JP2017507983A - Novel 3-indole substituted derivatives, pharmaceutical compositions, and methods of use - Google Patents

Abstract

The present invention relates to a compound of formula (I), or a pharmaceutically acceptable enantiomer, salt, or solvate thereof. The present invention further relates to the use of compounds of formula I as TDO2 inhibitors. The invention also relates to the use of compounds of formula I for the treatment and / or prevention of HIV, depression and obesity. The invention also relates to a process for the preparation of the compound of formula (I). [Chemical 1]

Description

  The present invention relates to novel 3- (indol-3-yl) -pyridine derivatives, including pharmaceutically acceptable enantiomers, salts, and solvates thereof. The compounds of the present invention are inhibitors of TDO2 (tryptophan 2,3-dioxygenase), and are particularly useful as therapeutic compounds in the treatment and / or prevention of cancer.

  Two decades after the discovery of the importance of tryptophan catabolism for the maintenance of placental immune privilege (Munn, DH et al., Science, 1998, 281, 1191 to 1193), the accumulated evidence from the organism The scientific relevance has expanded beyond the scope of immune tolerance to non-self. According to a generally accepted concept, the essential amino acid tryptophan is catabolized in the local microenvironment of tumors, immune privileged sites, or inflammatory sites (Meller AL and Munn DH, Nat Rev Immunol, 2008, 8, 74). ~ 80). In these tissues, cancer cells, immune cells, or specialized epithelial cells (eg, placental syncytiotrophoblasts) create an immunosuppressive environment in the tumor, where tryptophan depletion and immunosuppressive properties are created. Induction of T cell anergy and apoptosis through the accumulation of tryptophan catabolism blocks the anti-tumor immune response in tumors and tumor draining lymph nodes (Munn DH et al., J Exp Med., 1999, 189, 1363-1372). Fallarino F et al., Cell Death Differ., 2002, 9, 1069-1077).

  Recently, tryptophan 2,3-dioxygenase (TDO2), a key enzyme of tryptophan catabolism, which is thought to be responsible for the regulation of systemic tryptophan levels in the liver, is, for example, bladder cancer, liver cancer, melanoma , Mesothelioma, neuroblastoma, sarcoma, breast cancer, leukemia, renal cell carcinoma, colorectal cancer, head and neck cancer, lung cancer, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic cancer, etc. It has been discovered that it is constitutively expressed in a variety of cancers (Pilotte L et al., Proc Natl Acad Sci USA, 2012, 109 (7), 2497-502). When TDO2 is expressed in tumor cells, local degradation of tryptophan prevents tumor monitoring by the immune system, thus preventing tumor rejection (Opitz CA et al., Nature, 2011, 478 (7368), 197 ~ 203). Initial evidence for this came from the fact that a small molecule that suppressed tumor growth in the P815 mastocytoma tumor model by a prophylactic vaccination approach inhibited TDO2 (Pilotte L et al., Proc Natl Acad Sci USA). 2012, 109 (7), 2497-502). Tumors expressing P815mTDO2 were not rejected compared to P815 tumors transfected with an empty vector, clearly showing that TDO2-expressing tumors have growth advantages. Inhibition with TDO2 inhibitors strongly reduced tumor growth in tumors implanted with P815mTDO2. Anti-tumor activity with TDO2 inhibitors was equally observed in tumors implanted with TDO2 negative, P815 controls, thus providing evidence that it was an effect of TDO2 expressed in the animal's immune system. For the first time, such experiments provided clear evidence for the role of TDO2 in regulating tumor growth through expression in cancer cells as well as in the immune compartment.

  Consistent with its expression profile in the liver, TDO2 has been found mostly in hepatocellular carcinoma (HCC) (Pilotte L et al., Proc Natl Acad Sci USA, 2012, 109 (7), 2497- 502). By inhibiting tryptophan catabolism, restoring tryptophan concentration and reducing downstream metabolite production may prove beneficial in the context of liver disease that is progressing to the stage of liver cancer There is. More specifically, (i) some reports show evidence that increased tryptophan availability by supplementation allows the direct use of tryptophan for protein synthesis, for example beneficial for cirrhotic liver. (Ohta et al., Amino Acids, 1996, 10 (4), 369-78), (ii) There is a correlation between an increase in downstream serum tryptophan metabolites such as quinolinic acid and liver dysfunction in cirrhotic patients ( Lahdou et al., Hum Immunol, 2013, 74 (1), 60-6), (iii) Increased secretion of another tryptophan metabolite, indole-3-lactic acid, was associated with alcohol-induced liver disease in mice. (Manna et al., J Proteome Res, 2011, 10 (9), 4120-33). In terms of liver cancer itself, very high RNA expression is a suitable indicator for therapeutic evaluation of TDO2 inhibitors (Pilotte L et al., Proc Natl Acad Sci USA, 2012, 109 (7), 2497-502). Thus, the above evidence reveals the rationale for modulating TDO2 activity in the control of liver tumor progression.

  In addition to expression in the liver, TDO2 is also expressed in neurons, microglia and astrocytes, and the potential benefit of TDO2 inhibition in the glioma context has been shown in another animal model. . Platten and co-workers have shown that the tryptophan catabolic product kynurenine produced by TDO expressed in tumor cells suppresses the anti-tumor immune response via AHR in the form of autocrine / paracrine, and tumor cell survival and motility. It has been demonstrated to promote sex (Opitz CA et al., Nature, 2011, 478 (7368), 197-203). The TDO-AHR pathway is active in human brain tumors and is associated with malignant progression and unexpected survival. Further evidence was the accumulation of the downstream metabolite quinolinic acid, which accumulates in human gliomas and is associated with a malignant phenotype (Sahm et al., Cancer Res, 2013, 73 (11), 3225. ~ 34). Here, it was shown that tryptophan catabolism also occurs in microglia. Therefore, the above data is the basis for TDO2 targeting with small brain penetrating molecules in glioma.

  Other tumor types in which TDO2 mRNA was found are breast cancer, bladder, kidney cells, pancreas, colorectal, head and neck cancer, lung cancer, and melanoma, and therefore the scope of TDO2 targeting is HCC and glioma (Pilotte L et al., Proc Natl Acad Sci USA, 2012, 109 (7), 2497-502).

  The enhanced tryptophan degradation observed in patients with gynecological cancers (ovarian cancer, cervical cancer, endometrial cancer) is a further rationale for TDO2 targeting in these cancers (Sperner). -Underweger B et al., Immunology, 2011, 216 (3); 296-301).

  Tryptophan catabolism in some cancers may also be increased by the expression of indoleamine 2,3-dioxygenase (IDO1) by tumor cells (Uyttenhove, C. et al., Nat. Med., 2003, 9, 1269 to 1274).

  Tryptophan catabolism is believed to be an endogenous mechanism that is induced by inflammatory mediators, particularly IFN-γ, thus limiting excessive immune responses and thereby preventing immunopathology. However, for cancer, there is strong evidence that suppression of anti-tumor immune responses by tryptophan catabolism in precancerous and established cancers promotes tumor growth, so such catabolism is It is an attractive target for therapeutic intervention (Dolusic E and Frederick R, Expert Opin Ther Pat., 2013, 23 (10), 1367-81). Thus, selective and effective for tryptophan catabolism that enhances the effectiveness of conventional chemotherapy, immune checkpoint drugs (Holmagard RB et al., J Exp Med., 2013, 210 (7), 1389-402), or therapeutic vaccines. Considerable efforts have been made to identify inhibitors.

  Regarding neurological encephalopathy, TDO2 expression has been demonstrated in neurons, cerebral vasculature, as well as in astrocytes in the case of schizophrenia (Miller C et al., 2004, Neurobiology Dis, 15 ( 3): 618-29). The kynurenine pathway currently has cognitive disorders such as bipolar disorder and Tourette symptoms, neurodegenerative disorders such as Alzheimer, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, or Parkinson's disease It is considered to be a therapeutic target in motor neuron disease (Stone TW, 2013, Br J of Pharmacol, 169 (6): 1211-27; Wu et al., 2013, Plos One, 8 (4): e59749; Fuvesi et al. , 2012, J Neural Trans, 119 (2): 225-34; Widner et al., 2002, J Neural Trans, 109 (2): 181-9; Comings et al., 1996, Pharmacogenetics, 6 (4): 307-18; Forres , 2010, J Neurochem, 112 (1): 112~22).

  Cognitive changes associated with tryptophan catabolism have also been shown in patients infected with type 1 human immunodeficiency virus (HIV), called HIV-related neurocognitive impairment (HAND) (Davies et al., 2010, Int J of Tryptophan Res. 3: 121-40). In addition, T cell hyporesponsiveness has recently been associated with tryptophan catabolism pathways in HIV-infected patients and may be extended to other chronic infectious diseases such as hepatitis C.

  Several TDO2 inhibitors are described in WO 2010/008427 and Dolusic, E .; (Dolusic et al., J. Med. Chem., 2011, 54, 5320-5334), but its affinity for the target is limited, or its pharmacokinetic properties are It is not suitable for development as a drug to be used.

  Accordingly, there is a need for new TDO2 inhibitors with improved efficacy for cancer treatment and / or prevention.

  The present invention has a condition or disease in which it is desirable to regulate, particularly reduce, TDO2 levels, including but not limited to patients diagnosed with cancer or any subject at risk of developing cancer. A new TDO2 inhibitor is provided that can be administered to a mammalian subject. Compositions containing such compounds and uses thereof are also provided.

  In one aspect, the compound of formula I, or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, Y1, Y2, Y4, R1, R2, R3, X1, and X3 are as defined herein. , Solvents, or solvates are provided.

In one embodiment, the first one of A ¹ , A ² , and A ³ is N, the ^{second of} A ¹ , A ² , and A ³ is C; The ^third of A ¹ , A ² , and A ³ is N or O. In another embodiment, A ² is N, one of A ¹ and A ³ is N or S, and the other is C. In yet another embodiment, A ¹ or A ³ is S and A ¹ -Y ¹ or A ³ -Y ³ is SO ₂ . In yet another embodiment, A ² is C, one of A ¹ and A ³ is N, and the other is N or O. In yet another embodiment, A ¹ or A ³ is O, C is substituted with CR ⁶ R ⁷ R ^{8 as} defined herein, and R ⁶ , R ⁷ , R ⁸ One of which is a1, A1 or A3 is O, C is substituted with CR ⁶ R ⁷ R ⁸ , and R ⁶ , R ⁷ , or R ⁸ is heterocyclyl or C1-heterocyclyl And heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or 2,6-diazaspiro [3.3] heptane, all of which are C1-C3 alkyl, amino, hydroxyl, halogen, COCH ₃ , COOH, Alternatively, one or more of SO ₂ CH ₃ may be substituted. In yet another embodiment, ^one of A ¹ , A ² , or A ³ is S, or A ¹ -Y ¹ , A ² -Y ² , or A ³ -Y ³ is SO _2. And ^one of A ¹ , A ² , or A ³ is N or C, and one of A ¹ , A ² , and A ³ is C. In another embodiment, X ¹ and X ² are independently H or F. In yet another embodiment, R ¹ , R ² , and R ³ each independently represent H, halogen, or methyl, or each may be H.

  In another aspect, a compound according to Formula I, or a pharmaceutically acceptable enantiomer, salt, or solvate thereof, and at least one carrier, diluent, pharmaceutical additive, and / or pharmaceutically acceptable A pharmaceutical composition comprising an adjuvant is provided.

  In yet another aspect, there is provided a medicament comprising a compound according to formula I, or a pharmaceutically acceptable enantiomer, salt, or solvate thereof.

  In yet another aspect, for use in the treatment and / or prevention of cancer, Parkinson's disease, Alzheimer's disease, neurodegenerative disorders such as Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, or Provided are compounds of formula I, or a pharmaceutically acceptable enantiomer, salt, or solvate thereof, for use as a TDO2 inhibitor.

  In yet another aspect, treat and / or prevent cancer, Parkinson's disease, Alzheimer's disease, neurodegenerative disorders such as Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, or inhibit TD02 A method is provided. The method includes administering a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a process for preparing a compound of formula I, or a pharmaceutically acceptable enantiomer, salt, or solvate thereof. This method
(A1) Compound of formula (i)

［式中、
Ｘ^１およびＸ^２は、それぞれ独立に、Ｈ、ハロゲン、アルキル、ハロアルキルを表し、
Ｚ^１は、Ｈまたはアミノ保護基を表し、
Ｙは、ハロゲン、１〜６個の炭素原子を有するアルキルスルホニルオキシ、または６〜１０個の炭素原子を有するアリールスルホニルオキシを表す］を、
式（ｉｉ）の化合物

[Where:
X ¹ and X ² each independently represent H, halogen, alkyl, haloalkyl,
Z ¹ represents H or an amino protecting group,
Y represents halogen, alkylsulfonyloxy having 1 to 6 carbon atoms, or arylsulfonyloxy having 6 to 10 carbon atoms].
Compound of formula (ii)

［式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、本明細書で規定するとおりであり、
Ｚ^２およびＺ^３は、Ｈまたはアルキル基を表すか、Ｚ^２およびＺ^３は、環を形成していてもよい］と反応させて、
式（ｉｉｉ）の化合物

[Where:
R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are as defined herein,
Z ² and Z ³ represent H or an alkyl group, or Z ² and Z ³ may form a ring]
Compound of formula (iii)

［式中、Ｚ^１、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、本明細書で規定するとおりである］を得るステップと、
（ｂ１）Ｚ^１がＨでない場合、式（ｉｉｉ）の化合物のインドールアミンを脱保護して、式Ｉの化合物を得るステップと
を含む。

[Wherein Z ¹ , X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are as defined herein] Obtaining a certain],
(B1) if Z ¹ is not H, deprotecting the indoleamine of the compound of formula (iii) to give a compound of formula I.

  Still other aspects and advantages of the present invention will become apparent from the following detailed description of the invention.

Compound The present invention is a compound of formula I

または薬学的に許容できるその鏡像異性体、塩、もしくは溶媒和物に関し、式中、
Ｘ^１およびＸ^２は、それぞれ独立に、Ｈ、ハロゲン、アルキル、またはハロアルキルを表し、
Ｒ^１、Ｒ^２、およびＲ^３は、それぞれ独立に、Ｈ、ハロゲン、Ｃ１〜Ｃ６アルキル、アルコキシ、またはハロアルキルを表し、これらは、ハロゲン、ヒドロキシル、ＯＲ^４、ＣＯＯＲ^４、ＣＯＮＲ^４Ｒ^５、ＮＲ^４ＣＯＲ^５、ＮＲ^４Ｒ^５、ＳＯ_２Ｒ^４、ＳＯ_２ＮＲ^４Ｒ^５、ＮＲ^４ＳＯ_２Ｒ^５、ＳＯ_２Ｒ^４、アリール、ＣＯ−アルキル、または、ハロゲン、ヒドロキシル、アミノもしくはＣＯＯＨから選択される１つまたは複数の基で置換されていてもよいＣ１〜Ｃ６アルキルから選択される１つまたは複数の置換基で置換されていてもよく、Ｒ^４およびＲ^５は、それぞれ独立に、水素原子、またはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表し、
Ａ^１、Ａ^２、およびＡ^３は、それぞれ独立に、Ｃ、Ｎ、Ｓ、またはＯを表し、Ａ^１、Ａ^２、またはＡ^３がＳである場合、Ａ^１−Ｙ^１、Ａ^２−Ｙ^２、またはＡ^３−Ｙ^３は、ＳＯ_２であってもよく、
Ｙ^１、Ｙ^２、およびＹ^３のそれぞれは、不在であるか、または独立に、
ａ）水素原子、
ｂ）オキソ、
ｃ）ＳＨ、
ｄ）ＣＲ^６Ｒ^７Ｒ^８、ＮＲ^６Ｒ^７、およびＯＲ^６
を表し、Ｒ^６、Ｒ^７、およびＲ^８は、それぞれ独立に、
ｉ）水素原子、
ｉｉ）ハロゲン、
ｉｉｉ）ヒドロキシル、
ｉｖ）ＯＲ^９もしくはＮＲ^９Ｒ^１０［Ｒ^９およびＲ^１０は、それぞれ独立に、水素原子、またはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、アミノ、ＣＯ−アルキル、もしくはＳＯ_２Ｒ^１１から選択される置換されていてもよい基を表し、Ｒ^１１は、水素原子、またはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、ヒドロキシル、もしくはアミノから選択される置換されていてもよい基を表す］、
ｖ）直鎖もしくは分岐Ｃ１〜Ｃ１０アルキル［ハロゲン、ヒドロキシル、ＯＲ^９、ＣＯＯＲ^９、ＣＯＮＲ^９Ｒ^１０、ＮＲ^９ＣＯＲ^１０、ＮＲ^９Ｒ^１０、ＳＯ_２Ｒ^９、ＳＯ_２ＮＲ^９Ｒ^１０、ＮＲ^９ＳＯ_２Ｒ^１０、ＳＯＲ^９、アリール、またはＣＯ−アルキルから選択される３つまでの置換基で置換されていてもよく、Ｒ^９およびＲ^１０は、それぞれ独立に、水素原子、またはＣ１〜Ｃ６アルキル、ヘテロシクリル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表す］、
ｖｉ）ヘテロシクリルまたはＣ１〜Ｃ２アルキル−ヘテロシクリル［ヘテロシクリルは、３つまでの置換基ハロゲン、ヒドロキシル、オキソ、ＯＲ^９、ＣＯＯＲ^９、ＣＯＮＲ^９Ｒ^１０、ＮＲ^９ＣＯＲ^１０、ＮＲ^９Ｒ^１０、ＳＯ_２Ｒ^９、ＳＯ_２ＮＲ^９Ｒ^１０、ＮＲ^９ＳＯ_２Ｒ^１０、ＳＯ_２Ｒ^９、アリール、ＣＯ−アルキル、またはアルキルで置換されていてもよく、アルキル基は、ハロゲン、ヒドロキシル、アミノ、またはＣＯＯＨから選択される１つまたは複数の基で置換されていてもよく、Ｒ^９およびＲ^１０は、それぞれ独立に、水素原子、またはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表す］、
ｖｉｉ）−ＣＯ−Ｒ^１１もしくは−ＳＯ_２Ｒ^１１［Ｒ^１１は、ヒドロキシ、アミン、アルキル、ヘテロシクリルから選択される基を表し、ハロゲン、ヒドロキシル、ＯＲ^９、ＣＯＯＲ^９、ＣＯＮＲ^９Ｒ^１０、ＮＲ^９ＣＯＲ^１０、ＮＲ^９Ｒ^１０、ＳＯ_２Ｒ^９、ＳＯ_２ＮＲ^９Ｒ^１０、ＮＲ^９ＳＯ_２Ｒ^１０、ＳＯＲ^９、アリール、ＣＯ−アルキル、または、ハロゲン、ヒドロキシル、アミノもしくはＣＯＯＨから選択される１つまたは複数の基で置換されていてもよいＣ１〜Ｃ６アルキルを含む群から選択される３つまでの置換基で置換されていてもよく、Ｒ^９およびＲ^１０は、それぞれ独立に、水素原子、またはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表す］
を表し、
ｖｉｉｉ）Ｙ１、Ｙ２、もしくはＹ３がＣＲ^６Ｒ^７Ｒ^８である場合、Ｒ^６、Ｒ^７、およびこれらが結合している炭素原子は、一緒になって、
シクロアルキル［ハロゲン、ヒドロキシル、ＯＲ^９、ＣＯＯＲ^９、ＣＯＮＲ^９Ｒ^１０、ＮＲ^９ＣＯＲ^１０、ＮＲ^９Ｒ^１０、ＳＯ_２Ｒ^９、ＳＯ_２ＮＲ^９Ｒ^１０、ＮＲ^９ＳＯ_２Ｒ^１０、ＳＯ_２Ｒ^９、アリール、ＣＯ−アルキル、または、ハロゲン、ヒドロキシル、アミノもしくはＣＯＯＨから選択される１つまたは複数の基で置換されていてもよいＣ１〜Ｃ６アルキルから選択される３つまでの置換基で置換されていてもよく、Ｒ^９およびＲ^１０は、それぞれ独立に、水素原子、またはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表す］もしくは
ヘテロシクリル［ハロゲン、ヒドロキシル、ＯＲ^９、ＣＯＯＲ^９、ＣＯＮＲ^９Ｒ^１０、ＮＲ^９ＣＯＲ^１０、ＮＲ^９Ｒ^１０、ＳＯ_２Ｒ^９、ＳＯ_２ＮＲ^９Ｒ^１０、ＮＲ^９ＳＯ_２Ｒ^１０、ＳＯ_２Ｒ^９、アリール、ＣＯ−アルキル、または、ハロゲン、ヒドロキシル、アミノもしくはＣＯＯＨから選択される１つまたは複数の基で置換されていてもよいＣ１〜Ｃ６アルキルを含む群から選択される３つまでの置換基で置換されていてもよく、Ｒ^９およびＲ^１０は、それぞれ独立に、水素原子、またはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表す］
から選択される環を形成していてもよく、または
ｉｘ）Ｙ１、Ｙ２、もしくはＹ３がＮＲ^６Ｒ^７である場合、Ｒ^６、Ｒ^７、およびこれらが結合している窒素原子は、一緒になって、環を形成していてもよく、環は、ハロゲン、ヒドロキシル、ＯＲ^９、ＣＯＯＲ^９、ＣＯＮＲ^９Ｒ^１０、ＮＲ^９ＣＯＲ^１０、ＮＲ^９Ｒ^１０、ＳＯ_２Ｒ^９、ＳＯ_２ＮＲ^９Ｒ^１０、ＮＲ^９ＳＯ_２Ｒ^１１、ＳＯ_２Ｒ^９、アリール、ＣＯ−アルキル、または、ハロゲン、ヒドロキシル、アミノもしくはＣＯＯＨから選択される１つもしくは複数の基で置換されていてもよいＣ１〜Ｃ６アルキルから選択される３つまでの置換基で置換されていてもよく、Ｒ^９およびＲ^１０は、それぞれ独立に、水素原子、もしくはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表し、Ｒ^１１は、水素原子、もしくはアリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表し、もしくはＲ^１１は、ハロゲン、ヒドロキシル、ＯＲ^１２、ＣＯＯＲ^１２、ＣＯＮＲ^１２Ｒ^１３、ＮＲ^１２ＣＯＲ^１３、ＮＲ^１２Ｒ^１３、ＳＯ_２Ｒ^１２、ＳＯ_２ＮＲ^１２Ｒ^１３、ＮＲ^１２ＳＯ_２Ｒ^１３、ＳＯ_２Ｒ^１２、もしくはアリールから選択される３つまでの置換基で置換されていてもよいアルキル基を表し、Ｒ^１２およびＲ^１３は、それぞれ独立に、水素原子、もしくはＣ１〜Ｃ６アルキル、アリール、アリールアルキル、アルキルアリール、ヘテロアリール、ヘテロアリールアルキル、アルキルヘテロアリール、もしくはアミノから選択される置換されていてもよい基を表し、
点線は、単結合または二重結合を表し、
但し、Ａ^１、Ａ^２、およびＡ^３は、すべてがＣになることはなく、
但し、Ａ^１またはＡ^３のうちの１つがＮである場合、他の２つは、両方ともがＣになることはなく、但し、Ａ^１、Ａ^２、およびＡ^３のうちの１つがＳである場合、１つだけＳが存在し、他の２つの少なくとも一方はＣであり、他方はＣまたはＮであり、
但し、式Ｉの化合物は、３−（ベンゾフラン−５−イル）−６−クロロ−１Ｈ−インドールまたは３−（ベンゾ［ｄ］［１，３］ジオキソール−５−イル）−１Ｈ−インドールではない。

Or a pharmaceutically acceptable enantiomer, salt, or solvate thereof, wherein
X ¹ and X ² each independently represent H, halogen, alkyl, or haloalkyl,
R ¹ , R ² , and R ³ each independently represent H, halogen, C1-C6 alkyl, alkoxy, or haloalkyl, which are halogen, hydroxyl, OR ⁴ , COOR ⁴ , CONR ⁴ R ⁵ , NR ⁴ COR ⁵ , NR ⁴ R ⁵ , SO ₂ R ⁴ , SO ₂ NR ⁴ R ⁵ , NR ⁴ SO ₂ R ⁵ , SO ₂ R ⁴ , aryl, CO-alkyl, or selected from halogen, hydroxyl, amino or COOH Optionally substituted with one or more substituents selected from C1-C6 alkyl optionally substituted with one or more groups wherein R ⁴ and R ⁵ are each independently hydrogen Atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl Represents an optionally substituted group selected from: alkylheteroaryl, or amino;
A ¹ , A ² , and A ³ each independently represent C, N, S, or O, and when A ¹ , A ² , or A ³ is S, A ¹ -Y ¹ , A ^2- Y ² or A ³ -Y ³ may be SO ₂ ,
Each of Y ¹ , Y ² , and Y ³ is absent or, independently,
a) a hydrogen atom,
b) oxo,
c) SH,
^{d) CR 6 R 7 R 8} , NR 6 R 7, and OR ⁶
R ⁶ , R ⁷ , and R ⁸ are each independently
i) a hydrogen atom,
ii) halogen,
iii) hydroxyl,
iv) OR ⁹ or NR ⁹ R ¹⁰ [R ⁹ and R ¹⁰ are each independently a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino Represents an optionally substituted group selected from CO ₂ , CO-alkyl, or SO ₂ R ¹¹ , wherein R ¹¹ is a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl Represents an optionally substituted group selected from alkyl, alkylheteroaryl, hydroxyl, or amino],
v) straight or branched C1~C10 alkyl [with halogen, ^{hydroxyl, OR 9, COOR 9, CONR} 9 R 10, NR 9 COR 10, NR 9 R 10, SO 2 R 9, SO 2 NR 9 R 10, NR 9 Optionally substituted with up to three substituents selected from SO ₂ R ¹⁰ , SOR ⁹ , aryl, or CO-alkyl, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C ¹ -C 6. Represents an optionally substituted group selected from alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino],
vi) heterocyclyl or C1~C2 alkyl - heterocyclyl [heterocyclyl substituent halogen, up to three, hydroxyl, ^{oxo, OR 9, COOR 9, CONR} 9 R 10, NR 9 COR 10, NR 9 R 10, SO 2 R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, or alkyl, the alkyl group is from halogen, hydroxyl, amino, or COOH R ⁹ and R ¹⁰ may each independently be a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl, optionally substituted with one or more selected groups Alkyl, alkylheteroaryl, or amino It represents the optionally substituted group selected,
vii) —CO—R ¹¹ or —SO ₂ R ¹¹ [R ¹¹ represents a group selected from hydroxy, amine, alkyl, heterocyclyl, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, or 1 selected from halogen, hydroxyl, amino or COOH R ⁹ and R ¹⁰ are each independently a hydrogen atom, optionally substituted with up to three substituents selected from the group comprising C1-C6 alkyl optionally substituted with one or more groups Or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl Ruarukiru, alkyl heteroaryl or group which may be substituted are selected from amino,]
Represents
viii) when Y 1, Y 2, or Y 3 is CR ⁶ R ⁷ R ⁸ , R ⁶ , R ⁷ , and the carbon atom to which they are attached together,
Cycloalkyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ substituted with up to 3 substituents selected from aryl, CO-alkyl, or C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino Represents an optionally substituted group] or heterocyclyl [Halogen, ^{hydroxyl, OR 9, COOR 9, CONR} 9 R 10, NR 9 COR 10, NR 9 R 10, SO 2 R 9, SO 2 NR 9 R 10, NR 9 SO 2 R 10, SO 2 R 9, With up to three substituents selected from the group comprising aryl, CO-alkyl, or C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH Optionally substituted, R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino Represents an optionally substituted group]
Or ix) when Y 1, Y 2, or Y 3 is NR ⁶ R ⁷ , R ⁶ , R ⁷ , and the nitrogen atom to which they are attached together And may form a ring, and the ring is halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹¹ , SO ₂ R ⁹ , aryl, CO-alkyl, or C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH may be substituted with up to three substituents selected from, R ⁹ and R ¹⁰ each independently represent a hydrogen atom, or a C1~C6 alkyl, Le represents arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkyl heteroaryl or optionally substituted group selected from amino, R ¹¹ is a hydrogen atom or an aryl, arylalkyl, alkylaryl Represents an optionally substituted group selected from:, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino, or R ¹¹ is halogen, hydroxyl, OR ¹² , COOR ¹² , CONR ¹² R ¹³ , NR ¹² Substituted with up to three substituents selected from COR ¹³ , NR ¹² R ¹³ , SO ₂ R ¹² , SO ₂ NR ¹² R ¹³ , NR ¹² SO ₂ R ¹³ , SO ₂ R ¹² , or aryl Represents a good alkyl group, R ¹² and R ¹³ are each independently a hydrogen atom or a substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino. Represents a group,
The dotted line represents a single bond or a double bond,
However, A ¹ , A ² and A ³ are not all C,
However, if ^one of A ¹ or A ³ is N, the other two are not both C, provided that ^one of A ¹ , A ² , and A ³ is S , There is only one S, at least one of the other two is C, the other is C or N,
However, the compound of formula I is not 3- (benzofuran-5-yl) -6-chloro-1H-indole or 3- (benzo [d] [1,3] dioxol-5-yl) -1H-indole. .

In another embodiment, in Formula I:
X ¹ and X ² each independently represent H, halogen, alkyl, haloalkyl, preferably H or F;
R ¹ , R ² , and R ³ each independently represent H, halogen, C1-C6 alkyl, alkoxy, haloalkyl, which are halogen, hydroxyl, OR ⁴ , COOR ⁴ , CONR ⁴ R ⁵ , NR ^{4 _{COR 5, NR 4 R 5,}} SO 2 R 4, SO 2 NR 4 R 5, NR 4 SO 2 R 5, SO 2 R 4, aryl, CO- alkyl, one or more selected from the group comprising alkyl The alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH, and R ⁴ and R ⁵ are each independently And a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl Represents an optionally substituted group selected from: alkylheteroaryl, amino;
Preferably, R ¹ , R ² and R ³ each independently represent H, halogen or alkyl,
Preferably, R ¹ , R ² and R ³ each independently represent H, halogen or methyl,
Preferably, R ¹ , R ² and R ³ each represent H
A ¹ , A ² , and A ³ each independently represent C, N, or O;
Each of Y ¹ , Y ² , and Y ³ is absent or, independently,
-Hydrogen atom,
-Oxo,
^{- CR 6 R 7 R 8,} NR 6 R 7 and OR ^6,
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
A halogen, preferably F, Cl or I, more preferably F,
Hydroxyl,
OR ⁹ or NR ⁹ R ¹⁰ [R ⁹ and R ¹⁰ are each independently a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, represents an optionally substituted group selected from SO ₂ R ¹¹ , where R ¹¹ is a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, Alkylheteroaryl, which represents an optionally substituted group selected from amino],
Linear or branched C1-C10 alkyl, preferably methyl, ethyl, or propyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, optionally substituted with up to 3 substituents selected from the group comprising CO-alkyl, wherein R ⁹ and R ¹⁰ are each Independently represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino],
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino,
-CO-R ¹¹ or -SO ₂ R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl , OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, May be substituted with up to three substituents selected from the group comprising alkyl, and the alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH well, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, Ali Le, arylalkyl, alkylaryl, represents heteroaryl, heteroarylalkyl, alkylheteroaryl, group which may be substituted are selected from amino]
Represents
In CR ⁶ R ⁷ R ⁸ , R ⁶ , R ⁷ , and the carbon atom to which they are bonded together form a ring, and the ring is
Cycloalkyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , optionally substituted with up to three substituents selected from the group comprising aryl, CO-alkyl, alkyl, wherein the alkyl group is one or more selected from halogen, hydroxyl, amino, or COOH R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino Represents an optionally substituted group selected from
Heterocyclyl preferably selected from morpholine, piperazine, or piperidine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, hydroxyl, R ⁹ and R ¹⁰ may each independently be a hydrogen atom, or a C1-C6 alkyl, aryl, arylalkyl, alkylaryl, optionally substituted with one or more groups selected from amino, or COOH Heteroaryl, heteroarylalkyl, alkylheteroaryl, amino It represents the optionally substituted group selected from '
Is preferably selected from
In NR ⁶ R ⁷ , R ⁶ , R ⁷ and the nitrogen atom to which they are bonded together form a ring, which is selected from morpholine, piperazine, or piperidine Preferred are heterocyclyl, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO Optionally substituted with up to three substituents selected from the group comprising ₂ R ¹¹ , SO ₂ R ⁹ , aryl, CO-alkyl, alkyl, wherein the alkyl group is from halogen, hydroxyl, amino, or COOH It may be substituted with one or more groups selected, R ⁹ and R ¹⁰ each independently represent a hydrogen atom, or The C1~C6 alkyl, aryl, arylalkyl, an alkyl aryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, a group which may be substituted are selected from amino, R ¹¹ is a hydrogen atom or an aryl, Represents an optionally substituted group selected from arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, or R ¹¹ represents halogen, hydroxyl, OR ¹² , COOR ¹² , CONR ¹² R ¹³ , NR ¹² COR ¹³ , NR ¹² R ¹³ , SO ₂ R ¹² , SO ₂ NR ¹² R ¹³ , NR ¹² SO ₂ R ¹³ , SO ₂ R ¹² , up to 3 substituents selected from the group comprising aryl Alkyl group optionally substituted by R ¹² and R ¹³ are each independently a hydrogen atom or a substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino Represents a group that may be
The dotted line represents a single bond or a double bond,
However, A ¹ , A ² and A ³ are not all C,
However, if ^one of A ¹ , A ² , and A ³ is N, the other two are not both C,
However, the compound of formula I is not 3- (benzofuran-5-yl) -6-chloro-1H-indole or 3- (benzo [d] [1,3] dioxol-5-yl) -1H-indole. .

  According to one embodiment, the fused heterocycle that replaces the indole ring in Formula I is aromatic. In another embodiment, the fused heterocycle that replaces the indole ring in Formula I is partially aromatic. In another embodiment, the heterocycle replacing the indole ring in Formula I is not aromatic.

According to a preferred embodiment, in formula I, X ¹ and X ² each independently represent H or halogen, preferably H or F. According to a particular embodiment, X ¹ represents H and X ² represents F. According to a preferred embodiment, in Formula I, R ¹ , R ² , and R ³ each represent H. According to a particular embodiment, in formula I, X ¹ and X ² each independently represent H or halogen, R ¹ , R ² , and R ³ each represent H, preferably X ¹ Represents H, X ² represents F, and R ¹ , R ² , and R ³ each represent H.

According to one embodiment, in Formula I, the ^{first one} of A ¹ , A ² , and A ³ is N and the ^{second of} A ¹ , A ² , and A ³ Is C, and the ^third of A ¹ , A ² , and A ³ is N or O.

According to one embodiment, in Formula I, A ² is N, one of A ¹ and A ³ is N or Sr, and the other is C.

According to one embodiment, in Formula I, A ² is C, one of A ¹ and A ³ is N, and the other is N or O. In one embodiment wherein A ¹ or A ³ is O, C is substituted with CR ⁶ R ⁷ R ⁸ , and R ⁶ , R ⁷ , or R ⁸ is heterocyclyl or C1-heterocyclyl, heterocyclyl is piperidine , pyrrolidine, piperazine, morpholine or 2,6-diazaspiro [3.3] heptane, either of which, C1 to C3 alkyl, amino, hydroxyl, _halogen, COCH 3, COOH or of _SO 2 CH _3, May be substituted with one or more of

According to another embodiment, in Formula I, A ¹ or A ³ is S and A ¹ -Y ¹ or A ³ -Y ³ is SO ₂ . Optionally, when one of A ¹ , A ² , or A ³ is S, or A ¹ -Y ¹ , A ² -Y ² , or A ³ -Y ³ is SO ₂ , then A ^{One of 1} , A ² , or A ³ is N or C, and one of A ¹ , A ² , and A ³ is C.

  In one embodiment, preferred compounds of formula I are compounds of formula II-1

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ³ , Y ¹ , Y ² , And Y ³ are as defined in Formula I.

According to one embodiment, in Formula II-1, A ¹ and A ³ are not both C. According to another embodiment, ^one of A ¹ and A ¹ is S and the other is C, A ¹ -Y ¹ or A ³ -Y ³ may be SO ₂ and C 1 May be substituted with oxo.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ³ , Y ¹ , Y ² , And Y ³ are as defined in Formula I.

According to one embodiment, in Formula II-1, {A ¹ , A ³ } is not {C, N}, {N, C}, or {C, C}.

  In one embodiment, preferred compounds of formula I are compounds of formula II-1a

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , Y ¹ , Y ² , and Y ^3. Is as defined in Formula I.

  In one embodiment, preferred compounds of formula I are compounds of formula II-1b

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ³ , Y ¹ , Y ² , and Y ^3. Is as defined in Formula I.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2a

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , Y ¹ , Y ² , and Y ^3. Is as defined in Formula I.

According to one embodiment, in formula II-2a, A ¹ is not C.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2b

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ³ , Y ¹ , Y ² , and Y ^3. Is as defined in Formula I.

According to one embodiment, in formula II-2b, A ³ is not C.

  In one embodiment, preferred compounds of formula I are compounds of formula II-1a1

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^１、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , Y ¹ , and Y ³ are as defined in Formula I Just as you did.

According to a preferred embodiment, in formula II-1a1, Y ¹ represents H, Y ³ is as defined in formula I, preferably Y ³ is
-Hydrogen atom,
-CR ⁶ R ⁷ R ⁸
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
Linear or branched C1-C10 alkyl, preferably methyl, ethyl, or propyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , _{^{SO 2 NR 9 R 10, NR}} 9 SO 2 R 10, SOR 9, aryl may be substituted with up to three substituents selected from the group comprising CO- alkyl, ^{R 9} and ^{R 10,} Each independently represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino],
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino,
-CO-R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, alkyl The alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH, and R ⁹ and R ^{9 10} are independently a hydrogen atom or a C1~C6 alkyl, aryl, arylalkyl Alkylaryl, heteroaryl, heteroarylalkyl, alkyl heteroaryl, optionally substituted group selected from amino]
Represents
R ⁶ , R ⁷ and the carbon atom to which they are bonded together form a ring, which is preferably a heterocyclyl selected from morpholine, piperazine, or piperidine Preferably, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is one selected from halogen, hydroxyl, amino, or COOH or may be substituted by a plurality of groups, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, It represents aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, the substituents on these also groups selected from amino.

  In one embodiment, preferred compounds of formula I are compounds of formula II-1a2

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^１、およびＹ^２は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , Y ¹ , and Y ² are defined by formula I As you did.

According to a preferred embodiment, in formula II-1a2, Y ¹ represents H, Y ² is as defined in formula I, preferably Y ² is
-Hydrogen atom,
-CR ⁶ R ⁷ R ⁸
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
Linear or branched C1-C10 alkyl, preferably methyl, ethyl, or propyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , _{^{SO 2 NR 9 R 10, NR}} 9 SO 2 R 10, SOR 9, aryl may be substituted with up to three substituents selected from the group comprising CO- alkyl, ^{R 9} and ^{R 10,} Each independently represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino],
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino,
-CO-R ¹¹ or -SO ₂ R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl , OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, May be substituted with up to three substituents selected from the group comprising alkyl, and the alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH well, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, Ali Le, arylalkyl, alkylaryl, represents heteroaryl, heteroarylalkyl, alkylheteroaryl, group which may be substituted are selected from amino]
Represents
R ⁶ , R ⁷ and the carbon atom to which they are bonded together form a ring, which is preferably a heterocyclyl selected from morpholine, piperazine, or piperidine Preferably, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is one selected from halogen, hydroxyl, amino, or COOH or may be substituted by a plurality of groups, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, It represents aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, the substituents on these also groups selected from amino.

  In one embodiment, preferred compounds of formula I are compounds of formula II-1b1

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^１、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , Y ¹ , and Y ³ are as defined in Formula I Just as you did.

According to a preferred embodiment, in formula II-1b1, Y ³ represents H, Y ¹ is as defined in formula I, and preferably Y ¹ is
-Hydrogen atom,
-CR ⁶ R ⁷ R ⁸
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
Linear or branched C1-C10 alkyl, preferably methyl, ethyl, or propyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , _{^{SO 2 NR 9 R 10, NR}} 9 SO 2 R 10, SOR 9, aryl may be substituted with up to three substituents selected from the group comprising CO- alkyl, ^{R 9} and ^{R 10,} Each independently represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino],
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino,
-CO-R ¹¹ or -SO ₂ R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl , OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, May be substituted with up to three substituents selected from the group comprising alkyl, and the alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH well, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, Ali Le, arylalkyl, alkylaryl, represents heteroaryl, heteroarylalkyl, alkylheteroaryl, group which may be substituted are selected from amino]
Represents
R ⁶ , R ⁷ and the carbon atom to which they are bonded together form a ring, which is preferably a heterocyclyl selected from morpholine, piperazine, or piperidine Preferably, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is one selected from halogen, hydroxyl, amino, or COOH or may be substituted by a plurality of groups, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, It represents aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, the substituents on these also groups selected from amino.

  In one embodiment, preferred compounds of formula I are compounds of formula II-1b2

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , Y ² , and Y ³ are defined by formula I Just as you did.

According to a preferred embodiment, in formula II-1b2, Y ³ represents H, Y ² is as defined in formula I, preferably Y ² is
-Hydrogen atom,
-CR ⁶ R ⁷ R ⁸
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
Linear or branched C1-C10 alkyl, preferably methyl, ethyl, or propyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , _{^{SO 2 NR 9 R 10, NR}} 9 SO 2 R 10, SOR 9, aryl may be substituted with up to three substituents selected from the group comprising CO- alkyl, ^{R 9} and ^{R 10,} Each independently represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino],
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino,
-CO-R ¹¹ or -SO ₂ R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl , OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, May be substituted with up to three substituents selected from the group comprising alkyl, and the alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH well, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, Ali Le, arylalkyl, alkylaryl, represents heteroaryl, heteroarylalkyl, alkylheteroaryl, group which may be substituted are selected from amino]
Represents
R ⁶ , R ⁷ and the carbon atom to which they are bonded together form a ring, which is preferably a heterocyclyl selected from morpholine, piperazine, or piperidine Preferably, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is one selected from halogen, hydroxyl, amino, or COOH or may be substituted by a plurality of groups, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, It represents aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, the substituents on these also groups selected from amino.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2a1

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^１、およびＹ^２は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , Y ¹ , and Y ² are defined by formula I As you did.

