾過し、そしてより多くのエーテルで洗浄した。濾液を飽和ＮａＨＣＯ_３溶液、ブラインで洗浄し、乾燥させた。真空中の濃縮はイソチアゾールアルデヒド（４１８ｍｇ；９３％）を与えた。

Step A: Dess-Martin periodide (1.3 g, 3.1 mmol) is added to a solution of isothiazole alcohol (450 mg; 1 mmol) in 30 mL THF containing 0.06 mL water, and the reaction mixture is added at room temperature. Stir for 45 minutes. The reaction was diluted with ether, filtered and washed with more ether. The filtrate was washed with saturated NaHCO ₃ solution, brine and dried. Concentration in vacuo gave isothiazole aldehyde (418 mg; 93%).

工程Ｂ：−１０℃に冷却した３．６ｍＬのＤＭＳＯおよび３．６ｍＬのＴＨＦの混合物中の水素化ナトリウム（鉱油中６０％；１６９ｍｇ；４．２ｍｍｏｌ）の溶液に、３．６ｍＬのＤＭＳＯ中のトリメチルスルホニウムヨーダイド（８６３ｍｇ；４．２ｍｍｏｌ）の溶液を滴下して加えた。続いて、５．６ｍＬの無水ＴＨＦ中のアルデヒド（３６３ｍｇ；０．８４ｍｍｏｌ）の溶液の添加を行い、これは一度に加えた。室温で１時間の攪拌後、この反応混合物は氷水でクエンチした。有機生成物は酢酸エチルで抽出した。合わせた水層を酢酸エチルで逆抽出した。すべての有機抽出物をプールし、水、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、そして濃縮して、粗生成物を得た。ヘキサン中２５％ ＥｔＯＡｃを使用するフラッシュシリカゲルからの主要スポットの溶出は、所望のイソチアゾールエポキシド（３１６ｍｇ；８５％）を与えた。

Step B: To a solution of sodium hydride (60% in mineral oil; 169 mg; 4.2 mmol) in a mixture of 3.6 mL DMSO and 3.6 mL THF cooled to −10 ° C. in 3.6 mL DMSO A solution of trimethylsulfonium iodide (863 mg; 4.2 mmol) was added dropwise. Subsequently, a solution of aldehyde (363 mg; 0.84 mmol) in 5.6 mL of anhydrous THF was added, which was added in one portion. After stirring for 1 hour at room temperature, the reaction mixture was quenched with ice water. The organic product was extracted with ethyl acetate. The combined aqueous layer was back extracted with ethyl acetate. All organic extracts were pooled, washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give the crude product. Elution of the main spot from flash silica gel using 25% EtOAc in hexanes gave the desired isothiazole epoxide (316 mg; 85%).

工程Ｃ：メタノール中メトキシドナトリウムの溶液（２５重量％；４．５ｍｍｏｌ；１ｍＬ）を、ＤＭＦ−メタノールの１：１混合物（４ｍＬ）中のエポキシド（２０１ｍｇ；０．４５ｍｍｏｌ）の溶液に加えた。得られた溶液を６０℃に３．５時間加熱し、次いで、室温まで冷却し、そして水でクエンチした。有機生成物をＥｔＯＡｃで抽出し、有機抽出物を水およびブラインで洗浄し、そしてＮａ_２ＳＯ_４で乾燥させた。濃縮は粗生成物を与えた。ＣＨ_２Ｃｌ_２およびＥｔＯＡｃの１：１混合物を使用するフラッシュシリカゲルクロマトグラフィーは、所望のメトキシメチルカルビノールを無色油状物（１８０ｍｇ；８４％）として与えた。

Step C: A solution of sodium methoxide in methanol (25 wt%; 4.5 mmol; 1 mL) was added to a solution of epoxide (201 mg; 0.45 mmol) in a 1: 1 mixture of DMF-methanol (4 mL). The resulting solution was heated to 60 ° C. for 3.5 hours, then cooled to room temperature and quenched with water. The organic product was extracted with EtOAc, the organic extract was washed with water and brine and dried over Na ₂ SO ₄ . Concentration gave the crude product. Flash silica gel chromatography using a 1: 1 mixture of CH ₂ Cl ₂ and EtOAc gave the desired methoxymethyl carbinol as a colorless oil (180 mg; 84%).