According to a preferred embodiment, in formula II-2a1, Y ¹ represents H, Y ² is as defined in formula I, preferably Y ² is
-Hydrogen atom,
^{- CR 6 R 7 R 8,} NR 6 R 7 and OR ^6,
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
OR ⁹ or NR ⁹ R ¹⁰ [R ⁹ and R ¹⁰ are each independently a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, represents an optionally substituted group selected from SO ₂ R ¹¹ , where R ¹¹ is a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, Alkylheteroaryl, which represents an optionally substituted group selected from amino],
Linear or branched C1-C10 alkyl, preferably methyl, ethyl, or propyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , _{^{SO 2 NR 9 R 10, NR}} 9 SO 2 R 10, SOR 9, aryl may be substituted with up to three substituents selected from the group comprising CO- alkyl, ^{R 9} and ^{R 10,} Each independently represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino],
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino,
-CO-R ¹¹ or -SO ₂ R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl , OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, May be substituted with up to three substituents selected from the group comprising alkyl, and the alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH well, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, Ali Le, arylalkyl, alkylaryl, represents heteroaryl, heteroarylalkyl, alkylheteroaryl, group which may be substituted are selected from amino]
Represents
R ⁶ , R ⁷ and the carbon atom to which they are bonded together form a ring, which is preferably a heterocyclyl selected from morpholine, piperazine, or piperidine Preferably, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is one selected from halogen, hydroxyl, amino, or COOH or may be substituted by a plurality of groups, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, It represents aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, the substituents on these also groups selected from amino.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2a2

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、およびＹ^２は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , and Y ² are as defined in Formula I. is there.

According to a preferred embodiment, in Formula II-2a2, Y ² is
-Hydrogen atom,
^{- CR 6 R 7 R 8,} NR 6 R 7 and OR ^6,
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino,
-CO-R ¹¹ or -SO ₂ R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl , OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, May be substituted with up to three substituents selected from the group comprising alkyl, and the alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH well, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, Ali It represents Le, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, the substituents on these also groups selected from amino.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2b1

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , Y ² , and Y ³ are defined by formula I Just as you did.

According to a preferred embodiment, in formula II-2b1, Y ³ represents H, Y ² is as defined in formula I, preferably Y ² is
-Hydrogen atom,
-CR ⁶ R ⁷ R ⁸
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
OR ⁹ or NR ⁹ R ¹⁰ [R ⁹ and R ¹⁰ are each independently a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, represents an optionally substituted group selected from SO ₂ R ¹¹ , where R ¹¹ is a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, Alkylheteroaryl, which represents an optionally substituted group selected from amino],
Linear or branched C1-C10 alkyl, preferably methyl, ethyl, or propyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , _{^{SO 2 NR 9 R 10, NR}} 9 SO 2 R 10, SOR 9, aryl may be substituted with up to three substituents selected from the group comprising CO- alkyl, ^{R 9} and ^{R 10,} Each independently represents a hydrogen atom or an optionally substituted group selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino],
A heterocyclyl preferably selected from piperidine, pyrrolidine, piperazine, morpholine [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, optionally substituted with up to three substituents selected from the group comprising alkyl, wherein the alkyl group is halogen, Optionally substituted with one or more groups selected from hydroxyl, amino, or COOH, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkylheteroary Represents an optionally substituted group selected from amino]
Represents.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2b2

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、およびＹ^２は、式Ｉで規定したとおりであり、点線は、不在であるか、または結合である。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , and Y ² are as defined in Formula I. Yes, dotted line is absent or a bond.

According to a preferred embodiment, in formula II-2b2, when a dotted line is absent and there is a single bond between N and C, Y2 is oxo and a dotted line is present and two between N and C When there is a double bond, Y ² is
-Hydrogen atom,
^{- CR 6 R 7 R 8,} NR 6 R 7 and OR ^6,
R ⁶ , R ⁷ , and R ⁸ are each independently
・ Hydrogen atom,
· Piperidine, pyrrolidine, piperazine, morpholine or 2,6-diazaspiro [3.3] that is selected from heptane are preferred heterocyclyl or C1- heterocyclyl [halogen, ^{hydroxyl, OR 9, COOR 9, CONR} 9 R 10, NR Up to three selected from the group comprising ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, alkyl The alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH, and R ⁹ and R ¹⁰ are each independently A hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkyl Aryl, heteroaryl, heteroarylalkyl, alkyl heteroaryl, group which may be substituted are selected from amino,
-CO-R ¹¹ or -SO ₂ R ¹¹ [R ¹¹ represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide), halogen, hydroxyl , OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, May be substituted with up to three substituents selected from the group comprising alkyl, and the alkyl group may be substituted with one or more groups selected from halogen, hydroxyl, amino, or COOH well, ^{R 9} and ^{R 10} each independently represent a hydrogen atom or a C1~C6 alkyl, Ali Le, arylalkyl, alkylaryl, represents heteroaryl, heteroarylalkyl, alkylheteroaryl, group which may be substituted are selected from amino]
Represents.

In one embodiment, one or more heterocycles, H or _SO 2 _CH 3,, C1 to C3 lower alkyl, preferably substituted with at least one group selected from CH _3, or COOH.

  In one embodiment, preferred compounds of formula I are compounds of formula II-2b3

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物であり、式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである。

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , Y ¹ , Y ² , and Y ³ are of the formula As defined in I.

In one embodiment of Formula II-2b3, R ¹ , R ² , or R ³ are each independently H, halogen, or C1-C6 alkyl, preferably C1 alkyl. In another embodiment of formula II-2b3, X ¹ and X ² are independently H or halogen.

  Particularly preferred compounds of the formula I according to the invention are those listed in Table 1 below.

  In Table 1, the term “Cpd” means a compound.

  The compounds in Table 1 were named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

  Compounds of formula I and its subformulas may contain asymmetric centers and therefore may exist as different stereoisomeric forms. Accordingly, the present invention encompasses all possible stereoisomers and includes not only racemates but also individual enantiomers and non-racemic mixtures thereof. Compounds are desired as single enantiomers, stereospecific synthesis, resolution of the final product or any convenient intermediate, respectively, as known in the art, or chiral chromatography Can be obtained by law. Resolution of the final product, intermediate, or starting material can be done by any suitable method known in the art.

  The compounds of the present invention may be in the form of “pharmaceutically acceptable salts”. Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, lactobionate, benzenesulfonate, laurate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, Borate, camsylate, citrate, cyclamate, edicylate, esylate, formate, fumarate, glucoceptate, gluconate, glucuronate, hexafluorophosphate, hibenz Acid salt, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mandelate, tartaric acid Hydrogen salt, Methyl bromide, Bromide, Methyl nitrate, Calcium edetate, Mucoate, Napsylate, Chloride, Clavulanate, Noleate, Edetoate, Estolate ), Pantothenate, polygalacturonate, salicylate, glutamate, glycolylarsanylate, sulfate, hexyl resorcinate, hypoacetate, hydrabamine, hydroxynaphthoate ( hydronaphthaphthalate, etolate, trietoiodide, valerate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate , Pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, sugar salt, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetic acid Salt, and xinofoate e), and the like. Suitable base salts are generated from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, allamine, ornithine, N, N-dibenzylethylenediamine, piperazine, triazine (Hydroxymethylaminomethane, tetramethylammonium hydroxide, methylgucamine, ammonium salt, potassium, sodium, tromethamine, 2- (diethylamino) ethanol, ethanolamine, morpholine, 4- (2-hydroxyethyl) morpholine, and zinc Salts of acids and bases, such as hemisulfate and halfcalcium salts, may be produced. Preferred salts, hydrochloride / chloride, hydrobromide / bromide, hydrogen sulfate / sulfate, nitrate, citrate, and acetate salts.

  When a compound of the present invention contains a basic group in addition to an acidic group, the compound of the present invention may form an inner salt, and such a compound is within the scope of the present invention. . When the compound of the present invention contains a hydrogen donor heteroatom (for example, NH), the present invention covers salts and / or isomers formed by transferring the hydrogen atom to a basic group or atom in the molecule. To do.

A pharmaceutically acceptable salt of a compound of formula I is one or more of these methods (i) reacting a compound of formula I with the desired acid,
(Ii) reacting the compound of formula I with the desired base;
(Iii) removing an acid or base labile protecting group from a suitable precursor of a compound of formula I, or opening a suitable cyclic precursor, such as a lactone or lactam, using the desired acid. Or (iv) converting one salt of a compound of formula I to another salt by reaction with a suitable acid or by a suitable ion exchange column,
Can be prepared.
All these reactions are usually carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the salt can vary from complete ionization to almost non-ionized.

  The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts as defined above. Such salts can be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. When basic groups such as amino are present, acidic salts, ie hydrochlorides, hydrobromides, acetates, pamoates, etc. can be used as dosage forms.

  It is also known in the art to alter pharmaceutically acceptable esters such as acetates, maleates, pivaloyloxymethyl, and solubilities or hydrolysis properties when an alcohol group is present. Known esters may be used as long acting or prodrug formulations.

  All references to compounds of formula I throughout this specification, including references to their enantiomers, salts, solvates, polymorphs, multicomponent complexes, and liquid crystals, are sub-formulas of formula II (II -1, II-1a, II-1a1, II-1a2, II-1b, II-1b1, II-1b2, II-2, II-2a, II-2a1, II-2a2, II-2b, II-2b1 II-2b2 and II-2b3).

  The compounds of the invention include compounds of formula I as defined above, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric forms), As well as isotopically-labelled compounds of formula I.

  In addition, in general, with respect to salts of the compounds of the present invention, although pharmaceutically acceptable salts are preferred, in a broad sense, the present invention may be used, for example, for the isolation and / or purification of the compounds of the present invention. It should be noted that good pharmaceutically unacceptable salts are also included. For example, salts formed for optically active acids or bases can be used to produce diastereomeric salts that can facilitate the separation of optically active isomers of compounds of Formula I above. .

  The present invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of compounds of Formula I.

Methods of Manufacture Compounds of formula I can be prepared by different methods using reactions known to those skilled in the art.

  The present invention further relates to compounds of formula I

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである］の第一の製造方法であって、
（ａ１）式（ｉ）の化合物

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ^2. And Y ³ is as defined in Formula I],
(A1) Compound of formula (i)

［式中、
Ｘ^１およびＸ^２は、式Ｉで規定したとおりであり、
Ｚ^１は、Ｈ、または、たとえばアリールスルホニル、ｔｅｒｔ−ブトキシカルボニル、メトキシメチル、パラメトキシベンジル、ベンジル、もしくは当業者に知られている適切な他のいずれかの保護基などのアミノ保護基を表し、
Ｙは、ハロゲン（好ましくは、ヨウ素、臭素、または塩素）、１〜６個の炭素原子を有するアルキルスルホニルオキシ（好ましくは、メチルスルホニルオキシまたはトリフルオロメチルスルホニルオキシ）、または６〜１０個の炭素原子を有するアリールスルホニルオキシ（好ましくは、フェニルまたはｐ−トリルスルホニルオキシ）、または当業者に知られているいずれかの脱離基を表す］を、
式（ｉｉ）の化合物

[Where:
X ¹ and X ² are as defined in Formula I,
Z ¹ represents H or an amino protecting group such as arylsulfonyl, tert-butoxycarbonyl, methoxymethyl, paramethoxybenzyl, benzyl or any other suitable protecting group known to those skilled in the art. ,
Y is halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy), or 6 to 10 carbons An arylsulfonyloxy having an atom (preferably phenyl or p-tolylsulfonyloxy) or any leaving group known to those skilled in the art]
Compound of formula (ii)

［式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりであり、
Ｚ^２およびＺ^３は、Ｈまたはアルキル基を表すか、Ｚ^２およびＺ^３は、環を形成していてもよい］と反応させて、式（ｉｉｉ）の化合物

[Where:
R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are as defined in Formula I;
Z ² and Z ³ represent H or an alkyl group, or Z ² and Z ³ may form a ring] to give a compound of formula (iii)

［式中、Ｚ^１、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、上で規定したとおりである］を得るステップと、
（ｂ１）Ｚ^１がＨでない場合、式（ｉｉｉ）の化合物のインドールアミンを脱保護して、式Ｉの化合物を得るステップと
を含む製造方法に関する。

[Wherein Z ¹ , X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are as defined above] And getting the steps
(B1) when Z ¹ is not H, deprotecting the indoleamine of the compound of formula (iii) to obtain a compound of formula I.

According to one embodiment, step (a1) of the method of the invention includes, but is not limited to, Pd ₂ (dba) ₃ , Pd (PPh ₃ ) ₄ , dichlorobis (triphenylphosphine) palladium (II) or 1, With or without a catalyst such as 1′-bis (diphenylphosphino) ferrocenedichloropalladium (II), Pd (OAc) ₂ , Pd / C, but not limited to, X-Phos, S-Phos, P In the presence or absence of additional ligands, such as (oTol) ₃ , PPh ₃ , BINAP, P (tBu) ₃ , or any other suitable phosphine ligand known to those skilled in the art Can be implemented below.

According to one embodiment, step (a1) of the method of the invention can be carried out in the presence of a base such as, but not limited to, K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ .

  According to one embodiment, step (a1) of the method of the invention is preferably in the presence of a suitable solvent such as, but not limited to, dioxane, THF, DMF, water, or mixtures thereof. It can be carried out in a mixture of THF and water.

  According to one embodiment, step (a1) of the method of the present invention is carried out at a temperature in the range of 20 ° C. to about 180 ° C. with or without microwave irradiation for 10 minutes to several hours, for example 10 It can be carried out over a period ranging from minutes to 24 hours.

According to one embodiment, deprotection (b1) can be performed by treatment with a base such as, but not limited to, sodium hydroxide, potassium hydroxide, potassium carbonate, depending on the nature of the group Z ^1. . According to one embodiment, the deprotection is in the presence or absence of a suitable solvent such as but not limited to methanol, ethanol, isopropanol, tert-butanol, THF, DMF, dioxane, water, or mixtures thereof. Can be done. According to one embodiment, the deprotection can be carried out at a temperature in the range of 20 ° C. to 100 ° C., preferably about 85 ° C., for several hours, for example 1 hour to 24 hours.

According to an alternative embodiment, deprotection (b1) can be performed in the presence of a strong acid such as, but not limited to, HCl, TFA, HF, HBr, depending on the nature of the group Z ¹ . According to one embodiment, deprotection can be performed in the presence or absence of a suitable solvent such as methanol, ethanol, isopropanol, tert-butanol, THF, DMF, dioxane, water, or mixtures thereof. . According to one embodiment, the deprotection can be performed at a temperature between about 20 ° C. and about 100 ° C. over a period comprised between 10 minutes and several hours, for example 10 minutes to 24 hours.

  The present invention further relates to compounds of formula I

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりであり、
但し、Ｙ^１、Ｙ^２、およびＹ^３のうちの少なくとも１つは、Ｈまたは不在でない］の第二の製造方法であって、
（ａ２）式（ｉｖ）の化合物

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ^2. , And Y ³ are as defined in Formula I;
Provided that at least one of Y ¹ , Y ² , and Y ³ is not H or absent],
(A2) Compound of formula (iv)

［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３は、式Ｉで規定したとおりであり、
Ｙ^１’、Ｙ^２’、およびＹ^３’は、それぞれ、式Ｉで規定したとおりのＹ^１、Ｙ^２、およびＹ^３を表し、但し、Ｙ^１’、Ｙ^２’、およびＹ^３’のうちの少なくとも１つは、Ｈであり、
Ｚ^１は、Ｈ、または、たとえばアリールスルホニル、ｔｅｒｔ−ブトキシカルボニル、メトキシメチル、パラメトキシベンジル、ベンジル、もしくは当業者に知られている適切な他のいずれかの保護基などのアミノ保護基を表す］をアルキル化して、式（ｖ）の化合物

[Wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ are as defined in Formula I;
Y ^{1 ′} , Y ^{2 ′} , and Y ^{3 ′} each represent Y ¹ , Y ² , and Y ³ as defined in Formula I, provided that Y ^{1 ′} , Y ^{2 ′} , and Y ^{3 ′} At least one of them is H,
Z ¹ represents H or an amino protecting group such as arylsulfonyl, tert-butoxycarbonyl, methoxymethyl, paramethoxybenzyl, benzyl, or any other suitable protecting group known to those skilled in the art A compound of formula (v)

［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、Ｙ^３、およびＺ^１は、上記のとおりに規定され、但し、Ｙ^１、Ｙ^２、およびＹ^３のうちの少なくとも１つは、Ｈまたは不在でない］を得るステップと、
（ｂ２）Ｚ^１がＨでない場合、式（ｖ）の化合物のインドール窒素を脱保護して、式Ｉの化合物を得るステップと
を含む製造方法に関する。

[Wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , Y ³ , and Z ¹ are defined as above, provided that , At least one of Y ¹ , Y ² , and Y ³ is not H or absent]
(B2) when Z ¹ is not H, deprotecting the indole nitrogen of the compound of formula (v) to obtain a compound of formula I.

According to one embodiment, the alkylation step (a2) comprises the compound Y ⁴ -X of formula (vi)
In which Y ⁴ represents Y ¹ , Y ² , or Y ³ as defined in formula I, provided that Y ⁴ is not H or absent,
X is halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy), 6 to 10 carbon atoms Represents arylsulfonyloxy (preferably phenyl or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art.

  According to one embodiment, step (a2) of the method of the invention includes, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, It can be carried out in the presence of a base such as sodium hydride, lithium diisopropylamide, butyl lithium and the like.

  According to one embodiment, step (a2) of the method of the invention comprises the presence of a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, tert-butanol, THF, dioxane, dichloromethane, water, etc. Can be implemented below.

  According to one embodiment, step (a2) of the method of the invention is carried out in the presence or absence of a catalytic amount of a suitable iodide salt, such as but not limited to tetrabutylammonium iodide. Can do.

  According to one embodiment, step (a2) of the method of the invention can be carried out at a temperature in the range of 20 ° C. to about 180 ° C. with or without microwave irradiation.

  According to one embodiment, step (a2) of the method of the invention can be carried out for a period ranging from 10 minutes to several hours, for example 10 minutes to 24 hours.

  According to one embodiment, the deprotection step (b2) can be performed under the conditions described above for deprotection (b1).

The present invention further relates to compounds of formula II-2a1 wherein Y ¹ is H

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、およびＹ^２は、式Ｉで規定したとおりである］の第三の製造方法であって、
（ａ３）式（ｖｉｉ）の化合物

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , and Y ² are as defined in Formula I. The third manufacturing method of
(A3) Compound of formula (vii)

［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３は、上で規定したとおりであり、
Ｚ^１は、Ｈ、または、たとえばアリールスルホニル、ｔｅｒｔ−ブトキシカルボニル、メトキシメチル、パラメトキシベンジル、ベンジル、もしくは当業者に知られている適切な他のいずれかの保護基などのアミノ保護基を表す］を、
式（ｖｉｉｉ）の化合物

[Wherein X ¹ , X ² , R ¹ , R ² , R ³ are as defined above,
Z ¹ represents H or an amino protecting group such as arylsulfonyl, tert-butoxycarbonyl, methoxymethyl, paramethoxybenzyl, benzyl, or any other suitable protecting group known to those skilled in the art ]
Compound of formula (viii)

［式中、Ｙ^２は、上記のとおりに規定され、
Ｙは、ヒドロキシル、ハロゲン（好ましくは、ヨウ素、臭素、または塩素）、１〜６個の炭素原子を有するアルキルスルホニルオキシ（好ましくは、メチルスルホニルオキシまたはトリフルオロメチルスルホニルオキシ）、６〜１０個の炭素原子を有するアリールスルホニルオキシ（好ましくは、フェニルまたはｐ−トリルスルホニルオキシ）、または当業者に知られている他のいずれかの脱離基を表す］と反応させて、
式（ｉｘ）の化合物

[Wherein Y ² is defined as above,
Y is hydroxyl, halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy), 6 to 10 Reaction with arylsulfonyloxy having a carbon atom (preferably phenyl or p-tolylsulfonyloxy, or any other leaving group known to those skilled in the art)
Compound of formula (ix)

［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｙ^２、およびＺ^１は、上記のとおりに規定される］を得るステップと、
（ｂ３）Ｚ^１がＨでない場合、式（ｉｘ）の化合物のインドールアミンを脱保護して、Ｙ^１がＨであるＩＩ−２ａ１の化合物を得るステップと
を含む製造方法に関する。

Obtaining X ¹ , X ² , R ¹ , R ² , R ³ , Y ² and Z ¹ as defined above;
(B3) when Z ¹ is not H, deprotecting the indoleamine of the compound of formula (ix) to obtain a compound of II-2a1 in which Y ¹ is H.

  According to one embodiment, when Y represents hydroxyl, step (a3) of the method of the invention is present in the presence of a suitable amide coupling reagent such as but not limited to HATU, DCC, DIC, BOP, PyBOP Below, this can be done with or without additional additives such as, but not limited to, HOBt.

  According to one embodiment, step (a3) of the method of the invention comprises a base such as, but not limited to, triethylamine, diisopropylethylamine, DBU, cesium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide. Can be carried out in the presence of

  According to one embodiment, step (a3) of the method of the invention can be carried out in the presence of a suitable solvent such as, but not limited to, dichloromethane, DMF, THF, dioxane.

  According to one embodiment, step (a3) further comprises adding a suitable acid, such as but not limited to acetic acid, whenever necessary to complete the cyclization.

  According to one embodiment, step (a3) of the method of the invention can be carried out at a temperature in the range of 20 ° C. to about 180 ° C. with or without microwave irradiation.

  According to one embodiment, step (a3) of the method of the invention can be carried out for a period ranging from 10 minutes to several hours, for example 10 minutes to 24 hours.

  According to one embodiment, the deprotection step (b3) can be performed under the conditions described above for deprotection (b1).

  The present invention further relates to compounds of formula I

ならびに薬学的に許容できるその鏡像異性体、塩、および溶媒和物［式中、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりである］の第四の製造方法であって、
（ａ４）式（ｘ）の化合物

And pharmaceutically acceptable enantiomers, salts, and solvates thereof, wherein X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ^2. And Y ³ is as defined in formula I],
(A4) Compound of formula (x)

［式中、
Ｘ^１およびＸ^２は、式Ｉで規定したとおりであり、
Ｚ^１は、Ｈ、または、たとえばアリールスルホニル、ｔｅｒｔ−ブトキシカルボニル、メトキシメチル、パラメトキシベンジル、ベンジル、もしくは当業者に知られている適切な他のいずれかの保護基などのアミノ保護基を表し、
Ｚ^２およびＺ^３は、Ｈまたはアルキル基を表すか、Ｚ^２およびＺ^３は、環を形成していてもよい］を、
式（ｘｉ）の化合物

[Where:
X ¹ and X ² are as defined in Formula I,
Z ¹ represents H or an amino protecting group such as arylsulfonyl, tert-butoxycarbonyl, methoxymethyl, paramethoxybenzyl, benzyl or any other suitable protecting group known to those skilled in the art. ,
Z ² and Z ³ represent H or an alkyl group, or Z ² and Z ³ may form a ring]
Compound of formula (xi)

［式中、
Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、式Ｉで規定したとおりであり、
Ｙは、ハロゲン（好ましくは、ヨウ素、臭素、または塩素）、１〜６個の炭素原子を有するアルキルスルホニルオキシ（好ましくは、メチルスルホニルオキシまたはトリフルオロメチルスルホニルオキシ）、６〜１０個の炭素原子を有するアリールスルホニルオキシ（好ましくは、フェニルまたはｐ−トリルスルホニルオキシ）、または当業者に知られているいずれかの脱離基を表す］と反応させて、
式（ｘｉｉ）の化合物

[Where:
R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are as defined in Formula I;
Y is halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy), 6 to 10 carbon atoms An arylsulfonyloxy having a formula (preferably phenyl or p-tolylsulfonyloxy) or any leaving group known to those skilled in the art]
Compound of formula (xii)

［式中、Ｚ^１、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ａ^１、Ａ^２、Ａ^３、Ｙ^１、Ｙ^２、およびＹ^３は、上で規定したとおりである］を得るステップと、
（ｂ４）Ｚ^１がＨでない場合、式（ｘｉｉ）の化合物のインドールアミンを脱保護して、式Ｉの化合物を得るステップと
を含む製造方法に関する。

[Wherein Z ¹ , X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are as defined above] And getting the steps
(B4) when Z ¹ is not H, deprotecting the indoleamine of the compound of formula (xii) to obtain a compound of formula I.

According to one embodiment, step (a4) of the method of the invention includes, but is not limited to, Pd ₂ (dba) ₃ , Pd (PPh ₃ ) ₄ , dichlorobis (triphenylphosphine) palladium (II) or 1, Catalysts such as 1′-bis (diphenylphosphino) ferrocenedichloropalladium (II), Pd (OAc) ₂ , Pd / C are not limited, but include X-Phos, S-Phos, P (oTol) ₃ , PPh. ₃ , BINAP, P (tBu) ₃ , or any other suitable phosphine ligand known to those skilled in the art, with or without the use of additional ligands, Can be implemented.

According to one embodiment, step (a4) of the method of the invention can be carried out in the presence of a base, such as but not limited to K ₃ PO ₄ , K ₂ CO ₃ , Na ₂ CO _3. .

  According to one embodiment, step (a4) of the method of the invention is preferably in the presence of a suitable solvent, such as but not limited to dioxane, THF, DMF, water, or mixtures thereof. Or it can be carried out in a mixture of THF and water.

  According to one embodiment, step (a4) of the method of the invention comprises a period in the range of 10 minutes to several hours at a temperature in the range of 20 ° C. to about 180 ° C. with or without microwave irradiation. For example, it can be carried out for 10 minutes to 24 hours.

  According to one embodiment, the deprotection step (b4) can be performed under the conditions described above for deprotection (b1).

  In general, the route of synthesis of any individual compound of formula (I) depends on the availability of the specific substituents on each molecule and the required intermediates, and these factors are also well recognized by those skilled in the art. ing.

  According to another general method, compounds of formula I can be converted to alternative compounds of formula I using suitable interchange techniques well known to those skilled in the art.

  Compounds of formula I and related formulas can also be obtained by liberating compounds of formula I from one of its functional derivatives by treatment with solvolytic or hydrocracking agents.

Preferred starting materials for solvolysis or hydrogenolysis are those of the formula I and except that instead of one or more free amino and / or hydroxyl groups, the corresponding protected amino / or hydroxyl groups are included. Consistent with the relevant formulas, preferably those having an amino protecting group instead of the H atom bonded to the N atom, in particular the R ^* -N group instead of the HN group [R ^* means an amino protecting group And / or having a hydroxyl protecting group in place of the H atom of the hydroxyl group, eg, a —COOR ^** group in place of a —COOH group [R ^** means a hydroxyl protecting group] Except having, it is in accordance with Formula I.

  There may be multiple protected amino and / or hydroxyl groups in the starting material molecule, the same or different. If the protecting groups present are different from one another, these protecting groups can often be selectively detached.

  The term “amino-protecting group” is known in general terms and is suitable for protecting (blocking) an amino group against chemical reactions, but carrying out the desired chemical reaction elsewhere in the molecule. Pertains to groups that are easily removed after being removed. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting group is removed after the desired reaction (or subsequent reaction), its type and size are still not so important, but 1-20, especially 1-8 carbon atoms Those having the following are preferred. The term “acyl group” is understood in a broad sense in connection with the present method. The term refers to an acyl group derived from an aliphatic, araliphatic, aromatic, or heterocyclic carboxylic acid or sulfonic acid, in particular an alkoxycarbonyl, aryloxycarbonyl, in particular an aralkoxycarbonyl group. Is included. Examples of such acyl groups are: alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl and tolyl; aryloxyalkanoyl such as POA; methoxycarbonyl, ethoxycarbonyl, 2,2,2- Alkoxycarbonyls such as trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkoxycarbonyls such as CBZ (“carbobenzoxy”), 4-methoxybenzyloxycarbonyl, FMOC; and Mtr Arylsulfonyl. Preferred amino protecting groups are BOC and Mtr, as well as CBZ, Fmoc, benzyl and acetyl.

  The term “hydroxyl protecting group” is also known in general terms and is suitable for protecting hydroxyl groups against chemical reactions, but the desired chemical reaction has been carried out elsewhere in the molecule. Related to groups that are easily removed later. Typical of such groups are unsubstituted or substituted aryl, aralkyl, or acyl groups referred to above, and also alkyl groups. The nature and size of the hydroxyl protecting group is not critical as such protecting groups are also removed after the desired chemical reaction or subsequent reaction, with 1-20, especially 1-10 carbon atoms. The group having is preferable. Examples of hydroxyl protecting groups are in particular benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

  Depending on the protecting group used, the compounds of formula I and related formulas can be, for example, strong inorganic acids such as hydrochloric acid, perchloric acid, sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid, TFA, or benzene or p-toluene. Freed from sulfonic acids, such as sulfonic acids, and functional derivatives thereof. The presence of an additional inert solvent can be considered but is not necessary. Suitable inert solvents are organic, for example, carboxylic acids such as acetic acid, ethers such as tetrahydrofuran and dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol, isopropanol, and water. It is preferable that Further suitable are mixtures of the solvents mentioned above. TFA is preferably used in excess without the addition of a separate solvent, and perchloric acid is preferably used in the form of a 9: 1 ratio mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is advantageously between about 0 ° C. and about 50 ° C., preferably between 15 ° C. and 30 ° C. (room temperature).

  BOC, OtBu, and Mtr groups can be preferably cleaved using, for example, TFA in dichloromethane or using approximately 3-5N HCl dioxane solution at 15-30 ° C. It can be cleaved using approximately 5-50% DMF solution of dimethylamine, diethylamine, or piperidine at 30 ° C.

  Protecting groups that can be removed by hydrogenolysis (eg, liberation of amidino groups from CBZ, benzyl, or oxadiazole derivatives thereof) are, for example, catalysts (eg noble metal catalysts such as palladium, preferably carbon and the like). It can be separated by hydrogen treatment in the presence of the support). Suitable solvents here are those indicated above, in particular, for example, alcohols such as methanol and ethanol, or amides such as DMF. The hydrogenolysis is generally carried out at a temperature between about 0 ° C. and 100 ° C., a pressure between about 1 bar and 200 bar, preferably 20-30 ° C. and 1-10 bar. Hydrogenolysis of the CBZ group can be accomplished, for example, using 5-10% Pd / C in methanol, or Pd / C in methanol / DMF at 20-30 ° C. (instead of hydrogen) with ammonium formate. Use with good results.

  Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene, xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform, dichloromethane Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol and tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) and dioxane; ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether ( Glycol ethers such as diglyme); ketones such as acetone and butanone; acetamide, dimethylacetamide, N-methylpyrrolidone (N P), amides such as dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid and acetic acid; nitro compounds such as nitromethane and nitrobenzene; An ester, or a mixture of said solvents.

Esters use, for example, HCl, H ₂ SO ₄ or LiOH, NaOH, or water at a temperature between 0 ° C. and 100 ° C. in water, water / THF, water / THF / ethanol, or water / dioxane. It can be hydrolyzed using KOH.

  Furthermore, the free amino group can be acylated conventionally using acyl chloride or anhydrous acyl, or advantageously in an inert solvent such as dichloromethane or THF and / or such as triethylamine or pyridine. Alkylation can be carried out using unsubstituted or substituted alkyl halides in the presence of a base at temperatures between −60 ° C. and + 30 ° C.

  All of the protection and deprotection methods are described in Philip J. et al. Kocienski, “Protecting Groups”, Georg Thieme Verlag, Stuttgart, New York, 1994, and Theodora W. Greene and Peter G. M.M. See Wuts, “Protective Groups in Organic Synthesis”, Wiley Interscience, 3rd edition, 1999.

  The reaction schemes described in the Examples section are merely illustrative and should not be construed as limiting the invention in any way.

Fields of Application The present invention is further directed to the use of the compounds of the invention or pharmaceutically acceptable enantiomers, salts, and solvates thereof as TDO2 inhibitors.

  Accordingly, in a particularly preferred embodiment, the present invention provides compounds of formula I, and subformulae, particularly those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, TDO2 Relates to use as an inhibitor.

  Accordingly, in another aspect, the invention relates to the use of such compounds, or enantiomers, salts, and solvates thereof, for synthesizing active pharmaceutical ingredients such as TDO2 inhibitors.

  In one embodiment, the present invention relates to immunorecognition of cancer cells of compounds of formula I and subformulas, particularly those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof. And for use to enhance destruction.

  Therefore, the compounds of the present invention are useful as pharmaceuticals, particularly in the prevention and / or treatment of cancer.

  In one aspect, the compound of the invention, or a pharmaceutically acceptable enantiomer, salt, or solvate thereof, is a neurodegenerative disorder such as cancer, Parkinson's disease, Alzheimer's disease, Huntington's disease, HCV and HIV, etc. For use in the treatment and / or prevention of chronic viral infections, depression, and obesity.

  The present invention further provides a method for treating or preventing cancer, Parkinson's disease, Alzheimer's disease, neurodegenerative disorders such as Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity. To a mammalian species comprising a therapeutically effective amount of a compound according to the invention, or a pharmaceutically acceptable enantiomer, salt, or solvate thereof.

  Various cancers are known in the art. The cancer may be metastatic or non-metastatic. The cancer may be familial or scattered. In some embodiments, the cancer is selected from the group consisting of leukemia and multiple myeloma. Additional cancers that can be treated using the methods of the present invention include, for example, benign and malignant solid tumors and benign and malignant non-solid tumors.

  Examples of solid tumors include but are not limited to biliary tract cancer, brain tumors (including glioblastoma and medulloblastoma), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer , Esophageal cancer, stomach cancer, intraepithelial neoplasia (including Bowen and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (epithelial cells) , Including those arising from stromal cells, embryonic cells, and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumor), sarcoma (leiomyosarcoma, Including rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), including skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), embryonic tumors Testicular cancer (seminal epithelioma, and malformation) And non-seminomas, such as choriocarcinoma), stromal tumors, germ cell tumor, and include thyroid cancer (thyroid gland cancer and medullary carcinoma), and the like.

  Examples of non-solid tumors include, but are not limited to, hematopoietic neoplasms. As used herein, hematopoietic neoplasm is a terminology that encompasses lymphoid disorders, myeloid disorders, and AIDS-related leukemias.

  Lymphatic disorders include, but are not limited to, acute lymphoblastic leukemia and chronic lymphoproliferative disorders (eg, lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin lymphoma, and lymphocytic lymphoma. Chronic lymphocytic leukemia includes, for example, T cell chronic lymphocytic leukemia and B cell chronic lymphocytic leukemia.

  The present invention also includes administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable enantiomer, salt, and solvate thereof. Provide a method of delaying the onset of cancer in

  The patient is preferably a warm-blooded animal, more preferably a human.

  The compounds of the present invention are particularly useful in the treatment and / or prevention of cancer.

  In certain embodiments, the compounds of the invention are particularly useful in the treatment and / or prevention of cancer.

  The present invention further provides the use of a compound of formula I, or a pharmaceutically acceptable enantiomer, salt, and solvate thereof, for the manufacture of a medicament for treating and / or preventing cancer.

  According to another feature of the present invention, a method of modulating TDO2 activity in a patient in need of such treatment, preferably a warm-blooded animal, more preferably a human, comprising: Provided is a method comprising administering a compound of the invention, or a pharmaceutically acceptable enantiomer, salt, and solvate thereof.

Formulations The invention also includes a compound of Formula I or a pharmaceutically acceptable enantiomer, salt, and solvate thereof and at least one carrier, diluent, pharmaceutical additive, and / or pharmaceutically acceptable Pharmaceutical compositions comprising an adjuvant are provided. As indicated above, the present invention contains additional therapeutic agents and / or active ingredients in addition to the compounds of the present invention as active ingredients, pharmaceutically acceptable enantiomers, salts, and solvates thereof. The pharmaceutical composition is also covered.

  Another object of the invention is a medicament comprising as active ingredient at least one compound of the invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.

  According to another feature of the invention, a compound of formula I or a pharmaceutically acceptable enantiomer, salt, and salt for the manufacture of a medicament that modulates TDO2 activity in a patient in need of such treatment, and The use of a solvate, wherein such treatment comprises administering to said patient an effective amount of a compound of the invention, or a pharmaceutically acceptable enantiomer, salt, and solvate thereof. Use is provided.

  In general, the compounds of the present invention, for use as a medicament, with at least one compound of the present invention and at least one pharmaceutically acceptable carrier, diluent, pharmaceutical additive, and / or adjuvant, Can be formulated as a pharmaceutical preparation comprising one or more other pharmaceutically active compounds.

  By way of non-limiting example, such formulations can be administered orally, parenterally (such as by intravenous, intramuscular, or subcutaneous injection, or intravenous infusion), topical (including intraocular), inhalation, skin It can be in a form suitable for administration by patches, implants, suppositories and the like. Such suitable dosage forms and methods, which can be solid, semi-solid or liquid depending on the mode of administration, and the carriers, diluents and pharmaceutical additives used in the preparation thereof will be apparent to those skilled in the art, The latest version of Remington's Pharmaceutical Sciences is helpful.

  Some preferred but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, Aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions, and sterilization for administration as a bolus and / or continuous administration (usually restored before use) Packaging powders, which are carriers, pharmaceutical additives, and diluents suitable for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, Tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, polyethylene glycol , Cellulose, may be formulated with (sterile) water, methylcellulose, methyl- and propyl, talc, magnesium stearate, edible oils, vegetable oils, and mineral oils or suitable mixtures thereof. Formulations include lubricants, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, bulking agents, excipients, preservatives, sweeteners, flavoring agents, flow control agents, release agents, etc. Other substances commonly used in pharmaceutical formulations may optionally be included. The composition can also be formulated so that immediate, sustained, delayed release of the active compound it contains is achieved.

  The pharmaceutical preparation of the present invention is preferably in unit dosage form, eg, a box, blister, vial, bottle, sachet, ampoule, or any other suitable single or multi-dose holder or container (appropriate Can be appropriately packaged, optionally with one or more folded prints containing product information and / or instructions for use.

  The active compounds of the invention may be administered substantially as a single daily dose, in one or more divided daily doses or using, for example, infusion, depending on the condition to be prevented or treated and the route of administration. Can be administered continuously.

Definitions In the present invention, the following terms have the following meanings.
In the case where a group may be substituted, such a group may be substituted with one or more substituents, preferably one, two or three substituents. Substituents may be selected from the group including, but not limited to, for example, halogen, hydroxyl, oxo, nitro, amide, carboxy, amino, cyano, haloalkoxy, and haloalkyl.

  The term “halogen” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The following definitions are used in connection with the compounds described herein. In general, the number of carbon atoms present in a given group is indicated by “C _x -C _y ”, where x and y are the lower and upper limits, respectively. The number of carbons used in the definition in the present specification refers to a carbon main chain and a carbon branch, but does not include carbon atoms of substituents such as alkoxy substituents. Unless otherwise indicated, nomenclature of substituents not explicitly defined herein is determined by naming the terminal portion of the functional group followed by the functional group adjacent to the point of attachment from left to right. As used herein, “optionally substituted” means that at least one hydrogen atom of the optionally substituted group is replaced.

The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl radical of the formula C _n H _{2n + 1} where n is a number greater than or equal to 1. Alkyl groups contain 1-10 (including 1 and 10) carbons, ie, C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10, ie, C1-C10 alkyl. It's okay. In certain embodiments, the alkyl groups of the present invention contain 1-6 carbon atoms, preferably 1-4 carbon atoms, more preferably 1-3 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and its isomers (eg, n-pentyl, iso- Pentyl), and hexyl and its isomers (eg, n-hexyl, iso-hexyl).

  The term “haloalkyl”, alone or in combination, refers to an alkyl radical having the meaning as defined above, wherein one or more hydrogens have been replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl and the like. In one example, a haloalkyl is a C1-C6 alkyl group that is substituted with at least one halogen. In another example, haloalkyl is a C1-C4 alkyl group substituted with at least one halogen. Each halogen substitution may be independently selected.

  The term “cycloalkyl” as used herein is a cyclic alkyl group, in other words a monovalent saturated or unsaturated hydrocarbyl group having one or two cyclic structures. Cycloalkyl includes mono- or bicyclic hydrocarbyl groups. Cycloalkyl groups may contain 3 or more carbon atoms in the ring, generally according to the present invention 3-10, more preferably 3-8 carbon atoms, even more preferably 3-3 carbon atoms. Contains 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

  The term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom.

  When at least one carbon atom in the cycloalkyl group is replaced with a heteroatom, the resulting ring is referred to herein as “heterocyclyl”.

  The term “heterocyclyl” or “heterocycle” as used herein, alone or as part of another group, has at least one heteroatom in at least one carbon-containing atomic ring (eg, 3 Refers to a non-aromatic fully saturated or partially unsaturated cyclic group containing ˜7 membered monocyclic, 7-11 membered bicyclic, or a total of 3-10 ring atoms. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, and nitrogen and sulfur heterogeneous The atom may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Heterocycles can accommodate 3-7 (including 3 and 7) or an integer number of carbon atoms in between. Any of the carbon atoms of the heterocyclic group may be substituted with oxo (eg, piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system that is permitted in terms of valence. The rings of the polycyclic heterocycle may be fused, bridged and / or linked via one or more spiro atoms. Typical non-limiting heterocyclic groups include piperidinyl, azetidinyl, tetrahydropyranyl, piperazinyl, imidazolinyl, morpholinyl, oxetanyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazo Examples include lysinyl, indolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and pyrrolidinyl.