工程Ｄ〜Ｆ：このシークエンスの工程は、実施例７６のために記載されたように、３工程シークエンスについて全体で６４％収率で実行した。
ＨＰＬＣ−ＭＳ ｔ_Ｒ＝２．８５。Ｃ_２１Ｈ_２７ＦＮ_６ＯＳの質量計算値４３０．２、実測値（Ｍ−Ｈ）^＋（ＬＣＭＳ）４３１．２（ｍ／ｚ）（ＵＶ_{２５４ｎｍ}）。

Steps D to F: This sequence step was performed in 64% overall yield for the three step sequence as described for Example 76.
_HPLC-MS t R = 2.85. Calculated mass of C ₂₁ H ₂₇ FN ₆ OS 430.2, found (M−H) ⁺ (LCMS) 431.2 (m / z) (UV _{254 nm} ).

Assay:
Aurora Enzyme Assay An in vitro assay was developed utilizing a recombinant Aurora A or Aurora B as the enzyme source and a PKA based peptide as the substrate.

Aurora A assay The Aurora A kinase assay was performed in low protein binding 384 well plates (Corning Inc). All reagents were thawed on ice. The compound was diluted to the desired concentration in 100% DMSO. Each reaction consists of 8 nM enzyme (Aurora A, Upstate catalog number 14-511), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-GRTGRNRNISOCOOH), 25 μM ATP (Roche), 1 mM DTT (Pierce), and 10 mM buffer solution. 10 mM MgCl2, 0.01% Tween 20). For each reaction, 14 μL containing TAMRA-PKAtide, ATP, DTT, and kinase buffer was combined with 1 μL of diluted compound. The kinase reaction was initiated by the addition of 5 μL of diluted enzyme. The reaction was allowed to proceed for 2 hours at room temperature. The reaction was stopped by adding 60 μL IMAP beads (1: 400 beads, progressive (94.7% buffer A: 5.3% buffer B) 1 × buffer, 24 mM NaCl). After an additional 2 hours, fluorescence polarization was measured using Analyst AD (Molecular devices).

Aurora B Assay Aurora B kinase assay was performed in low protein binding 384 well plates (Corning Inc). All reagents were thawed on ice. The compound was diluted to the desired concentration in 100% DMSO. Each reaction consists of 26 nM enzyme (Aurora B, Invitrogen catalog number pv3970), 100 nM Tamra-PKAtide (Molecular Devices, 5TAMRA-GRTGRNRNISOCOOH), 50 μM ATP (Roche), 1 mM DTT (Pierce), and 10 mM DTT (Pierce). MgCl2, 0.01% Tween 20). For each reaction, 14 μL containing TAMRA-PKAtide, ATP, DTT, and kinase buffer was combined with 1 μL of diluted compound. The kinase reaction was initiated by the addition of 5 μL of diluted enzyme. The reaction was allowed to proceed for 2 hours at room temperature. The reaction was stopped by adding 60 μL IMAP beads (1: 400 beads, progressive (94.7% buffer A: 5.3% buffer B) 1 × buffer, 24 mM NaCl). After an additional 2 hours, fluorescence polarization was measured using Analyst AD (Molecular devices).

IC ₅₀ determined dose-response curves were plotted from inhibition data generated in duplicate, each from 8 point serial dilutions of the inhibitor compound. Compound concentrations were plotted against kinase activity and calculated by the degree of fluorescence polarization. In order to generate IC ₅₀ values, the dose-response curves were then fitted to a standard sigmoidal curve and IC ₅₀ values were derived by non-linear regression analysis.

The compounds of the present invention exhibit Aurora A IC ₅₀ values from about 4 nM to about 3000 nM, Aurora B IC ₅₀ values from about 13 nM to about 3000 nM, and p-HH3 IC ₅₀ values from about 1 nM to about 10,000 nM.

  Although the present invention has been described with the specific embodiments set forth above, many alternatives, modifications, and many variations will be apparent to those skilled in the art. All such alternatives, modifications and variations are intended to be included within the spirit and scope of the present invention.

Claims (45)

Formula I:

Or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
R is H, CN, —NR ⁵ R ⁶ , cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C (O) NR ⁵ R ⁶ , —N (R ⁵ ) C (O) R ⁶ , heterocyclyl, (CH ₂ ) _1-3 NR ⁵ R ⁶ substituted heteroaryl, unsubstituted alkyl, or substituted with one or more moieties that may be the same or different, each moiety being —OR ⁵ , heterocyclyl, —N (R ⁵ ) C (O) N (R ⁵ R ⁶ ), —N (R ⁵ ) —C (O) OR ⁶ , — (CH ₂ ) _1-3 —N (R ⁵ R ⁶ ) and —NR ⁵ R ^6. Alkyl independently selected from the group;
R ¹ is H, halo, aryl, or heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or can be substituted with one or more moieties that can be the same or different; each part is halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, _{^{heterocyclyl, -CH 2 OR 5, -C (}} O) NR 5 R 6, -C (O) OH, -C (O) NH ₂ , —NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ together with N of the —NR ⁵ R ⁶ form a heterocyclyl ring), —S (O) R ⁵ , —S (O ₂ ^{) R 5, -CN, -CHO,} -SR 5, -C (O) oR 5, -C (O) R 5, and are independently selected from the group consisting of -OR ^5;
R ² is H, halo, aryl, arylalkyl, or heteroaryl, wherein each of said aryl, arylalkyl, and heteroaryl is unsubstituted or can be the same or different and optionally be independently substituted with moieties, each moiety halo, amido, alkyl, alkenyl, alkynyl, cycloalkyl, _{aryl, -C (O) OH, -C} (O) NH 2, -NR 5 R ⁶ (wherein R ⁵ and R ⁶ together with N of —NR ⁵ R ⁶ form a heterocyclyl ring), —CN, arylalkyl, —CH ₂ OR ⁵ , —S (O) R ⁵ , Independently selected from the group consisting of —S (O ₂ ) R ⁵ , —CN, —CHO, —SR ⁵ , —C (O) OR ⁵ , —C (O) R ⁵ , heteroaryl, and heterocyclyl; Selected;
R ³ is heterocyclyl- (CR ⁷ R ⁸ ) _n —X, heterocyclenyl- (CR ⁷ R ⁸ ) _n —X, heteroaryl- (CR ⁷ R ⁸ ) _n —X, or aryl- (CR ⁷ R ⁸ ) _n is -X, wherein said ^{R 3} heterocyclyl -, heterocyclenyl -, heteroaryl - or aryl - each part is unsubstituted or -CONR ⁵ R ^6, -OR ^5, and alkyl One or more parts independently selected from the group consisting of:
n is 1-6,
X is selected from the group consisting of —NR ⁵ R ⁶ , —OR ⁵ , —SO—R ⁵ , —SR ⁵ , SO ₂ R ⁵ , heteroaryl, heterocyclyl, and aryl, wherein said heteroaryl or aryl is , Unsubstituted or substituted with one or more moieties independently selected from the group consisting of —O-alkyl, alkyl, halo, or NR ⁵ R ⁶ ;
R ⁷ and R ⁸ are each independently hydrogen, alkyl, heterocyclyl, aryl, heteroaryl, or cycloalkyl;
R ⁵ is hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl , Alkyl N (alkyl) ₂ , alkyl NH (alkyl), alkyl N (alkenyl) ₂ , -alkyl N (alkoxyl) ₂ , -alkyl-SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl Wherein said alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloal Kill, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN (alkyl) ₂ , alkylNH (alkyl), alkylN (alkenyl) ₂ , -alkylN (alkoxyl) ₂ , -alkyl Each of —SH, hydroxyalkyl, trihaloalkyl, dihaloalkyl, monohaloalkyl is unsubstituted or alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, Heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -al Le SH, alkoxyl, -S- alkyl, can be substituted with one or more moieties independently selected from the group consisting of hydroxyalkyl, and aminoalkyl;