  As used herein, the term “aryl” refers to a single ring (ie, phenyl) or multiple aromatics that are fused or covalently bonded, usually containing 5 to 12, preferably 6 to 10 atoms. Refers to a polyunsaturated aromatic hydrocarbyl group having a ring (eg, naphthyl) and at least one ring being aromatic. The aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to encompass partially hydrogenated derivatives of the carbocyclic (carbocyclic ring) systems listed herein. Non-limiting examples of aryl include phenyl, biphenylyl, biphenylenylnaphthalenyl, indenyl.

  As used herein, the term “heteroaryl”, by itself or as part of another group, includes, but is not limited to, a fused or covalently bonded 1 containing usually 5 to 6 atoms. Contains two rings, at least one of which is aromatic, and one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen, and / or sulfur atoms , Refers to an aromatic ring or ring system of 5 to 12 carbon atoms, nitrogen and sulfur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. Such a ring may be fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl ring. Non-limiting examples of such heteroaryl include pyridazinyl, pyridinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl , Pyrazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

  The term “arylalkyl” refers to any -alkyl-aryl group. The term “alkylaryl” refers to any -aryl-alkyl group.

  The term “heteroarylalkyl” refers to any -alkyl-heteroaryl group. The term “alkylheteroaryl” refers to any -heteroaryl-alkyl group.

  The term “alkoxy” refers to any O-alkyl group. The term “haloalkoxy” refers to any O-haloalkyl group.

  The term “oxo” refers to the ═O moiety.

  The term “amino” refers to the group —NH 2 or any group derived therefrom by replacing one or two hydrogen atoms with an organic aliphatic or aromatic group. The group derived from —NH 2 is preferably an “alkylamino” group including monoalkylamino and dialkylamino, ie, an N-alkyl group. Non-limiting examples of the term “amino” include NH 2, NHMe, or NMe 2.

  The term “amino protecting group” refers to a protecting group for an amine functionality. According to a preferred embodiment, the amino protecting group is selected in the group comprising arylsulfonyl, tert-butoxycarbonyl, methoxymethyl, paramethoxybenzyl, or benzyl.

  The term “leaving group” refers to a molecular fragment that is separated with a pair of electrons in a heterogeneous bond cleavage. According to a preferred embodiment, the leaving group is halogen, preferably iodine, bromine or chlorine, alkylsulfonyloxy having 1 to 6 carbon atoms, preferably methylsulfonyloxy or trifluoromethylsulfonyloxy, or 6 Selected in the group comprising arylsulfonyloxy having 10 carbon atoms, preferably phenyl- or p-tolylsulfonyloxy.

  The term “solvate”, as used herein, describes a compound in the present invention that contains one or more pharmaceutically acceptable solvent molecules, eg, ethanol, in a stoichiometric or substoichiometric amount. Used for In general, solvates do not substantially alter the physiological activity or toxicity of the compound, and as such, as pharmacological equivalents of the non-solvate compounds of formula I and its subformulas as defined herein. Can function. As used herein, the term “solvate” is a complex, physical association, and / or solvation of a compound of the invention with a solvent molecule. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In one particular example, a solvate can be isolated, such as when one or more solvent molecules are incorporated into a crystalline lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. “Solvate” may include solvates of salts of the compounds of Formula I.

The term “hydrate” refers to the case where the solvent molecule is water, which may be an inorganic salt containing nH ₂ O, where n is the number of water molecules per formula unit of the salt. N may be an integer of 1/2, 1 and 1/2, or 1-10. Hydrate that lost water.

  The compounds of the present invention include compounds of formula I as defined above, including all polymorphs and crystal habits thereof, prodrugs and prodrugs thereof, and isotopically-labelled compounds of formula I .

  The present invention also generally encompasses all pharmaceutically acceptable pre- and prodrugs of compounds of Formula I.

  As used herein, the term “prodrug” refers to a pharmacologically acceptable compound of Formula I, such as, for example, an ester whose in vivo biotransformation product yields a biologically active drug. Derivative means. Prodrugs are generally characterized by increased bioavailability and are readily metabolized in vivo to biologically active compounds.

  As used herein, the term “pre-drug” means any compound that is modified to produce a drug species, and the modification can be either internal or external to the body, and It may be before or after the pre-drug reaches the body region to which the administration of the drug is indicated.

  The term “patient” refers to a warm-blooded animal, more preferably a human, who is waiting to receive medical care, is receiving medical care, or is a subject of medical treatment.

  The term “human” refers to a subject of both sexes in any developmental stage (ie, neonate, child, young, adolescent, adult).

  As used herein, the terms “treat”, “treating”, and “treatment” include alleviating, alleviating, or eliminating a condition or disease and / or associated symptoms. To do.

  As used herein, the terms “prevent”, “preventing”, and “prevention” refer to a patient experiencing a condition or disease that delays or prevents the onset of the condition or disease and / or associated symptoms. It refers to a method of preventing or reducing the risk that a patient will suffer from a condition or disease.

  As used herein, the term “therapeutically effective amount” (or more simply “effective amount”) is an active agent or activity that is sufficient to obtain the desired therapeutic or prophylactic effect in the patient to whom it is administered. Means the amount of ingredients.

  The term “administration” or variations thereof (eg, “administering”) refers to an active agent or active ingredient, alone or pharmaceutically acceptable composition, in a patient to be treated or prevented from a condition, symptom, or disease. It is meant to be provided as part of the product.

  “Pharmaceutically acceptable” means that the components of the pharmaceutical composition are compatible with each other and are not harmful to the patient.

  The term “pharmaceutical vehicle” as used herein means a carrier or inert medium used as a solvent or diluent in which a pharmaceutically active agent is contained and formulated and / or administered. To do. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

  The words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively. The words “consisting”, “consisting” and variations thereof are interpreted inclusively rather than inclusively.

  As used herein, the term “about” means 10% variability from a given criterion, unless otherwise specified.

  The invention will be better understood with reference to the following examples. These examples are representative of specific embodiments of the invention and are not intended to limit the scope of the invention.

I. Chemical Examples Mass spectrometry (MS) data provided in the examples described below were obtained as follows. Mass spectrum: LC / MS Agilent 6110 (electrospray ionization, ESI) or Waters Acquity SQD (ESI).

  The NMR data provided in the examples described below was obtained as follows. Bruker Ultrashield ™ 400PLUS and Bruker Fourier 300 MHz. TMS was used as an internal standard.

  Microwave chemical reactions were performed on an Initiator Microwave System EU, Biotage's single-mode microwave reactor.

Preparative high performance liquid chromatography (HPLC) purification was performed on a Waters mass automated purification Fractionlynx equipped with an Xbridge ™ Prep C18 OBD column 19 × 150 mm 5 μm unless otherwise reported. All HPLC purifications were CH ₃ CN / H ₂ O / NH ₄ HCO ₃ (5 mM), CH ₃ CN / H ₂ O / TFA (0.1%), or CH ₃ CN / H ₂ O / NH ₃ H _2. Performed with a gradient of O (0.1%).

The following abbreviations are used herein and have the definitions shown.
ACN is acetonitrile, DMSO is dimethyl sulfoxide, DCM is dichloromethane, DIPEA is diisopropylethylamine, DMF is N, N-dimethylformamide, dppf is 1,1′- Bis (diphenylphosphino) ferrocene, EtOH is ethanol, HATU is 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluoro Phosphate methanaminium, Hz is hertz, KOAc is potassium acetate, MeOH is methanol, MHz is megahertz, mM is millimolar, mL is milliliters , min is minute, mol is the molar, ^{M +} is, A child ions, [M + ^{H] +} is a protonated molecular ion, N represents a normality, NMR is nuclear magnetic resonance, PPh ₃ is triphenyl phosphine, psi is Square inches per pound, PPM is parts per million, qd po means daily by mouth, rt is room temperature, RT is retention time, TLC is thin layer chromatography TFA is trifluoroacetic acid and TEA is triethylamine.

I. 1. Intermediate Synthesis Intermediate 1: 6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole

表題化合物は、報告されている（ＷＯ２０１０／１３６４９１Ａ１）手順と同じ手順を用いて調製した。

The title compound was prepared using the same procedure as reported (WO2010 / 136491A1).

Intermediate 2:
tert-Butyl 6-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylate

表題化合物は、報告されている（ＵＳ２０１４／２５６７０６Ａ１）手順と同じ手順を用いて調製した。

The title compound was prepared using the same procedure as reported (US2014 / 256706A1).

Intermediate 3: 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole

ＤＭＦ（２０ｍＬ）中の６−ブロモ−１Ｈ−インダゾール（７００ｍｇ；３．５５ｍｍｏｌ）、４，４，４’，４’，５，５，５’，５’−オクタメチル−２，２’−ビ（１，３，２−ジオキサボロラン）（１．５０ｇ；５．９１ｍｍｏｌ）、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＤＣＭ（２９０ｍｇ；０．３６ｍｍｏｌ）およびＫＯＡｃ（１．０４ｇ；１０．６ｍｍｏｌ）の混合物を、窒素下１００℃で１５時間撹拌した。混合物を真空中で濃縮し、ＥｔＯＡｃ（３０ｍＬ）中に懸濁させ、セライトに通して濾過し、濃縮して、８６６ｍｇ（１００％）の表題化合物を褐色半固体として得、これをさらに精製することなく直接使用した。C₁₃H₁₇BN₂O₂+H⁺
[M+H]⁺のLC-MS: 計算値
245.1; 実測値: 245.0.

6-Bromo-1H-indazole (700 mg; 3.55 mmol), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (DMF (20 mL)) 1,3,2-dioxaborolane) (1.50 g; 5.91 mmol), Pd (dppf) Cl ₂ .DCM (290 mg; 0.36 mmol) and KOAc (1.04 g; 10.6 mmol) under nitrogen Stir at 100 ° C. for 15 hours. Concentrate the mixture in vacuo, suspend in EtOAc (30 mL), filter through celite, and concentrate to give 866 mg (100%) of the title compound as a brown semi-solid that is further purified. Used directly without. C ₁₃ H ₁₇ BN ₂ O ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
245.1; found: 245.0.

Intermediate 4: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole

ＤＭＥ（９ｍＬ）および水（３ｍＬ）中の６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１；４００ｍｇ；１．００ｍｍｏｌ）、６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インダゾール（中間体３；３６６ｍｇ；１．５０ｍｍｏｌ）およびＣｓ_２ＣＯ_３（９７８ｍｇ；３．００ｍｍｏｌ）の混合物に、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＤＣＭ（８２ｍｇ；０．１ｍｍｏｌ）を窒素下で添加した。混合物をマイクロ波反応器内１５０℃で１時間加熱した。混合物をセライトに通して濾過し、ＥｔＯＡｃ（１００ｍＬ）および水（１００ｍＬ）で希釈した。水層をＥｔＯＡｃ（５０ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜２／１）により精製して、３９０ｍｇ（１００％）の表題化合物を黄色固体として得た。C₂₁H₁₄FN₃O₂S+H⁺
[M+H]⁺のLC-MS: 計算値392.1;
実測値: 391.8. ¹H NMR (300 MHz, DMSO-d₆)
δ [ppm]: 13.13 (s, 1H), 8.20 - 8.11 (m, 4H), 7.93 -
7.78 (m, 4H), 7.77 - 7.70 (m, 1H), 7.65 - 7.60 (m, 2H), 7.44 (dd, J = 9.3, 2.1
Hz, 1H), 7.26 (ddd, J = 9.3, 9.0, 2.1 Hz, 1H).

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 400 mg; 1.00 mmol), 6- (4,4,5,5) in DME (9 mL) and water (3 mL). To a mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (Intermediate 3; 366 mg; 1.50 mmol) and Cs ₂ CO ₃ (978 mg; 3.00 mmol) was added Pd ( dppf) Cl ₂ · DCM (82 mg; 0.1 mmol) was added under nitrogen. The mixture was heated in a microwave reactor at 150 ° C. for 1 hour. The mixture was filtered through celite and diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 5/1 to 2/1) to give 390 mg (100 %) Of the title compound as a yellow solid. C ₂₁ H ₁₄ FN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: calcd 392.1;
Found: 391.8. ¹ H NMR (300 MHz, DMSO-d ₆ )
δ [ppm]: 13.13 (s, 1H), 8.20-8.11 (m, 4H), 7.93-
7.78 (m, 4H), 7.77-7.70 (m, 1H), 7.65-7.60 (m, 2H), 7.44 (dd, J = 9.3, 2.1
Hz, 1H), 7.26 (ddd, J = 9.3, 9.0, 2.1 Hz, 1H).

Intermediate 5: tert-butyl 4-((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidine-1-carboxylate And tert-butyl 4-((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidine-1-carboxylate

ＤＭＦ（４０ｍＬ）中の６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１；１．００ｇ；２．５５ｍｍｏｌ）、ｔｅｒｔ−ブチル４−（（（メチルスルホニル）オキシ）メチル）ピペリジン−１−カルボキシレート（１．１０ｇ；３．７５ｍｍｏｌ）およびＣｓ_２ＣＯ_３（１．６６ｇ；５．０９ｍｍｏｌ）の混合物を、窒素下６０℃で終夜撹拌した。混合物を室温に冷却し、ＥｔＯＡｃ（１００ｍＬ）で希釈し、濾過し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝６／１〜２／１）により精製して、１．１１ｇ（７４％）の表題化合物の混合物を黄色固体として得た。C₃₂H₃₃FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
589.2; 実測値: 588.9.

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 1.00 g; 2.55 mmol), tert-butyl 4-(((methylsulfonyl) oxy) in DMF (40 mL) A mixture of)) methyl) piperidine-1-carboxylate (1.10 g; 3.75 mmol) and Cs ₂ CO ₃ (1.66 g; 5.09 mmol) was stirred at 60 ° C. overnight under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), filtered, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 6/1 to 2/1) to give 1.11 g (74%). Of the title compound as a yellow solid. C ₃₂ H ₃₃ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
589.2; found: 588.9.

Intermediate 6: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole hydrochloride and 6- (6-fluoro- 1- (Phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H-indazole hydrochloride

ＭｅＯＨ（４０ｍＬ）中のｔｅｒｔ−ブチル４−（（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール−１−イル）メチル）ピペリジン−１−カルボキシレートおよびｔｅｒｔ−ブチル４−（（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２Ｈ−インダゾール−２−イル）メチル）ピペリジン−１−カルボキシレート（中間体５；１．０６ｇ；１．８０ｍｍｏｌ）の溶液に、濃ＨＣｌ水溶液（１６ｍＬ；３７％）を添加した。反応混合物を１時間撹拌し、真空中で濃縮して、１．５５ｇ（定量的）の表題化合物を黄色固体として得、これをさらに精製することなく直接使用した。C₂₇H₂₅FN₄O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
489.2; 実測値: 488.9.

Tert-Butyl 4-((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidine-1-in MeOH (40 mL) Carboxylate and tert-butyl 4-((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidine-1-carboxylate ( To a solution of Intermediate 5; 1.06 g; 1.80 mmol) was added concentrated aqueous HCl (16 mL; 37%). The reaction mixture was stirred for 1 h and concentrated in vacuo to give 1.55 g (quantitative) of the title compound as a yellow solid, which was used directly without further purification. C ₂₇ H ₂₅ FN ₄ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
489.2; found: 488.9.

Intermediate 7: 1- (4-((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) Ethanon

ＤＣＭ（３０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１−（ピペリジン−４−イルメチル）−１Ｈ−インダゾール塩酸塩および６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イルメチル）−２Ｈ−インダゾール塩酸塩（中間体６；６５０ｍｇ；１．２４ｍｍｏｌ）およびＥｔ_３Ｎ（３７２ｍｇ；３．６８ｍｍｏｌ）の溶液に、塩化アセチル（１１６．６ｍｇ；１．４８ｍｍｏｌ）を窒素下で添加した。反応混合物を１時間撹拌し、飽和ＮａＨＣＯ_３水溶液（３０ｍＬ）でクエンチした。水層をＤＣＭ（７０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、分取ＴＬＣ（ＥｔＯＡｃ）により精製して、２６７ｍｇ（４０％）の表題化合物を黄色固体として得た。C₂₉H₂₇FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
531.2; 実測値: 530.9.

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole hydrochloride in DCM (30 mL) and 6- (6- Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H-indazole hydrochloride (Intermediate 6; 650 mg; 1.24 mmol) and Et ₃ N (372 mg) Acetyl chloride (116.6 mg; 1.48 mmol) was added to a solution of 3.68 mmol) under nitrogen. The reaction mixture was stirred for 1 h and quenched with saturated aqueous NaHCO ₃ (30 mL). The aqueous layer was extracted with DCM (70 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (EtOAc) to give 267 mg (40%) of the title compound as a yellow solid Got as. C ₂₉ H ₂₇ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
531.2; Found: 530.9.

Intermediate 8: 3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) propanamide

ＤＭＦ（６ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール（中間体４；２００ｍｇ；０．５１ｍｍｏｌ）、３−ブロモプロパンアミド（３８９ｍｇ；２．５６ｍｍｏｌ）、Ｋ_２ＣＯ_３（２１１ｍｇ；１．５３ｍｍｏｌ）およびＫＩ（８５ｍｇ；０．５１ｍｍｏｌ）の混合物を、マイクロ波反応器内１３０℃で２時間加熱した。混合物をＨ_２Ｏ（２０ｍＬ）に注ぎ入れ、水層をＥｔＯＡｃ（５０ｍＬ×２）で抽出した。合わせた有機層をブライン（１００ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝２／１〜０／１）により精製して、９５ｍｇ（４０％）の表題化合物を黄色固体として得た。C₂₄H₁₉FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
463.1; 実測値: 462.8.

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 4; 200 mg; 0.51 mmol), 3-bromopropanamide (DMF (6 mL)) 389 mg; 2.56 mmol), K ₂ CO ₃ (211 mg; 1.53 mmol) and KI (85 mg; 0.51 mmol) were heated in a microwave reactor at 130 ° C. for 2 hours. The mixture was poured into H ₂ O (20 mL) and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 2/1 to 0/1). Afforded 95 mg (40%) of the title compound as a yellow solid. C ₂₄ H ₁₉ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
463.1; found: 462.8.

Intermediate 9: tert-butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) piperidine-1-carboxylate and tert- Butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate

ＤＭＦ（２２ｍＬ）中の６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１；５６０ｍｇ；１．４３ｍｍｏｌ）、ｔｅｒｔ−ブチル４−（（メチルスルホニル）オキシ）ピペリジン−１−カルボキシレート（０．６０ｇ；２．１５ｍｍｏｌ）およびＣｓ_２ＣＯ_３（１．００ｇ；３．０７ｍｍｏｌ）の混合物を、窒素下６０℃で終夜撹拌した。混合物を室温に冷却し、ＥｔＯＡｃ（１００ｍＬ）で希釈し、濾過し、濃縮して、８２０ｍｇ（定量的）の表題化合物の混合物を黄色固体として得、これをさらに精製することなく直接使用した。C₃₁H₃₁FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
575.2; 実測値: 574.8.

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 560 mg; 1.43 mmol), tert-butyl 4-((methylsulfonyl) oxy) piperidine- in DMF (22 mL) A mixture of 1-carboxylate (0.60 g; 2.15 mmol) and Cs ₂ CO ₃ (1.00 g; 3.07 mmol) was stirred overnight at 60 ° C. under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), filtered and concentrated to give 820 mg (quantitative) of the title compound mixture as a yellow solid, which was used directly without further purification. C ₃₁ H ₃₁ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
575.2; found: 574.8.

Intermediate 10: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazole hydrochloride and 6- (6-fluoro- 1- (Phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-yl) -2H-indazole hydrochloride

ｔｅｒｔ−ブチル４−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール−１−イル）ピペリジン−１−カルボキシレートおよびｔｅｒｔ−ブチル４−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２Ｈ−インダゾール−２−イル）ピペリジン−１−カルボキシレート（中間体９；８２０ｍｇ；１．４３ｍｍｏｌ）から出発し、中間体６で概説した一般的方法に従って、７３０ｍｇ（１００％）の表題化合物の混合物を黄色固体として得、これをさらに精製することなく直接使用した。C₂₆H₂₃FN₄O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
475.2; 実測値: 474.8.

tert-Butyl 4- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) piperidine-1-carboxylate and tert-butyl 4- ( Starting from 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (Intermediate 9; 820 mg; 1.43 mmol) According to the general procedure outlined in Intermediate 6, 730 mg (100%) of the title compound mixture was obtained as a yellow solid, which was used directly without further purification. C ₂₆ H ₂₃ FN ₄ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
475.2; found: 474.8.

Intermediate 11: 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole

ＤＭＦ（１０ｍＬ）中の５−ブロモ−１Ｈ−インダゾール（５００ｍｇ；２．５４ｍｍｏｌ）、４，４，４’，４’，５，５，５’，５’−オクタメチル−２，２’−ビ（１，３，２−ジオキサボロラン）（１．２９ｇ；５．０８ｍｍｏｌ）、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＤＣＭ（２００ｍｇ；０．２４ｍｍｏｌ）およびＫＯＡｃ（１．２４ｇ；１２．６ｍｍｏｌ）の混合物を、窒素下９０℃で１５時間撹拌した。混合物を真空中で濃縮し、ＥｔＯＡｃ（１００ｍＬ）で希釈し、Ｈ_２Ｏ（５０ｍＬ×２）、ブライン（５０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、セライトに通して濾過し、濃縮して、１．１８ｇ（定量的）の表題化合物を黄色油状物として得、これをさらに精製することなく直接使用した。C₁₃H₁₇BN₂O₂+H⁺
[M+H]⁺のLC-MS: 計算値
245.1; 実測値: 245.2.

5-Bromo-1H-indazole (500 mg; 2.54 mmol), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi in DMF (10 mL) 1,3,2-dioxaborolane) (1.29 g; 5.08 mmol), Pd (dppf) Cl ₂ .DCM (200 mg; 0.24 mmol) and KOAc (1.24 g; 12.6 mmol) under nitrogen. Stir at 90 ° C. for 15 hours. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with H ₂ O (50 mL × 2), brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered through celite and concentrated. 1.18 g (quantitative) of the title compound was obtained as a yellow oil which was used directly without further purification. C ₁₃ H ₁₇ BN ₂ O ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
245.1; found: 245.2.

Intermediate 12: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole

ＤＭＥ（６ｍＬ）および水（２ｍＬ）中の６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１；２００ｍｇ；０．５０ｍｍｏｌ）、５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インダゾール（中間体１１；３４５ｍｇの粗製物；０．７４ｍｍｏｌ）およびＣｓ_２ＣＯ_３（４８８ｍｇ；１．５０ｍｍｏｌ）の混合物に、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＤＣＭ（４０ｍｇ；０．０５ｍｍｏｌ）を窒素下で添加した。混合物をマイクロ波反応器内１５０℃で３０分間加熱した。混合物をセライトに通して濾過し、ＥｔＯＡｃ（１００ｍＬ）および水（１００ｍＬ）で希釈した。水層をＥｔＯＡｃ（５０ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、３００ｍｇ（定量的）の表題化合物を黄色油状物として得、これをさらに精製することなく直接使用した。C₂₁H₁₄FN₃O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
392.1; 実測値: 392.0.

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 200 mg; 0.50 mmol), 5- (4,4,5,5) in DME (6 mL) and water (2 mL). To a mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (Intermediate 11; 345 mg crude; 0.74 mmol) and Cs ₂ CO ₃ (488 mg; 1.50 mmol) , Pd (dppf) Cl ₂ · DCM (40 mg; 0.05 mmol) was added under nitrogen. The mixture was heated in a microwave reactor at 150 ° C. for 30 minutes. The mixture was filtered through celite and diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 300 mg (quantitative) of the title compound as a yellow oil that was used directly without further purification. did. C ₂₁ H ₁₄ FN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
392.1; found: 392.0.

Intermediate 13: 2- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) acetamide and 2- (5- (6-fluoro- 1- (Phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) acetamide

ＤＭＦ（１２ｍＬ）中の５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール（中間体１２；５００ｍｇ；１．２８ｍｍｏｌ）、２−ブロモアセトアミド（９００ｍｇ；６．５２ｍｍｏｌ）、Ｋ_２ＣＯ_３（５４０ｍｇ；３．９１ｍｍｏｌ）およびＫＩ（２２０ｍｇ；１．３３ｍｍｏｌ）の混合物を、マイクロ波反応器内１３０℃で４時間加熱した。混合物をＨ_２Ｏ（１０ｍＬ）に注ぎ入れ、ＥｔＯＡｃ（２０ｍＬ×４）で抽出した。合わせた有機層をブライン（２０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、３５３ｍｇ（６２％）の表題化合物の混合物を褐色固体として得、これをさらに精製することなく直接使用した。C₂₃H₁₇FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
449.1; 実測値: 448.8.

5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 12; 500 mg; 1.28 mmol), 2-bromoacetamide (900 mg) in DMF (12 mL) 6.52 mmol), K ₂ CO ₃ (540 mg; 3.91 mmol) and KI (220 mg; 1.33 mmol) were heated in a microwave reactor at 130 ° C. for 4 hours. The mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (20 mL × 4). The combined organic layers are washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 353 mg (62%) of the title compound mixture as a brown solid, which is further purified. Used directly without. C ₂₃ H ₁₇ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
449.1; found: 448.8.

Intermediate 14: tert-butyl 4-((5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidine-1-carboxylate And tert-butyl 4-((5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidine-1-carboxylate

５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール（中間体１２；１．５０ｇ；３．８３ｍｍｏｌ）およびｔｅｒｔ−ブチル４−（（（メチルスルホニル）オキシ）メチル）ピペリジン−１−カルボキシレート（１．３４ｇ；４．５７ｍｍｏｌ）から出発し、中間体５で概説した一般的方法に従って、１．９７ｇ（８８％）の表題化合物の混合物を褐色油状物として得、これをさらに精製することなく直接使用した。C₃₂H₃₃FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
589.2; 実測値: 588.8.

5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 12; 1.50 g; 3.83 mmol) and tert-butyl 4-(((methylsulfonyl Starting from) oxy) methyl) piperidine-1-carboxylate (1.34 g; 4.57 mmol) and following the general procedure outlined in Intermediate 5, 1.97 g (88%) of a mixture of the title compounds was obtained as a brown oil Which was used directly without further purification. C ₃₂ H ₃₃ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
589.2; found: 588.8.

Intermediate 15: tert-butyl 4-((5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidine-1-carboxylate

ＭｅＯＨ（４０ｍＬ）中のｔｅｒｔ−ブチル４−（（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール−１−イル）メチル）ピペリジン−１−カルボキシレートおよびｔｅｒｔ−ブチル４−（（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２Ｈ−インダゾール−２−イル）メチル）ピペリジン−１−カルボキシレート（中間体１４；２．００ｇ；３．４０ｍｍｏｌ）の溶液に、水（２ｍＬ）中のＮａＯＨ（６７９ｍｇ；１７．０ｍｍｏｌ）の溶液を添加した。反応混合物を８５℃で３０分間撹拌し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝３／１）により精製して、１．１８ｇ（７７％）の表題化合物を黄色固体として得た。C₂₆H₂₉FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値
449.2; 実測値: 448.9

Tert-Butyl 4-((5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidine-1-in MeOH (40 mL) Carboxylate and tert-butyl 4-((5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidine-1-carboxylate ( To a solution of intermediate 14; 2.00 g; 3.40 mmol) was added a solution of NaOH (679 mg; 17.0 mmol) in water (2 mL). The reaction mixture was stirred at 85 ° C. for 30 min, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 3/1) to give 1.18 g (77%) of the title compound as a yellow solid. C ₂₆ H ₂₉ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
449.2; found: 448.9

Intermediate 16: 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) propanamide and 3- (5- (6-fluoro -1- (Phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) propanamide

５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール（中間体１２；４９０ｍｇ；１．２５ｍｍｏｌ）から出発し、中間体８で概説した一般的方法に従って、４９２ｍｇ（８５％）の表題化合物の混合物を褐色固体として得、これをさらに精製することなく直接使用した。C₂₄H₁₉FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
463.2; 実測値: 462.8.

General method outlined in Intermediate 8 starting from 5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 12; 490 mg; 1.25 mmol) Gave a mixture of 492 mg (85%) of the title compound as a brown solid, which was used directly without further purification. C ₂₄ H ₁₉ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
463.2; found: 462.8.

Intermediate 17: tert-butyl 4- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) piperidine-1-carboxylate

ＤＭＦ（３５ｍＬ）中の５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール（中間体１２；１．８０ｇ；４．６０ｍｍｏｌ）およびＣｓ_２ＣＯ_３（３．７５ｇ；１１．５ｍｍｏｌ）の混合物に、ｔｅｒｔ−ブチル４−（メチルスルホニルオキシ）ピペリジン−１−カルボキシレート（１．９３ｇ；６．９１ｍｍｏｌ）を窒素下で添加した。反応混合物を７０℃で終夜撹拌した。混合物を氷水（１８０ｍＬ）に注ぎ入れ、ＥｔＯＡｃ（８０ｍＬ×３）で抽出した。合わせた有機層を水（５０ｍＬ）、ブライン（５０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜２／１）により精製して、１．７５ｇ（６６％）の表題化合物を黄色固体として得た。C₃₁H₃₁FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
575.2; 実測値: 574.9.

5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 12; 1.80 g; 4.60 mmol) and Cs ₂ CO _{3 in} DMF (35 mL) To a mixture of (3.75 g; 11.5 mmol), tert-butyl 4- (methylsulfonyloxy) piperidine-1-carboxylate (1.93 g; 6.91 mmol) was added under nitrogen. The reaction mixture was stirred at 70 ° C. overnight. The mixture was poured into ice water (180 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and silica gel chromatography (petroleum ether / EtOAc = 5/1 to 2/1) To give 1.75 g (66%) of the title compound as a yellow solid. C ₃₁ H ₃₁ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
575.2; found: 574.9.

Intermediate 18: tert-butyl 4- (5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) piperidine-1-carboxylate

ＭｅＯＨ（６０ｍＬ）中のｔｅｒｔ−ブチル４−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール−１−イル）ピペリジン−１−カルボキシレート（中間体１７；１．７５ｇ；３．０５ｍｍｏｌ）の溶液に、水（６ｍＬ）中のＮａＯＨ（８００ｍｇ；２０．０ｍｍｏｌ）の溶液を添加した。反応混合物を８５℃で６時間撹拌し、真空中で濃縮した。残留物をＥｔＯＡｃ（８０ｍＬ）に溶解し、水（４０ｍＬ）、ブライン（４０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜２／１）により精製して、６００ｍｇ（４５％）の表題化合物を黄色油状物として得た。C₂₅H₂₇FN₄O₂+H⁺-(CH₃)₂C=CH₂
[M+H-(CH₃)₂C=CH₂]⁺のLC-MS: 計算値 379.2; 実測値: 378.9.

Tert-Butyl 4- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) piperidine-1-carboxylate (60 mL) in MeOH (60 mL) To a solution of Intermediate 17; 1.75 g; 3.05 mmol) was added a solution of NaOH (800 mg; 20.0 mmol) in water (6 mL). The reaction mixture was stirred at 85 ° C. for 6 hours and concentrated in vacuo. The residue was dissolved in EtOAc (80 mL), washed with water (40 mL), brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and silica gel chromatography (petroleum ether / EtOAc = 5 / Purification by 1-2 / 1) gave 600 mg (45%) of the title compound as a yellow oil. C ₂₅ H ₂₇ FN ₄ O ₂ + H ⁺ -(CH ₃ ) ₂ C = CH _{2
[M + H- (CH 3)} 2 C = CH 2] + of LC-MS: calc 379.2; found: 378.9.

Intermediate 19: 1- (4-((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidin-1-yl) Ethanon

分取ＴＬＣ（ＥｔＯＡｃ）により中間体７の位置異性体として精製した後、３５８ｍｇ（５４％）の表題化合物を黄色固体として得た。C₂₉H₂₇FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
531.2; 実測値: 530.9.

After purification as a regioisomer of intermediate 7 by preparative TLC (EtOAc), 358 mg (54%) of the title compound were obtained as a yellow solid. C ₂₉ H ₂₇ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
531.2; Found: 530.9.

Intermediate 20: 3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) propanamide

中間体８の調製中、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝２／１〜０／１）による精製後に、表題化合物（７０ｍｇ、２９％）を黄色固体として得た。

During the preparation of Intermediate 8, after purification by silica gel chromatography (petroleum ether / EtOAc = 2/1 to 0/1), the title compound (70 mg, 29%) was obtained as a yellow solid.

Intermediate 21: tert-butyl 4-((5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidine-1-carboxylate

中間体１５の調製中、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝３／１）による精製後に、表題化合物（３７７ｍｇ、２５％）を黄色固体として得た。C₂₆H₂₉FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値
449.2; 実測値: 448.9

During the preparation of intermediate 15, after purification by silica gel chromatography (petroleum ether / EtOAc = 3/1), the title compound (377 mg, 25%) was obtained as a yellow solid. C ₂₆ H ₂₉ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
449.2; found: 448.9

Intermediate 22: 5- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H-indazole

１，４−ジオキサン中飽和ＨＣｌ（１０ｍＬ）中のｔｅｒｔ−ブチル４−（（５−（６−フルオロ−１Ｈ−インドール−３−イル）−２Ｈ−インダゾール−２−イル）メチル）ピペリジン−１−カルボキシレート（中間体２１；１８９ｍｇ；０．４２ｍｍｏｌ）の溶液を、室温で１時間撹拌した。反応混合物を真空中で濃縮し、水（２０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。水層をＮａＯＨ水溶液でｐＨ＝１３に塩基性化し、ＥｔＯＡｃ（８０ｍＬ×３）で抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、分取ＴＬＣ（ＤＣＭ／ＭｅＯＨ＝１０／１）により精製して、１３６ｍｇ（９３％）の表題化合物を黄色固体として得た。C₂₁H₂₁FN₄+H⁺ [M+H]⁺のLC-MS: 計算値 349.2; 実測値: 348.9.

Tert-Butyl 4-((5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidine-1-in saturated HCl (10 mL) in 1,4-dioxane A solution of carboxylate (Intermediate 21; 189 mg; 0.42 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, diluted with water (20 mL) and extracted with EtOAc (50 mL × 3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with EtOAc (80 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (DCM / MeOH = 10/1) to give 136 mg (93%) of the title compound as a yellow solid. It was. LC-MS for C ₂₁ H ₂₁ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 349.2; Found: 348.9.

Intermediate 23: tert-butyl 4- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate

中間体１７の調製中、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜２／１）による精製後に、表題化合物（３８０ｍｇ、１４％）を黄色固体として得た。C₃₁H₃₁FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
575.2; 実測値: 574.9.

During the preparation of intermediate 17, after purification by silica gel chromatography (petroleum ether / EtOAc = 5/1 to 2/1), the title compound (380 mg, 14%) was obtained as a yellow solid. C ₃₁ H ₃₁ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
575.2; found: 574.9.

Intermediate 24: tert-butyl 4- (5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate

ｔｅｒｔ−ブチル４−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２Ｈ−インダゾール−２−イル）ピペリジン−１−カルボキシレート（中間体２３；１．７５ｇ；３．０４ｍｍｏｌ）から出発し、中間体１５で概説した一般的方法に従って、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜２／１）よる精製後に、０．６ｇ（４５％、あまり純粋ではない）の表題化合物を黄色油状物として得た。C₂₅H₂₇FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値
435.5; 実測値: 434.9.

tert-Butyl 4- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (Intermediate 23; 1. Starting from 75 g; 3.04 mmol) and after purification by silica gel chromatography (petroleum ether / EtOAc = 5/1 to 2/1) according to the general procedure outlined in intermediate 15, 0.6 g (45%, less The impure title compound was obtained as a yellow oil. C ₂₅ H ₂₇ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
435.5; found: 434.9.

Intermediate 25: tert-butyl 5-bromo-1H-benzo [d] imidazole-1-carboxylate and tert-butyl 6-bromo-1H-benzo [d] imidazole-1-carboxylate

ＴＨＦ（５０ｍＬ）中の５−ブロモ−１Ｈ−ベンゾ［ｄ］イミダゾール（１．００ｇ；５．０８ｍｍｏｌ）の混合物に、Ｂｏｃ_２Ｏ（１．３３ｇ；６．０９ｍｍｏｌ）、Ｅｔ_３Ｎ（７７０ｍｇ；７．６１ｍｍｏｌ）およびＤＭＡＰ（６２ｍｇ；０．５１ｍｍｏｌ）を添加した。混合物を窒素下室温で終夜撹拌し、真空中で濃縮した。残留物をＥｔＯＡｃ（１５０ｍＬ）に溶解し、Ｈ_２Ｏ（８０ｍＬ×２）、ブライン（８０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、１．３０ｇ（８６％）の表題化合物の混合物を黄色油状物として得、これをさらに精製することなく直接使用した。C₁₂H₁₃BrN₂O₂+H⁺-(CH₃)₂C=CH₂
[M+H-(CH₃)₂C=CH₂]⁺のLC-MS: 計算値241.0; 実測値:
240.9. ¹H NMR (300 MHz, CDCl₃) δ [ppm]: 8.42 (s, 0.5H), 8.40 (s, 0.5H), 8.20 (s, 0.5H), 7.95 (s,
0.5H), 7.88 (d, J = 8.7 Hz, 0.5H), 7.66 (d, J = 8.7 Hz, 0.5H), 7.55 - 7.44 (m,
1H), 1.71 (s, 9H), 互変異性体の混合物.

To a mixture of 5-bromo-1H-benzo [d] imidazole (1.00 g; 5.08 mmol) in THF (50 mL) was added Boc ₂ O (1.33 g; 6.09 mmol), Et ₃ N (770 mg; 7 .61 mmol) and DMAP (62 mg; 0.51 mmol) were added. The mixture was stirred overnight at room temperature under nitrogen and concentrated in vacuo. The residue was dissolved in EtOAc (150 mL), washed with H ₂ O (80 mL × 2), brine (80 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to 1.30 g (86% ) Was obtained as a yellow oil which was used directly without further purification. C ₁₂ H ₁₃ BrN ₂ O ₂ + H ⁺ -(CH ₃ ) ₂ C = CH ₂
LC-MS for [M + H- (CH ₃ ) ₂ C═CH ₂ ] ⁺ : Calculated 241.0; Found:
240.9. ¹ H NMR (300 MHz, CDCl ₃ ) δ [ppm]: 8.42 (s, 0.5H), 8.40 (s, 0.5H), 8.20 (s, 0.5H), 7.95 (s,
0.5H), 7.88 (d, J = 8.7 Hz, 0.5H), 7.66 (d, J = 8.7 Hz, 0.5H), 7.55-7.44 (m,
1H), 1.71 (s, 9H), a mixture of tautomers.

Intermediate 26: tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-1-carboxylate and tert-butyl 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-1-carboxylate

ｔｅｒｔ−ブチル５−ブロモ−１Ｈ−ベンゾ［ｄ］イミダゾール−１−カルボキシレートおよびｔｅｒｔ−ブチル６−ブロモ−１Ｈ−ベンゾ［ｄ］イミダゾール−１−カルボキシレート（中間体２５；５００ｍｇ；１．６８ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、１．０９ｇ（定量的）の表題化合物の混合物を黄色油状物として得、これをさらに精製することなく直接使用した。C₁₈H₂₅BN₂O₄+H⁺
[M+H]⁺のLC-MS: 計算値
345.2; 実測値: 345.0.

tert-Butyl 5-bromo-1H-benzo [d] imidazole-1-carboxylate and tert-butyl 6-bromo-1H-benzo [d] imidazole-1-carboxylate (intermediate 25; 500 mg; 1.68 mmol) Starting from, following the general method outlined in Intermediate 3, 1.09 g (quantitative) of the title compound mixture was obtained as a yellow oil which was used directly without further purification. C ₁₈ H ₂₅ BN ₂ O ₄ + H ⁺
[M + H] ⁺ LC-MS: Calculated
345.2; found: 345.0.

Intermediate 27: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazole

ｔｅｒｔ−ブチル５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−カルボキシレートおよびｔｅｒｔ−ブチル６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−カルボキシレート（中間体２６；７３０ｍｇの粗製物；０．４６ｍｍｏｌ）および６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１；３００ｍｇ；０．７５ｍｍｏｌ）から出発し、中間体４で概説した一般的方法に従って、５５０ｍｇ（定量的）の表題化合物を黒色油状物として得、これをさらに精製することなく直接使用した。C₂₁H₁₄FN₃O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
392.1; 実測値: 391.9.

tert-Butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-1-carboxylate and tert-butyl 6- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-1-carboxylate (intermediate 26; 730 mg crude; 0.46 mmol) and Starting from 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 300 mg; 0.75 mmol) and following the general method outlined in Intermediate 4, 550 mg (quantitative) The title compound was obtained as a black oil that was used directly without further purification. C ₂₁ H ₁₄ FN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
392.1; found: 391.9.

Intermediate 28: tert-butyl 5-bromo-2-methyl-1H-benzo [d] imidazole-1-carboxylate

５−ブロモ−２−メチル−１Ｈ−ベンゾ［ｄ］イミダゾール（３．０ｇ；１３．５１ｍｍｏｌ）から出発し、中間体２５で概説した一般的方法に従って、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝８／１〜５／１）による精製後に、１．１４ｇ（２７％）の表題化合物を白色固体として得た。C₁₃H₁₅BrN₂O₂+H⁺-(CH₃)₂C=CH₂
[M+H-(CH₃)₂C=CH₂]⁺のLC-MS: 計算値256.0; 実測値:
256.8. ¹H NMR (300 MHz, CDCl₃) δ [ppm]: 7.79 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.76 (m,
2H), 7.41 (dd, J = 8.7, 2.0 Hz, 1H), 2.82 (s, 3H), 1.72 (s, 9H).

Starting from 5-bromo-2-methyl-1H-benzo [d] imidazole (3.0 g; 13.51 mmol), follow silica gel chromatography (petroleum ether / EtOAc = 8 / After purification by 1-5 / 1), 1.14 g (27%) of the title compound were obtained as a white solid. C ₁₃ H ₁₅ BrN ₂ O ₂ + H ⁺ -(CH ₃ ) ₂ C = CH ₂
LC-MS for [M + H- (CH ₃ ) ₂ C═CH ₂ ] ⁺ : Calculated 256.0; Found:
256.8. ¹ H NMR (300 MHz, CDCl ₃ ) δ [ppm]: 7.79 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.76 (m,
2H), 7.41 (dd, J = 8.7, 2.0 Hz, 1H), 2.82 (s, 3H), 1.72 (s, 9H).

Intermediate 29: tert-butyl 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-1-carboxylate

ｔｅｒｔ−ブチル５−ブロモ−２−メチル−１Ｈ−ベンゾ［ｄ］イミダゾール−１−カルボキシレート（中間体２８；１．１４ｇ；３．６７ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１）による精製後に、１．５１ｇ（定量的）の表題化合物を白色固体として得た。C₁₉H₂₇BN₂O₄+H⁺
[M+H]⁺のLC-MS: 計算値359.2;
実測値: 359.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 7.91 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.64
(d, J = 8.2 Hz, 1H), 2.72 (s, 3H), 1.66 (s, 9H), 1.32 (s, 12H).

Starting from tert-butyl 5-bromo-2-methyl-1H-benzo [d] imidazole-1-carboxylate (Intermediate 28; 1.14 g; 3.67 mmol) and following the general procedure outlined for Intermediate 3 After purification by silica gel chromatography (petroleum ether / EtOAc = 5/1), 1.51 g (quantitative) of the title compound was obtained as a white solid. C ₁₉ H ₂₇ BN ₂ O ₄ + H ⁺
[M + H] ⁺ LC-MS: calcd 359.2;
Found: 359.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 7.91 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.64
(d, J = 8.2 Hz, 1H), 2.72 (s, 3H), 1.66 (s, 9H), 1.32 (s, 12H).

Intermediate 30: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-methyl-1H-benzo [d] imidazole

ｔｅｒｔ−ブチル２−メチル−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−カルボキシレート（中間体２９；１．０８ｇ；３．０１ｍｍｏｌ）および６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１；８０２ｍｇ；１．９９ｍｍｏｌ）から出発し、中間体４で概説した一般的方法に従って、シリカゲルクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝４０／１〜２０／１）による精製後に、８７０ｍｇ（定量的）の表題化合物を黒色固体として得た。C₂₂H₁₆FN₃O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
406.1; 実測値: 405.8.

tert-Butyl 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-1-carboxylate (Intermediate 29) 1.08 g; 3.01 mmol) and 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 802 mg; 1.99 mmol), and outlined in Intermediate 4 According to standard methods, after purification by silica gel chromatography (DCM / MeOH = 40/1 to 20/1), 870 mg (quantitative) of the title compound were obtained as a black solid. C ₂₂ H ₁₆ FN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
406.1; found: 405.8.

Intermediate 31: 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzene-1,2-diamine

ジオキサン（２００ｍＬ）中の４−ブロモベンゼン−１，２−ジアミン（１０．８ｇ；５７．７ｍｍｏｌ）、ＫＯＡｃ（１７．０ｇ；１７３ｍｍｏｌ）および４４，４，４’，４’，５，５，５’，５’−オクタメチル−２，２’−ビ（１，３，２−ジオキサボロラン）（１６．１ｇ；６３．４ｍｍｏｌ）の混合物に、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＤＣＭ（２．３６ｇ；２．８９ｍｍｏｌ）を窒素下で添加した。反応混合物を１００℃で１６時間撹拌し、室温に冷却し、濾過し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜２／１）により精製して、１１．６ｇ（８６％）の表題化合物を褐色油状物として得た。C₁₂H₁₉BN₂O₂+H⁺
[M+H]⁺のLC-MS: 計算値235.2;
実測値: 235.0. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 7.22 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), d, J =
7.7 Hz, 1H, 1.32 (s, 12H).

4-Bromobenzene-1,2-diamine (10.8 g; 57.7 mmol), KOAc (17.0 g; 173 mmol) and 44,4,4 ′, 4 ′, 5,5,5 in dioxane (200 mL) To a mixture of ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (16.1 g; 63.4 mmol), Pd (dppf) Cl ₂ · DCM (2.36 g; 2. 89 mmol) was added under nitrogen. The reaction mixture was stirred at 100 ° C. for 16 hours, cooled to room temperature, filtered, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 5/1 to 2/1) to give 11.6 g (86% ) Was obtained as a brown oil. C ₁₂ H ₁₉ BN ₂ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 235.2;
Found: 235.0. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 7.22 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), d, J =
7.7 Hz, 1H, 1.32 (s, 12H).

Intermediate 32: 4- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine

ジオキサン（３００ｍＬ）および水（６０ｍＬ）中の６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１；１９．９ｇ；４９．６ｍｍｏｌ）、４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゼン−１，２−ジアミン（中間体３１；１１．６ｇ；４９．６ｍｍｏｌ）、Ｐｄ（ｄｐｐｆ）Ｃｌ_２・ＤＣＭ（２．０ｇ；２．４５ｍｍｏｌ）、Ｋ_２ＣＯ_３（２０．５ｇ；１４８ｍｍｏｌ）の混合物を、窒素下１００℃で２時間撹拌した。反応混合物を室温に冷却し、濾過し、濃縮し、シリカゲルクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝２００／１〜２０／１）により精製して、７．０ｇ（３７％）の表題化合物を褐色油状物として得た。C₂₀H₁₆FN₃O₂S+H⁺
[M+H]⁺のLC-MS: 計算値382.1;
実測値: 381.8. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 7.90 (d, J = 7.6 Hz, 1H), 7.77 (dd, J = 9.7,
2.0 Hz, 1H), 7.68 (dd, J = 8.7, 5.3 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.49 - 7.43
(m, 2H), 7.01 (ddd, J = 9.3, 8.7, 2.3 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.78 (d, J =
7.6 Hz, 1H).

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1; 19.9 g; 49.6 mmol), 4- (4,4,4) in dioxane (300 mL) and water (60 mL). 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzene-1,2-diamine (intermediate 31; 11.6 g; 49.6 mmol), Pd (dppf) Cl ₂ · DCM (2 0.0 g; 2.45 mmol), K ₂ CO ₃ (20.5 g; 148 mmol) was stirred at 100 ° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered, concentrated and purified by silica gel chromatography (DCM / MeOH = 200/1 to 20/1) to give 7.0 g (37%) of the title compound as a brown oil. Obtained. C ₂₀ H ₁₆ FN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: calcd 382.1;
Found: 381.8. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 7.90 (d, J = 7.6 Hz, 1H), 7.77 (dd, J = 9.7,
2.0 Hz, 1H), 7.68 (dd, J = 8.7, 5.3 Hz, 1H), 7.58-7.53 (m, 2H), 7.49-7.43
(m, 2H), 7.01 (ddd, J = 9.3, 8.7, 2.3 Hz, 1H), 6.94-6.89 (m, 2H), 6.78 (d, J =
(7.6 Hz, 1H).

Intermediate 33: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (2- (methylthio) ethyl) -1H-benzo [d] imidazole

０℃のＤＣＭ（１０ｍＬ）中の４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゼン−１，２−ジアミン（中間体３２；５００ｍｇ；１．３１ｍｍｏｌ）および３−（メチルチオ）プロパン酸（１５７ｍｇ；１．３１ｍｍｏｌ）の混合物に、ＨＡＴＵ（７４８ｍｇ；１．９７ｍｍｏｌ）およびＥｔ_３Ｎ（２６５ｍｇ；２．６２ｍｍｏｌ）を窒素下で添加した。反応混合物を室温で３０分間撹拌し、ＤＣＭ（６０ｍＬ）で希釈し、水（３０ｍＬ）、ブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物をトルエン（１０ｍＬ）で希釈し、１６時間加熱還流した。反応混合物を真空中で濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝１００／１〜６／１）により精製して、４６０ｍｇ（７５％）の表題化合物を褐色油状物として得、これをさらに精製することなく直接使用した。C₂₄H₂₀FN₃O₂S₂+H⁺
[M+H]⁺のLC-MS: 計算値
466.1; 実測値: 465.8.

4- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (Intermediate 32; 500 mg; 1.31 mmol) in DCM (10 mL) at 0 ° C. and To a mixture of 3- (methylthio) propanoic acid (157 mg; 1.31 mmol) was added HATU (748 mg; 1.97 mmol) and Et ₃ N (265 mg; 2.62 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 30 minutes, diluted with DCM (60 mL), washed with water (30 mL), brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was diluted with toluene (10 mL) and heated to reflux for 16 hours. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (petroleum ether / EtOAc = 100/1 to 6/1) to give 460 mg (75%) of the title compound as a brown oil, which was further purified Used directly without. C ₂₄ H ₂₀ FN ₃ O ₂ S ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
466.1; found: 465.8.

Intermediate 34: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) -1H-benzo [d] imidazole

０℃のＤＣＭ（１５ｍＬ）中の５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（２−（メチルチオ）エチル）−１Ｈ−ベンゾ［ｄ］イミダゾール（中間体３３；４６０ｍｇ；０．９９ｍｍｏｌ）の溶液に、ｍＣＰＢＡ（５００ｍｇ；２．４６ｍｍｏｌ；８５％）を少量ずつ添加した。反応混合物をゆっくりと室温に加温し、３０分間撹拌した。混合物を飽和ＮａＨＳＯ_３水溶液（２０ｍＬ）で洗浄し、水層をＤＣＭ（３０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、１７０ｍｇ（３４％）の表題化合物を褐色固体として得、これをさらに精製することなく直接使用した。C₂₄H₂₀FN₃O₄S₂-H^-
[M-H]^-のLC-MS: 計算値496.1; 実測値: 495.9. ¹H NMR
(300 MHz, CDCl₃) δ [ppm]: 7.97 - 7.89 (m,
2H), 7.83 - 7.75 (m, 1H), 7.75 - 7.66 (m, 3H), 7.65 - 7.52 (m, 2H), 7.51 - 7.41
(m, 3H), 7.09 - 6.98 (m, 1H), 3.70 - 3.61 (m, 2H), 3.59 - 3.48 (m, 2H), 2.97
(s, 3H).

5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (2- (methylthio) ethyl) -1H-benzo [d] imidazole in DCM (15 mL) at 0 ° C. To a solution of (Intermediate 33; 460 mg; 0.99 mmol), mCPBA (500 mg; 2.46 mmol; 85%) was added in small portions. The reaction mixture was slowly warmed to room temperature and stirred for 30 minutes. The mixture was washed with saturated aqueous NaHSO ₃ (20 mL) and the aqueous layer was extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 170 mg (34%) of the title compound as a brown solid without further purification. Used directly. _{C 24 H 20 FN 3 O 4} S 2 -H -
. [MH] ^- the LC-MS: calc 496.1; found: 495.9 ¹ H NMR
(300 MHz, CDCl ₃ ) δ [ppm]: 7.97-7.89 (m,
2H), 7.83-7.75 (m, 1H), 7.75-7.66 (m, 3H), 7.65-7.52 (m, 2H), 7.51-7.41
(m, 3H), 7.09-6.98 (m, 1H), 3.70-3.61 (m, 2H), 3.59-3.48 (m, 2H), 2.97
(s, 3H).

Intermediate 35:
tert-Butyl 2- (2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenylamino) -2-oxoethyl (methyl) carbamate and tert-butyl 2- ( 2-Amino-4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenylamino) -2-oxoethyl (methyl) carbamate

ＴＨＦ（１０ｍＬ）およびＤＭＦ（１ｍＬ）中の２−（ｔｅｒｔ−ブトキシカルボニル（メチル）アミノ）酢酸（１６５ｍｇ、０．８７ｍｍｏｌ）およびＨＡＴＵ（３６４ｍｇ、０．９６ｍｍｏｌ）の溶液に、ＤＩＰＥＡ（１８７ｍｇ、１．４５ｍｍｏｌ）を添加した。反応混合物を１０分間撹拌した後、４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゼン−１，２−ジアミン（中間体３２、５００ｍｇ、１．３１ｍｍｏｌ）を添加した。混合物を室温で６０分間撹拌した。混合物を真空中で濃縮し、ＥｔＯＡｃ（３０ｍＬ）で希釈し、水（３０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、６７０ｍｇ（＞１００％）の表題化合物を黒色固体として得、これをさらに精製することなく直接使用した。C₂₂H₁₇ClFN₃O₃S+H⁺-(CH₃)₂C=CH₂
[M+H-(CH₃)₂C=CH₂]⁺のLC-MS: 計算値 497.1; 実測値: 496.8.

To a solution of 2- (tert-butoxycarbonyl (methyl) amino) acetic acid (165 mg, 0.87 mmol) and HATU (364 mg, 0.96 mmol) in THF (10 mL) and DMF (1 mL) was added DIPEA (187 mg, 1.. 45 mmol) was added. The reaction mixture was stirred for 10 minutes before 4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol). Added. The mixture was stirred at room temperature for 60 minutes. The mixture was concentrated in vacuo, diluted with EtOAc (30 mL), washed with water (30 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to 670 mg (> 100%) of the title. The compound was obtained as a black solid and used directly without further purification. C ₂₂ H ₁₇ ClFN ₃ O ₃ S + H ⁺ -(CH ₃ ) ₂ C = CH _{2
[M + H- (CH 3)} 2 C = CH 2] + of LC-MS: calc 497.1; found: 496.8.

Intermediate 36: tert-butyl (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl (methyl) carbamate

ＡｃＯＨ（１０ｍＬ）中のｔｅｒｔ−ブチル２−（２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェニルアミノ）−２−オキソエチル（メチル）カルバメートおよびｔｅｒｔ−ブチル２−（２−アミノ−４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェニルアミノ）−２−オキソエチル（メチル）カルバメート（中間体３５、６７０ｍｇの粗製物、０．８７ｍｍｏｌ）の混合物を、５０℃で６時間撹拌した。混合物を室温に冷却し、飽和Ｎａ_２ＣＯ_３水溶液でｐＨ＝８に中和し、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、６４０ｍｇ（１００％）の表題化合物を黒色固体として得、これをさらに精製することなく直接使用した。C₂₈H₂₇FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
535.2; 実測値: 534.8.

Tert-Butyl 2- (2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenylamino) -2-oxoethyl (methyl) carbamate in AcOH (10 mL) and tert-Butyl 2- (2-amino-4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenylamino) -2-oxoethyl (methyl) carbamate (Intermediate 35, 670 mg of The mixture of crude, 0.87 mmol) was stirred at 50 ° C. for 6 hours. The mixture was cooled to room temperature, neutralized with saturated aqueous Na ₂ CO ₃ to pH = 8 and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 640 mg (100%) of the title compound as a black solid that was used directly without further purification. C ₂₈ H ₂₇ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
535.2; Found: 534.8.

Intermediate 37: tert-butyl (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl (methyl) carbamate

ｔｅｒｔ−ブチル（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）メチル（メチル）カルバメート（中間体３６、６４０ｍｇの粗製物、０．８７ｍｍｏｌ）から出発し、中間体１５で概説した一般的方法に従って、４７０ｍｇ（１００％）の表題化合物を黒色固体として得、これをさらに精製することなく直接使用した。C₂₂H₂₃FN₄O₂+H⁺[M+H]⁺のLC-MS: 計算値 395.2; 実測値: 394.9.

tert-Butyl (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl (methyl) carbamate (Intermediate 36, 640 mg Of crude, 0.87 mmol), and following the general procedure outlined in Intermediate 15, 470 mg (100%) of the title compound was obtained as a black solid, which was used directly without further purification. _{C 22 H 23 FN 4 O 2} + H + [M + H] + of LC-MS: calc 395.2; found: 394.9.

Intermediate 38: N- (2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) -2-chloroacetamide and N- (2-amino-4- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) -2-chloroacetamide

０℃のＤＣＭ（４０ｍＬ）中の４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゼン−１，２−ジアミン（中間体３２、３．８１ｇ、１０．０ｍｍｏｌ）、クロロ酢酸（９４５ｍｇ、１０．０ｍｍｏｌ）およびＥｔ_３Ｎ（２．０２ｇ、２０．０ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（３．８０ｇ、１０．０ｍｍｏｌ）を添加した。反応混合物を室温で１時間撹拌し、水（５０ｍＬ）で希釈し、真空中で濃縮して大部分のＤＣＭを除去した。水性混合物をＥｔＯＡｃ（４０ｍＬ×３）で抽出した。合わせた有機層をブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、３．９６ｇ（８７％）の表題化合物を褐色油状物として得、これをさらに精製することなく直接使用した。
C₂₂H₁₇ClFN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
458.1; 実測値: 457.7.

4- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (Intermediate 32, 3.81 g, 10.0 mmol) in DCM (40 mL) at 0 ° C. ), Chloroacetic acid (945 mg, 10.0 mmol) and Et ₃ N (2.02 g, 20.0 mmol) were added to HATU (3.80 g, 10.0 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with water (50 mL) and concentrated in vacuo to remove most of the DCM. The aqueous mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 3.96 g (87%) of the title compound as a brown oil. Used directly without further purification.
C ₂₂ H ₁₇ ClFN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
458.1; found: 457.7.

Intermediate 39: 2- (Chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazole

ＡｃＯＨ（２０ｍＬ）中のＮ−（２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェニル）−２−クロロアセトアミドおよびＮ−（２−アミノ−４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェニル）−２−クロロアセトアミド（中間体３８、３．９６ｇ、８．６５ｍｍｏｌ）の混合物を、５０℃で１６時間撹拌した。混合物を真空中で濃縮して、大部分のＡｃＯＨを除去した。残留物をＥｔＯＡｃ（１００ｍＬ）で希釈し、飽和ＮａＨＣＯ_３水溶液（３０ｍＬ×２）、ブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、シリカゲルクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝２００／１〜５０／１）により精製して、３．２０ｇ（８４％）の表題化合物を褐色固体として得た。C₂₂H₁₅ClFN₃O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
440.1; 実測値: 439.8.

N- (2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) -2-chloroacetamide and N- (2-amino-) in AcOH (20 mL) A mixture of 4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) -2-chloroacetamide (Intermediate 38, 3.96 g, 8.65 mmol) was added at 50 ° C. at 16 ° C. Stir for hours. The mixture was concentrated in vacuo to remove most of the AcOH. The residue was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO ₃ (30 mL × 2), brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and silica gel chromatography ( Purification by DCM / MeOH = 200/1 to 50/1) gave 3.20 g (84%) of the title compound as a brown solid. C ₂₂ H ₁₅ ClFN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
440.1; found: 439.8.

Intermediate 40: 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) propanoic acid

１，４−ジオキサン（８ｍＬ）中の４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゼン−１，２−ジアミン（中間体３２、５００ｍｇ、１．３１ｍｍｏｌ）および無水コハク酸（１６０ｍｇ、１．６０ｍｍｏｌ）の溶液を、８０℃で４８時間加熱した。混合物を濃縮し、シリカゲルクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝１８／１）により精製して、０．６０ｇ（９９％）の表題化合物を白色固体として得た。C₂₄H₁₈FN₃O₄S+H⁺
[M+H]⁺のLC-MS: 計算値464.1;
実測値: 464.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 12.30 (s, 1H), 8.15 (d, J = 7.7 Hz, 2H), 8.06
(s, 1H), 7.87 - 7.80 (m, 2H), 7.77 - 7.70 (m, 2H), 7.66 - 7.60 (m, 2H), 7.57
(d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.24 (ddd, J = 9.3, 8.7, 2.2 Hz,
1H), 3.57 (s, 1H), 3.07 (t, J = 7.1 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H).

4- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol) in 1,4-dioxane (8 mL) And a solution of succinic anhydride (160 mg, 1.60 mmol) was heated at 80 ° C. for 48 hours. The mixture was concentrated and purified by silica gel chromatography (DCM / MeOH = 18/1) to give 0.60 g (99%) of the title compound as a white solid. C ₂₄ H ₁₈ FN ₃ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: calcd 464.1;
Found: 464.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 12.30 (s, 1H), 8.15 (d, J = 7.7 Hz, 2H), 8.06
(s, 1H), 7.87-7.80 (m, 2H), 7.77-7.70 (m, 2H), 7.66-7.60 (m, 2H), 7.57
(d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.24 (ddd, J = 9.3, 8.7, 2.2 Hz,
1H), 3.57 (s, 1H), 3.07 (t, J = 7.1 Hz, 2H), 2.82 (t, J = 7.1 Hz, 2H).

Intermediate 41: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2,3-dihydro-1H-benzo [d] pyrrolo [1,2-a] imidazole-1 -ON

ＴＨＦ（１５ｍＬ）中の３−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）プロパン酸（中間体４０、５２１ｍｇ、１．１２ｍｍｏｌ）、ＨＡＴＵ（８５５ｍｇ、２．２５ｍｍｏｌ）およびＥｔ_３Ｎ（４５４ｍｇ、４．４９ｍｍｏｌ）の溶液に、ＮＨ_４Ｃｌ（１２０ｍｇ、２．２４ｍｍｏｌ）を窒素下で添加した。混合物を室温で２時間撹拌した。混合物を水（３０ｍＬ）で希釈し、ＤＣＭ（５０ｍＬ×２）およびＥｔＯＡｃ（５０ｍＬ×２）で抽出した。合わせた有機層をブライン（４０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、５５６ｍｇ（＞１００％）の表題化合物を黄色固体として得、これをさらに精製することなく直接使用した。C₂₄H₁₆FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
446.1; 実測値: 446.0.

3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) propanoic acid (intermediate 40) in THF (15 mL) To a solution of 521 mg, 1.12 mmol), HATU (855 mg, 2.25 mmol) and Et ₃ N (454 mg, 4.49 mmol), NH ₄ Cl (120 mg, 2.24 mmol) was added under nitrogen. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with DCM (50 mL × 2) and EtOAc (50 mL × 2). The combined organic layers are washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 556 mg (> 100%) of the title compound as a yellow solid that is further purified. Used directly without. C ₂₄ H ₁₆ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
446.1; found: 446.0.

Intermediate 42: 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] oxazole

５−ブロモベンゾ［ｄ］オキサゾール（５００ｍｇ、２．５２ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝１００／１〜３０／１）による精製後に、５７６ｍｇ（９３％）の表題化合物を白色固体として得た。C₁₃H₁₆BNO₃+H⁺ [M+H]⁺のLC-MS: 計算値246.1; 実測値:
246.0. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.26 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.58
(d, J = 8.0 Hz, 1H), 1.37 (s, 12H).

After purification by silica gel chromatography (petroleum ether / EtOAc = 100/1 to 30/1) according to the general method outlined in intermediate 3, starting from 5-bromobenzo [d] oxazole (500 mg, 2.52 mmol) 576 mg (93%) of the title compound were obtained as a white solid. LC-MS for C ₁₃ H ₁₆ BNO ₃ + H ⁺ [M + H] ⁺ : Calculated 246.1; Found:
246.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.26 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.58
(d, J = 8.0 Hz, 1H), 1.37 (s, 12H).

Intermediate 43: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole

５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾ［ｄ］オキサゾール（中間体４２、３３０ｍｇ、１．３５ｍｍｏｌ）および６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、５４０ｍｇ、１．３５ｍｍｏｌ）から出発し、中間体４で概説した一般的方法に従って、ＭｅＯＨでの再結晶による精製後に、４２３ｍｇ（８０％）の表題化合物を白色固体として得た。C₂₁H₁₃FN₂O₃S+H⁺[M+H]⁺のLC-MS: 計算値393.1; 実測値:
392.8. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.16 (s, 1H), 7.99 - 7.93 (m, 3H), 7.81 (dd, J = 9.5, 2.1
Hz, 1H), 7.73 -7.65 (m, 3H), 7.62 - 7.57 (m, 2H), 7.53 - 7.47 (m, 2H), 7.07
(ddd, J = 9.2, 8.7, 2.2 Hz, 1H).

5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] oxazole (intermediate 42, 330 mg, 1.35 mmol) and 6-fluoro-3-iodo Starting with -1- (phenylsulfonyl) -1H-indole (Intermediate 1, 540 mg, 1.35 mmol) and following purification by recrystallization with MeOH according to the general procedure outlined in Intermediate 4, 423 mg (80% ) Was obtained as a white solid. LC-MS for C ₂₁ H ₁₃ FN ₂ O ₃ S + H ⁺ [M + H] ⁺ : Calculated 393.1; Found:
392.8. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.16 (s, 1H), 7.99-7.93 (m, 3H), 7.81 (dd, J = 9.5, 2.1
Hz, 1H), 7.73 -7.65 (m, 3H), 7.62-7.57 (m, 2H), 7.53-7.47 (m, 2H), 7.07
(ddd, J = 9.2, 8.7, 2.2 Hz, 1H).

Intermediate 44: 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] oxazole

５−ブロモ−２−メチルベンゾ［ｄ］オキサゾール（５６４ｍｇ、２．６６ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、６８８ｍｇ（１００％）の表題化合物を褐色半固体として得、これをさらに精製することなく直接使用した。C₁₄H₁₈BNO₃+H⁺ [M+H]⁺のLC-MS: 計算値 260.1; 実測値: 260.0.

Starting from 5-bromo-2-methylbenzo [d] oxazole (564 mg, 2.66 mmol) and following the general procedure outlined in Intermediate 3, 688 mg (100%) of the title compound was obtained as a brown semi-solid which Used directly without further purification. LC-MS for C ₁₄ H ₁₈ BNO ₃ + H ⁺ [M + H] ⁺ : Calculated 260.1; Found: 260.0.

Intermediate 45: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-methylbenzo [d] oxazole

２−メチル−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾ［ｄ］オキサゾール（中間体４４、６８８ｍｇ、２．６６ｍｍｏｌ）および６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、７１１ｍｇ、１．７７ｍｍｏｌ）から出発し、中間体４で概説した一般的方法に従って、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜２／１）による精製後に、７１８ｍｇ（１００％）の表題化合物を黄色固体として得た。C₂₂H₁₅FN₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値407.1;
実測値: 406.8. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 8.20 - 8.14 (m, 3H), 7.97 (d, J = 0.8 Hz, 1H),
7.88 - 7.81 (m, 2H), 7.79 - 7.70 (m, 2H) , 7.69 - 7.60 (m, 3H), 7.23 (ddd, J =
9.2, 8.8, 2.4 Hz, 1H), 2.65 (s, 3H) .

2-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] oxazole (intermediate 44, 688 mg, 2.66 mmol) and 6-fluoro Starting with -3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 711 mg, 1.77 mmol), silica gel chromatography (petroleum ether / EtOAc = After purification by 5/1 to 2/1), 718 mg (100%) of the title compound were obtained as a yellow solid. C ₂₂ H ₁₅ FN ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 407.1;
Found: 406.8. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 8.20-8.14 (m, 3H), 7.97 (d, J = 0.8 Hz, 1H),
7.88-7.81 (m, 2H), 7.79-7.70 (m, 2H), 7.69-7.60 (m, 3H), 7.23 (ddd, J =
9.2, 8.8, 2.4 Hz, 1H), 2.65 (s, 3H).

Intermediate 46: tert-butyl (2-((2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) amino) -2-oxoethyl) carbamate

無水ＴＨＦ／ＤＭＦ（１０ｍＬ／１ｍＬ）中のｔｅｒｔ−ブトキシカルボニルアミノ酢酸（１５３ｍｇ、０．８７ｍｍｏｌ）およびＤＩＥＡ（１８８．１４ｍｇ、１．４６ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（３６３．６６ｍｇ、０．９６ｍｍｏｌ）を０℃で添加した。混合物を１０分間撹拌し、４−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゼン−１，２−ジアミン（中間体３２、５００ｍｇ、１．３１ｍｍｏｌ）を添加した。反応混合物を室温で１時間撹拌した。混合物を水（２０ｍＬ）でクエンチし、ＥｔＯＡｃ（３０ｍＬ×３）で抽出した。合わせた有機層をブライン（２０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、６７８ｍｇ（９６％）の表題化合物を黒色半固体として得、これをさらに精製することなく直接使用した。C₂₇H₂₇FN₄O₅S+H⁺:
[M+H]⁺のLC-MS: 計算値
539.2; 実測値: 538.8

To a stirred solution of tert-butoxycarbonylaminoacetic acid (153 mg, 0.87 mmol) and DIEA (188.14 mg, 1.46 mmol) in anhydrous THF / DMF (10 mL / 1 mL) was added HATU (363.66 mg, 0.96 mmol). Was added at 0 ° C. The mixture was stirred for 10 minutes and 4- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 678 mg (96%) of the title compound as a black semi-solid that was used directly without further purification. C ₂₇ H ₂₇ FN ₄ O ₅ S + H ⁺ :
[M + H] ⁺ LC-MS: Calculated
539.2; Found: 538.8

Intermediate 47: tert-butyl ((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) carbamate

ＡｃＯＨ（１０ｍＬ）中のｔｅｒｔ−ブチル（２−（（２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェニル）アミノ）−２−オキソエチル）カルバメート（中間体４６、６７８ｍｇ、１．３１ｍｍｏｌ）の混合物を、窒素下５１℃で６時間撹拌した。混合物をＮａ_２ＣＯ_３の水溶液でｐＨ＝８に中和し、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブライン（１００ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、６３７ｍｇ（９３％）の表題化合物を黒色半固体として得、これをさらに精製することなく直接使用した。C₂₇H₂₅FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値521.2;
実測値: 520.8. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]:12.29 (d, J = 20.0 Hz, 1H), 8.16 (d, J = 7.8
Hz, 2H), 8.08 (d, J = 11.5 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.74 (ddd, J = 11.4,
3.6, 1.2 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.57 - 7.44 (m, 3H), 7.29 - 7.21 (m,
1H), 4.38 (d, J = 5.7 Hz, 2H), 2.70 (d, J = 8.2 Hz, 1H), 1.42 (s, 9H).

Tert-Butyl (2-((2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) amino) -2-oxoethyl) carbamate in AcOH (10 mL) A mixture of (Intermediate 46, 678 mg, 1.31 mmol) was stirred at 51 ° C. under nitrogen for 6 hours. The mixture was neutralized with an aqueous solution of Na ₂ CO ₃ to pH = 8 and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 637 mg (93%) of the title compound as a black semi-solid, which was used directly without further purification. C ₂₇ H ₂₅ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: calcd 521.2;
Found: 520.8. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 12.29 (d, J = 20.0 Hz, 1H), 8.16 (d, J = 7.8
Hz, 2H), 8.08 (d, J = 11.5 Hz, 1H), 7.87-7.80 (m, 2H), 7.74 (ddd, J = 11.4,
3.6, 1.2 Hz, 1H), 7.69-7.60 (m, 2H), 7.57-7.44 (m, 3H), 7.29-7.21 (m,
1H), 4.38 (d, J = 5.7 Hz, 2H), 2.70 (d, J = 8.2 Hz, 1H), 1.42 (s, 9H).

Intermediate 48: tert-butyl ((6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) carbamate

ＭｅＯＨ（３０ｍＬ）中の（（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）メチル）カルバメート（中間体４７、５８７ｍｇ、１．１３ｍｍｏｌ）の溶液に、ＮａＯＨ（４５１ｍｇ、１１．２８ｍｍｏｌ）を添加した。混合物を８５℃で２時間撹拌した。反応混合物を室温に冷却し、濃縮して、４２９ｍｇ（１００％）の表題化合物を黒色半固体として得、これをさらに精製することなく直接使用した。C₂₁H₂₁FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値
381.2; 実測値: 380.9.

((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) carbamate (Intermediate 47) in MeOH (30 mL) , 587 mg, 1.13 mmol) was added NaOH (451 mg, 11.28 mmol). The mixture was stirred at 85 ° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated to give 429 mg (100%) of the title compound as a black semi-solid, which was used directly without further purification. C ₂₁ H ₂₁ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
381.2; found: 380.9.

Intermediate 49: N- (2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) -2- (dimethylamino) acetamide

無水ＴＨＦ（１０ｍＬ）中のジメチルアミノ酢酸（１１０ｍｇ、０．７９ｍｍｏｌ）およびＤＩＥＡ（２０１ｍｇ、１．５６ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（３８５ｍｇ、１．０１ｍｍｏｌ）を０℃で添加した。混合物を１０分間撹拌し、４−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゼン−１，２−ジアミン（中間体３２、３００ｍｇ、０．７８ｍｍｏｌ）を添加した。反応混合物を室温で１時間撹拌した。混合物を水（２０ｍＬ）でクエンチし、ＥｔＯＡｃ（３０ｍＬ×３）で抽出した。合わせた有機層をブライン（２０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、３６３ｍｇ（１００％）の表題化合物を黒色半固体として得、これをさらに精製することなく直接使用した。C₂₄H₂₃FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
467.2 実測値: 466.8.

To a stirred solution of dimethylaminoacetic acid (110 mg, 0.79 mmol) and DIEA (201 mg, 1.56 mmol) in anhydrous THF (10 mL) was added HATU (385 mg, 1.01 mmol) at 0 ° C. The mixture was stirred for 10 minutes and 4- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzene-1,2-diamine (Intermediate 32, 300 mg, 0.78 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 363 mg (100%) of the title compound as a black semi-solid that was used directly without further purification. C ₂₄ H ₂₃ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
467.2 Actual value: 466.8.

Intermediate 50: 1- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-dimethylmethanamine

ＡｃＯＨ（１５ｍＬ）中のＮ−［２−アミノ−５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェニル］−２−ジメチルアミノ−アセトアミド（中間体４９、３６３ｍｇ、０．７８ｍｍｏｌ）の混合物を、窒素下５１℃で５時間撹拌した。混合物をＮａ_２ＣＯ_３の水溶液でｐＨ＝８に中和し、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブライン（１００ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、４４１ｍｇ（９３％）の表題化合物を黒色半固体として得、これをさらに精製することなく直接使用した。C₂₄H₂₁FN₄O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
449.1; 実測値: 449.0.

N- [2-amino-5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenyl] -2-dimethylamino-acetamide (Intermediate 49, 363 mg, in AcOH (15 mL) 0.78 mmol) was stirred at 51 ° C. under nitrogen for 5 hours. The mixture was neutralized with an aqueous solution of Na ₂ CO ₃ to pH = 8 and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 441 mg (93%) of the title compound as a black semi-solid, which was used directly without further purification. C ₂₄ H ₂₁ FN ₄ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
449.1; found: 449.0.

Intermediate 51: tert-butyl (2-(((6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) amino) -2-oxoethyl) Carbamate

無水ＴＨＦ／ＤＭＦ（２０／２ｍＬ）中のｔｅｒｔ−ブトキシカルボニルアミノ酢酸（２５０ｍｇ、１．４３ｍｍｏｌ）およびＤＩＥＡ（３０８ｍｇ、２．３９ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（６５１ｍｇ、１．７１ｍｍｏｌ）を０℃で添加した。混合物を１０分間撹拌し、（６−（６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）メタンアミン（化合物２７、４００ｍｇ、１．４３ｍｍｏｌ）を添加した。反応混合物を室温で１時間撹拌した。反応混合物を水（２０ｍＬ）でクエンチし、ＥｔＯＡｃ（３０ｍＬ×３）で抽出した。合わせた有機層をブライン（２０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、６２４ｍｇ（１００％）の表題化合物を黒色半油状物として得、これをさらに精製することなく直接使用した。C₂₃H₂₄FN₅O₃+H⁺
[M+H]⁺のLC-MS: 計算値
438.2; 実測値: 437.9

To a stirred solution of tert-butoxycarbonylaminoacetic acid (250 mg, 1.43 mmol) and DIEA (308 mg, 2.39 mmol) in anhydrous THF / DMF (20/2 mL) was added HATU (651 mg, 1.71 mmol) at 0 ° C. Added. The mixture was stirred for 10 minutes and (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methanamine (Compound 27, 400 mg, 1.43 mmol) was added. . The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 624 mg (100%) of the title compound as a black semi-oil, which was used directly without further purification. C ₂₃ H ₂₄ FN ₅ O ₃ + H ⁺
[M + H] ⁺ LC-MS: Calculated
438.2; found: 437.9

Intermediate 52: 2-acetamido-N- (2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide

ＴＨＦ（１０ｍＬ）およびＤＭＦ（１ｍＬ）中のＮ−アセチルグリシン（１０２ｍｇ、０．８７ｍｍｏｌ）およびＤＩＰＥＡ（２２６ｍｇ、１．７５ｍｍｏｌ）の溶液に、ＨＡＴＵ（３６５ｍｇ、０．９６ｍｍｏｌ）を添加した。反応混合物を０℃で２０分間撹拌した後、４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゼン−１，２−ジアミン（中間体３２、５００ｍｇ、１．３１ｍｍｏｌ）を添加した。混合物を室温で２時間撹拌し、濃縮し、ＥｔＯＡｃ（５０ｍＬ）および水（４０ｍＬ）で希釈した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、４５８ｍｇ（＞１００％）の粗表題化合物を褐色固体として得、これをさらに精製することなく直接使用した。C₂₄H₂₁FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
481.1; 実測値: 480.8.

To a solution of N-acetylglycine (102 mg, 0.87 mmol) and DIPEA (226 mg, 1.75 mmol) in THF (10 mL) and DMF (1 mL) was added HATU (365 mg, 0.96 mmol). The reaction mixture was stirred at 0 ° C. for 20 minutes before 4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (Intermediate 32, 500 mg, 1. 31 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated and diluted with EtOAc (50 mL) and water (40 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 458 mg (> 100%) of the crude title compound as a brown solid, which was used directly without further purification. C ₂₄ H ₂₁ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
481.1; found: 480.8.

Intermediate 53: N-((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) acetamide

ＨＯＡｃ（１５ｍＬ）中の２−アセトアミド−Ｎ−（２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェニル）アセトアミド（中間体５２、４５８ｍｇの粗製物、０．８７ｍｍｏｌ）の混合物を、窒素下５０℃で２．５時間撹拌した。反応混合物を室温に冷却し、飽和ＮａＨＣＯ_３水溶液でｐＨ＝７に調整し、ＥｔＯＡｃ（２０ｍＬ）で抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、４７０ｍｇ（１００％）の粗表題化合物を黒色固体として得、これをさらに精製することなく直接使用した。C₂₄H₁₉FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
463.1; 実測値: 462.8.

2-acetamido-N- (2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) acetamide (Intermediate 52, 458 mg crude in HOAc (15 mL) Product, 0.87 mmol) was stirred at 50 ° C. under nitrogen for 2.5 hours. The reaction mixture was cooled to room temperature, adjusted to pH = 7 with saturated aqueous NaHCO ₃ and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 470 mg (100%) of the crude title compound as a black solid, which was used directly without further purification. C ₂₄ H ₁₉ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
463.1; found: 462.8.

Intermediate 54: tert-butyl 4-((2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) carbamoyl) piperidine-1-carboxylate

ＴＨＦ（１０ｍＬ）およびＤＭＦ（１ｍＬ）中の１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸（４３０ｍｇ、１．８８ｍｍｏｌ）、ＤＩＰＥＡ（５２０ｍｇ、４．０２ｍｍｏｌ）およびＨＡＴＵ（１．０ｇ、２．６３ｍｍｏｌ）の混合物を、室温で１５分間撹拌した後、４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゼン−１，２−ジアミン（中間体３２、１．０ｇ、２．６２ｍｍｏｌ）を添加した。混合物を室温で１２時間撹拌した後、これを濃縮した。混合物を水でクエンチし、ＥｔＯＡｃで抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、１．６ｇ（＞１００％）の粗表題化合物を黒色油状物として得、これをさらに精製することなく直接使用した。C₃₁H₃₃FN₄O₅S+H⁺
[M+H]⁺のLC-MS: 計算値
593.2; 実測値: 592.9.

1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (430 mg, 1.88 mmol), DIPEA (520 mg, 4.02 mmol) and HATU (1.0 g, 2.mL) in THF (10 mL) and DMF (1 mL). 63 mmol) was stirred for 15 minutes at room temperature and then 4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (intermediate 32, 1.. 0 g, 2.62 mmol) was added. After the mixture was stirred at room temperature for 12 hours, it was concentrated. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 1.6 g (> 100%) of the crude title compound as a black oil that was used directly without further purification. . C ₃₁ H ₃₃ FN ₄ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
593.2; found: 592.9.

Intermediate 55: tert-butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) piperidine-1-carboxy rate

ＨＯＡｃ（２０ｍＬ）中のｔｅｒｔ−ブチル４−（（２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェニル）カルバモイル）ピペリジン−１−カルボキシレート（中間体５４、１．６０ｇの粗製物、１．８８ｍｍｏｌ）の混合物を、窒素下５０℃で４時間撹拌した。反応混合物を室温に冷却し、濃縮し、Ｋ_２ＣＯ_３水溶液でｐＨ＝１１に調整し、ＥｔＯＡｃで抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、６６０ｍｇ（６０％）の粗表題化合物を黄色固体として得、これをさらに精製することなく直接使用した。C₃₁H₃₁FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
575.2; 実測値: 574.9.

Tert-Butyl 4-((2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenyl) carbamoyl) piperidine-1-carboxylate (20 mL) in HOAc (20 mL) A mixture of intermediate 54, 1.60 g crude, 1.88 mmol) was stirred at 50 ° C. under nitrogen for 4 hours. The reaction mixture was cooled to room temperature, concentrated, adjusted to pH = 11 with aqueous K ₂ CO ₃ and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 660 mg (60%) of the crude title compound as a yellow solid that was used directly without further purification. C ₃₁ H ₃₁ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
575.2; found: 574.9.

Intermediate 56: tert-butyl 4- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) piperidine-1-carboxylate

ｔｅｒｔ−ブチル４−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）ピペリジン−１−カルボキシレート（中間体５５、６６０ｍｇ、１．１５ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、６００ｍｇ（＞１００％）の粗表題化合物を黒色油状物として得、これをさらに精製することなく直接使用した。C₂₅H₂₇FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値
435.2; 実測値: 434.9.

tert-Butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) piperidine-1-carboxylate (intermediate) Starting from 55, 660 mg, 1.15 mmol) and following the general method outlined for compound 1, 600 mg (> 100%) of the crude title compound was obtained as a black oil which was used directly without further purification. C ₂₅ H ₂₇ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
435.2; found: 434.9.

Intermediate 57: 2-Amino-5- (6-fluoro-1H-indol-3-yl) phenol

ＭｅＯＨ（１００ｍＬ）中の６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール（７０２ｍｇ、１．８１ｍｍｏｌ）の溶液に、ＮａＯＨ（２１２ｍｇ、５．３１ｍｍｏｌ）を添加した。混合物を６５℃で３時間撹拌した。混合物を真空中で濃縮乾固して、５００ｍｇの表題化合物を褐色固体として得、これをさらに精製することなく直接使用した。C₁₄H₁₁FN₂O+H⁺ [M+H]⁺のLC-MS: 計算値 243.1; 実測値: 243.2.

To a solution of 6- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazole (702 mg, 1.81 mmol) in MeOH (100 mL) was added NaOH (212 mg, 5.31 mmol). did. The mixture was stirred at 65 ° C. for 3 hours. The mixture was concentrated to dryness in vacuo to give 500 mg of the title compound as a brown solid, which was used directly without further purification. _{C 14 H 11 FN 2 O +} H + [M + H] + of LC-MS: calc 243.1; found: 243.2.

Intermediate 58: N- [2-amino-5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenyl] -2-chloro-acetamide and N- [2-amino-4- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenyl] -2-chloro-acetamide

ＤＣＭ（４０ｍＬ）中の４−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゼン−１，２−ジアミン（３．８１ｇ、１０．０ｍｍｏｌ）、クロロ酢酸（９４５ｍｇ、１０．０ｍｍｏｌ）およびＴＥＡ（２．０ｇ、２０．０ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（３．８ｇ、１０．０ｍｍｏｌ）を０℃で添加した。反応混合物を室温で１時間撹拌し、水（５０ｍＬ）でクエンチし、濃縮して大部分のＤＣＭを除去した。水性混合物をＥｔＯＡｃ（４０ｍＬ×３）で抽出した。合わせた有機層をブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、３．９６ｇ（８７％）の表題化合物を褐色油状物として得、これをさらに精製することなく次のステップに使用した。C₂₂H₁₇ClFN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
458.1; 実測値: 457.7.

4- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzene-1,2-diamine (3.81 g, 10.0 mmol), chloroacetic acid (945 mg, 10 mL) in DCM (40 mL). .0 mmol) and TEA (2.0 g, 20.0 mmol) in a stirred solution of HATU (3.8 g, 10.0 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour, quenched with water (50 mL) and concentrated to remove most of the DCM. The aqueous mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 3.96 g (87%) of the title compound as a brown oil that was used in the next step without further purification. C ₂₂ H ₁₇ ClFN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
458.1; found: 457.7.

Intermediate 59: 6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-chloromethyl-1H-benzimidazole

ＡｃＯＨ（２０ｍＬ）中のＮ−［２−アミノ−５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェニル］−２−クロロ−アセトアミドおよびＮ−［２−アミノ−４−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェニル］−２−クロロ−アセトアミド（３．９６ｇ、８．６６ｍｍｏｌ）の混合物を、５０℃で１６時間撹拌し、濃縮して大部分のＡｃＯＨを除去した。残留物をＥｔＯＡｃ（１００ｍＬ）で希釈し、ＮａＨＣＯ_３水溶液（３０ｍＬ×２）、ブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して残留物を得、これをシリカゲルクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝２００／１〜５０／１）により精製して、３．２０ｇ（８４％）の表題化合物を褐色固体として得た。C₂₂H₁₅ClFN₃O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
440.1; 実測値: 439.8.

N- [2-Amino-5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenyl] -2-chloro-acetamide and N- [2-amino- in AcOH (20 mL) A mixture of 4- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenyl] -2-chloro-acetamide (3.96 g, 8.66 mmol) was stirred at 50 ° C. for 16 hours, Concentrated to remove most of the AcOH. The residue was diluted with EtOAc (100 mL), washed with aqueous NaHCO ₃ (30 mL × 2), brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel chromatography (DCM / MeOH = 200/1 to 50/1) to give 3.20 g (84%) of the title compound as a brown solid. C ₂₂ H ₁₅ ClFN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
440.1; found: 439.8.

Intermediate 60: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) -1H-benzo [d] imidazole

ＤＭＦ（３ｍＬ）中の６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−クロロメチル−１Ｈ−ベンゾイミダゾール（中間体５９、２００ｍｇ、０．４５６ｍｍｏｌ）、１−メチル−ピペラジン（７３ｍｇ、０．７２９ｍｍｏｌ）およびＴＥＡ（９２ｍｇ、０．９１ｍｍｏｌ）の混合物を、５０℃で１時間撹拌した。混合物を水（２０ｍＬ）で希釈し、ＤＣＭ（３０ｍＬ×３）で抽出し、ブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮乾固して、２９０ｍｇ（＞１００％）の粗表題化合物を褐色油状物として得た。C₂₇H₂₆FN₅O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
504.2; 実測値: 503.8.

6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-chloromethyl-1H-benzimidazole (Intermediate 59, 200 mg, 0.456 mmol) in DMF (3 mL), 1- A mixture of methyl-piperazine (73 mg, 0.729 mmol) and TEA (92 mg, 0.91 mmol) was stirred at 50 ° C. for 1 hour. The mixture was diluted with water (20 mL), extracted with DCM (30 mL × 3), washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness to give 290 mg (> 100%) of the crude title compound as a brown oil. C ₂₇ H ₂₆ FN ₅ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
504.2; found: 503.8.

Intermediate 61: 2-(((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) amino) ethanol

ＤＭＦ（３ｍＬ）中の６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−クロロメチル−１Ｈ−ベンゾイミダゾール（中間体５９、２００ｍｇ、０．４５６ｍｍｏｌ）、２−アミノ−エタノール（５５ｍｇ、０．９１１ｍｍｏｌ）およびＴＥＡ（９２ｍｇ、０．９１１ｍｍｏｌ）の混合物を、５０℃で２時間撹拌した。次いで、これをＥｔＯＡｃ（５０ｍＬ）で希釈し、ブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮乾固して、１１６ｍｇ（５５％）の粗表題化合物を褐色固体として得た。C₂₄H₂₁FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
465.1; 実測値: 464.9.

6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-chloromethyl-1H-benzimidazole (Intermediate 59, 200 mg, 0.456 mmol) in DMF (3 mL), 2- A mixture of amino-ethanol (55 mg, 0.911 mmol) and TEA (92 mg, 0.911 mmol) was stirred at 50 ° C. for 2 hours. It was then diluted with EtOAc (50 mL), washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness to give 116 mg (55%) of the crude title compound as a brown solid. C ₂₄ H ₂₁ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
465.1; found: 464.9.

Intermediate 62: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperazin-1-ylmethyl) -1H-benzo [d] imidazole

ＤＭＦ（５ｍＬ）中の６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−クロロメチル−１Ｈ−ベンゾイミダゾール（中間体５９、４３９ｍｇ、１．０ｍｍｏｌ）およびピペラジン（２５８ｍｇ、３．０ｍｍｏｌ）の混合物を、６０℃で０．５時間撹拌した。次いで、混合物を水（５０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×２）で抽出した。有機層をブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝２０／１から５／１）により精製して、１７６ｍｇ（３６％）の表題化合物を黄色固体として得た。
C₂₆H₂₄FN₅O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
490.2; 実測値: 490.5.

6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-chloromethyl-1H-benzimidazole (intermediate 59, 439 mg, 1.0 mmol) and piperazine (5 mL) in DMF (5 mL) 258 mg, 3.0 mmol) was stirred at 60 ° C. for 0.5 h. The mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH = 20/1 to 5/1) to give 176 mg (36%) of the title compound as a yellow solid.
C ₂₆ H ₂₄ FN ₅ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
490.2; found: 490.5.

Intermediate 63: tert-butyl (2- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethyl) carbamate

ＴＨＦ（１００ｍＬ）中の３−ｔｅｒｔ−ブトキシカルボニルアミノ−プロピオン酸（２．０ｇ、１０．５ｍｍｏｌ）、ＨＡＴＵ（４．５ｇ、１１．５ｍｍｏｌ）およびＤＩＰＥＡ（１７．８ｇ、１７．８ｍｍｏｌ）の溶液を、室温で１０分間撹拌した後、（４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゼン−１，２−ジアミン（中間体３２、６．０ｇ、１５．８ｍｍｏｌ）を添加した。混合物を室温で２時間撹拌した。次いで、これをＥｔＯＡｃ（１００ｍＬ）で希釈し、水（１００ｍＬ×３）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、粗生成物を得、これをさらに精製することなく次のステップに使用する。
粗生成物をＡｃＯＨ（１０ｍＬ）に溶解し、５０℃で６時間撹拌した後、これをＮａＨＣＯ_３水溶液でクエンチした。ｐＨを７に調整した。混合物をＥｔＯＡｃ（１００ｍＬ×３）で抽出し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、粗生成物（４．１７ｇ）を得、これをさらに精製することなく次のステップに使用する。

A solution of 3-tert-butoxycarbonylamino-propionic acid (2.0 g, 10.5 mmol), HATU (4.5 g, 11.5 mmol) and DIPEA (17.8 g, 17.8 mmol) in THF (100 mL). After stirring at room temperature for 10 minutes, (4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzene-1,2-diamine (intermediate 32, 6.0 g, 15. The mixture was stirred at room temperature for 2 h, then it was diluted with EtOAc (100 mL), washed with water (100 mL × 3), dried over Na ₂ SO ₄ , concentrated and crude. The product is obtained and used in the next step without further purification.
The crude product was dissolved in AcOH (10 mL) and stirred at 50 ° C. for 6 h before it was quenched with aqueous NaHCO ₃ solution. The pH was adjusted to 7. The mixture is extracted with EtOAc (100 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product (4.17 g), which is used in the next step without further purification.

Intermediate 64: 2- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethanamine

｛２−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミダゾール−２−イル］−エチル｝−カルバミン酸ｔｅｒｔ−ブチルエステル（中間体６３、４．１７ｇ、７．８０ｍｍｏｌ）を、ＨＣｌ／ＣＨ_３ＯＨ（４０ｍＬ）に溶解し、室温で１時間撹拌した。混合物をＥｔＯＡｃ（１００ｍＬ）で希釈し、ブライン（５０ｍＬ×３）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、粗生成物を得、これを分取ＨＰＬＣにより精製して、表題化合物（１．８０ｇ、５３％）を黄色固体として得る。¹H NMR (400 MHz, CDCl₃) δ [ppm]: 7.93 (d, J = 8.8 Hz, 2H), 7.80 (dd, J = 9.6, 2.0 Hz, 1H),
7.74 - 7.67 (m, 1H), 7.65 (s, 1H), 7.59 - 7.55 (m, 2H), 7.49 - 7.39 (m, 4H),
7.04 (td, J = 8.8, 1.6 Hz, 1H), 3.24 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 5.2 Hz,
2H).

{2- [6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-benzimidazol-2-yl] -ethyl} -carbamic acid tert-butyl ester (intermediates 63, 4 .17 g, 7.80 mmol) was dissolved in HCl / CH ₃ OH (40 mL) and stirred at room temperature for 1 hour. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL × 3), dried over Na ₂ SO ₄ and concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (1.80 g, 53%) is obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 7.93 (d, J = 8.8 Hz, 2H), 7.80 (dd, J = 9.6, 2.0 Hz, 1H),
7.74-7.67 (m, 1H), 7.65 (s, 1H), 7.59-7.55 (m, 2H), 7.49-7.39 (m, 4H),
7.04 (td, J = 8.8, 1.6 Hz, 1H), 3.24 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 5.2 Hz,
2H).

Intermediate 65: N- {2- [6- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-benzimidazol-2-yl] -ethyl} -methanesulfonamide

ＤＣＭ（２０ｍＬ）中の２−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミダゾール−２−イル］−エチルアミン（中間体６４、７００ｍｇ、１．６１ｍｍｏｌ）の溶液に、ＴＥＡ（４８８ｍｇ、４．８３ｍｍｏｌ）を添加し、混合物を室温で１０分間撹拌した。次いで、ＭｓＣｌ（１４７ｍｇ、１．２９ｍｍｏｌ）を反応混合物に添加した。反応物を室温で終夜撹拌し、次いでＤＣＭ（５０ｍＬ）で希釈した。混合物を水（５０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、生成物（４３０ｍｇ、５２％）を得た。

2- [6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-benzimidazol-2-yl] -ethylamine (Intermediate 64, 700 mg, 1.M) in DCM (20 mL). To a solution of 61 mmol) TEA (488 mg, 4.83 mmol) was added and the mixture was stirred at room temperature for 10 minutes. MsCl (147 mg, 1.29 mmol) was then added to the reaction mixture. The reaction was stirred at room temperature overnight and then diluted with DCM (50 mL). The mixture was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated to give the product (430 mg, 52%).

Intermediate 66: N- (2- (6- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethyl) acetamide

ＤＣＭ（２０ｍＬ）中の２−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミダゾール−２−イル］−エチルアミン（中間体６４、７００ｍｇ、１．６１ｍｍｏｌ）の溶液に、ＴＥＡ（４８８ｍｇ、４．８３ｍｍｏｌ）を添加し、混合物を室温で１０分間撹拌した後、ＡｃＣｌ（１０１ｍｇ、１．２９ｍｍｏｌ）を反応混合物に添加した。反応物を室温で終夜撹拌し、次いでＤＣＭ（５０ｍＬ）で希釈した。混合物を水（５０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、生成物（４２９ｍｇ、５７％）を得た。

2- [6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-benzimidazol-2-yl] -ethylamine (Intermediate 64, 700 mg, 1.M) in DCM (20 mL). To a solution of 61 mmol) TEA (488 mg, 4.83 mmol) was added and the mixture was stirred at room temperature for 10 minutes before AcCl (101 mg, 1.29 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight and then diluted with DCM (50 mL). The mixture was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the product (429 mg, 57%).

Intermediate 67: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((4- (methylsulfonyl) piperazin-1-yl) methyl) -1H-benzo [ d] Imidazole

ＤＣＭ（１０ｍＬ）中の６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−ピペラジン−１−イルメチル−１Ｈ−ベンゾイミダゾール（中間体６２、９６ｍｇ、０．１９６ｍｍｏｌ）およびＴＥＡ（５９ｍｇ、０．５８８ｍｍｏｌ）の撹拌溶液に、ＭｓＣｌ（２７ｍｇ、０．２３６ｍｍｏｌ）を０℃で添加した。混合物を室温で０．５時間撹拌し、ＥｔＯＡｃ（５０ｍＬ）で希釈し、水（３０ｍＬ）およびブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝１００／１から２０／１）により精製して、８０ｍｇ（７２％）の表題化合物を褐色固体として得た。

6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-piperazin-1-ylmethyl-1H-benzimidazole (Intermediate 62, 96 mg, 0.196 mmol) in DCM (10 mL) To a stirred solution of and TEA (59 mg, 0.588 mmol) was added MsCl (27 mg, 0.236 mmol) at 0 ° C. The mixture was stirred at room temperature for 0.5 h, diluted with EtOAc (50 mL), washed with water (30 mL) and brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH = 100/1 to 20/1) to give 80 mg (72%) of the title compound as a brown solid.

Intermediate 68: 2- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) acetonitrile

ＤＣＭ（１０ｍＬ）中の４−（６−フルオロ−１Ｈ−インドール−３−イル）−ベンゼン−１，２−ジアミン（中間体３２、２９６ｍｇ、１．２３ｍｍｏｌ）、シアノ酢酸（１０４ｍｇ、１．２３ｍｍｏｌ）およびＴＥＡ（２４８ｍｇ、２．４６ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（４６７ｍｇ、１．２３ｍｍｏｌ）を０℃で添加した。混合物を室温で１時間撹拌し、次いで濃縮した。残留物をＥｔＯＡｃ（５０ｍＬ）で希釈し、ブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、ＡｃＯＨ（１０ｍＬ）を添加した。混合物を６５℃で３時間撹拌した。混合物を冷却し、ＡｃＯＨを除去した。混合物をＮａ_２ＣＯ_３水溶液（２０ｍＬ、１Ｍ）で塩基性化し、ＥｔＯＡｃ（３０ｍＬ×２）で抽出した。合わせた有機層をブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝１００／１から２０／１）により精製して、１８６ｍｇ（５２％）の表題化合物を褐色固体として得た。C₁₇H₁₁FN₄+H⁺ [M+H]⁺のLC-MS: 計算値 291.1; 実測値: 291.3.

4- (6-Fluoro-1H-indol-3-yl) -benzene-1,2-diamine (Intermediate 32, 296 mg, 1.23 mmol), cyanoacetic acid (104 mg, 1.23 mmol) in DCM (10 mL) And HATU (467 mg, 1.23 mmol) was added at 0 ° C. to a stirred solution of TEA (248 mg, 2.46 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was diluted with EtOAc (50 mL), washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and AcOH (10 mL) was added. The mixture was stirred at 65 ° C. for 3 hours. The mixture was cooled and AcOH was removed. The mixture was basified with aqueous Na ₂ CO ₃ (20 mL, 1M) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH = 100/1 to 20/1) to give 186 mg (52%) of the title compound as a brown solid. LC-MS for C ₁₇ H ₁₁ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 291.1; Found: 291.3.

Intermediate 69: 2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenol

６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、６．０ｇ、２５．５３ｍｍｏｌ）および２−アミノ−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノール（６．８３ｇ、１７．０２ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、４．３ｇ（６６％）の表題化合物を白色固体として得た。C₂₀H₁₅FN₂O₃S-H- [M-H]^-のLC-MS: 計算値381.1; 実測値:
381.3. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 9.20 (s, 1H), 8.10 (d, J = 7.5 Hz, 2H), 7.89 - 7.66 (m, 4H),
7.61 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 8.1 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J =
7.9 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.77(s, 2H).

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 6.0 g, 25.53 mmol) and 2-amino-5- (4,4,5,5-tetramethyl- Starting from 1,3,2-dioxaborolan-2-yl) phenol (6.83 g, 17.02 mmol), 4.3 g (66%) of the title compound was obtained as a white solid according to the general procedure outlined in Intermediate 32 Got as. C ₂₀ H ₁₅ FN ₂ O ₃ SH- [MH] ^- the LC-MS: calc 381.1; found:
381.3. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 9.20 (s, 1H), 8.10 (d, J = 7.5 Hz, 2H), 7.89-7.66 (m, 4H),
7.61 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 8.1 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J =
7.9 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.77 (s, 2H).

Intermediate 70: 2-Amino-4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenol

２−アミノ−４−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−フェノール（１１．０ｇ、４６．７ｍｍｏｌ）および６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、１２．５ｇ、３１．２ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、７．２ｇ（６０％）の表題化合物を褐色固体として得た。¹H NMR (400 MHz, CDCl₃) δ [ppm]: 7.91 (s, 1H), 7.89 (s, 1H), 7.77 (dd, J = 10.0, 2.0 Hz, 1H),
7.66 (dd, J = 8.8, 4.8 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.51 - 7.44 (m, 2H), 7.02
(td, J = 8.8, 2.0 Hz, 1H), 6.94 (s, 1H), 6.89 - 6.85 (m, 1H), 6.83 - 6.79 (m,
1H), 4.99 (brs, 1H), 3.80 - 3.69 (m, 2H).

2-Amino-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (11.0 g, 46.7 mmol) and 6-fluoro-3-iodo Starting from -1- (phenylsulfonyl) -1H-indole (Intermediate 1, 12.5 g, 31.2 mmol) and following the general procedure outlined for Intermediate 32, 7.2 g (60%) of the title compound was obtained. Obtained as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 7.91 (s, 1H), 7.89 (s, 1H), 7.77 (dd, J = 10.0, 2.0 Hz, 1H),
7.66 (dd, J = 8.8, 4.8 Hz, 1H), 7.59-7.53 (m, 2H), 7.51-7.44 (m, 2H), 7.02
(td, J = 8.8, 2.0 Hz, 1H), 6.94 (s, 1H), 6.89-6.85 (m, 1H), 6.83-6.79 (m,
1H), 4.99 (brs, 1H), 3.80-3.69 (m, 2H).

Intermediate 71: 2- (Chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole

０℃のＤＣＭ（２５ｍＬ）中の２−アミノ−４−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体７０、２．５ｇ、６．５４ｍｍｏｌ）の撹拌混合物に、クロロアセチルクロリド（８８７ｍｇ、７．８５ｍｍｏｌ）、次いでＴＥＡ（９９０ｍｇ、９．８１ｍｍｏｌ）をゆっくりと添加した。混合物を室温で３０分間撹拌した後、これを濃縮して、褐色油状物を得た。上記残留物をＡｃＯＨ（２０ｍＬ）で希釈し、窒素下で１６時間還流させた。次いで、これを室温に冷却し、濃縮した。残留物を飽和ＮａＨＣＯ_３（５０ｍＬ）で懸濁させ、ＥｔＯＡｃ（５０ｍＬ×２）で抽出した。合わせた有機層をブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝１０／１〜５／１）により精製して、１．１ｇ（３８％）の表題化合物を褐色固体として得た。C₂₂H₁₄ClFN₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
441.0; 実測値: 441.4.

Stirring 2-amino-4- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenol (Intermediate 70, 2.5 g, 6.54 mmol) in DCM (25 mL) at 0 <0> C. To the mixture was slowly added chloroacetyl chloride (887 mg, 7.85 mmol) followed by TEA (990 mg, 9.81 mmol). After the mixture was stirred at room temperature for 30 minutes, it was concentrated to give a brown oil. The residue was diluted with AcOH (20 mL) and refluxed for 16 hours under nitrogen. It was then cooled to room temperature and concentrated. The residue was suspended in saturated NaHCO ₃ (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 10/1 to 5/1) to give 1.1 g (38%) of the title compound as a brown solid. C ₂₂ H ₁₄ ClFN ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
441.0; found: 441.4.

Intermediate 72: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperazin-1-ylmethyl) benzo [d] oxazole

６０℃のＤＭＦ（５ｍＬ）中のピペラジン（中間体７１、１９５ｍｇ、２．２７ｍｍｏｌ）の撹拌溶液に、２−（クロロメチル）−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７１、１００ｍｇ、０．２３ｍｍｏｌ）を添加した。混合物を３０分間撹拌した。次いで、これを室温に冷却し、ＥｔＯＡｃ（５０ｍＬ）で希釈し、ブライン（３０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮乾固して、８０ｍｇ（７２％）の表題化合物を褐色油状物として得た。C₂₆H₂₃FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
491.2; 実測値: 491.6.

To a stirred solution of piperazine (Intermediate 71, 195 mg, 2.27 mmol) in DMF (5 mL) at 60 ° C. was added 2- (chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -1H-indole. -3-yl) benzo [d] oxazole (Intermediate 71, 100 mg, 0.23 mmol) was added. The mixture was stirred for 30 minutes. It was then cooled to room temperature, diluted with EtOAc (50 mL), washed with brine (30 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness to give 80 mg (72%) of the title compound as a brown oil. C ₂₆ H ₂₃ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
491.2; found: 491.6.

Intermediate 73: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) benzo [d] oxazole

２−（クロロメチル）−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７１、２００ｍｇ、０．４５ｍｍｏｌ）を、ＤＭＦ（３ｍＬ）中の１−メチル−ピペラジン（４５０ｍｇ、４．５ｍｍｏｌ）の撹拌溶液に６０℃で添加した。混合物を３０分間撹拌し、冷却し、ＥｔＯＡｃ（５０ｍＬ）で希釈した。有機層をブライン（３０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮乾固して、１６０ｍｇ（７０％）の表題化合物を褐色固体として得た。C₂₇H₂₂FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
505.2; 実測値: 505.5.

2- (Chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 71, 200 mg, 0.45 mmol) was added to DMF (3 mL). To a stirred solution of 1-methyl-piperazine (450 mg, 4.5 mmol) in) at 60 ° C. The mixture was stirred for 30 minutes, cooled and diluted with EtOAc (50 mL). The organic layer was washed with brine (30 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness to give 160 mg (70%) of the title compound as a brown solid. C ₂₇ H ₂₂ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
505.2; found: 505.5.

Intermediate 74: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (morpholinomethyl) benzo [d] oxazole

ＤＭＦ（５ｍＬ）中のモルホリン（３９１ｍｇ、４．５ｍｍｏｌ）の撹拌溶液に、２−（クロロメチル）−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７１、２００ｍｇ、０．４５ｍｍｏｌ）を６０℃で添加した。混合物を３０分間撹拌し、冷却し、ＥｔＯＡｃ（５０ｍＬ）で希釈した。有機層をブライン（３０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮乾固して、１００ｍｇ（４５％）の表題化合物を褐色固体として得た。C₂₆H₂₂FN₃O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
492.1; 実測値: 492.5.

To a stirred solution of morpholine (391 mg, 4.5 mmol) in DMF (5 mL) was added 2- (chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [ d] Oxazole (Intermediate 71, 200 mg, 0.45 mmol) was added at 60 ° C. The mixture was stirred for 30 minutes, cooled and diluted with EtOAc (50 mL). The organic layer was washed with brine (30 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness to give 100 mg (45%) of the title compound as a brown solid. C ₂₆ H ₂₂ FN ₃ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
492.1; found: 492.5.

Intermediate 75: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2 (3H) -one

無水ＴＨＦ（２０ｍＬ）中の２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェノール（中間体６９、５００ｍｇ、１．３ｍｍｏｌ）およびＣＤＩ（２３３ｍｇ、１．４３ｍｍｏｌ）の撹拌溶液に、ＴＥＡ（１．０８ｍＬ）を窒素下で添加した。混合物を窒素下室温で８時間撹拌した。反応混合物を水（３０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、５３１ｍｇ（１００％）の表題化合物を赤色固体として得た。C₂₁H₁₃FN₂O₄S-H^-
[M-H]^-のLC-MS: 計算値
407.1; 実測値: 406.8. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]:11.94 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.87 -
7.78 (m, 1H), 7.76 - 7.70 (m, 0H), 7.68 - 7.60 (m, 2H), 7.49 (d, J = 7.9 Hz,
0H), 7.23 (td, J = 9.1, 2.2 Hz, 0H), 7.18 (d, J = 7.8 Hz, 1H), 7.02 (s, 2H).

2-Amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenol (intermediate 69, 500 mg, 1.3 mmol) and CDI (233 mg, in anhydrous THF (20 mL)) To a stirred solution of 1.43 mmol), TEA (1.08 mL) was added under nitrogen. The mixture was stirred at room temperature under nitrogen for 8 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 531 mg (100%) of the title compound as a red solid. _{C 21 H 13 FN 2 O 4} SH -
[MH] ^- of LC-MS: Calculated
407.1; Found: 406.8. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.94 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.87-
7.78 (m, 1H), 7.76-7.70 (m, 0H), 7.68-7.60 (m, 2H), 7.49 (d, J = 7.9 Hz,
0H), 7.23 (td, J = 9.1, 2.2 Hz, 0H), 7.18 (d, J = 7.8 Hz, 1H), 7.02 (s, 2H).

Intermediate 76: 2- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide

ＮＭＰ（６ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（中間体７５、２００ｍｇ、０．４８ｍｍｏｌ）およびＫ_２ＣＯ_３（２４６ｍｇ、１．７８ｍｍｏｌ）の撹拌溶液に、２−ブロモアセトアミド（６１ｍｇ、０．４５ｍｍｏｌ）を添加した。混合物を６０℃で６時間撹拌した。反応混合物を濾過した。濾液を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、１８３ｍｇ（８０％）の表題化合物を黄色固体として得た。C₂₃H₁₆FN₃O₅S+H⁺
[M+H]⁺のLC-MS: 計算値
466.1; 実測値: 465.8.

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2 (3H) -one (Intermediate 75, 200 mg, 0.48 mmol) in NMP (6 mL) ) And K ₂ CO ₃ (246 mg, 1.78 mmol) was added 2-bromoacetamide (61 mg, 0.45 mmol). The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 183 mg (80%) of the title compound as a yellow solid. C ₂₃ H ₁₆ FN ₃ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
466.1; found: 465.8.

Intermediate 77: 5- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1,3-dihydro-benzimidazol-2-one

ＴＨＦ中の４−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゼン−１，２−ジアミン（中間体３２、２００ｍｇ、０．５０ｍｍｏｌ）の溶液に、ＣＤＩ（１７０ｍｇ、１．０５ｍｍｏｌ）を添加した。混合物を室温で終夜撹拌した。溶媒を除去して、１８５ｍｇ（８８％）の表題化合物を褐色油状物として得た。C₂₁H₁₄FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
408.1; 実測値: 408.4.

To a solution of 4- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzene-1,2-diamine (intermediate 32, 200 mg, 0.50 mmol) in THF was added CDI (170 mg, 1.05 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed to give 185 mg (88%) of the title compound as a brown oil. C ₂₁ H ₁₄ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
408.1; found: 408.4.

Intermediate 78: 2-Chloro-N- (4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-hydroxyphenyl) acetamide

０℃のＴＨＦ（２００ｍＬ）中の２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェノール（中間体６９、２．０ｇ、５．２ｍｍｏｌ）の撹拌溶液に、ＴＥＡ（７８７ｍｇ、７．８ｍｍｏｌ）、続いてクロロアセチルクロリド（７１２ｍｇ、６．３ｍｍｏｌ）を添加した。混合物を室温で２時間撹拌した後、これを濃縮した。残留物をＥｔＯＡｃで抽出し、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮乾固して、１．４ｇ（６１％）の表題化合物を褐色固体として得た。

Of 2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenol (intermediate 69, 2.0 g, 5.2 mmol) in THF (200 mL) at 0 ° C. To the stirred solution was added TEA (787 mg, 7.8 mmol) followed by chloroacetyl chloride (712 mg, 6.3 mmol). After the mixture was stirred at room temperature for 2 hours, it was concentrated. The residue was extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness to give 1.4 g (61%) of the title compound as a brown solid.

Intermediate 79: 2- (Chloromethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole

キシレン（５ｍＬ）中の２−クロロ−Ｎ−（４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ヒドロキシフェニル）アセトアミド（中間体７８、１．２２ｇ、２．７ｍｍｏｌ）の撹拌溶液に、ＰＰＴＳ（０．６７ｇ、２．７ｍｍｏｌ）を添加した。混合物を１５０℃で４時間撹拌した。反応混合物を室温に冷却し、濃縮した。残留物を水（１００ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。有機相を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラム（石油エーテル／酢酸エチル＝２／１）により精製して、７４６ｍｇ（６４％）の表題化合物を褐色固体として得た。C₂₂H₁₄ClFN₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
441.0; 実測値: 441.0.

2-Chloro-N- (4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-hydroxyphenyl) acetamide (Intermediate 78, 1.22 g) in xylene (5 mL) PPTS (0.67 g, 2.7 mmol) was added to a stirred solution of 2.7 mmol). The mixture was stirred at 150 ° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The organic phase was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column (petroleum ether / ethyl acetate = 2/1) to give 746 mg (64%) of the title compound as a brown solid. C ₂₂ H ₁₄ ClFN ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
441.0; Found: 441.0.

Intermediate 80: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (morpholinomethyl) benzo [d] oxazole

６０℃のＤＭＦ（２０ｍＬ）中の２−（クロロメチル）−６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７９、１５０ｍｇ、０．３４ｍｍｏｌ）の撹拌溶液に、ＤＭＦ中のモルホリン（５９ｍｇ、０．６８ｍｍｏｌ）を滴下添加した。混合物を６０℃で１時間撹拌し、室温に冷却し、濃縮した。残留物をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（４０ｍＬ×４）で洗浄した。有機相を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、１３０ｍｇ（８０％）の表題化合物を褐色固体として得た。C₂₆H₂₂FN₃O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
492.1; 実測値: 492.1.

2- (Chloromethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 79, 150 mg) in DMF (20 mL) at 60 ° C. To a stirred solution of 0.34 mmol) morpholine (59 mg, 0.68 mmol) in DMF was added dropwise. The mixture was stirred at 60 ° C. for 1 hour, cooled to room temperature and concentrated. The residue was diluted with EtOAc (50 mL) and washed with water (40 mL × 4). The organic phase was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 130 mg (80%) of the title compound as a brown solid. C ₂₆ H ₂₂ FN ₃ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
492.1; found: 492.1.

Intermediate 81: 3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propanamide

ＮＭＰ（６ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（中間体７５、３００ｍｇ、０．７３ｍｍｏｌ）およびＫ_２ＣＯ_３（４０６ｍｇ、２．９４ｍｍｏｌ）の撹拌溶液に、３−ブロモプロパンアミド（１０１ｍｇ、０．６７ｍｍｏｌ）を添加した。混合物を６３℃で６時間撹拌した。反応物を濾過した。濾液を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、２８０ｍｇ（８０％）の表題化合物を黄色固体として得た。C₂₄H₁₈FN₃O₅S-H^-
[M-H]^-のLC-MS: 計算値
478.1; 実測値: 477.7.

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2 (3H) -one (Intermediate 75, 300 mg, 0.73 mmol) in NMP (6 mL) ) And K ₂ CO ₃ (406 mg, 2.94 mmol) in a stirred solution of 3-bromopropanamide (101 mg, 0.67 mmol). The mixture was stirred at 63 ° C. for 6 hours. The reaction was filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 280 mg (80%) of the title compound as a yellow solid. _{C 24 H 18 FN 3 O 5} SH -
[MH] ^- of LC-MS: Calculated
478.1; found: 477.7.

Intermediate 82: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) benzo [d] oxazole

６０℃のＤＭＦ（２０ｍＬ）中の２−（クロロメチル）−６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７９、３００ｍｇ、０．６８ｍｍｏｌ）の撹拌溶液に、ＤＭＦ中の１−メチル−ピペラジン（１３６ｍｇ、１．３６ｍｍｏｌ）を滴下添加した。混合物を６０℃で１時間撹拌し、室温に冷却し、濃縮した。残留物をＥｔＯＡｃ（５０ｍＬ）で希釈し、水（４０ｍＬ×４）で洗浄した。有機相を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、２８５ｍｇ（８４％）の表題化合物を褐色固体として得た。C₂₇H₂₅FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
505.2; 実測値: 504.9.

2- (Chloromethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 79, 300 mg) in DMF (20 mL) at 60 ° C. 0.68 mmol) of 1-methyl-piperazine (136 mg, 1.36 mmol) in DMF was added dropwise. The mixture was stirred at 60 ° C. for 1 hour, cooled to room temperature and concentrated. The residue was diluted with EtOAc (50 mL) and washed with water (40 mL × 4). The organic phase was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 285 mg (84%) of the title compound as a brown solid. C ₂₇ H ₂₅ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
505.2; found: 504.9.

Intermediate 83: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2 (3H) -one

ＴＨＦ（５０ｍＬ）中の２−アミノ−４−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェノール（中間体７０、１．００ｇ、２．６１ｍｍｏｌ）およびＣＤＩ（０．６３ｇ、３．８９ｍｍｏｌ）の溶液を、室温で３時間撹拌した。混合物を濃縮して、１．６０ｇ（＞１００％）の粗表題化合物を黒色油状物として得、これをさらに精製することなく直接使用した。C₂₁H₁₃FN₂O₄S+H⁺
[M+H]⁺のLC-MS: 計算値
409.1; 実測値: 408.8.

2-amino-4- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenol (intermediate 70, 1.00 g, 2.61 mmol) and CDI (0 .63 g, 3.89 mmol) was stirred at room temperature for 3 hours. The mixture was concentrated to give 1.60 g (> 100%) of the crude title compound as a black oil that was used directly without further purification. C ₂₁ H ₁₃ FN ₂ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
409.1; found: 408.8.

Intermediate 84: 2- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide

ＤＭＦ（１０ｍＬ）中の５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（中間体８３、８００ｍｇの粗製物、１．３ｍｍｏｌ）、２−ブロモアセトアミド（２１５ｍｇ、１．５６ｍｍｏｌ）およびＫ_２ＣＯ_３（５５０ｍｇ、３．９８ｍｍｏｌ）の混合物を、室温で１２時間撹拌した。混合物を水中に添加し、ＥｔＯＡｃで抽出した。合わせた有機層を濃縮して、６００ｍｇ（９９％）の粗表題化合物を黄色油状物として得、これをさらに精製することなく直接使用した。C₂₃H₁₆FN₃O₅S+H⁺
[M+H]⁺のLC-MS: 計算値
466.1; 実測値: 465.8.

5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2 (3H) -one (Intermediate 83, 800 mg crude) in DMF (10 mL) 1.3 mmol), 2-bromoacetamide (215 mg, 1.56 mmol) and K ₂ CO ₃ (550 mg, 3.98 mmol) were stirred at room temperature for 12 hours. The mixture was added in water and extracted with EtOAc. The combined organic layers were concentrated to give 600 mg (99%) of the crude title compound as a yellow oil that was used directly without further purification. C ₂₃ H ₁₆ FN ₃ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
466.1; found: 465.8.

Intermediate 85: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-amine

６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、１．５５ｇ、３．８６ｍｍｏｌ）および６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−アミン（１．３０ｇ、５．０２ｍｍｏｌ；ＵＳ２００７０１１７８１８に記載されている通りに調製した）から出発し、中間体３２で概説した一般的方法に従って、２６０ｍｇ（１７％）の表題化合物を褐色固体として得た。C₂₁H₁₅FN₄O₂S+H⁺
[M+H]⁺のLC-MS: 計算値
407.1; 実測値: 407.4.

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 1.55 g, 3.86 mmol) and 6- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -1H-benzo [d] imidazol-2-amine (1.30 g, 5.02 mmol; prepared as described in US20070117818) and outlined in Intermediate 32 According to the general method, 260 mg (17%) of the title compound were obtained as a brown solid. C ₂₁ H ₁₅ FN ₄ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
407.1; found: 407.4.

Intermediate 86: tert-butyl ((5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) (methylsulfonyl) carbamate

ＤＭＦ（３ｍＬ）中の（ｔｅｒｔ−ブトキシ）−Ｎ−（メチルスルホニル）カルボキサミド（５３ｍｇ、０．２７３ｍｍｏｌ）、２−（クロロメチル）−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７１、１００ｍｇ、０．２２７ｍｍｏｌ）およびＫ_２ＣＯ_３（７８ｍｇ、０．５６８ｍｍｏｌ）の混合物を、５０℃で２時間撹拌した。次いで、これを室温に冷却し、水（１０ｍＬ）でクエンチした。混合物をＥｔＯＡｃ（１０ｍＬ×３）で抽出し、ブライン（１０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＴＬＣ（石油エーテル／ＥｔＯＡｃ＝４／１）により精製して、５０ｍｇ（３７％）の表題化合物を黄色固体として得た。C₂₈H₂₆FN₃O₇S₂+H⁺
[M+H]⁺のLC-MS: 計算値
600.1; 実測値: 600.5.

(Tert-Butoxy) -N- (methylsulfonyl) carboxamide (53 mg, 0.273 mmol), 2- (chloromethyl) -5- (6-fluoro-1- (phenylsulfonyl) -1H— in DMF (3 mL) A mixture of indol-3-yl) benzo [d] oxazole (Intermediate 71, 100 mg, 0.227 mmol) and K ₂ CO ₃ (78 mg, 0.568 mmol) was stirred at 50 ° C. for 2 hours. It was then cooled to room temperature and quenched with water (10 mL). The mixture was extracted with EtOAc (10 mL × 3), washed with brine (10 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative TLC (petroleum ether / EtOAc = 4/1) to give 50 mg (37%) of the title compound as a yellow solid. C ₂₈ H ₂₆ FN ₃ O ₇ S ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
600.1; Found: 600.5.

Intermediate 87: N-((5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide

ＥｔＯＡｃ（２ｍＬ）中のＮ−［５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イルメチル］−メタンスルホンアミド（中間体８６、１００ｍｇ、０．１７ｍｍｏｌ）の溶液に、ＨＣｌ／ＥｔＯＡｃ（２ｍＬ、４Ｍ）を添加した。反応物を室温で１６時間撹拌し、次いで混合物を濃縮乾固して、８３ｍｇ（１００％）の表題化合物を黄色固体として得た。C₂₃H₁₈FN₃O₅S₂+H⁺
[M+H]⁺のLC-MS: 計算値
500.1; 実測値: 499.9.

N- [5- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazol-2-ylmethyl] -methanesulfonamide (Intermediate 86, 100 mg, 0. 1) in EtOAc (2 mL). HCl / EtOAc (2 mL, 4M) was added to a solution of 17 mmol). The reaction was stirred at room temperature for 16 hours, then the mixture was concentrated to dryness to give 83 mg (100%) of the title compound as a yellow solid. C ₂₃ H ₁₈ FN ₃ O ₅ S ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
500.1; Found: 499.9.

Intermediate 88: 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propanamide

ＮＭＰ（８ｍＬ）中の５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−３Ｈ−ベンゾオキサゾール−２−オン（中間体８３、３７０ｍｇ、０．９１ｍｍｏｌ）、３−ブロモ−プロピオンアミド（１２７ｍｇ、０．９１ｍｍｏｌ）およびＫ_２ＣＯ_３（４５８ｍｇ、３．３１ｍｍｏｌ）の混合物を、６５℃で終夜撹拌した。反応混合物をＥＡで希釈し、水（５０ｍＬ×４）およびブラインで洗浄した。溶媒を除去して、２７０ｍｇ（６２％）を橙色固体として得た。C₂₄H₁₈FN₃O₅S-H^-
[M-H]^-のLC-MS: 計算値
408.1; 実測値: 477.8.

5- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -3H-benzoxazol-2-one (intermediate 83, 370 mg, 0.91 mmol), 3-bromo in NMP (8 mL) A mixture of propionamide (127 mg, 0.91 mmol) and K ₂ CO ₃ (458 mg, 3.31 mmol) was stirred at 65 ° C. overnight. The reaction mixture was diluted with EA and washed with water (50 mL × 4) and brine. The solvent was removed to give 270 mg (62%) as an orange solid. _{C 24 H 18 FN 3 O 5} SH -
[MH] ^- of LC-MS: Calculated
408.1; found: 477.8.

Intermediate 89: 2-Benzo [b] thiophen-5-yl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

５−ブロモ−ベンゾ［ｂ］チオフェン（５００ｍｇ、２．３５ｍｍｏｌ）および４，４，５，５，４’，４’，５’，５’−オクタメチル−［２，２’］ビ［［１，３，２］ジオキサボロラニル］（７７６ｍｇ、３．０６ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、表題化合物（７２０ｍｇ、＞１００％、粗製）を黄色油状物として得た。
¹H NMR
(400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.89 (d, J
= 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 5.4 Hz, 1H), 7.35 (d, J =
5.2 Hz, 1H), 1.37 (s, 12H).

5-Bromo-benzo [b] thiophene (500 mg, 2.35 mmol) and 4,4,5,5,4 ′, 4 ′, 5 ′, 5′-octamethyl- [2,2 ′] bi [[1, 3,2] dioxaborolanyl] (776 mg, 3.06 mmol) and the title compound (720 mg,> 100%, crude) was obtained as a yellow oil following the general procedure outlined in Intermediate 3. .
¹ H NMR
(400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.89 (d, J
= 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 5.4 Hz, 1H), 7.35 (d, J =
5.2 Hz, 1H), 1.37 (s, 12H).

Intermediate 90: 3- (Benzo [b] thiophen-5-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole

ジオキサン（１２ｍＬ）および水（３ｍＬ）中の６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、４０１ｍｇ、１．０ｍｍｏｌ）、２−ベンゾ［ｂ］チオフェン−５−イル−４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン（４２３ｍｇ、１．３０ｍｍｏｌ、粗製）およびＫ_３ＰＯ_４（６３６ｍｇ、３．０ｍｍｏｌ）の混合物を、窒素で５分間バブリングさせた。Ｐｄ（ｄｐｐｆ）Ｃｌ_２（７３ｍｇ、０．１ｍｍｏｌ）を添加し、混合物を窒素でさらに５分間バブリングさせた。混合物をマイクロ波反応器に入れ、窒素下９０℃で１．５時間撹拌した。溶媒を除去した。残留物をＰＥ／ＥＡ（１００ｍＬ、ＰＥ／ＥＡ＝３／１）に溶解し、シリカのショートプラグに通して濾過した。溶媒を除去して、５００ｍｇの表題化合物を黄色油状物として得た。

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 401 mg, 1.0 mmol), 2-benzo [b] thiophene-5 in dioxane (12 mL) and water (3 mL). A mixture of -yl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (423 mg, 1.30 mmol, crude) and K ₃ PO ₄ (636 mg, 3.0 mmol) was added with nitrogen 5 Bubbled for a minute. Pd (dppf) Cl ₂ (73 mg, 0.1 mmol) was added and the mixture was bubbled with nitrogen for an additional 5 minutes. The mixture was placed in a microwave reactor and stirred at 90 ° C. under nitrogen for 1.5 hours. The solvent was removed. The residue was dissolved in PE / EA (100 mL, PE / EA = 3/1) and filtered through a short plug of silica. The solvent was removed to give 500 mg of the title compound as a yellow oil.

Intermediate 91: tert-butyl ((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) (methylsulfonyl) carbamate

ＤＭＦ（１５ｍＬ）中のｔｅｒｔ−ブチルメチルスルホニルカルバメート（１５５ｍｇ、０．８２ｍｍｏｌ）、Ｋ_２ＣＯ_３（２３５ｍｇ、１．７０ｍｍｏｌ）の撹拌溶液に、２−（クロロメチル）−６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７９、３００ｍｇ、０．６８ｍｍｏｌ）を添加した。混合物を５０℃で５時間撹拌した。反応混合物を室温に冷却し、濾過した。濾液を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（２０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、１９８ｍｇ（４９％）の表題化合物を黄色固体として得た。C₂₈H₂₆FN₃O₇S₂+H⁺
[M+H]⁺のLC-MS: 計算値
600.1; 実測値: 599.8.

To a stirred solution of tert-butylmethylsulfonylcarbamate (155 mg, 0.82 mmol), K ₂ CO ₃ (235 mg, 1.70 mmol) in DMF (15 mL) was added 2- (chloromethyl) -6- (6-fluoro- 1- (Phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 79, 300 mg, 0.68 mmol) was added. The mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 198 mg (49%) of the title compound as a yellow solid. C ₂₈ H ₂₆ FN ₃ O ₇ S ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
600.1; found: 599.8.

Intermediate 92: tert-butyl ((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) (methylsulfonyl) carbamate

ＭｅＯＨ（１５ｍＬ）中のｔｅｒｔ−ブチル（（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）（メチルスルホニル）カルバメート（中間体９１、１４８ｍｇ、０．２５ｍｍｏｌ）の撹拌溶液に、ＮａＯＨ（９９ｍｇ、２．５ｍｍｏｌ）を添加した。混合物を８５℃で１時間撹拌した。反応混合物を室温に冷却し、ＨＣｌ（１２Ｍ）で中和した。混合物を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層をブライン（３０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、１１４ｍｇ（１００％）の表題化合物を黒色固体として得た。C₂₂H₂₂FN₃O₅S+H⁺
[M-Boc+H]⁺のLC-MS: 計算値 360.1; 実測値: 360.0.

Tert-Butyl ((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) (methylsulfonyl) carbamate in MeOH (15 mL) To a stirred solution of (Intermediate 91, 148 mg, 0.25 mmol) was added NaOH (99 mg, 2.5 mmol). The mixture was stirred at 85 ° C. for 1 hour. The reaction mixture was cooled to room temperature and neutralized with HCl (12M). The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 114 mg (100%) of the title compound as a black solid. C ₂₂ H ₂₂ FN ₃ O ₅ S + H ⁺
LC-MS for [M-Boc + H] ⁺ : calc. 360.1; found: 360.0.

Intermediate 93: tert-butyl N-({6- [1- (benzenesulfonyl) -6-fluoro-1H-indol-3-yl] -1,3-benzoxazol-2-yl} methyl) -N- [(Tert-Butoxy) carbonyl] carbamate

ＤＭＦ（３０ｍＬ）中のジ−ｔｅｒｔ−ブチルイミノジカルボキシレート（６４０ｍｇ、２．９５ｍｍｏｌ）、Ｋ_２ＣＯ_３（９００ｍｇ、６．５ｍｍｏｌ）およびＫＩ（３４ｍｇ、０．２ｍｍｏｌ）の撹拌溶液に、２−（クロロメチル）−６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７９、１ｇ、２．２７ｍｍｏｌ）を６０℃で添加した。混合物を６０℃で５時間撹拌した。反応物をＨＣｌ（１２Ｍ）で中和し、濾過した。濾液を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、１．４ｇ（１００％）の表題化合物を黒色油状物として得た。C₃₂H₃₂FN₃O₇S₂+H⁺
[M-Boc+H]⁺のLC-MS: 計算値 522.2 ; 実測値: 522.9.

To a stirred solution of di-tert-butyliminodicarboxylate (640 mg, 2.95 mmol), K ₂ CO ₃ (900 mg, 6.5 mmol) and KI (34 mg, 0.2 mmol) in DMF (30 mL) was added 2- (Chloromethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 79, 1 g, 2.27 mmol) was added at 60 ° C. The mixture was stirred at 60 ° C. for 5 hours. The reaction was neutralized with HCl (12M) and filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 1.4 g (100%) of the title compound as a black oil. C ₃₂ H ₃₂ FN ₃ O ₇ S ₂ + H ⁺
LC-MS of [M-Boc + H] ⁺ : calculated 522.2; found: 522.9.

Intermediate 94: tert-butyl N-[(tert-butoxy) carbonyl] -N-{[6- (6-fluoro-1H-indol-3-yl) -1,3-benzoxazol-2-yl] methyl } Carbamate

ＭｅＯＨ（５０ｍＬ）中のｔｅｒｔ−ブチルＮ−（｛６−［１−（ベンゼンスルホニル）−６−フルオロ−１Ｈ−インドール−３−イル］−１，３−ベンゾオキサゾール−２−イル｝メチル）−Ｎ−［（ｔｅｒｔ−ブトキシ）カルボニル］カルバメート（中間体９３；１．３６ｇ、２．２０ｍｍｏｌ）の撹拌溶液に、ＮａＯＨ（８７８ｍｇ、２１．９６ｍｍｏｌ）を添加した。混合物を８５℃で１時間撹拌した。反応混合物を室温に冷却し、ＨＣｌ（１２Ｍ）で中和し、濾過した。濾液を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（７０ｍＬ×３）で抽出した。合わせた有機層をブライン（３０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝６／１〜２／１）により精製して、４０６ｍｇ（３９％）の表題化合物を黄色固体として得た。C₂₆H₂₈FN₃O₅+H⁺
[M-Boc+H]⁺のLC-MS: 計算値 382.2; 実測値: 381.9.

Tert-Butyl N-({6- [1- (benzenesulfonyl) -6-fluoro-1H-indol-3-yl] -1,3-benzoxazol-2-yl} methyl)-in MeOH (50 mL)- To a stirred solution of N-[(tert-butoxy) carbonyl] carbamate (Intermediate 93; 1.36 g, 2.20 mmol) was added NaOH (878 mg, 21.96 mmol). The mixture was stirred at 85 ° C. for 1 hour. The reaction mixture was cooled to room temperature, neutralized with HCl (12M) and filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 6/1 to 2/1) to give 406 mg (39%) of the title compound as a yellow solid. C ₂₆ H ₂₈ FN ₃ O ₅ + H ⁺
LC-MS for [M-Boc + H] ⁺ : calc. 382.2; found: 381.9.

Intermediate 95: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperazin-1-ylmethyl) benzo [d] oxazole

６０℃のＤＭＦ（２０ｍＬ）中の２−（クロロメチル）−６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７９、５００ｍｇ、１．１３ｍｍｏｌ）の撹拌溶液に、ＤＭＦ中のピペラジン（１９５ｍｇ、２．２６ｍｍｏｌ）を滴下添加した。反応物を６０℃で１時間撹拌した後、これを室温に冷却し、濃縮した。残留物を水（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２０ｍＬ×４）で抽出した。有機相を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、２７７ｍｇ（５０％）の表題化合物を褐色固体として得た。C₂₆H₂₃FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
491.2; 実測値: 490.8.

2- (Chloromethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 79, 500 mg) in DMF (20 mL) at 60 ° C. 1.13 mmol) piperazine (195 mg, 2.26 mmol) in DMF was added dropwise. The reaction was stirred at 60 ° C. for 1 hour before it was cooled to room temperature and concentrated. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL × 4). The organic phase was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 277 mg (50%) of the title compound as a brown solid. C ₂₆ H ₂₃ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
491.2; found: 490.8.

Intermediate 96: 2- (benzo [b] thiophen-6-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

６−ブロモ−ベンゾ［ｂ］チオフェン（１．０ｇ、４．７ｍｍｏｌ）および４，４，４’，４’，５，５，５’，５’−オクタメチル−２，２’−ビ（１，３，２−ジオキサボロラン（１．７８ｇ、７．０ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、２．０ｇ（粗製）の表題化合物を黒色固体として得、これをさらに精製することなく直接使用した。

6-Bromo-benzo [b] thiophene (1.0 g, 4.7 mmol) and 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1, Starting from 3,2-dioxaborolane (1.78 g, 7.0 mmol) and following the general procedure outlined in Intermediate 3, 2.0 g (crude) of the title compound was obtained as a black solid, which was further purified Used directly without.

Intermediate 97: 3- (Benzo [b] thiophen-6-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole

６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、５００ｍｇ、１．２ｍｍｏｌ）および２−（ベンゾ［ｂ］チオフェン−６−イル）−４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（中間体９６、４２０ｍｇ、１．６ｍｍｏｌ）から出発し、中間体９０で概説した一般的方法に従って、３３８ｍｇ（７０％）の表題化合物を白色固体として得た。

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 500 mg, 1.2 mmol) and 2- (benzo [b] thiophen-6-yl) -4, 4, 5, Starting from 5-tetramethyl-1,3,2-dioxaborolane (Intermediate 96, 420 mg, 1.6 mmol) and following the general procedure outlined in Intermediate 90, 338 mg (70%) of the title compound as a white solid Obtained.

Intermediate 98: 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (2- (methylthio) ethyl) benzo [d] oxazole

−１０℃のＤＣＭ（１５ｍＬ）中の３−メチルスルファニル−プロピオン酸（１９８ｍｇ、１．６５ｍｍｏｌ）の撹拌溶液に、ＴＥＡ（３１７ｍｇ、３．１４ｍｍｏｌ）、続いてクロロギ酸イソブチル（３２１ｍｇ、２．３６ｍｍｏｌ）を添加した。白色懸濁液を０℃で２０分間撹拌した後、２−アミノ−４−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体７０、６００ｍｇ、１．５７ｍｍｏｌ）を添加した。混合物を室温で３０分間撹拌した後、これを濃縮乾固した。残留物をＡｃＯＨ（１０ｍＬ）で希釈し、１６時間還流させ、室温に冷却し、濃縮した。残留物をＮａＨＣＯ_３水溶液（３０ｍＬ）で懸濁させ、ＥｔＯＡｃ（４０ｍＬ×２）で抽出した。合わせた有機層をブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を蒸発させ、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝２０／１から５／１）により精製して、３２０ｍｇ（４４％）の表題化合物を褐色固体として得た。C₂₄H₁₉FN₂O₃S₂+H⁺
[M+H]⁺のLC-MS: 計算値467.1;
実測値: 467.5. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 7.97 - 7.92 (m, 2H), 8.85 (d, J = 1.6 Hz, 1H),
7.80 (dd, J = 9.6, 2.4 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.62 - 7.55 (m, 2H), 7.53
- 7.46 (m, 3H), 7.06 (td, J = 8.8, 2.4 Hz, 1H), 3.28 (t, J = 7.2 Hz, 2H), 3.06
(t, J = 7.2 Hz, 2H), 2.19 (s, 3H).

To a stirred solution of 3-methylsulfanyl-propionic acid (198 mg, 1.65 mmol) in DCM (15 mL) at −10 ° C. was added TEA (317 mg, 3.14 mmol) followed by isobutyl chloroformate (321 mg, 2.36 mmol). Was added. The white suspension was stirred at 0 ° C. for 20 minutes before 2-amino-4- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenol (intermediate 70, 600 mg, 1.57 mmol). ) Was added. After the mixture was stirred at room temperature for 30 minutes, it was concentrated to dryness. The residue was diluted with AcOH (10 mL), refluxed for 16 hours, cooled to room temperature and concentrated. The residue was suspended in aqueous NaHCO ₃ (30 mL) and extracted with EtOAc (40 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was evaporated and purified by silica gel column chromatography (petroleum ether / EtOAc = 20/1 to 5/1) to give 320 mg (44%) of the title compound as a brown solid. C ₂₄ H ₁₉ FN ₂ O ₃ S ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 467.1;
Found: 467.5. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 7.97-7.92 (m, 2H), 8.85 (d, J = 1.6 Hz, 1H),
7.80 (dd, J = 9.6, 2.4 Hz, 1H), 7.71-7.66 (m, 2H), 7.62-7.55 (m, 2H), 7.53
-7.46 (m, 3H), 7.06 (td, J = 8.8, 2.4 Hz, 1H), 3.28 (t, J = 7.2 Hz, 2H), 3.06
(t, J = 7.2 Hz, 2H), 2.19 (s, 3H).

Intermediate 99: 5- (6-Fluoro-1H-indol-3-yl) -2- (2- (methylthio) ethyl) benzo [d] oxazole

ＭｅＯＨ（１０ｍＬ）中の５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−（２−メチルスルファニル−エチル）−ベンゾオキサゾール（３２０ｍｇ、０．６８７ｍｍｏｌ）およびＮａＯＨ（１３７ｍｇ、３．４３ｍｍｏｌ）の混合物を、６５℃で１時間撹拌した後、これを室温に冷却した。混合物を水（３０ｍＬ）で希釈し、ＥｔＯＡｃ（３０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を蒸発させ、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝２０／１から５／１）により精製して、７０ｍｇ（３１％）の表題化合物を黄色固体として得た。C₁₈H₁₅FN₂OS+H⁺ [M+H]⁺のLC-MS: 計算値327.1; 実測値:
327.4. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.28 (brs, 1H), 7.91 (s, 1H), 7.82 (dd, J = 8.8, 5.2 Hz,
1H), 7.59 - 7.53 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 9.6, 2.4 Hz,
1H), 6.96 (td, J = 9.2, 2.0 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.42 (s, 3H),
3.25 (t, J = 6.4 Hz, 2H).

5- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2- (2-methylsulfanyl-ethyl) -benzoxazole (320 mg, 0.687 mmol) and NaOH (10 mL) in MeOH (10 mL). 137 mg, 3.43 mmol) was stirred at 65 ° C. for 1 h before it was cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was evaporated and purified by silica gel column chromatography (petroleum ether / EtOAc = 20/1 to 5/1) to give 70 mg (31%) of the title compound as a yellow solid. LC-MS for C ₁₈ H ₁₅ FN ₂ OS + H ⁺ [M + H] ⁺ : Calculated 327.1; Found:
327.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.28 (brs, 1H), 7.91 (s, 1H), 7.82 (dd, J = 8.8, 5.2 Hz,
1H), 7.59-7.53 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 9.6, 2.4 Hz,
1H), 6.96 (td, J = 9.2, 2.0 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.42 (s, 3H),
3.25 (t, J = 6.4 Hz, 2H).

Intermediate 100: tert-butyl 6-fluoro-3- (2- (2- (methylthio) ethyl) benzo [d] oxazol-5-yl) -1H-indole-1-carboxylate

ＤＣＭ（１０ｍＬ）中の５−（６−フルオロ−１Ｈ−インドール−３−イル）−２−（２−メチルスルファニル−エチル）−ベンゾオキサゾール（７０ｍｇ、０．２１５ｍｍｏｌ）の溶液に、Ｂｏｃ_２Ｏ（９３ｍｇ、０．４２９ｍｍｏｌ）を０℃で添加し、続いてＤＭＡＰ（８ｍｇ、０．００６４ｍｍｏｌ）を添加した。混合物を３０分間撹拌した後、これを氷水（２０ｍＬ）でクエンチし、ＤＣＭ（３０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮乾固して、５６ｍｇ（６１％）の表題化合物を白色固体として得た。C₂₃H₂₃FN₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
427.1; 実測値: 427.6.

To a solution of 5- (6-fluoro-1H-indol-3-yl) -2- (2-methylsulfanyl-ethyl) -benzoxazole (70 mg, 0.215 mmol) in DCM (10 mL) was added Boc ₂ O ( 93 mg, 0.429 mmol) was added at 0 ° C., followed by DMAP (8 mg, 0.0064 mmol). After the mixture was stirred for 30 minutes, it was quenched with ice water (20 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to dryness to give 56 mg (61%) of the title compound as a white solid. C ₂₃ H ₂₃ FN ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
427.1; found: 427.6.

Intermediate 101: tert-butyl 6-fluoro-3- (2- (2- (methylsulfonyl) ethyl) benzo [d] oxazol-5-yl) -1H-indole-1-carboxylate

ＤＣＭ（５ｍＬ）中の６−フルオロ−３−［２−（２−メチルスルファニル−エチル）−ベンゾオキサゾール−５−イル］−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（５６ｍｇ、０．１３ｍｍｏｌ）の撹拌溶液に、ｍ−ＣＰＢＡ（８０ｍｇ、０．３９ｍｍｏｌ、８５％）を０℃で添加した。反応物を室温で２０分間撹拌した。混合物をＮａＨＣＯ_３水溶液（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＴＬＣ（石油エーテル／ＥｔＯＡｃ＝３／１）により精製して、４５ｍｇ（７５％）の表題化合物を白色固体として得た。C₂₃H₂₃FN₂O₅S+H⁺
[M+H]⁺のLC-MS: 計算値459.1;
実測値: 459.6. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 8.18-8.00 (m, 1H), 7.99 - 7.90 (m, 1H), 7.88
(s, 1H), 7.72 - 7.66 (m, 1H), 7.58 - 7.50 (m, 1H), 7.40 - 7.30 (m, 1H), 7.04
(td, J = 8.8, 2.0 Hz, 1H), 3.69 (t, J = 7.2 Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H),
3.03 (s, 3H), 1.68 (s, 9H).

Of 6-fluoro-3- [2- (2-methylsulfanyl-ethyl) -benzoxazol-5-yl] -indole-1-carboxylic acid tert-butyl ester (56 mg, 0.13 mmol) in DCM (5 mL) To the stirred solution, m-CPBA (80 mg, 0.39 mmol, 85%) was added at 0 ° C. The reaction was stirred at room temperature for 20 minutes. The mixture was diluted with aqueous NaHCO ₃ (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative TLC (petroleum ether / EtOAc = 3/1) to give 45 mg (75%) of the title compound as a white solid. C ₂₃ H ₂₃ FN ₂ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: calcd 459.1;
Found: 459.6. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 8.18-8.00 (m, 1H), 7.99-7.90 (m, 1H), 7.88
(s, 1H), 7.72-7.66 (m, 1H), 7.58-7.50 (m, 1H), 7.40-7.30 (m, 1H), 7.04
(td, J = 8.8, 2.0 Hz, 1H), 3.69 (t, J = 7.2 Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H),
3.03 (s, 3H), 1.68 (s, 9H).

Intermediate 102: tert-butyl N-({5- [1- (benzenesulfonyl) -6-fluoro-1H-indol-3-yl] -1,3-benzoxazol-2-yl} methyl) -N- [(Tert-Butoxy) carbonyl] carbamate

ＤＭＦ（５ｍＬ）中の５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−クロロメチル−ベンゾオキサゾール（中間体７１、１００ｍｇ、０．２２７ｍｍｏｌ）、ｔｅｒｔ−ブチル［（ｔｅｒｔ−ブトキシ）カルボニルアミノ］ホルメート（１４８ｍｇ、０．６８２ｍｍｏｌ）、ＫＩ（３８ｍｇ、０．２２７ｍｍｏｌ）およびＫ_２ＣＯ_３（９４ｍｇ、０．６８２ｍｍｏｌ）の混合物を、６０℃で５時間撹拌した。次いで、これを室温に冷却し、ＥｔＯＡｃ（３０ｍＬ）で希釈し、ブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５０／１から１５／１）により精製して、１１４ｍｇ（８１％）の表題化合物を黄色固体として得た。C₃₂H₃₂FN₃O₇S+H⁺
[M+H]⁺のLC-MS: 計算値
622.2; 実測値: 622.7.

5- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-chloromethyl-benzoxazole (Intermediate 71, 100 mg, 0.227 mmol), tert-butyl [5 mL] in DMF (5 mL). A mixture of (tert-butoxy) carbonylamino] formate (148 mg, 0.682 mmol), KI (38 mg, 0.227 mmol) and K ₂ CO ₃ (94 mg, 0.682 mmol) was stirred at 60 ° C. for 5 hours. It was then cooled to room temperature, diluted with EtOAc (30 mL), washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 50/1 to 15/1) to give 114 mg (81%) of the title compound as a yellow solid. C ₃₂ H ₃₂ FN ₃ O ₇ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
622.2; found: 622.7.

Intermediate 103: tert-butyl ((5- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) carbamate

ＭｅＯＨ（８ｍＬ）中のｔｅｒｔ−ブチルＮ−（｛５−［１−（ベンゼンスルホニル）−６−フルオロ−１Ｈ−インドール−３−イル］−１，３−ベンゾオキサゾール−２−イル｝メチル）−Ｎ−［（ｔｅｒｔ−ブトキシ）カルボニル］カルバメート（中間体１０２、１１４ｍｇ、０．１８３ｍｍｏｌ）の溶液に、ＮａＯＨ（７３ｍｇ、１．８３ｍｍｏｌ）を添加した。混合物を４時間還流させた後、これを室温に冷却した。溶媒を除去した。残留物を水（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝１０／１から３／１）により精製して、６３ｍｇ（９０％）の表題化合物を褐色油状物として得た。¹H NMR (300 MHz, CDCl₃) δ [ppm]: 8.31 (brs, 1H), 7.92 (s, 1H), 7.82 (dd, J = 9.3, 5.4 Hz,
1H), 7.63 - 7.54 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 9.3, 2.4 Hz,
1H), 6.97 (td, J = 9.3, 2.4 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 1.49 (s, 9H).

Tert-Butyl N-({5- [1- (benzenesulfonyl) -6-fluoro-1H-indol-3-yl] -1,3-benzoxazol-2-yl} methyl)-in MeOH (8 mL)- To a solution of N-[(tert-butoxy) carbonyl] carbamate (Intermediate 102, 114 mg, 0.183 mmol) was added NaOH (73 mg, 1.83 mmol). After the mixture was refluxed for 4 hours, it was cooled to room temperature. The solvent was removed. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 10/1 to 3/1) to give 63 mg (90%) of the title compound as a brown oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ [ppm]: 8.31 (brs, 1H), 7.92 (s, 1H), 7.82 (dd, J = 9.3, 5.4 Hz,
1H), 7.63-7.54 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 9.3, 2.4 Hz,
1H), 6.97 (td, J = 9.3, 2.4 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 1.49 (s, 9H).

Intermediate 104: 3- (benzofuran-5-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole

６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、４１２ｍｇ、１．０３ｍｍｏｌ）およびベンゾフラン−５−イルボロン酸（２５０ｍｇ、１．５４ｍｍｏｌ）から出発し、中間体９０で概説した一般的方法に従って、３４０ｍｇ（８５％）の表題化合物を白色固体として得た。C₂₂H₁₄FNO₃S+H⁺ [M+H]⁺のLC-MS: 計算値392.1; 実測値:
391.8. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.17 - 8.13 (m, 2H), 8.12 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H),
7.99 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.8, 5.3 Hz, 1H), 7.82 (dd, J = 9.9,
2.4 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.67 - 7.60 (m, 3H), 7.24 (ddd, J = 9.5, 8.8,
2.4 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H).

Starting from 6-fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (intermediate 1, 412 mg, 1.03 mmol) and benzofuran-5-ylboronic acid (250 mg, 1.54 mmol), intermediate 90 According to the general method outlined in 340 mg (85%) of the title compound was obtained as a white solid. LC-MS for C ₂₂ H ₁₄ FNO ₃ S + H ⁺ [M + H] ⁺ : Calculated 392.1; Found:
391.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.17-8.13 (m, 2H), 8.12 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H),
7.99 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.8, 5.3 Hz, 1H), 7.82 (dd, J = 9.9,
2.4 Hz, 1H), 7.76-7.69 (m, 2H), 7.67-7.60 (m, 3H), 7.24 (ddd, J = 9.5, 8.8,
2.4 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H).

Intermediate 105: tert-butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidine-1-carboxylate

乾燥ＤＣＭ（１０ｍＬ）中の４−カルバモイル−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（３９４ｍｇ、１．７３ｍｍｏｌ）の溶液に、トリメチルオキソニウムテトラフルオロボレート（２５６ｍｇ、１．７３ｍｍｏｌ）を窒素下室温で少量ずつ添加した。混合物を室温で２４時間撹拌した。次いで、２−アミノ−５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体６９、７２６ｍｇ、１．９０ｍｍｏｌ）を一度に添加した。混合物を室温で４時間撹拌した後、これをＮａＨＣＯ_３水溶液（２０ｍＬ）で希釈し、ＤＣＭ（３０ｍＬ×３）で抽出した。合わせた有機層をブライン（５０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルクロマトグラフィー（ＰＥ／ＥｔＯＡｃ＝２／１）により精製して、５４０ｍｇ（５４％）の表題化合物を褐色固体として得た。C₃₁H₃₀FN₃O₅S+H⁺
[M+H]⁺のLC-MS: 計算値576.2;
実測値: 576.7. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 8.21 (s, 1H), 8.15 (d, J = 7.6 Hz, 2H), 8.04
(s, 1H), 7.89 (dd, J = 4.8, 8.8 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.75 - 7.68 (m,
2H), 7.63 (t, J = 7.6 Hz, 2H), 7.24 (td, J = 1.6, 8.8 Hz, 1H), 3.97 (d, J =
12.8 Hz, 2H), 3.32 - 3.25 (m, 1H), 3.01 (brs, 2H), 2.11 (d, J = 10.8 Hz, 2H),
1.75 - 1.65 (m, 2H), 1.42 (s, 9H).

To a solution of 4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (394 mg, 1.73 mmol) in dry DCM (10 mL) was added trimethyloxonium tetrafluoroborate (256 mg, 1.73 mmol) at room temperature under nitrogen. Small portions were added. The mixture was stirred at room temperature for 24 hours. Then 2-amino-5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenol (intermediate 69, 726 mg, 1.90 mmol) was added in one portion. After the mixture was stirred at room temperature for 4 hours, it was diluted with aqueous NaHCO ₃ (20 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel chromatography (PE / EtOAc = 2/1) to give 540 mg (54%) of the title compound as a brown solid. C ₃₁ H ₃₀ FN ₃ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: calcd 576.2;
Found: 576.7. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 8.21 (s, 1H), 8.15 (d, J = 7.6 Hz, 2H), 8.04
(s, 1H), 7.89 (dd, J = 4.8, 8.8 Hz, 1H), 7.84-7.78 (m, 2H), 7.75-7.68 (m,
2H), 7.63 (t, J = 7.6 Hz, 2H), 7.24 (td, J = 1.6, 8.8 Hz, 1H), 3.97 (d, J =
12.8 Hz, 2H), 3.32-3.25 (m, 1H), 3.01 (brs, 2H), 2.11 (d, J = 10.8 Hz, 2H),
1.75-1.65 (m, 2H), 1.42 (s, 9H).

Intermediate 106: tert-butyl 4- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidine-1-carboxylate

メタノール（１００ｍＬ）中のｔｅｒｔ−ブチル４−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）ピペリジン−１−カルボキシレート（中間体１０５、１．６２ｇ、２．８２ｍｍｏｌ）の溶液に、ＮａＯＨ（１．１３ｇ、２８．２ｍｍｏｌ）を室温で添加した。混合物を６０℃で２時間撹拌した。混合物を室温に冷却し、濃縮した。残留物を水（１００ｍＬ）で希釈し、ＥｔＯＡｃ（１００ｍＬ×３）で抽出した。合わせた有機層をブライン（１００ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、１．２３ｇ（９９％）の表題化合物を灰色固体として得た。C₂₅H₂₆FN₃O₃+H⁺
[M+H]⁺のLC-MS: 計算値
436.2; 実測値: 436.6.

Tert-Butyl 4- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidine-1-carboxylate in methanol (100 mL) To a solution of (Intermediate 105, 1.62 g, 2.82 mmol) was added NaOH (1.13 g, 28.2 mmol) at room temperature. The mixture was stirred at 60 ° C. for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 1.23 g (99%) of the title compound as a gray solid. C ₂₅ H ₂₆ FN ₃ O ₃ + H ⁺
[M + H] ⁺ LC-MS: Calculated
436.2; found: 436.6.

Intermediate 107: methyl 3- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) propanoate

１，２−ジクロロエタン（１０ｍＬ）中のスクシンアミド酸メチルエステル（５００ｍｇ、３．８２ｍｍｏｌ）の撹拌溶液に、Ｍｅｅｒｗｅｉｎ試薬（６２１ｍｇ、４．２０ｍｍｏｌ）を室温で滴下添加した。混合物を１６時間撹拌した後、無水ＭｅＯＨ（１５ｍＬ）中の２−アミノ−５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体６９、１．４６ｇ、３．８２ｍｍｏｌ）の溶液を添加した。混合物をさらに３時間撹拌した後、これをＮａＨＣＯ_３水溶液（５０ｍＬ）でクエンチし、ＥｔＯＡｃ（３０ｍＬ×３）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝１０／１から５／１）により精製して、１１０ｍｇ（６％）の表題化合物を褐色固体として得た。C₂₅H₁₉FN₂O₅S+H⁺
[M+H]⁺のLC-MS: 計算値479.1;
実測値: 479.6. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 8.21 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 8.04
(s, 1H), 7.93-7.59 (m, 7H), 7.23 (td, J = 9.0, 1.8 Hz, 1H), 3.62 (s, 3H), 3.24
(t, J = 9.2 Hz, 2H), 2.94 (t, J = 9.2 Hz, 2H).

To a stirred solution of succinamic acid methyl ester (500 mg, 3.82 mmol) in 1,2-dichloroethane (10 mL), Meerwein reagent (621 mg, 4.20 mmol) was added dropwise at room temperature. The mixture was stirred for 16 h before 2-amino-5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenol (intermediate 69, 1.46 g, in anhydrous MeOH (15 mL). 3.82 mmol) of solution was added. After the mixture was stirred for an additional 3 h, it was quenched with aqueous NaHCO ₃ (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 10/1 to 5/1) to give 110 mg (6%) of the title compound as a brown solid. C ₂₅ H ₁₉ FN ₂ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: calcd 479.1;
Found: 479.6. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 8.21 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 8.04
(s, 1H), 7.93-7.59 (m, 7H), 7.23 (td, J = 9.0, 1.8 Hz, 1H), 3.62 (s, 3H), 3.24
(t, J = 9.2 Hz, 2H), 2.94 (t, J = 9.2 Hz, 2H).

Intermediate 108: 3- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) propanoic acid

ＥｔＯＨ（８ｍＬ）中の３−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イル］−プロピオン酸メチルエステル（中間体１０７、６０ｍｇ、０．１２６ｍｍｏｌ）およびＮａＯＨ（５０ｍｇ、１．２６ｍｍｏｌ）の混合物を、７６℃で１時間撹拌した。次いで、これを室温に冷却し、濃縮した。混合物を水（１０ｍＬ）で希釈し、石油エーテル／ＥｔＯＡｃ＝１／１（１０ｍＬ、ｖ／ｖ）で懸濁させた。水層を１Ｍ ＨＣｌでｐＨ＝４に酸性化し、ＥｔＯＡｃ（２０ｍＬ×３）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を蒸発乾固させて、５２ｍｇ（７０％）の表題化合物を褐色油状物として得た。C₁₈H₁₃FN₂O₃+H⁺
[M+H]⁺のLC-MS: 計算値
325.1; 実測値: 325.3.

3- [6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazol-2-yl] -propionic acid methyl ester (Intermediate 107, 60 mg, 0) in EtOH (8 mL) .126 mmol) and NaOH (50 mg, 1.26 mmol) were stirred at 76 ° C. for 1 h. It was then cooled to room temperature and concentrated. The mixture was diluted with water (10 mL) and suspended in petroleum ether / EtOAc = 1/1 (10 mL, v / v). The aqueous layer was acidified with 1M HCl to pH = 4 and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was evaporated to dryness to give 52 mg (70%) of the title compound as a brown oil. C ₁₈ H ₁₃ FN ₂ O ₃ + H ⁺
[M + H] ⁺ LC-MS: Calculated
325.1; found: 325.3.

Intermediate 109: 2- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide and 2- (5- ( 6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide

ＮＭＰ（３０ｍＬ）中の５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール（中間体２７、１．００ｇ、２．５５ｍｍｏｌ）、２−ブロモアセトアミド（４５０ｍｇ、３．２６ｍｍｏｌ）およびＫ_２ＣＯ_３（７００ｍｇ、５．０６ｍｍｏｌ）の混合物を、室温で４８時間撹拌した。混合物を水中に滴下添加した。黄色沈殿物を真空濾過により収集した。固体をＥｔＯＡｃに溶解し、ブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルクロマトグラフィー（ＤＣＭ〜ＤＣＭ／ＭｅＯＨ＝９／１、ｖ／ｖ）により精製して、表題化合物とその領域異性体との混合物４００ｍｇ（３５％）を黄色固体として得た。これをキラル分取ＨＰＬＣ（ＳＦＣ）によりさらに精製して、１００ｍｇ（９％）の表題化合物を白色固体として、および６０ｍｇ（５％）の他の位置異性体である２−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−イル）アセトアミドを白色固体として得た。C₂₃H₁₇FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
449.1; 実測値: 448.8.

5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazole (Intermediate 27, 1.00 g, 2.55 mmol) in NMP (30 mL), A mixture of 2-bromoacetamide (450 mg, 3.26 mmol) and K ₂ CO ₃ (700 mg, 5.06 mmol) was stirred at room temperature for 48 hours. The mixture was added dropwise into water. A yellow precipitate was collected by vacuum filtration. The solid was dissolved in EtOAc, washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM to DCM / MeOH = 9/1, v / v) to give 400 mg (35%) of the title compound and its region isomer as a yellow solid. This was further purified by chiral preparative HPLC (SFC) to give 100 mg (9%) of the title compound as a white solid and 60 mg (5%) of the other regioisomer, 2- (5- (6- Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide was obtained as a white solid. C ₂₃ H ₁₇ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
449.1; found: 448.8.

Intermediate 110: ethyl 3- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) propanoate

ＤＭＦ（６０ｍＬ）中の５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール（中間体１２、６．５ｇ、１．６６ｍｍｏｌ）、アクリル酸エチルエステル（３．３２ｇ、３３．２ｍｍｏｌ）およびＣｓ_２ＣＯ_３（１６．２ｇ、４９．８ｍｍｏｌ）の混合物を、室温で３時間撹拌した。次いで、反応混合物を水に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物をシリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１〜１／１）により精製して、３．５ｇ（４３％）の表題化合物を白色固体として得た。C₂₆H₂₂FN₃O₄S+H⁺
[M+H]⁺のLC-MS: 計算値492.1;
実測値: 491.8. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 8.16-8.13 (m, 4H), 8.08 (s, 1H), 7.91 - 7.87
(m, 1H), 7.85 - 7.79 (m, 2H), 7.75 - 7.70 (m, 2H), 7.66 - 7.61 (m, 2H), 7.25
(td, J = 9.2, 2.4 Hz, 1H), 4.68 (t, J = 6.4 Hz, 2H), 4.00 (q, J = 7.2 Hz, 2H),
2.95 (t, J = 6.4 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H).

5- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-indazole (Intermediate 12, 6.5 g, 1.66 mmol), acrylic acid ethyl ester (3 .32 g, 33.2 mmol) and Cs ₂ CO ₃ (16.2 g, 49.8 mmol) were stirred at room temperature for 3 hours. The reaction mixture was then poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5/1 to 1/1) to give 3.5 g (43%) of the title compound as a white solid. C ₂₆ H ₂₂ FN ₃ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: calcd 492.1;
Found: 491.8. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 8.16-8.13 (m, 4H), 8.08 (s, 1H), 7.91-7.87
(m, 1H), 7.85-7.79 (m, 2H), 7.75-7.70 (m, 2H), 7.66-7.61 (m, 2H), 7.25
(td, J = 9.2, 2.4 Hz, 1H), 4.68 (t, J = 6.4 Hz, 2H), 4.00 (q, J = 7.2 Hz, 2H),
2.95 (t, J = 6.4 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H).

Intermediate 111: 3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanoic acid

５０ｍＬのメタノール中のＮａＯＨ（８５５ｍｇ、２１．４ｍｍｏｌ）および３−［５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオン酸エチルエステル（中間体１１０、３．５ｇ、７．１３ｍｍｏｌ）の混合物を、７５℃で３０分間撹拌した。混合物を濃縮した。残留物を１Ｎ ＨＣｌで中和した。混合物を濃縮して、４．２ｇの表題化合物を黄色固体として得、これをさらに精製することなく次のステップに使用した。C₁₈H₁₄FN₃O₂+H⁺
[M+H]⁺のLC-MS: 計算値 324.1;
実測値: 323.9.

NaOH (855 mg, 21.4 mmol) and 3- [5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -indazol-1-yl] -propionic acid ethyl ester in 50 mL methanol ( A mixture of intermediate 110, 3.5 g, 7.13 mmol) was stirred at 75 ° C. for 30 minutes. The mixture was concentrated. The residue was neutralized with 1N HCl. The mixture was concentrated to give 4.2 g of the title compound as a yellow solid that was used in the next step without further purification. C ₁₈ H ₁₄ FN ₃ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 324.1;
Actual value: 323.9.

Intermediate 112: tert-butyl 4- (3- (5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanoyl) piperazine-1-carboxylate

ＤＭＦ（５ｍＬ）中の３−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオン酸（中間体１１１、３００ｍｇ、粗製、０．９３ｍｍｏｌ）、ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（１７３ｍｇ、０．９３ｍｍｏｌ）、ＨＡＴＵ（５３０ｍｇ、１．４ｍｍｏｌ）およびＤＩＥＡ（３６０ｍｇ、２．８ｍｍｏｌ）の混合物を、室温で２時間撹拌した。次いで、混合物を水に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を分取ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ＝３０％〜７５％、ＮＨ_４ＨＣＯ_３）により精製して、９８ｍｇ（２１％）の表題化合物を黄色固体として得た。C₂₇H₃₀FN₅O₃+H⁺
[M+H]⁺のLC-MS: 計算値
492.2; 実測値: 491.9.

3- [5- (6-Fluoro-1H-indol-3-yl) -indazol-1-yl] -propionic acid (intermediate 111, 300 mg, crude, 0.93 mmol), piperazine- in DMF (5 mL) A mixture of 1-carboxylic acid tert-butyl ester (173 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) was stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O = 30% -75%, NH ₄ HCO ₃ ) to give 98 mg (21%) of the title compound as a yellow solid. C ₂₇ H ₃₀ FN ₅ O ₃ + H ⁺
[M + H] ⁺ LC-MS: Calculated
492.2; Found: 491.9.

Intermediate 113: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) indoline-2-one

ジオキサン（１０ｍＬ）および水（１ｍＬ）中の６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、６００ｍｇ、１．５０ｍｍｏｌ）、６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）インドリン−２−オン（２５９ｍｇ、１．００ｍｍｏｌ、ＷＯ２０１４１４００７５に記載されている通りに調製した）およびＫ_２ＣＯ_３（２７６ｍｇ、２．００ｍｍｏｌ）の混合物に、Ｐｄ（ＰＰｈ_３）_４（１１６ｍｇ、０．１０ｍｍｏｌ）を添加した。混合物を１２０℃で２時間撹拌した後、これを濃縮した。残留物をシリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１、ｖ／ｖ）により精製して、４００ｍｇ（９８％）の表題化合物を黄色固体として得た。¹H NMR (300 MHz, CDCl₃) δ [ppm]: 7.96 - 7.90 (m, 2H), 7.81 (dd, J = 9.6, 2.4 Hz, 1H), 7.70 -
7.63 (m, 3H), 7.61 - 7.56 (m, 1H), 7.54 - 7.45 (m, 2H), 7.31 (d, J = 7.7 Hz,
1H), 7.22 (dd, J = 7.7, 1.5 Hz, 1H), 7.10 - 7.01 (m, 2H), 3.59 (s, 2H).

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 600 mg, 1.50 mmol), 6- (4,4,5,5) in dioxane (10 mL) and water (1 mL). 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) indoline-2-one (259 mg, 1.00 mmol, prepared as described in WO2014140075) and K ₂ CO ₃ (276 mg, 2. Pd (PPh ₃ ) ₄ (116 mg, 0.10 mmol) was added to the (00 mmol) mixture. After the mixture was stirred at 120 ° C. for 2 hours, it was concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5/1, v / v) to give 400 mg (98%) of the title compound as a yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ [ppm]: 7.96-7.90 (m, 2H), 7.81 (dd, J = 9.6, 2.4 Hz, 1H), 7.70-
7.63 (m, 3H), 7.61-7.56 (m, 1H), 7.54-7.45 (m, 2H), 7.31 (d, J = 7.7 Hz,
1H), 7.22 (dd, J = 7.7, 1.5 Hz, 1H), 7.10-7.01 (m, 2H), 3.59 (s, 2H).

Intermediate 114: 3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide and 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide

ＮＭＰ（１０ｍＬ）中の５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール（中間体２７、１．６６ｇ、４．２４ｍｍｏｌ）、３−ブロモプロピオンアミド（９７０ｍｇ、６．３８ｍｍｏｌ）、ＫＩ（１００ｍｇ、０．６０ｍｍｏｌ）およびＫ_２ＣＯ_３（８７６ｍｇ、６．３４ｍｍｏｌ）の混合物を、６０℃で１２時間撹拌した。別のバッチの３−ブロモプロピオンアミド（２ｍｇ、１２．７ｍｍｏｌ）およびＫ_２ＣＯ_３（２ｍｇ、１２．７ｍｍｏｌ）を添加し、混合物を６０℃でさらに２４時間撹拌した。混合物を水（１５０ｍＬ）に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、シリカゲルクロマトグラフィー（ＤＣＭ〜ＤＣＭ／ＭｅＯＨ＝１０／１）により精製して、表題化合物とその領域異性体との混合物７００ｍｇ（３７％）を無色油状物として得、これをキラル分取ＨＰＬＣ（ＳＦＣ）によりさらに精製して、１４０ｍｇ（７％）の表題化合物を白色固体として、および１８０ｍｇ（９％）の他の位置異性体である３−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−イル）プロパンアミドを白色固体として得た。C₂₄H₁₉FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
463.1; 実測値: 462.8.

5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazole (Intermediate 27, 1.66 g, 4.24 mmol) in NMP (10 mL), A mixture of 3-bromopropionamide (970 mg, 6.38 mmol), KI (100 mg, 0.60 mmol) and K ₂ CO ₃ (876 mg, 6.34 mmol) was stirred at 60 ° C. for 12 hours. Another batch of 3-bromopropionamide (2 mg, 12.7 mmol) and K ₂ CO ₃ (2 mg, 12.7 mmol) was added and the mixture was stirred at 60 ° C. for a further 24 hours. The mixture was poured into water (150 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (DCM to DCM / MeOH = 10/1) to give the title compound and its region isomer. Of 700 mg (37%) as a colorless oil, which was further purified by chiral preparative HPLC (SFC) to give 140 mg (7%) of the title compound as a white solid and 180 mg (9%) of others 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide as a white solid Obtained. C ₂₄ H ₁₉ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
463.1; found: 462.8.

Intermediate 115: 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indoline-2-one

５−ブロモ−１，３−ジヒドロ−インドール−２−オン（１．００ｇ、４．７２ｍｍｏｌ）および４，４，５，５，４’，４’，５’，５’−オクタメチル−［２，２’］ビ［［１，３，２］ジオキサボロラニル］（１．５６ｇ、６．１４ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、表題化合物（１．２０ｇ、粗製）を黄色固体として得た。C₁₄H₁₈BNO₃+H⁺ [M+H]⁺のLC-MS: 計算値 2620.1; 実測値: 260.4.

5-Bromo-1,3-dihydro-indol-2-one (1.00 g, 4.72 mmol) and 4,4,5,5,4 ′, 4 ′, 5 ′, 5′-octamethyl- [2, 2 ′] bi [[1,3,2] dioxaborolanyl] (1.56 g, 6.14 mmol) and according to the general procedure outlined in Intermediate 3, the title compound (1.20 g, crude ) Was obtained as a yellow solid. LC-MS for C ₁₄ H ₁₈ BNO ₃ + H ⁺ [M + H] ⁺ : calculated 2620.1; found: 260.4.

Intermediate 116: 1-benzenesulfonyl-6-fluoro-1 ', 3'-dihydro-1H- [3,5'] biindolyl-2'-one

６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、０．９６ｇ、２．４ｍｍｏｌ）および５−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−１，３−ジヒドロ−インドール−２−オン（０．８４ｇ、２．０ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、表題化合物（４４０ｍｇ、４５％）を黄色固体として得た。C₂₂H₁₅FN₂O₃S-H- [M-H]^-のLC-MS: 計算値405.1; 実測値:
405.4. ¹H NMR (400 MHz, DMSO) δ 10.49
(s, 1H), 8.12 (d, J = 7.6 Hz, 2H), 8.01 (s, 1H), 7.86 - 7.76 (m, 2H), 7.72 (t,
J = 7.5 Hz, 1H), 7.62 (t, J = 7.7 Hz, 2H), 7.55 (s, 1H), 7.51 (d, J = 7.9 Hz,
1H), 7.22 (td, J = 9.1, 2.3 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.54 (s, 2H).

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 0.96 g, 2.4 mmol) and 5- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -1,3-dihydro-indol-2-one (0.84 g, 2.0 mmol) and following the general procedure outlined for intermediate 32, the title compound (440 mg, 45%) as a yellow solid. C ₂₂ H ₁₅ FN ₂ O ₃ SH- [MH] ^- the LC-MS: calc 405.1; found:
405.4. ¹ H NMR (400 MHz, DMSO) δ 10.49
(s, 1H), 8.12 (d, J = 7.6 Hz, 2H), 8.01 (s, 1H), 7.86-7.76 (m, 2H), 7.72 (t,
J = 7.5 Hz, 1H), 7.62 (t, J = 7.7 Hz, 2H), 7.55 (s, 1H), 7.51 (d, J = 7.9 Hz,
1H), 7.22 (td, J = 9.1, 2.3 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.54 (s, 2H).

Intermediate 117: 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] oxazol-2-amine

６−ブロモ−ベンゾオキサゾール−２−イルアミン（２．４０ｇ、１１．３ｍｍｏｌ）および４，４，５，５，４’，４’，５’，５’−オクタメチル−［２，２’］ビ［［１，３，２］ジオキサボロラニル］（３．７３ｇ、１４．７ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、表題化合物（２．６６ｇ、９０％）を黄色固体として得た。C₁₃H₁₇BN₂O₃+H⁺
[M+H]⁺のLC-MS: 計算値261.1;
実測値: 261.4. ¹H NMR (300 MHz, DMSO-d₆)
δ [ppm]: 7.58 (s, 2H), 7.48 (s, 1H), 7.46 - 7.43 (m,
1H), 7.18 (d, J = 7.8 Hz, 1H), 1.29 (s, 12H).

6-Bromo-benzoxazol-2-ylamine (2.40 g, 11.3 mmol) and 4,4,5,5,4 ′, 4 ′, 5 ′, 5′-octamethyl- [2,2 ′] bi [ Starting from [1,3,2] dioxaborolanyl] (3.73 g, 14.7 mmol), the title compound (2.66 g, 90%) was obtained as a yellow solid following the general procedure outlined in Intermediate 3 Got as. C ₁₃ H ₁₇ BN ₂ O ₃ + H ⁺
[M + H] ⁺ LC-MS: calcd 261.1;
Found: 261.4. ¹ H NMR (300 MHz, DMSO-d ₆ )
δ [ppm]: 7.58 (s, 2H), 7.48 (s, 1H), 7.46-7.43 (m,
1H), 7.18 (d, J = 7.8 Hz, 1H), 1.29 (s, 12H).

Intermediate 118: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-amine

６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、２．７７ｇ、６．９０ｍｍｏｌ）および６−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−ベンゾオキサゾール−２−イルアミン（１．５０ｇ、５．７７ｍｍｏｌ）から出発し、中間体９０で概説した一般的方法に従って、表題化合物（１．５０ｇ、６４％）を黄色固体として得た。C₂₁H₁₄FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
408.1; 実測値: 408.5.

6-Fluoro-3-iodo-1- (phenylsulfonyl) -1H-indole (intermediate 1,2.77 g, 6.90 mmol) and 6- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -benzoxazol-2-ylamine (1.50 g, 5.77 mmol) and according to the general procedure outlined for intermediate 90, the title compound (1.50 g, 64%) Was obtained as a yellow solid. C ₂₁ H ₁₄ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
408.1; found: 408.5.

Intermediate 119: N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) ethenesulfonamide

ＤＣＭ（３０ｍＬ）中の（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メタンアミン塩酸塩（化合物７６、４００ｍｇ、１．２６ｍｍｏｌ）、ＴＥＡ（０．５ｍＬ、３．７８ｍｍｏｌ）の撹拌溶液に、２−クロロエタンスルホニルクロリド（０．１７ｍＬ、１．３０ｍｍｏｌ）を窒素下０℃で添加した。混合物を窒素下室温で３時間撹拌した。反応混合物をＥｔＯＡｃ（６０ｍＬ）で希釈し、濾過した。濾液を濃縮し、シリカゲルカラム（石油エーテル／ＥｔＯＡｃ＝２／１）により精製して、１４７ｍｇ（３２％）の表題化合物を黄色油状物として得た。C₁₈H₁₄FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
372.1; 実測値: 372.5.

(6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine hydrochloride (Compound 76, 400 mg, 1.26 mmol), TEA (0. To a stirred solution of 5 mL, 3.78 mmol) was added 2-chloroethanesulfonyl chloride (0.17 mL, 1.30 mmol) at 0 ° C. under nitrogen. The mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was diluted with EtOAc (60 mL) and filtered. The filtrate was concentrated and purified by silica gel column (petroleum ether / EtOAc = 2/1) to give 147 mg (32%) of the title compound as a yellow oil. C ₁₈ H ₁₄ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
372.1; found: 372.5.

Intermediate 120: 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-vinylbenzo [d] oxazole

６−ブロモ−２−（２−クロロ−エチル）−ベンゾオキサゾール（９５０ｍｇ、３．６７ｍｍｏｌ）およびＢ_２Ｐｉｎ_２（１．１２ｇ、４．４ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、７００ｍｇ（７０％）の表題化合物を無色油状物として得た。
¹H NMR
(400 MHz, CDCl₃) δ [ppm]: 7.95 (s, 1H), 7.78
(d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.76 (dd, J = 17.6, 11.2 Hz,
1H), 6.50 (dd, J = 17.6, 0.8 Hz, 1H), 5.88 (dd, J = 11.6, 0.8 Hz, 1H), 1.37 (s,
12 H).

General method outlined in Intermediate 3 starting from 6-bromo-2- (2-chloro-ethyl) -benzoxazole (950 mg, 3.67 mmol) and B ₂ Pin ₂ (1.12 g, 4.4 mmol) To give 700 mg (70%) of the title compound as a colorless oil.
¹ H NMR
(400 MHz, CDCl ₃ ) δ [ppm]: 7.95 (s, 1H), 7.78
(d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.76 (dd, J = 17.6, 11.2 Hz,
1H), 6.50 (dd, J = 17.6, 0.8 Hz, 1H), 5.88 (dd, J = 11.6, 0.8 Hz, 1H), 1.37 (s,
12 H).

Intermediate 121: tert-butyl 6-fluoro-3- (2-vinylbenzo [d] oxazol-6-yl) -1H-indole-1-carboxylate

６−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−２−ビニル−ベンゾオキサゾール（７００ｍｇ、２．５８ｍｍｏｌ）および３−ブロモ−６−フルオロ−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（９７０ｍｇ、３．１０ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、５２０ｍｇ（５３％）の表題化合物を白色固体として得た。¹H NMR (400 MHz, CDCl₃) δ [ppm]: 7.96 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.4, 0.4 Hz, 1H),
7.76 - 7.70 (m, 3H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (td, J = 8.8, 2.4 Hz,
1H), 6.79 (dd, J = 17.6, 11.2 Hz, 1H), 6.50 (dd, J = 17.6, 0.8 Hz, 1H), 5.89
(dd, J = 11.2, 0.8 Hz, 1H), 1.70 (s, 9H).

6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -2-vinyl-benzoxazole (700 mg, 2.58 mmol) and 3-bromo-6-fluoro- Starting from indole-1-carboxylic acid tert-butyl ester (970 mg, 3.10 mmol), following the general procedure outlined for intermediate 32, 520 mg (53%) of the title compound were obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 7.96 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.4, 0.4 Hz, 1H),
7.76-7.70 (m, 3H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (td, J = 8.8, 2.4 Hz,
1H), 6.79 (dd, J = 17.6, 11.2 Hz, 1H), 6.50 (dd, J = 17.6, 0.8 Hz, 1H), 5.89
(dd, J = 11.2, 0.8 Hz, 1H), 1.70 (s, 9H).

Intermediate 122: tert-butyl 6-fluoro-3- (2- (2- (methylthio) ethyl) benzo [d] oxazol-6-yl) -1H-indole-1-carboxylate

無水ＴＨＦ（６ｍＬ）中の６−フルオロ−３−（２−ビニル−ベンゾオキサゾール−６−イル）−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１２１、５２０ｍｇ、１．３７ｍｍｏｌ）の溶液に、ＮａＳＭｅ（１４４ｍｇ、２．０６ｍｍｏｌ）を０℃で添加した。混合物をゆっくりと室温に加温し、６０℃で３０分間加熱した。混合物を冷却し、ＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２０ｍＬ）、ブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝２０／１から１０／１）により精製して、４８０ｍｇ（８２％）の表題化合物を白色固体として得た。¹H NMR (400 MHz, CDCl₃) δ [ppm]: 7.96 (d, J = 9.2 Hz, 1H), 7.78 - 7.69 (m, 4H), 7.57 (dd, J =
8.0, 1.2 Hz, 1H), 7.06 (td, J = 8.8, 2.4 Hz, 1H), 3.29 (t, J = 7.6 Hz, 2H),
3.06 (t, J = 7.6 Hz, 2H), 2.20 (s, 3H), 1.70 (s, 9H).

To a solution of 6-fluoro-3- (2-vinyl-benzoxazol-6-yl) -indole-1-carboxylic acid tert-butyl ester (intermediate 121, 520 mg, 1.37 mmol) in anhydrous THF (6 mL) , NaSMe (144 mg, 2.06 mmol) was added at 0 ° C. The mixture was slowly warmed to room temperature and heated at 60 ° C. for 30 minutes. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (20 mL), brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 20/1 to 10/1) to give 480 mg (82%) of the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 7.96 (d, J = 9.2 Hz, 1H), 7.78-7.69 (m, 4H), 7.57 (dd, J =
8.0, 1.2 Hz, 1H), 7.06 (td, J = 8.8, 2.4 Hz, 1H), 3.29 (t, J = 7.6 Hz, 2H),
3.06 (t, J = 7.6 Hz, 2H), 2.20 (s, 3H), 1.70 (s, 9H).

Intermediate 123: tert-butyl 6-fluoro-3- (2- (2- (methylsulfonyl) ethyl) benzo [d] oxazol-6-yl) -1H-indole-1-carboxylate

ＤＣＭ（１０ｍＬ）中の６−フルオロ−３−［２−（２−メチルスルファニル−エチル）−ベンゾオキサゾール−６−イル］−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（４８０ｍｇ、１．１３ｍｍｏｌ）の溶液に、ｍ−ＣＰＢＡ（３９１ｍｇ、２．２６ｍｍｏｌ）を０℃で添加した。混合物を室温で２０分間撹拌し、氷水（３０ｍＬ）に注ぎ入れ、ＥｔＯＡｃ（３０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を蒸発させ、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝１０／１から３／１）により精製して、３９０ｍｇ（７５％）の表題化合物を黄色固体として得た。C₂₃H₂₃FN₂O₅S+H⁺
[M+H]⁺のLC-MS: 計算値459.1;
実測値: 459.6. ¹H NMR (300 MHz, CDCl₃)
δ [ppm]: 7.96 (d, J = 8.7 Hz, 1H), 7.78-7.68 (m, 4H),
7.59 (dd, J = 8.4, 1.5 Hz, 1H), 7.07 (td, J = 9.0, 2.4 Hz, 1H), 3.70 (t, J =
7.8 Hz, 2H), 3.54 (t, J = 7.8 Hz, 2H), 3.03 (s, 3H), 1.70 (s, 9H).

Of 6-fluoro-3- [2- (2-methylsulfanyl-ethyl) -benzoxazol-6-yl] -indole-1-carboxylic acid tert-butyl ester (480 mg, 1.13 mmol) in DCM (10 mL). To the solution, m-CPBA (391 mg, 2.26 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 20 minutes, poured into ice water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was evaporated and purified by silica gel column chromatography (petroleum ether / EtOAc = 10/1 to 3/1) to give 390 mg (75%) of the title compound as a yellow solid. C ₂₃ H ₂₃ FN ₂ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: calcd 459.1;
Found: 459.6. ¹ H NMR (300 MHz, CDCl ₃ )
δ [ppm]: 7.96 (d, J = 8.7 Hz, 1H), 7.78-7.68 (m, 4H),
7.59 (dd, J = 8.4, 1.5 Hz, 1H), 7.07 (td, J = 9.0, 2.4 Hz, 1H), 3.70 (t, J =
7.8 Hz, 2H), 3.54 (t, J = 7.8 Hz, 2H), 3.03 (s, 3H), 1.70 (s, 9H).

Intermediate 124: N- (6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methanesulfonamide

ピリジン（８ｍＬ）中の６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イルアミン（中間体１１８、４００ｍｇ、０．９８ｍｍｏｌ）の溶液に、メタンスルホニルクロリド（２２４ｍｇ、１．９６ｍｍｏｌ）を添加し、混合物を室温で終夜撹拌した。溶媒を除去し、残留物をジクロロメタンに再溶解し、飽和ＮＨ_４Ｃｌ水溶液（２０ｍＬ×２）およびブライン（２０ｍＬ）で洗浄した。有機層を乾燥させ、濃縮して、３５０ｍｇの表題化合物（７４％）を黒色固体として得た。C₂₂H₁₆FN₃O₅S₂-H^-
[M-H]^-のLC-MS: 計算値
484.1; 実測値: 484.4.

To a solution of 6- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazol-2-ylamine (intermediate 118, 400 mg, 0.98 mmol) in pyridine (8 mL) was added methanesulfonyl. Chloride (224 mg, 1.96 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed and the residue was redissolved in dichloromethane and washed with saturated aqueous NH ₄ Cl (20 mL × 2) and brine (20 mL). The organic layer was dried and concentrated to give 350 mg of the title compound (74%) as a black solid. _{C 22 H 16 FN 3 O 5} S 2 -H -
[MH] ^- of LC-MS: Calculated
484.1; found: 484.4.

Intermediate 125: 2- (2-chloroethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole

ＤＣＭ（１０ｍＬ）中の２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェノール（中間体６９、１．６ｇ、４．１９ｍｍｏｌ）および３−クロロ−プロピオンイミド酸メチルエステル（３．６ｇ、２０．９４ｍｍｏｌ）の溶液を、窒素下室温で終夜撹拌した。反応混合物を濃縮し、水（５０ｍＬ）で希釈し、ＥｔＯＡｃ（１００ｍＬ×３）で抽出し、有機層を濃縮し、シリカゲル上でのフラッシュクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１）により精製して、２８０ｍｇ（１５％）の表題化合物を黄色固体として得た。C₂₃H₁₆ClFN₂O₃S+H⁺
[M +H]⁺のLC-MS: 計算値454.1;
実測値: 455.5. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 7.95 (d, J = 7.9 Hz, 2H), 7.81 (dd, J = 9.2,
1.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.73 -7.66 (m, 3H), 7.59 (t, J = 7.3 Hz,
1H), 7.54-7.48 (m, 3H), 7.07 (td, J = 9.2, 2.4 Hz, 1H), 4.04 (t, J = 6.8Hz,
2H), 3.45 (t, J = 6.8 Hz, 2H).

2-Amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenol (intermediate 69, 1.6 g, 4.19 mmol) and 3-chloro in DCM (10 mL) -A solution of propionimidic acid methyl ester (3.6 g, 20.94 mmol) was stirred overnight at room temperature under nitrogen. The reaction mixture is concentrated, diluted with water (50 mL), extracted with EtOAc (100 mL × 3), the organic layer is concentrated and purified by flash chromatography on silica gel (petroleum ether / EtOAc = 5/1). To give 280 mg (15%) of the title compound as a yellow solid. C ₂₃ H ₁₆ ClFN ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 454.1;
Found: 455.5. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 7.95 (d, J = 7.9 Hz, 2H), 7.81 (dd, J = 9.2,
1.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.73 -7.66 (m, 3H), 7.59 (t, J = 7.3 Hz,
1H), 7.54-7.48 (m, 3H), 7.07 (td, J = 9.2, 2.4 Hz, 1H), 4.04 (t, J = 6.8Hz,
2H), 3.45 (t, J = 6.8 Hz, 2H).

Intermediate 126: 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [d] oxazole

６−ブロモ−ベンゾオキサゾール（５１０ｍｇ、２．５８ｍｍｏｌ）および４，４，５，５，４’，４’，５’，５’−オクタメチル−［２，２’］ビ［［１，３，２］ジオキサボロラニル］（８５６ｍｇ、３．３７ｍｍｏｌ）から出発し、中間体３で概説した一般的方法に従って、表題化合物（７４０ｍｇ、＞１００％）を黄色固体として得た。C₁₃H₁₆BNO₃+H⁺ [M+H]⁺のLC-MS: 計算値246.1; 実測値:
246.4. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (s, 1H), 8.05 (s, 1H), 7.84 (dd, J = 8.0, 0.8 Hz, 1H), 7.80
(dd, J = 8.0, 0.5 Hz, 1H), 1.39 (s, 12H).

6-Bromo-benzoxazole (510 mg, 2.58 mmol) and 4,4,5,5,4 ′, 4 ′, 5 ′, 5′-octamethyl- [2,2 ′] bi [[1,3,2 The title compound (740 mg,> 100%) was obtained as a yellow solid according to the general procedure outlined in Intermediate 3, starting from] dioxaborolanyl] (856 mg, 3.37 mmol). LC-MS for C ₁₃ H ₁₆ BNO ₃ + H ⁺ [M + H] ⁺ : Calculated 246.1; Found:
246.4. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 8.05 (s, 1H), 7.84 (dd, J = 8.0, 0.8 Hz, 1H), 7.80
(dd, J = 8.0, 0.5 Hz, 1H), 1.39 (s, 12H).

Intermediate 127: 6- (1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole

１−ベンゼンスルホニル−３−ヨード−１Ｈ−インドール（５００ｍｇ、１．３０ｍｍｏｌ）および６−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−ベンゾオキサゾール（４４２ｍｇ、１．４３ｍｍｏｌ）から出発し、中間体９０で概説した一般的方法に従って、表題化合物（３４０ｍｇ、７０％）を黒色固体として得た。C₂₁H₁₄N₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
375.1; 実測値: 375.5.

1-Benzenesulfonyl-3-iodo-1H-indole (500 mg, 1.30 mmol) and 6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoxazole Starting from (442 mg, 1.43 mmol), the title compound (340 mg, 70%) was obtained as a black solid following the general method outlined in Intermediate 90. C ₂₁ H ₁₄ N ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
375.1; found: 375.5.

Intermediate 128: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole

６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２−ビニルベンゾ［ｄ］オキサゾール（３．０ｇ、１１．０７ｍｍｏｌ）および６−フルオロ−３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１、４．８ｇ、１２．１８ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、２．３ｇ（５０％）の表題化合物を白色固体として得た。C₂₃H₁₅FN₂O₃S+H⁺ [M+H]⁺のLC-Ms: 計算値419.1; 実測値:
419.6. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 7.95 (d, J = 7.4 Hz, 2H), 7.85 - 7.74 (m, 2H), 7.72 (q, J =
5.1 Hz, 3H), 7.60 (t, J = 7.5 Hz, 1H), 7.57 - 7.45 (m, 3H), 7.08 (td, J = 8.9,
2.4 Hz, 1H), 6.78 (dd, J = 17.6, 11.1 Hz, 1H), 6.51 (d, J = 17.6 Hz, 1H), 5.90
(d, J = 11.2 Hz, 1H).

6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-vinylbenzo [d] oxazole (3.0 g, 11.07 mmol) and 6-fluoro-3- 2.3 g (50%) of the title compound starting from iodo-1- (phenylsulfonyl) -1H-indole (Intermediate 1, 4.8 g, 12.18 mmol) and following the general procedure outlined in Intermediate 32 Was obtained as a white solid. LC-Ms for C ₂₃ H ₁₅ FN ₂ O ₃ S + H ⁺ [M + H] ⁺ : Calculated 419.1; Found:
419.6. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 7.95 (d, J = 7.4 Hz, 2H), 7.85-7.74 (m, 2H), 7.72 (q, J =
5.1 Hz, 3H), 7.60 (t, J = 7.5 Hz, 1H), 7.57-7.45 (m, 3H), 7.08 (td, J = 8.9,
2.4 Hz, 1H), 6.78 (dd, J = 17.6, 11.1 Hz, 1H), 6.51 (d, J = 17.6 Hz, 1H), 5.90
(d, J = 11.2 Hz, 1H).

Intermediate 129: 5- (6-Chloro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole

１−ベンゼンスルホニル−６−クロロ−３−ヨード−１Ｈ−インドール（５６８ｍｇ、１．３６ｍｍｏｌ）および５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾ［ｄ］オキサゾール（中間体４２、５００ｍｇ、２．０４ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、３４０ｍｇ（６１％）の表題化合物を白色固体として得た。
C₂₁H₁₃ClN₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値409.0;
実測値: 409.5. ¹H NMR (300 MHz, DMSO-d₆)
δ [ppm]: 8.82 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.13
(d, J = 1.5 Hz, 2H), 8.03 (d, J = 1.8 Hz, 1H), 7.88 (m, 2H), 7.85 (dd, J = 8.4,
1.7 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.6 Hz, 2H), 7.41 (dd, J =
8.6, 1.9 Hz, 1H).

1-benzenesulfonyl-6-chloro-3-iodo-1H-indole (568 mg, 1.36 mmol) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Starting from benzo [d] oxazole (Intermediate 42, 500 mg, 2.04 mmol) and following the general procedure outlined for Intermediate 32, 340 mg (61%) of the title compound was obtained as a white solid.
C ₂₁ H ₁₃ ClN ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 409.0;
Found: 409.5. ¹ H NMR (300 MHz, DMSO-d ₆ )
δ [ppm]: 8.82 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.13
(d, J = 1.5 Hz, 2H), 8.03 (d, J = 1.8 Hz, 1H), 7.88 (m, 2H), 7.85 (dd, J = 8.4,
1.7 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.6 Hz, 2H), 7.41 (dd, J =
(8.6, 1.9 Hz, 1H).

Intermediate 130: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole-2-thiol

エタノール（２０ｍＬ）中の２−アミノ−５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体６９、３００ｍｇ、０．７８ｍｍｏｌ）およびＫＯＨ（６３ｍｇ、０．９５ｍｍｏｌ、８５％）の混合物に、ＣＳ_２（２ｍＬ、３３．１６ｍｍｏｌ）を添加した。混合物を６０℃で終夜撹拌した。溶媒を除去して、４５０ｍｇ（粗製）の表題化合物を黄色固体として得た。C₂₁H₁₃FN₂O₃S₂-H^-
[M-H]^-のLC-MS: 計算値
423.1; 実測値: 423.3.

2-Amino-5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenol (intermediate 69, 300 mg, 0.78 mmol) and KOH (63 mg,. To a mixture of 95 mmol, 85%) was added CS ₂ (2 mL, 33.16 mmol). The mixture was stirred at 60 ° C. overnight. The solvent was removed to give 450 mg (crude) of the title compound as a yellow solid. _{C 21 H 13 FN 2 O 3} S 2 -H -
[MH] ^- of LC-MS: Calculated
423.1; Found: 423.3.

Intermediate 131: tert-butyl 4-((6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) piperidine-1-carboxy rate

ＤＣＭ（２５ｍＬ）中のｔｅｒｔ−ブチル４−（２−アミノ−２−オキソエチル）ピペリジン−１−カルボキシレート（５００ｍｇ、２．０７ｍｍｏｌ）の溶液に、Ｍｅ_３ＯＢＦ_４（３０６ｍｇ、２．０７ｍｍｏｌ）を添加した。混合物をＮ_２下室温で終夜撹拌した後、２−アミノ−５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）フェノール（中間体６９、８７２ｍｇ、２．２８ｍｍｏｌ）を添加した。混合物を４０℃で２時間、次いで室温で終夜撹拌した。混合物を濃縮し、残留物を、ＰＥ−ＥＡ（５／１〜１／１）を用いるシリカゲルカラムにより精製して、３５０ｍｇの表題化合物（２８％）を黄色固体として得た。C₃₂H₃₂FN₃O₅S+H⁺
[M+H]⁺のLC-MS: 計算値
590.2; 実測値: 590.2.

To a solution of tert-butyl 4- (2-amino-2-oxoethyl) piperidine-1-carboxylate (500 mg, 2.07 mmol) in DCM (25 mL) was added Me ₃ OBF ₄ (306 mg, 2.07 mmol). did. The mixture was stirred overnight at room temperature under N ₂ before 2-amino-5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) phenol (intermediate 69, 872 mg, 2.28 mmol). Was added. The mixture was stirred at 40 ° C. for 2 hours and then at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column with PE-EA (5/1 to 1/1) to give 350 mg of the title compound (28%) as a yellow solid. C ₃₂ H ₃₂ FN ₃ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
590.2; found: 590.2.

Intermediate 132: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) benzo [d] oxazole

ＥＡ（２ｍＬ）中のｔｅｒｔ−ブチル４−（（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）ピペリジン−１−カルボキシレート（３００ｍｇ、０．５１ｍｍｏｌ）の溶液に、ＥＡ−ＨＣｌ（２ｍＬ、３Ｎ）を添加した。混合物を室温で１時間撹拌した。混合物を濃縮して、表題生成物（２４９ｍｇ、１００％）を黄色固体として得た。C₂₇H₂₄FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値
490.2; 実測値: 490.2.

Tert-Butyl 4-((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) piperidine-1 in EA (2 mL) -To a solution of carboxylate (300 mg, 0.51 mmol) was added EA-HCl (2 mL, 3N). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the title product (249 mg, 100%) as a yellow solid. C ₂₇ H ₂₄ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
490.2; found: 490.2.

Intermediate 133: tert-butylmethylsulfonyl ((6- (1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) carbamate

ＤＭＦ（６０ｍＬ）中のｔｅｒｔ−ブチルメチルスルホニルカルバメート（９００ｍｇ、４．６２ｍｍｏｌ）、Ｋ_２ＣＯ_３（１．３ｇ、９．６３ｍｍｏｌ）の溶液に、２−（クロロメチル）−６−（１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体７９、１．４９ｇ、３．５２ｍｍｏｌ）を添加した。混合物を５０℃で９時間撹拌した。反応混合物を濾過した。濾液を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝６／１〜３／１）により精製して、１．２５ｇ（６１％）の表題化合物を黄色固体として得た。C₂₈H₂₇N₃O₇S₂+H⁺
[M+H]⁺のLC-MS: 計算値582.1; 実測値: 582.7. ¹H NMR
(400 MHz, DMSO-d₆) δ [ppm]:8.22 (s, 1H),
8.13 (d, J = 1.1 Hz, 1H), 8.11 (s, 1H), 8.09 (d, J = 1.3 Hz, 1H), 8.05 (d, J =
8.3 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.76 (dd, J =
8.3, 1.5 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.47 - 7.42
(m, 1H), 7.39 - 7.34 (m, 1H), 5.17 (s, 2H), 3.57 (s, 3H), 1.43 (s, 9H).

To a solution of tert-butylmethylsulfonylcarbamate (900 mg, 4.62 mmol), K ₂ CO ₃ (1.3 g, 9.63 mmol) in DMF (60 mL) was added 2- (chloromethyl) -6- (1- ( Phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 79, 1.49 g, 3.52 mmol) was added. The mixture was stirred at 50 ° C. for 9 hours. The reaction mixture was filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 6/1 to 3/1) to give 1.25 g (61%) of the title compound as a yellow solid. C ₂₈ H ₂₇ N ₃ O ₇ S ₂ + H ⁺
LC-MS of [M + H] ⁺ : calcd 582.1; found: 582.7. ¹ H NMR
(400 MHz, DMSO-d ₆ ) δ [ppm]: 8.22 (s, 1H),
8.13 (d, J = 1.1 Hz, 1H), 8.11 (s, 1H), 8.09 (d, J = 1.3 Hz, 1H), 8.05 (d, J =
8.3 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.76 (dd, J =
8.3, 1.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.47-7.42
(m, 1H), 7.39-7.34 (m, 1H), 5.17 (s, 2H), 3.57 (s, 3H), 1.43 (s, 9H).

Intermediate 134: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-methoxybenzo [d] oxazole

２−アミノ−５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体６９、２００ｍｇ、０．５２ｍｍｏｌ）、テトラメトキシ−メタン（１．４０ｇ、１０．５ｍｍｏｌ）およびトルエン−４−スルホン酸（２０ｍｇ、触媒）の混合物を、１００℃で４時間撹拌した。混合物を冷却し、濃縮し、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝２０／１から５／１）により精製して、１２０ｍｇ（５４％）の表題化合物を白色固体として得た。C₂₂H₁₅FN₂O₄S+H⁺
[M+H]⁺のLC-MS: 計算値423.1;
実測値: 423.6. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 7.95 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.80
(dd, J = 9.6, 2.4 Hz, 1H), 7.72 - 7.67 (m, 1H), 7.66 (s, 1H), 7.60 - 7.54 (m,
3H), 7.52 - 7.48 (m,2H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.06(td, J = 9.2, 2.4
Hz, 1H), 4.26 (s, 3H).

2-Amino-5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -phenol (intermediate 69, 200 mg, 0.52 mmol), tetramethoxy-methane (1.40 g, 10.5 mmol) ) And toluene-4-sulfonic acid (20 mg, catalyst) was stirred at 100 ° C. for 4 hours. The mixture was cooled, concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 20/1 to 5/1) to give 120 mg (54%) of the title compound as a white solid. C ₂₂ H ₁₅ FN ₂ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: calcd 423.1;
Found: 423.6. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 7.95 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.80
(dd, J = 9.6, 2.4 Hz, 1H), 7.72-7.67 (m, 1H), 7.66 (s, 1H), 7.60-7.54 (m,
3H), 7.52-7.48 (m, 2H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.06 (td, J = 9.2, 2.4
Hz, 1H), 4.26 (s, 3H).

Intermediate 135: tert-butoxycarbonylamino {[6- (6-fluoroindol-3-yl) benzoxazol-2-yl] methyl} sulfonamide

ジクロロメタン（０．８７ｍＬ）中のクロリドスルホニルイソシアネート（０．９５ｍＬ、１．１ｍｍｏｌ）の溶液を、氷浴中で冷却した。ｔｅｒｔ−ブタノール（０．１１ｍＬ、１．２ｍｍｏｌ）を添加し、次いでこれを室温で１時間撹拌した。フラスコに、Ｃ−［６−（６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イル］−メチルアミン塩酸塩（化合物７６、３１７ｍｇ、１．０ｍｍｏｌ）およびジクロロメタン（５ｍＬ）を入れた。氷塩浴を用いて−１５℃に冷却した後、ｔｅｒｔブチル［クロロスルホニル］カルバメートの溶液（上記の通り調製した）を添加した。１０分間撹拌した後、トリエチルアミン（６０６ｍｇ、６．６ｍｍｏｌ）を添加した。冷浴を取り外し、反応物を１０℃に加温した。反応をＴＬＣによりモニターした。反応が終わったら、混合物をジクロロメタンで希釈し、水およびブラインで洗浄した。有機層を乾燥させ、濃縮した。残留物をシリカゲルカラムクロマトグラフィー（ＤＣＭ／メタノール＝４０／１〜２０／１）により精製して、２４０ｍｇ（５２％）を黄色固体として得た。C₂₁H₂₁FN₄O₅S+H⁺
[M+H]⁺のLC-MS: 計算値461.1;
実測値: 461.6. ¹H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 11.02 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.92 (d, J
= 1.0 Hz, 1H), 7.87 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 - 7.70 (m, 2H), 7.69 (dd, J
= 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 6.97 (td, J = 9.6, 2.4 Hz,
1H), 4.49 (d, J = 6.0 Hz, 2H), 1.34 (s, 9H).

A solution of chloride sulfonyl isocyanate (0.95 mL, 1.1 mmol) in dichloromethane (0.87 mL) was cooled in an ice bath. Tert-butanol (0.11 mL, 1.2 mmol) was added and then it was stirred at room temperature for 1 hour. To the flask was added C- [6- (6-Fluoro-1H-indol-3-yl) -benzoxazol-2-yl] -methylamine hydrochloride (Compound 76, 317 mg, 1.0 mmol) and dichloromethane (5 mL). I put it in. After cooling to −15 ° C. using an ice-salt bath, a solution of tertbutyl [chlorosulfonyl] carbamate (prepared as described above) was added. After stirring for 10 minutes, triethylamine (606 mg, 6.6 mmol) was added. The cold bath was removed and the reaction was warmed to 10 ° C. The reaction was monitored by TLC. When the reaction was over, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (DCM / methanol = 40/1 to 20/1) to give 240 mg (52%) as a yellow solid. C ₂₁ H ₂₁ FN ₄ O ₅ S + H ⁺
[M + H] ⁺ LC-MS: calcd 461.1;
Found: 461.6. ¹ H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 11.02 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.92 (d, J
= 1.0 Hz, 1H), 7.87 (dd, J = 8.8, 5.4 Hz, 1H), 7.80-7.70 (m, 2H), 7.69 (dd, J
= 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 6.97 (td, J = 9.6, 2.4 Hz,
1H), 4.49 (d, J = 6.0 Hz, 2H), 1.34 (s, 9H).

Intermediate 136: 5- (1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole

３−ヨード−１−（フェニルスルホニル）−１Ｈ−インドール（６２５ｍｇ、１．６３ｍｍｏｌ）および５−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−ベンゾオキサゾール（４００ｍｇ、１．６３ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、５２５ｍｇ（８６％）の表題化合物を黄色固体として得た。
C₂₁H₁₄N₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値375.1;
実測値: 375.4
¹H NMR
(300 MHz, DMSO-d₆) δ [ppm]: 8.81 (s, 1H),
8.17 (s, 1H), 8.15 - 8.07 (m, 3H), 8.04 (d, J = 8.2 Hz, 1H), 7.90 - 7.81 (m,
2H), 7.79 (dd, J = 8.4, 1.8 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.43 - 7.38 (m, 1H),
7.37-7.35 (m, 1H).

3-Iodo-1- (phenylsulfonyl) -1H-indole (625 mg, 1.63 mmol) and 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)- Starting from benzoxazole (400 mg, 1.63 mmol) and following the general procedure outlined for intermediate 32, 525 mg (86%) of the title compound were obtained as a yellow solid.
C ₂₁ H ₁₄ N ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 375.1;
Actual value: 375.4
¹ H NMR
(300 MHz, DMSO-d ₆ ) δ [ppm]: 8.81 (s, 1H),
8.17 (s, 1H), 8.15-8.07 (m, 3H), 8.04 (d, J = 8.2 Hz, 1H), 7.90-7.81 (m,
2H), 7.79 (dd, J = 8.4, 1.8 Hz, 1H), 7.70-7.58 (m, 3H), 7.43-7.38 (m, 1H),
7.37-7.35 (m, 1H).

Intermediate 137: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((1- (methylsulfonyl) piperidin-4-yl) methyl) benzo [d] oxazole

ＤＣＭ（６ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イルメチル）ベンゾ［ｄ］オキサゾール（中間体１３２、３００ｍｇ、０．６１３ｍｍｏｌ）の溶液に、ＴＥＡ（１８６ｍｇ，１．８４ｍｍｏｌ）を室温で添加した。次いで、メタンスルホニルクロリド（８４ｍｇ、０．７４ｍｍｏｌ）を０℃で混合物中に添加した。混合物を０℃で２時間撹拌した。Ｈ_２Ｏ（１０ｍＬ）を添加した。混合物をＤＣＭ（１０ｍＬ×３）で抽出した。有機層をＮａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を、ＰＥ−ＥＡ（４／１〜１／１）を用いるシリカゲルカラムにより精製して、２７５ｍｇ（６８％）の表題化合物を白色固体として得た。C₂₈H₂₆FN₃O₅S₂+H⁺
[M+H]⁺のLC-MS: 計算値
568.1; 実測値: 568.1.

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) benzo [d] oxazole (Intermediate 132, 300 mg) in DCM (6 mL). To a solution of 0.613 mmol) TEA (186 mg, 1.84 mmol) was added at room temperature. Methanesulfonyl chloride (84 mg, 0.74 mmol) was then added into the mixture at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours. H ₂ O (10 mL) was added. The mixture was extracted with DCM (10 mL × 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column with PE-EA (4/1 to 1/1) to give 275 mg (68%) of the title compound as a white solid. C ₂₈ H ₂₆ FN ₃ O ₅ S ₂ + H ⁺
[M + H] ⁺ LC-MS: Calculated
568.1; found: 568.1.

Intermediate 138: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((1-methylpiperidin-4-yl) methyl) benzo [d] oxazole

ＤＣＭ／ＭｅＯＨ（６／３ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イルメチル）ベンゾ［ｄ］オキサゾール（中間体１３２、３３０ｍｇ、０．６７ｍｍｏｌ）の溶液に、ＡｃＯＨ（１２２ｍｇ、２．０２ｍｍｏｌ）、ＣＨ_２Ｏ／Ｈ_２Ｏ（３７％、２７１ｍｇ、３．３５ｍｍｏｌ）およびＮａＢＨ（ＯＡｃ）_３（４２８ｍｇ、２．０２ｍｍｏｌ）を添加した。混合物を室温で３時間撹拌した後、これをＨ_２Ｏ（１０ｍＬ）でクエンチした。混合物をＤＣＭ（１５ｍＬ×３）で抽出した。有機層をＮａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を、ＤＣＭ−ＭｅＯＨ（１００／２）を用いるシリカゲルカラムにより精製して、２５０ｍｇ（７４％）の表題化合物を黄色固体として得た。C₂₈H₂₆FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値504.2;
実測値: 504.2.

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) benzo [d] oxazole (intermediate) in DCM / MeOH (6/3 mL) 132, 330 mg, 0.67 mmol) was added to a solution of AcOH (122 mg, 2.02 mmol), CH ₂ O / H ₂ O (37%, 271 mg, 3.35 mmol) and NaBH (OAc) ₃ (428 mg, 2.02 mmol). ) Was added. After the mixture was stirred at room temperature for 3 h, it was quenched with H ₂ O (10 mL). The mixture was extracted with DCM (15 mL × 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column with DCM-MeOH (100/2) to give 250 mg (74%) of the title compound as a yellow solid. C ₂₈ H ₂₆ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 504.2;
Actual value: 504.2.

Intermediate 139: N- (2,4-dibromophenyl) -2- (2,5-dioxoimidazolidin-4-yl) acetamide

ＤＭＦ（５０ｍＬ）中のヒダントイン−５−酢酸（１．００ｇ、６．３２ｍｍｏｌ）、ＨＡＴＵ（２．８６ｇ、７．５２ｍｍｏｌ）および２，４，６−コリジン（１．４２ｇ、１１．７ｍｍｏｌ）の混合物を、室温で０．５時間撹拌した後、２，４−ジブロモアニリン（１．４５ｇ、５．７８ｍｍｏｌ）を添加した。混合物を室温で１２時間撹拌した後、これを水およびＥｔＯＡｃに注ぎ入れた。沈殿物を真空濾過により収集して、４５０ｍｇ（２０％）の粗表題化合物を白色固体として得、これをさらに精製することなく直接使用した。C₁₁H₉Br₂N₃O₃+H⁺
[M+H]⁺のLC-MS: 計算値389.9;
実測値: 389.6. ¹H NMR (300 MHz, DMSO-d₆)
δ [ppm]: 10.62 (br s, 1H), 9.64 (br s, 1H), 7.90 ( s,
2H), 7.64 - 7.56 (m, 2 H), 4.31 (td, J = 6.6, 4.2 Hz, 1H), 2.89 - 2.83 (m, 1H),
2.75 -2.50 (m, 1H).

Mixture of hydantoin-5-acetic acid (1.00 g, 6.32 mmol), HATU (2.86 g, 7.52 mmol) and 2,4,6-collidine (1.42 g, 11.7 mmol) in DMF (50 mL) Was stirred at room temperature for 0.5 h before 2,4-dibromoaniline (1.45 g, 5.78 mmol) was added. After the mixture was stirred at room temperature for 12 hours, it was poured into water and EtOAc. The precipitate was collected by vacuum filtration to give 450 mg (20%) of the crude title compound as a white solid that was used directly without further purification. C ₁₁ H ₉ Br ₂ N ₃ O ₃ + H ⁺
[M + H] ⁺ LC-MS: Calculated 389.9;
Found: 389.6. ¹ H NMR (300 MHz, DMSO-d ₆ )
δ [ppm]: 10.62 (br s, 1H), 9.64 (br s, 1H), 7.90 (s,
2H), 7.64-7.56 (m, 2 H), 4.31 (td, J = 6.6, 4.2 Hz, 1H), 2.89-2.83 (m, 1H),
2.75 -2.50 (m, 1H).

Intermediate 140: 5-((6-Bromobenzo [d] oxazol-2-yl) methyl) imidazolidine-2,4-dione

ＤＭＦ（５ｍＬ）中のＮ−（２，４−ジブロモフェニル）−２−（２，５−ジオキソイミダゾリジン−４−イル）アセトアミド（中間体１４１、２００ｍｇ、０．５１ｍｍｏｌ）、Ｋ_２ＣＯ_３（１０６ｍｇ、０．７７ｍｍｏｌ）、ＣｕＢｒ（１５０ｍｇ、１．０５ｍｍｏｌ）およびピリジン（０．５ｍＬ）の混合物を、マイクロ波反応器内１４０℃で２時間撹拌した。混合物をＥｔＯＡｃと飽和ＮａＨＣＯ_３水溶液との間で分配した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝１／１〜ＥｔＯＡｃ）により精製して、７５ｍｇ（４７％）の表題化合物を黄色半固体として得た。C₁₁H₈BrN₃O₃-H^-
[M-H]^-のLC-MS: 計算値
308.0; 実測値: 307.8.

N- (2,4-Dibromophenyl) -2- (2,5-dioxoimidazolidin-4-yl) acetamide (Intermediate 141, 200 mg, 0.51 mmol), K ₂ CO _{3 in} DMF (5 mL). A mixture of (106 mg, 0.77 mmol), CuBr (150 mg, 1.05 mmol) and pyridine (0.5 mL) was stirred in a microwave reactor at 140 ° C. for 2 hours. The mixture was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 1-EtOAc) to give 75 mg (47%) of the title compound as a yellow semi-solid Got as. _{C 11 H 8 BrN 3 O 3} -H -
[MH] ^- of LC-MS: Calculated
308.0; Found: 307.8.

Intermediate 141: tert-butyl 3- (2-((2,5-dioxoimidazolidin-4-yl) methyl) benzo [d] oxazol-6-yl) -6-fluoro-1H-indole-1- Carboxylate

５−（（６−ブロモベンゾ［ｄ］オキサゾール−２−イル）メチル）イミダゾリジン−２，４−ジオン（中間体１４２、３１０ｍｇ、１．００ｍｍｏｌ）およびｔｅｒｔ−ブチル６−フルオロ−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インドール−１−カルボキシレート（中間体２、５４３ｍｇ、１．５０ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、５０ｍｇ（１１％）の表題化合物を黄色固体として得た。
C₂₄H₂₁FN₄O₅+H⁺
[M+H]⁺のLC-MS: 計算値465.2;
実測値: 464.8. ¹H NMR (400 MHz, MeOH-d₄)
δ [ppm]: 7.94 (dd, J = 10.1, 2.3 Hz, 1H), 7.86 (d, J =
1.6 Hz, 1H), 7.81 (s, 1H). 7.80 (dd, J = 8.7, 5.4 Hz, 1H), 7.76 (d, J = 8.4 Hz,
1H), 7.66 (dd, J = 8.4, 1.6 Hz, 1H), 7.11 (ddd, J = 9.6, 8.7, 2.3 Hz, 1H), 4.70
(dd, J = 7.2, 4.6 Hz, 1H), 3.54 (dd, J = 16.3, 4.6 Hz, 1H), 3.40 (dd, J = 16.3,
7.2 Hz, 1H), 1.71 (s, 9H).

5-((6-Bromobenzo [d] oxazol-2-yl) methyl) imidazolidine-2,4-dione (intermediate 142, 310 mg, 1.00 mmol) and tert-butyl 6-fluoro-3- (4 Starting with 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylate (Intermediate 2, 543 mg, 1.50 mmol) and outlined in Intermediate 32 In general, 50 mg (11%) of the title compound was obtained as a yellow solid.
C ₂₄ H ₂₁ FN ₄ O ₅ + H ⁺
[M + H] ⁺ LC-MS: calcd 465.2;
Found: 464.8. ¹ H NMR (400 MHz, MeOH-d ₄ )
δ [ppm]: 7.94 (dd, J = 10.1, 2.3 Hz, 1H), 7.86 (d, J =
1.6 Hz, 1H), 7.81 (s, 1H). 7.80 (dd, J = 8.7, 5.4 Hz, 1H), 7.76 (d, J = 8.4 Hz,
1H), 7.66 (dd, J = 8.4, 1.6 Hz, 1H), 7.11 (ddd, J = 9.6, 8.7, 2.3 Hz, 1H), 4.70
(dd, J = 7.2, 4.6 Hz, 1H), 3.54 (dd, J = 16.3, 4.6 Hz, 1H), 3.40 (dd, J = 16.3,
7.2 Hz, 1H), 1.71 (s, 9H).

Intermediate 142: 6- (5-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2 (3H) -one

無水ＴＨＦ（３０ｍＬ）中の２−アミノ−５−（１−ベンゼンスルホニル−５−フルオロ−１Ｈ−インドール−３−イル）−フェノール（７７０ｍｇ、２．０１ｍｍｏｌ）およびＣＤＩ（３５９ｍｇ、２．２１ｍｍｏｌ）の撹拌溶液に、ＴＥＡ（１．６８ｍＬ）を窒素下で添加した。混合物を窒素下室温で１２時間撹拌した。反応物を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、８２０ｍｇ（１００％）の表題化合物を黄色固体として得た。C₂₁H₁₃FN₂O₄S-H^-
[M-H]^-のLC-MS: 計算値407.1;
実測値: 407.5. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.79 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 7.6
Hz, 2H), 8.03 (dd, J = 9.1, 4.5 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.65 - 7.57 (m,
3H), 7.50 (dd, J = 8.0, 1.2 Hz, 1H), 7.28 (td, J = 9.1, 2.5 Hz, 1H), 7.18 (d, J
= 8.1 Hz, 1H).

Of 2-amino-5- (1-benzenesulfonyl-5-fluoro-1H-indol-3-yl) -phenol (770 mg, 2.01 mmol) and CDI (359 mg, 2.21 mmol) in anhydrous THF (30 mL). To the stirring solution, TEA (1.68 mL) was added under nitrogen. The mixture was stirred at room temperature under nitrogen for 12 hours. The reaction was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 820 mg (100%) of the title compound as a yellow solid. _{C 21 H 13 FN 2 O 4} SH -
[MH] ^- the LC-MS: calc 407.1;
Found: 407.5. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.79 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 7.6
Hz, 2H), 8.03 (dd, J = 9.1, 4.5 Hz, 1H), 7.75-7.67 (m, 2H), 7.65-7.57 (m,
3H), 7.50 (dd, J = 8.0, 1.2 Hz, 1H), 7.28 (td, J = 9.1, 2.5 Hz, 1H), 7.18 (d, J
= 8.1 Hz, 1H).

Intermediate 143: 2- (6- (5-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide

ＮＭＰ（２０ｍＬ）中の６−（５−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（４００ｍｇ、０．９８ｍｍｏｌ）およびＫ_２ＣＯ_３（５４２ｍｇ、３．９２ｍｍｏｌ）の溶液に、２−ブロモアセトアミド（１３５ｍｇ、０．９８ｍｍｏｌ）を添加した。混合物を６０℃で６時間撹拌した。反応混合物を室温に冷却し、濾過した。濾液を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、１８３ｍｇ（８１％）の表題化合物を黄色固体として得た。C₂₃H₁₆FN₃O₅S-H^-
[M-H]^-のLC-MS: 計算値464.1;
実測値:464.4. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 8.22 (s, 1H), 8.13 - 8.07 (m, 2H), 8.04 (dd, J
= 9.2, 4.4 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.72 (t, J = 7.2 Hz, 1H), 7.66 - 7.55
(m, 4H), 7.40 (s, 1H), 7.33 - 7.26 (m, 2H), 4.50 (s, 2H).

6- (5-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2 (3H) -one (400 mg, 0.98 mmol) and K _{2 in} NMP (20 mL). To a solution of CO ₃ (542 mg, 3.92 mmol) was added 2-bromoacetamide (135 mg, 0.98 mmol). The mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 183 mg (81%) of the title compound as a yellow solid. _{C 23 H 16 FN 3 O 5} SH -
[MH] ^- the LC-MS: calc 464.1;
Found: 464.4. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 8.22 (s, 1H), 8.13-8.07 (m, 2H), 8.04 (dd, J
= 9.2, 4.4 Hz, 1H), 7.82-7.75 (m, 2H), 7.72 (t, J = 7.2 Hz, 1H), 7.66-7.55
(m, 4H), 7.40 (s, 1H), 7.33-7.26 (m, 2H), 4.50 (s, 2H).

Intermediate 144: Dimethyl 4- (1- (tert-butoxycarbonyl) -6-fluoro-1H-indol-3-yl) phthalate

４−ブロモ−フタル酸ジメチルエステル（３６２ｍｇ、１．３３ｍｍｏｌ）および６−フルオロ−３−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体２、４００ｍｇ、１．１０ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、表題化合物（４００ｍｇ、７２％）を赤色固体として得た。C₂₃H₂₂FNO₆+H⁺ [M+H]⁺のLC-MS: 計算値428.1; 実測値:
428.6. ¹H NMR (400 MHz, CDCl₃) δ [ppm] : 7.97 (d, J = 10.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.88
(d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H),7.77(s, 1H), 7.70 (dd, J =
8.8, 5.2 Hz, 1H), 7.07 (td, J = 8.8, 2.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H),
1.70 (s, 9H).

4-Bromo-phthalic acid dimethyl ester (362 mg, 1.33 mmol) and 6-fluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -indole- Starting from 1-carboxylic acid tert-butyl ester (Intermediate 2, 400 mg, 1.10 mmol) and following the general procedure outlined in Intermediate 32, the title compound (400 mg, 72%) was obtained as a red solid. LC-MS for C ₂₃ H ₂₂ FNO ₆ + H ⁺ [M + H] ⁺ : Calculated 428.1; Found:
428.6. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 7.97 (d, J = 10.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.88
(d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 7.77 (s, 1H), 7.70 (dd, J =
8.8, 5.2 Hz, 1H), 7.07 (td, J = 8.8, 2.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H),
1.70 (s, 9H).

Intermediate 145: 4- (6-Fluoro-1H-indol-3-yl) phthalic acid

メタノール（１０ｍＬ）中の６−フルオロ−３−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１４６、３６０ｍｇ、０．８４ｍｍｏｌ）の溶液に、ＮａＯＨ（１３５ｍｇ、３．３７ｍｍｏｌ）を添加し、混合物を室温で撹拌した。２時間後、ＮａＯＨ（１３５ｍｇ、３．３７ｍｍｏｌ）を添加し、混合物をさらに４時間撹拌した。溶媒を除去した。残留物を水（１０ｍＬ）で希釈し、ｐＨを１〜２に調整した。混合物をＥＡ（２０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過した。溶媒を除去して、１８０ｍｇ（７２％）の表題化合物を黄色固体として得た。C₁₆H₁₀FNO₄-H^- [M-H]^-のLC-MS: 計算値298.1; 実測値:
298.4. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 12.99 (brs, 2H), 11.64 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H),
7.88 (dt, J = 6.6, 3.0 Hz, 3H), 7.79 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 10.0,
2.4 Hz, 1H), 7.01 (td, J = 9.4, 2.4 Hz, 1H).

6-Fluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -indole-1-carboxylic acid tert-butyl ester (middle) in methanol (10 mL) To a solution of body 146, 360 mg, 0.84 mmol) was added NaOH (135 mg, 3.37 mmol) and the mixture was stirred at room temperature. After 2 hours, NaOH (135 mg, 3.37 mmol) was added and the mixture was stirred for an additional 4 hours. The solvent was removed. The residue was diluted with water (10 mL) and the pH was adjusted to 1-2. The mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and filtered. The solvent was removed to give 180 mg (72%) of the title compound as a yellow solid. ^{_{C 16 H 10 FNO 4 -H -}} [MH] - the LC-MS: calc 298.1; found:
298.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.99 (brs, 2H), 11.64 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H),
7.88 (dt, J = 6.6, 3.0 Hz, 3H), 7.79 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 10.0,
2.4 Hz, 1H), 7.01 (td, J = 9.4, 2.4 Hz, 1H).

Intermediate 146: tert-butyl 3- (2- (tert-butoxycarbonyl) isoindoline-5-yl) -6-fluoro-1H-indole-1-carboxylate

ｔｅｒｔ−ブチル６−フルオロ−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インドール−１−カルボキシレート（中間体２、２６０ｍｇ、０．７２ｍｍｏｌ）および５−ブロモ−１，３−ジヒドロ−イソインドール−２−カルボン酸ｔｅｒｔ−ブチルエステル（２７８ｍｇ、０．９３ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、１７８ｍｇ（５５％）の表題化合物を白色固体として得た。C₂₆H₂₉FN₂O₄+H⁺-56
[M+H-56]⁺のLC-MS: 計算値397.2;
実測値: 397.6. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 7.97 - 7.93 (m, 1H), 7.74 - 7.59 (m, 2H),
7.53-7.45(m, 2H), 7.37-7.28 (m, 1H), 7.07 - 7.02 (m, 1H), 4.76 - 4.71 (m, 4H),
1.69 (s, 9H), 1.54 (s, 9H).

tert-Butyl 6-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylate (Intermediate 2, 260 mg, 0 .72 mmol) and 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (278 mg, 0.93 mmol) and following the general procedure outlined in Intermediate 32, 178 mg (55 %) Of the title compound as a white solid. C ₂₆ H ₂₉ FN ₂ O ₄ + H ⁺ -56
[M + H-56] ⁺ LC-MS: calcd 397.2;
Found: 397.6. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 7.97-7.93 (m, 1H), 7.74-7.59 (m, 2H),
7.53-7.45 (m, 2H), 7.37-7.28 (m, 1H), 7.07-7.02 (m, 1H), 4.76-4.71 (m, 4H),
1.69 (s, 9H), 1.54 (s, 9H).

Intermediate 147: tert-butyl 3- (1,1-dioxide-2,3-dihydrobenzo [d] isothiazol-6-yl) -6-fluoro-1H-indole-1-carboxylate

６−ブロモ−２，３−ジヒドロ−ベンゾ［ｄ］イソチアゾール１，１−ジオキシド（７０ｍｇ、０．２８ｍｍｏｌ）および６−フルオロ−３−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体２、１３９ｍｇ、０．４２ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、５０ｍｇ（２９％）の表題化合物を黄色固体として得た。¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.13 (d, J = 8.7 Hz, 2H), 8.03 (dd, J = 8.4, 1.2 Hz, 1H),
7.92 - 7.83 (m, 3H), 7.67 (d, J = 8.1 Hz, 1H), 7.24 (td, J = 9.0, 1.5 Hz, 1H),
4.46 (s, 2H), 1.66 (s, 9H).

6-Bromo-2,3-dihydro-benzo [d] isothiazole 1,1-dioxide (70 mg, 0.28 mmol) and 6-fluoro-3- (4,4,5,5-tetramethyl- [1, 3,2] Dioxaborolan-2-yl) -indole-1-carboxylic acid tert-butyl ester (Intermediate 2, 139 mg, 0.42 mmol) and according to the general procedure outlined in Intermediate 32, 50 mg (29 %) Of the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.13 (d, J = 8.7 Hz, 2H), 8.03 (dd, J = 8.4, 1.2 Hz, 1H),
7.92-7.83 (m, 3H), 7.67 (d, J = 8.1 Hz, 1H), 7.24 (td, J = 9.0, 1.5 Hz, 1H),
4.46 (s, 2H), 1.66 (s, 9H).

Intermediate 148: 4- (1- (tert-butoxycarbonyl) -6-fluoro-1H-indol-3-yl) -2- (N-methylsulfamoyl) benzoic acid

６−ブロモ−２−メチルベンゾ［ｄ］イソチアゾール−３（２Ｈ）−オン１，１−ジオキシド（４００ｍｇ、１．４ｍｍｏｌ）および６−フルオロ−３−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体２、７９０ｍｇ、２．２ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、１５０ｍｇ（２５％）の表題化合物を白色固体として得た。¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.65 (s, 1H), 7.98 - 7.75 (m, 6H), 7.27 (td, J = 9.2, 2.8
Hz, 1H), 2.39 (s, 3H), 1.66 (s, 9H).

6-Bromo-2-methylbenzo [d] isothiazol-3 (2H) -one 1,1-dioxide (400 mg, 1.4 mmol) and 6-fluoro-3- (4,4,5,5-tetramethyl- Starting from [1,3,2] dioxaborolan-2-yl) -indole-1-carboxylic acid tert-butyl ester (Intermediate 2, 790 mg, 2.2 mmol) and following the general procedure outlined in Intermediate 32, 150 mg (25%) of the title compound were obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.65 (s, 1H), 7.98-7.75 (m, 6H), 7.27 (td, J = 9.2, 2.8
Hz, 1H), 2.39 (s, 3H), 1.66 (s, 9H).

Intermediate 149: tert-butyl 6-fluoro-3- (2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -1H-indole-1-carboxylate

６−ブロモ−３Ｈ−ベンゾオキサゾール−２−オン（６００ｍｇ、２．８０ｍｍｏｌ）および６−フルオロ−３−（４，４，５，５−テトラメチル−［１，３，２］ジオキサボロラン−２−イル）−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体２、１．２１ｇ、３．３６ｍｍｏｌ）から出発し、中間体３２で概説した一般的方法に従って、４５０ｍｇ（４５％）の表題化合物を白色固体として得た。¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.56 (s, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.69-7.64 (m, 1H),
7.46 (s, 1H), 7.42 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.06
(td, J = 8.8, 2.4 Hz, 1H), 3.71 (s, 1H), 1.70 (s, 9H).

6-Bromo-3H-benzoxazol-2-one (600 mg, 2.80 mmol) and 6-fluoro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl ) -Indole-1-carboxylic acid tert-butyl ester (Intermediate 2, 1.21 g, 3.36 mmol) and 450 mg (45%) of the title compound in white according to the general procedure outlined in Intermediate 32 Obtained as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.56 (s, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.69-7.64 (m, 1H),
7.46 (s, 1H), 7.42 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.06
(td, J = 8.8, 2.4 Hz, 1H), 3.71 (s, 1H), 1.70 (s, 9H).

Intermediate 150: tert-butyl 3- (3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -6 Fluoro-1H-indole-1-carboxylate

無水ＴＨＦ（１０ｍＬ）中の６−フルオロ−３−（２−オキソ−２，３−ジヒドロ−ベンゾオキサゾール−６−イル）−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１５１、４５０ｍｇ、１．２２ｍｍｏｌ）、４−ヒドロキシ−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（３６９ｍｇ、１．８３ｍｍｏｌ）およびＰＰｈ_３（４８０ｍｇ、１．８３ｍｍｏｌ）の撹拌溶液に、ＤＩＡＤ（３７０ｍｇ、１．８３ｍｍｏｌ）を０℃で添加した。混合物をＮ_２下室温で１６時間撹拌した後、これをＥｔＯＡｃ（５０ｍＬ）で希釈し、水（２０ｍＬ）およびブライン（２０ｍＬ×２）で洗浄した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝３０／１から１０／１）および分取ＴＬＣ（石油エーテル／ＥｔＯＡｃ＝１０／１）により精製して、１２５ｍｇ（１７％）の表題化合物を白色固体として得た。C₃₀H₃₄FN₃O₆+H⁺
[M+H]⁺のLC-MS: 計算値552.2;
実測値: 552.8. ¹H NMR (400 MHz, CDCl₃)
δ [ppm]: 7.94 (d, J = 10.0 Hz, 1H), 7.69 - 7.61 (m,
2H), 7.46 (s, 1H), 7.40 (dd, J = 8.0, 2.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H),
7.06 (td, J = 8.8, 2.4 Hz, 1H), 4.43 - 4.30 (m, 3H), 2.95 - 2.83 (m, 2H), 2.36
- 2.24 (m, 2H), 1.95 - 1.88 (m, 2H), 1.70 (s, 9H), 1.51 (s, 9H).

6-Fluoro-3- (2-oxo-2,3-dihydro-benzoxazol-6-yl) -indole-1-carboxylic acid tert-butyl ester (intermediate 151, 450 mg, 1 mL) in anhydrous THF (10 mL) .22 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (369 mg, 1.83 mmol) and PPh ₃ (480 mg, 1.83 mmol) in a stirred solution of DIAD (370 mg, 1.83 mmol) to 0. Added at 0C. After the mixture was stirred at room temperature under N ₂ for 16 hours, it was diluted with EtOAc (50 mL) and washed with water (20 mL) and brine (20 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 30/1 to 10/1) and preparative TLC (petroleum ether / EtOAc = 10/1) to give 125 mg (17%) of the title compound Was obtained as a white solid. C ₃₀ H ₃₄ FN ₃ O ₆ + H ⁺
[M + H] ⁺ LC-MS: calcd 552.2;
Found: 552.8. ¹ H NMR (400 MHz, CDCl ₃ )
δ [ppm]: 7.94 (d, J = 10.0 Hz, 1H), 7.69-7.61 (m,
2H), 7.46 (s, 1H), 7.40 (dd, J = 8.0, 2.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H),
7.06 (td, J = 8.8, 2.4 Hz, 1H), 4.43-4.30 (m, 3H), 2.95-2.83 (m, 2H), 2.36
-2.24 (m, 2H), 1.95-1.88 (m, 2H), 1.70 (s, 9H), 1.51 (s, 9H).

Intermediate 151: tert-butyl 6-fluoro-3- (2-methyl-1,1-dioxide-3-oxo-2,3-dihydrobenzo [d] isothiazol-5-yl) -1H-indole-1 Carboxylate

アセトン（１０ｍＬ）中のｔｅｒｔ−ブチル３−（１，１−ジオキシド−３−オキソ−２，３−ジヒドロベンゾ［ｄ］イソチアゾール−５−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート（化合物１３０ステップ１、２４６ｍｇ、０．５９ｍｍｏｌ）およびＫ_２ＣＯ_３（２４５ｍｇ、１．７７ｍｍｏｌ）の溶液に、ＭｅＩ（１２６ｍｇ、０．８９ｍｍｏｌ）を添加した。反応混合物を４０℃で終夜撹拌した。反応物を濾過し、濃縮し、ＭｅＯＨ中ですり混ぜて、６０ｍｇ（２４％）の表題化合物を黄色固体として得た。¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.43 - 8.38 (m, 2H), 8.35 (s, 1H), 8.33 (s, 1H), 7.97 - 7.91
(m, 2H), 7.28 (td, J = 9.2, 2.4 Hz, 1H), 3.21 (s, 3H), 1.67 (s, 9H).

Tert-Butyl 3- (1,1-dioxide-3-oxo-2,3-dihydrobenzo [d] isothiazol-5-yl) -6-fluoro-1H-indole-1-carboxyl in acetone (10 mL) To a solution of the rate (compound 130 steps 1,246 mg, 0.59 mmol) and K ₂ CO ₃ (245 mg, 1.77 mmol) was added MeI (126 mg, 0.89 mmol). The reaction mixture was stirred at 40 ° C. overnight. The reaction was filtered, concentrated and triturated in MeOH to give 60 mg (24%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.43-8.38 (m, 2H), 8.35 (s, 1H), 8.33 (s, 1H), 7.97-7.91
(m, 2H), 7.28 (td, J = 9.2, 2.4 Hz, 1H), 3.21 (s, 3H), 1.67 (s, 9H).

Intermediate 152: tert-butyl 6- (2- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) ethyl) -2,6-diazaspiro [3.3 ] Heptane-2-carboxylate

５０℃の乾燥ＭｅＯＨ（１０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１００ｍｇ、０．２４ｍｍｏｌ）の撹拌溶液に、２，６−ジアザ−スピロ［３．３］ヘプタン−２−カルボン酸ｔｅｒｔ−ブチルエステル（１４６ｍｇ、０．６ｍｍｏｌ；Ｏｒｇ．ｌｅｔｔ．、２００８、１０、３５２５により報告されている手順に従って作製した）を添加した。混合物を５０℃で終夜撹拌した。溶媒を除去した。残留物を水（３０ｍＬ）で希釈し、ＥＡ（１０ｍＬ×３）で抽出した。合わせた有機層をブライン（２０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、２００ｍｇの表題化合物を白色固体として得、これをさらに精製することなく次のステップに使用した。

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (Intermediate 128, 100 mg, 0.24 mmol) in dry MeOH (10 mL) at 50 ° C. ) In a stirred solution of 2,6-diaza-spiro [3.3] heptane-2-carboxylic acid tert-butyl ester (146 mg, 0.6 mmol; Org. Lett., 2008, 10, 3525). Prepared according to the procedure). The mixture was stirred at 50 ° C. overnight. The solvent was removed. The residue was diluted with water (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give 200 mg of the title compound as a white solid that was used in the next step without further purification.

Intermediate 153: tert-butyl 3- (benzofuran-6-yl) -6-fluoro-1H-indole-1-carboxylate

１，４−ジオキサン（１５ｍＬ）中の６−ブロモベンゾ［ｂ］フラン（１００ｍｇ、０．５０７ｍｍｏｌ）の撹拌溶液に、ｔｅｒｔ−ブチル６−フルオロ−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インドール−１−カルボキシレート（中間体２、１８０ｍｇ、０．５０７ｍｍｏｌ）、Ｋ_２ＣＯ_３（２１０ｍｇ、１．５２ｍｍｏｌ）およびＰｄ（ｄｐｐｆ）Ｃｌ_２（１９ｍｇ、０．０２５ｍｍｏｌ）を添加した。混合物を８０℃で１５時間撹拌した。溶媒を除去し、残留物を分取ＴＬＣ（ＥｔＯＡｃ／石油エーテル＝１／１０）により精製して、１１２．８ｍｇ（６３％）の表題化合物を得た。C₂₁H₁₈FNO₃+H⁺ [M+H]⁺のLC-MS: 計算値: 351.1; 実測値: 351.8. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 7.96 (d, J = 4.8 Hz, 1H), 7.79-7.76 (m, 2H),7.71-7.67 (m,
3H),7.50 (dd, J = 8.0 Hz,1.6Hz, 1H),7.06 (dd, J = 8.8, 2.4 Hz, 1H), 6.82
(d, J = 1.0 Hz, 1H), 1.70 (s, 9H).

To a stirred solution of 6-bromobenzo [b] furan (100 mg, 0.507 mmol) in 1,4-dioxane (15 mL) was added tert-butyl 6-fluoro-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylate (Intermediate ₂ , 180 mg, 0.507 mmol), K ₂ CO ₃ (210 mg, 1.52 mmol) and Pd (dppf) Cl ₂ (19 mg, 0.025 mmol) was added. The mixture was stirred at 80 ° C. for 15 hours. The solvent was removed and the residue was purified by preparative TLC (EtOAc / petroleum ether = 1/10) to give 112.8 mg (63%) of the title compound. LC-MS for C ₂₁ H ₁₈ FNO ₃ + H ⁺ [M + H] ⁺ : Calculated: 351.1; Found: 351.8. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 7.96 (d, J = 4.8 Hz, 1H), 7.79-7.76 (m, 2H), 7.71-7.67 (m,
3H), 7.50 (dd, J = 8.0 Hz, 1.6Hz, 1H), 7.06 (dd, J = 8.8, 2.4 Hz, 1H), 6.82
(d, J = 1.0 Hz, 1H), 1.70 (s, 9H).

I. 2. Synthesis of Final Compound Compound 1: 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indole- in 6- (6-Fluoro-1H-indol-3-yl) -1H-indazole MeOH (15 mL) To a solution of 3-yl) -1H-indazole (Intermediate 4; 390 mg; 1.00 mmol) was added a solution of NaOH (200 mg; 5.00 mmol) in water (2 mL). The reaction mixture was stirred at 80 ° C. for 2 h, concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 5/1 to 2/1) to give 50 mg (20%) of the title compound as a white solid. . LC-MS for C ₁₅ H ₁₀ FN ₃ + H ⁺ [M + H] ⁺ : Calculated 252.1; Found:
252.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 12.94 (s, 1H), 11.45 (s, 1H), 8.05 (s, 1H), 7.88 (dd, J =
8.8, 5.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.77-7.73 (m, 2H), 7.44 (d, J =
8.4 Hz, 1H), 7.24 (dd, J = 10.0, 2.2 Hz, 1H), 6.99 (ddd, J = 9.3, 8.8, 2.2 Hz,
1H).

Compound 2: 2- (6- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) acetamide 6- (6-Fluoro-1- (phenyl) in DMF (16.5 mL) Sulfonyl) -1H-indol-3-yl) -1H-indazole (intermediate 4; 300 mg; 0.77 mmol), 2-bromoacetamide (1.05 g; 7.61 mmol), KI (290 mg; 1.75 mmol), A mixture of K ₂ CO ₃ (986 mg; 7.13 mmol) was stirred at 60 ° C. for 48 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), filtered, concentrated and purified by preparative HPLC to give 25 mg (11%) of the title compound as a yellow solid. LC-MS for C ₁₇ H ₁₃ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
308.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.46 (s, 1H), 8.03 (s, 1H), 7.96 (dd, J = 8.7, 5.4 Hz, 1H),
7.80-7.77 (m, 2H), 7.76-7.73 (m, 2H), 7.55 (br s, 1H), 7.46 (dd, J = 8.3,
1.3 Hz, 1H), 7.26 (br s, 1H), 7.22 (dd, J = 9.9, 2.4 Hz, 1H), 6.96 (ddd, J =
9.6, 8.8, 2.4, 1H), 5.11 (s, 2H).

Compound 3: 6- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole hydrochloride 6- (6-Fluoro-1- (phenylsulfonyl) -1H- Indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole hydrochloride and 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidine By preparative HPLC starting from -4-ylmethyl) -2H-indazole hydrochloride (intermediate 6; 136 mg; 0.26 mmol) and following the general procedure outlined for compound 1 with 0.1% HCl as buffer. After purification, 3 mg (3%) of the title compound was obtained as a yellow solid. LC-MS for C ₂₁ H ₂₁ FN ₄ + H ⁺ [M + H] ⁺ : calculated 349.2; found:
349.0. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.52 (s, 1H), 9.26 (br s, 1H), 8.90 (br s, 1H), 8.39 (s,
1H), 7.87 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.77-771 (m, 2H), 7.41 (d,
J = 8.6 Hz, 1H), 7.24 (d, J = 9.9, 2.3 Hz, 1H), 6.97 (ddd, J = 9.4, 8.8, 2.3
Hz, 1H), 4.38 (d, J = 6.9 Hz, 2H), 3.18-3.18 (m, 2H), 2.91-2.72 (m, 2H),
2.38-2.22 (m, 1H), 1.73-1.59 (m, 2H), 1.58-1.40 (m, 2H).

Compound 4: 1- (4-((6- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone 1- (4-(( 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone (Intermediate 7; 267 mg; 0.50 mmol ) And after purification by preparative HPLC, 12 mg (6%) of the title compound was obtained as a white solid following the general procedure outlined for compound 1. ^{_{C 23 H 23 FN 4 OH -}} [MH] - the LC-MS: calc 389.2; found:
389.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.51 (s, 1H), 8.05 (s, 1H), 7.95 (dd, J = 8.8, 5.4 Hz, 1H),
7.87 (s, 1H), 7.80-7.76 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 9.9,
2.0 Hz, 1H), 6.99 (ddd, J = 9.4, 8.8, 2.0 Hz, 1H), 4.40-4.30 (m, 3H), 3.82-
3.73 (m, 1H), 2.99-2.89 (m, 1H), 2.50-2.40 (m, 1H), 2.26-2.14 (m, 1H),
1.95 (s, 3H), 1.56-1.44 (m, 2H), 1.30-1.16 (m, 2H).

Compound 5: 3- (6- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanamide 3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H -Indol-3-yl) -1H-indazol-1-yl) propanamide (Intermediate 8; 95 mg; 0.21 mmol) and by preparative TLC (EtOAc) according to the general procedure outlined for compound 1 After purification, 35 mg (53%) of the title compound were obtained as a white solid.
C ₁₈ H ₁₅ FN ₄ O + H ⁺
[M + H] ⁺ LC-MS: calcd 323.1;
Found: 323.1. ¹ H NMR (300 MHz, DMSO-d ₆ )
δ [ppm]: 11.48 (s, 1H), 8.05 (dd, J = 8.8, 5.6 Hz, 1H),
8.03 (s, 1H), 7.89 (s, 1H), 7.79-7.73 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.40
(br s, 1H), 7.24 (dd, J = 9.9, 2.2 Hz, 1H), 6.99 (ddd, J = 9.4, 8.8, 2.2 Hz,
1H), 6.87 (br s, 1H), 4.64 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.6 Hz, 2H).

Compound 6: 6- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazole 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indole- 3-yl) -1- (piperidin-4-yl) -1H-indazole hydrochloride and 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidine-4 -Yl) -2H-indazole hydrochloride (Intermediate 10; 700 mg crude; 1.37 mmol) and after purification by preparative HPLC according to the general procedure outlined for compound 1, 12.3 mg (3% ) Was obtained as a yellow solid. LC-MS for C ₂₀ H ₁₉ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 335.2; Found:
334.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.49 (s, 1H), 8.04 (s, 1H), 7.94 (dd, J = 9.0, 5.4 Hz, 1H),
7.88 (s, 1H), 7.80-7.75 (m, 2H), 7.46 (dd, J = 8.4, 1.3 Hz, 1H), 7.25 (dd, J
= 9.8, 2.4 Hz, 1H), 6.99 (ddd, J = 9.7, 8.9, 2.4 Hz, 1H), 4.87-4.75 (m, 1H),
3.20-3.10 (m, 2H), 2.86-2.75 (m, 2H), 2.10-2.00 (m, 2H), 2.00-1.92 (m,
2H).

Compound 7: 1- (4- (6- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) piperidin-1-yl) ethanone 6- (6 in DCM (30 mL) To a solution of -fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazole (Compound 6; 300 mg; 0.90 mmol) and Et ₃ N (5.0 mL; 36 mmol), AcCl (84.6 mg; 1.08 mmol) was added under nitrogen. The mixture was stirred for 1 h and quenched with saturated aqueous NaHCO ₃ (30 mL). The aqueous layer was extracted with DCM (60 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give 15 mg (4%) of the title compound as a yellow solid. . _{C 22 H 21 FN 4 O +} H + [M + H] + of LC-MS: calc 377.2; found:
376.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.49 (s, 1H), 8.05 (s, 1H), 7.96 (dd, J = 8.8, 5.4 Hz, 1H),
7.91 (s, 1H), 7.81-7.76 (m, 2H), 7.47 (dd, J = 8.4, 1.2 Hz, 1H), 7.25 (dd, J
= 9.9, 2.4 Hz, 1H), 6.99 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 5.08-4.95 (m, 1H),
4.58-4.48 (m, 1H), 4.03-3.93 (m, 1H), 3.33-3.27 (m, 1H), 2.90-2.78 (m,
1H), 2.07 (s, 3H), 2.10-1.88 (m, 4H).

Compound 8: 5- (6-Fluoro-1H-indole-3-yl) -1H-indazole 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indole-3-yl) -1H-indazole (intermediate) 40 mg (32%) of the title compound as a yellow solid after purification by preparative HPLC, following the general procedure outlined for compound 1, starting from body 12; 270 mg crude; 0.45 mmol). LC-MS for C ₁₅ H ₁₀ FN ₃ + H ⁺ [M + H] ⁺ : Calculated 252.1; Found:
252.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 13.02 (s, 1H), 11.34 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H),
7.86 (dd, J = 8.8, 5.4 Hz, 1H), 7.66 (dd, J = 9.0, 1.5 Hz, 1H), 7.64 (d, J =
1.5 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.95
(ddd, J = 9.7, 8.8, 2.4 Hz, 1H).

Compound 9: 2- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) acetamide 2- (5- (6-Fluoro-1- (phenylsulfonyl) -1H- Indol-3-yl) -1H-indazol-1-yl) acetamide and 2- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indole-3-yl) -2H-indazol-2-yl ) Starting from acetamide (intermediate 13; 353 mg; 0.79 mmol) and purifying by preparative HPLC and chiral preparative HPLC according to the general procedure outlined in compound 1, 34.1 mg (14%) of the title compound Obtained as a yellow solid. LC-MS for C ₁₇ H ₁₃ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
308.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.39 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (dd, J =
8.8, 5.3 Hz, 1H), 7.72-7.61 (m, 3H), 7.58 (br s, 1H), 7.30 (br s, 1H), 7.23
(dd, J = 10.0, 2.3 Hz, 2H), 6.99 (dd, J = 9