R ⁶ is hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl , -Alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl, aminoalkyl, -alkyl-OC (O) alkyl, -alkylOC (O) cycloalkyl, -alkylOC (O) aryl , - alkyl OC (O) aralkyl, - alkyl OC (O) NR ⁵ aryl, - alkyl OC (O) NR ⁵ alkyl, - alkyl OC (O) NR ⁵ heterocyclyl, - alkyl OC (O) NR ⁵ Heteroaryl, - alkyl OC (O) NR ⁵ cycloalkyl, - alkyl OC (O) heterocyclyl, alkyl C (O) OH, alkyl C (O) O-alkyl, - alkyl C (O) O cycloalkyl, - alkyl C ( O) O aryl, -alkyl C (O) O aralkyl, -alkyl C (O) ONR ⁵ aryl, -alkyl C (O) ONR ⁵ alkyl, -alkyl C (O) ONR ⁵ heterocyclyl, -alkyl C (O) Selected from the group consisting of ONR ⁵ heteroaryl, -alkyl C (O) ONR ⁵ cycloalkyl, -alkyl C (O) O heterocyclyl, alkyl C (O) OH, and alkyl C (O) O alkyl, wherein Aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl , Heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, -alkyl-OC (O) alkyl, -alkylOC (O) cycloalkyl, -alkylOC (O) aryl, -alkyl OC (O) aralkyl, -alkyl OC (O) NR ⁵ aryl, -alkyl OC (O) NR ⁵ alkyl, -alkyl OC (O) NR ⁵ heterocyclyl, -alkyl OC (O) NR ⁵ heteroaryl, -alkyl OC (O) NR ⁵ cycloalkyl, -alkyl OC (O) heterocyclyl, alkyl C (O) OH, alkyl C (O) O alkyl, -alkyl C (O) O cycloalkyl, -alkyl C (O) O aryl, -Alkyl C (O) O aralkyl, -alkyl C (O) NR ⁵ aryl, - alkyl C (O) ONR ⁵ alkyl, - alkyl C (O) ONR ⁵ heterocyclyl, - alkyl C (O) ONR ⁵ heteroaryl, - alkyl C (O) ONR ⁵ cycloalkyl, - alkyl C ( Each of O) O heterocyclyl, alkyl C (O) OH, and alkyl C (O) O alkyl is unsubstituted or alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cyclo Alkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl Aminoalkyl, amino, aminodialkyl, aminocycloalkyl, halo, trihaloalkyl, and can be substituted with one or more moieties independently selected from the group consisting of dihaloalkyl, and monohaloalkyl;
Furthermore, in any —NR ⁵ R ⁶ in Formula I, R ⁵ and R ⁶ can be optionally combined together with N in the —NR ⁵ R ⁶ to form a ring or a bridged ring, wherein Each of said rings or bridged rings may be unsubstituted or the same or different, hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -CO 2 _- alkyl, -CO 2 _- alkenyl, arylalkyl, Shikure alkenyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, Shikureniru, cycloalkyl, spiro-heterocyclyl, Spiroheterocyclenyl, spiroheteroaryl, One or more moieties independently selected from the group consisting of pyrocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-alkyl, heterocyclyl, heterocyclenyl, halo, trihaloalkyl, dihaloalkyl, CN, and monohaloalkyl Is replaceable,
A compound, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. The compound of claim 1, wherein R ² is unsubstituted heteroaryl or heteroaryl substituted with alkyl. The compound of claim 1, wherein R ² is heteroaryl substituted with alkyl. The compound of claim 1, wherein R ² is pyrazolyl. The compound of claim 1, wherein R ² is pyrazolyl substituted with alkyl. ^2. A compound according to claim 1 wherein R2 is 1-methyl-pyrazol-4-yl.   The compound of claim 1, wherein R is H.   2. A compound according to claim 1 wherein R is CN. The compound of claim 1, wherein R is —C (O) NR ⁵ R ⁶ . The compound of claim 1, wherein R is —C (O) NH ₂ .   2. A compound according to claim 1 wherein R is heterocyclenyl.   2. A compound according to claim 1 wherein R is tetrahydropyridinyl.   The compound of claim 1, wherein R is 1,2,3,6-tetrahydropyridinyl. Is alkyl R is substituted with one or more moieties to obtain also the same or different, each moiety being independently selected from the group consisting of -OR ¹ and -NR ⁵ R ^6, The compound of claim 1 . The compound of claim 1, wherein R is alkyl substituted with one or more —NR ⁵ R ⁶ . _2. The compound of claim 1, wherein R is alkyl substituted with -NH2.   The compound of claim 1, wherein R is alkyl substituted with —NH (methyl). The compound of claim 1, wherein R ³ is heteroaryl substituted with heterocyclylmethyl. R ³ is heteroaryl-CH ₂ —X, wherein X is —OR ⁵ , —SOR ⁵ , —NR ⁵ R ⁶ , or —SR ⁵ ; R ⁵ is hydrogen, -alkylN (alkyl) ₂ , heterocyclylalkyl, or heterocyclenylalkyl; R ⁶ or R ⁵ and R ⁶ can be optionally joined together with N of the above-mentioned —NR ⁵ R ⁶ to form a ring or a bridged ring, wherein Wherein the ring or bridged ring may be unsubstituted or the same or different, hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl Substitutable with one or more moieties independently selected from the group consisting of, heterospiroaryl, and —CO ₂ alkyl The compound of claim 1, wherein R ³ is heteroaryl-CH ₂ —X or heteroaryl-CHmethyl-X, wherein X is —NR ⁵ R ⁶ , R ⁵ is -alkylN (alkyl) ₂ , alkyl, alkoxyalkyl, Hydroxyalkyl, arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or -alkylSH, wherein the arylalkyl, heterocyclenylalkyl, cycloalkyl, cycloalkylalkyl, or hetero Each of the arylalkyl is unsubstituted or can be substituted with hydroxyalkyl, alkoxyalkyl, alkyl, or hydroxyl; R ⁶ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or -alkylN (alkyl Le) _2; or R ⁵ and R ⁶ are coupled together to the N and any of said -NR ⁵ R ^6, it is possible to form a ring or bridged ring, wherein said ring or bridged ring, Hydroxyl, alkyl, alkoxyl, alkoxylalkyl, hydroxyalkyl, arylalkyl, aryl, heterospirocyclyl, heterospirocyclenyl, heterospiroaryl, and —CO ₂ , which can be unsubstituted or the same or different 2. The compound of claim 1, wherein the compound is substitutable with one or more moieties independently selected from the group consisting of alkyl. R ³ is heteroaryl-CH ₂ —X, wherein the heteroaryl of said heteroaryl-CH ₂ —X is substituted with alkyl or —CONR ⁵ R ⁶ , wherein X is —NR ⁵ R ⁶ , R The compound according to claim 1, wherein ⁵ is alkyl, R ⁶ is alkyl, or R ⁵ and R ⁶ are optionally bonded together with N of the —NR ⁵ R ⁶ to form a ring. 2. R ³ is aryl-CH ₂ —X, wherein aryl of said aryl-CH ₂ —X is unsubstituted or can be substituted with alkyl, wherein X is heterocyclyl. Compound described in 1. R ³ is

2. The compound of claim 1, which is isothiazole, thiophene, or pyrimidine substituted with. R ³ is

Where X is selected from the group consisting of —NR ⁵ R ⁶ , —OR ⁵ , —SO—R ⁵ , and —SR ⁵ ;
R ⁵ is hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, heterocyclenyl , Alkyl N (alkyl) ₂ , alkyl NH (alkyl), alkyl N (alkenyl) ₂ , -alkyl N (alkoxyl) ₂ , -alkyl-SH, and hydroxyalkyl, wherein the aryl, Heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cyclenyl, heterocyclylalkoxyl, -S-alkylheterocyclyl, heterocyclyl, and heterocyclenyl Each of which is unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkoxyalkyl, and hydroxyalkyl;
R ⁶ is hydrogen, alkyl, alkenyl, aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl , -Alkyl-S-alkyl, -alkyl SH, alkoxyl, -S-alkyl, hydroxyalkyl, and aminoalkyl, wherein the aryl, cyclenyl, cycloalkyl, arylalkyl, cyclenylalkyl, Cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, and heterocycloalkylalkyl Each of which is unsubstituted or can be substituted with one or more alkyls;
Further, in any —NR ⁵ R ⁶ in Formula I, R ⁵ and R ⁶ are optionally joined together with N in the —NR ⁵ R ⁶ to form a ring or bridged ring, wherein Each of said rings or bridged rings may be unsubstituted or the same or different, hydroxyl, -SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, -S-alkyl, -CO ₂ - alkyl, -CO 2 _- alkenyl, arylalkyl, Shikure alkenyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, Shikureniru, cycloalkyl, spiro-heterocyclyl, spiro Cyclenyl, spiroheteroaryl, spirosi Lil, Supiroshikureniru, spiro aryl, alkoxyalkyl, - which can be substituted alkyl -S- alkyl, heterocyclyl, and independently from the group consisting of heterocyclenyl with one or more moieties selected by,
The compound of claim 1. The following chemical formula:

Or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.   2. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof in purified form.   2. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof in isolated form.   A therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof in combination with at least one pharmaceutically acceptable carrier. A pharmaceutical composition comprising.   30. The pharmaceutical composition of claim 28, further comprising one or more anticancer agents different from the compound of claim 2.   The one or more anticancer agents are a cytostatic, cisplatin, doxorubicin, liposomal doxorubicin (eg, Caelix (registered trademark), myoset (registered trademark), doxil (registered trademark)), taxotere, taxol, etoposide, irinotecan , Camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methoxytrexate, temozolomide, cyclophosphamide, SCH 66336, R115777 (registered trademark), L778, 123 (registered trademark), BMS 214662 (registered) (Trademark), Iressa (registered trademark), Tarceva (registered trademark), an antibody against EGFR, an antibody against IGFR (for example, US Patent Application Publication No. 2005/013 published on June 23, 2005) Including those published in US Pat. No. 6063), KSP inhibitors (eg, those published in WO 2006/098962 and WO 2006/098961, etc .; ispinesive, SB-743921 from Cytokinetics, etc.) Centrosome related protein E (“CENP-E”) inhibitors (eg GSK-923295), Gleevec®, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, Melphalan, chlorambucil, pipbloman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucobilin, ELOXATIN ™, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitramycin, deoxyco Formycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drmostanolone propionate, test lactone, megestrol acetate, methylprednisolone, methyltestosterone, Prednisolone, triamcinolone, chlorotrianicene, hydroxyproge Sterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, naberbene, anastrazole, letrazole , Capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexer, bortezomib ("Velcade"), zevaline, trisenox, xeloda, vinorelbine, porfimer, erbitux, liposomal, thiotepa, altretamine, melphalan, trastuzumab, Relozole, fulvestrant, exemestane, fulvestrant, ifosfamide, ritsu 30. The method of claim 29, selected from the group consisting of Shimab, C225 (R), Satriplatin, Milotag, Avastin, Rituxan, Panitubimab, Stent, Sorafinib, Spliceceb (Dastinib), Nilotinib, Tycarb (Lapatinib), and Campus. Pharmaceutical composition.   A method for inhibiting one or more Aurora kinases, wherein a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof is administered to a patient. Administering to the method.   A method of treating one or more diseases by inhibiting Aurora kinase, comprising a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester thereof. Or a method comprising administering a prodrug to a patient. A method of treating one or more diseases by inhibiting Aurora kinase, wherein a mammal in need of such treatment is provided,
A compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof in an amount of a first compound; and a different anticancer agent than the compound of claim 1. Administering at least one aliquot of a second compound,
Wherein the amount of the first compound and the second compound produces a therapeutic effect.   34. The method of any one of claims 31, 32, or 33, wherein the Aurora kinase is Aurora A.   34. The method of any one of claims 31, 32, or 33, wherein the Aurora kinase is Aurora B. The group consisting of:
Bladder tumor, breast tumor (including BRCA mutant breast cancer), colorectal tumor, colon tumor, kidney tumor, liver tumor, lung tumor, small cell lung cancer, non-small cell lung cancer, head and neck tumor, esophageal tumor, bladder tumor, gallbladder tumor Skin tumors, including ovarian tumors, pancreatic tumors, gastric tumors, cervical tumors, thyroid tumors, prostate tumors, and squamous cell carcinomas;
Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkitt lymphoma;
Chronic lymphocytic leukemia ("CLL");
Acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia;
Fibrosarcoma, rhabdomyosarcoma;
Head and neck tumor, mantle cell lymphoma, myeloma;
Astrocytoma, neuroblastoma, glioma, glioblastoma, malignant glioma, astrocytoma, hepatocellular carcinoma, gastrointestinal stromal tumor (“GIST”), and schwannoma;
34. Either of the claims 32 or 33, selected from melanoma, multiple myeloma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratophyte cell carcinoma, follicular thyroid carcinoma and Kaposi sarcoma The method described in 1.   34. The method of any one of claims 31, 32, or 33, further comprising radiation therapy.   The anticancer agent is a cell growth inhibitor, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methoxytrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies against EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobrommann, tri Ethylene melamine, triethylene thiophosphoramine, busulfan, carmustine, lomustine, strike Leptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucobilin, ELOXATIN ™, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin , Epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, test lactone, acetic acid Megestrol, methylprednisolone, methyltestosterone, prednisolo , Triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotan, mitoxantrone, levamisole , Navelben, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexer, velcade, zevalin, trisenox, xeloda, vinorelbine, porfimer, erbitux, liposome, thiotepa, altretamine, melphalan , Trastuzumab, relozole, fulvestrant, exemestane, fu Rubestrant, Ifosfamide, Rituximab, C225, Campus, Clofarabine, Cladribine, Aphidicolone, Rituxan, Sunitinib, Dasatinib, Tezacitabine, Sml1, Fludarabine, Pentostatin, Triapine, Zidox, Trimidox, Amidox, 3-AP, and MDL-101 34. The method of claim 33, wherein the method is selected from the group consisting of:   A method of inhibiting one or more kinases, wherein said kinase is selected from the group consisting of cyclin dependent kinases, checkpoint kinases, tyrosine kinases, and Pim-1 kinases, said method comprising a therapeutically effective amount of claim A method comprising administering at least one compound according to Item 1 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof to a patient in need of such inhibition.   A method of treating one or more diseases by inhibiting one or more kinases, wherein the kinase is selected from the group consisting of cyclin dependent kinases, checkpoint kinases, tyrosine kinases, and Pim-1 kinases. The method comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. Administering a step of administering.   The cyclin-dependent kinase is selected from CDK1 or CDK2, the checkpoint kinase is selected from CHK-1 or CHK-2, and the tyrosine kinase is VEGF-R2, EGFR, HER2, SRC, JAK, and TEK 41. The method of claim 39 or claim 40, wherein the method is more selected.   A method of treating cancer comprising administering a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof. Method.   A method of inhibiting one or more kinases, wherein said kinase is selected from the group consisting of cyclin dependent kinases, checkpoint kinases, tyrosine kinases, and Pim-1 kinases, said method comprising a therapeutically effective amount of claim 26. A method comprising administering at least one compound according to Item 25 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof to a patient in need of such inhibition. A method of inhibiting one or more diseases by inhibiting Aurora kinase, wherein a mammal in need of such treatment is provided,
26. An amount of a first compound that is a compound of claim 25, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof; and a different anticancer agent than the compound of claim 25. Administering at least one aliquot of a second compound,
Wherein the amount of the first compound and the second compound produces a therapeutic effect.   26. A therapeutically effective amount of at least one compound according to claim 25, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier. A pharmaceutical composition comprising: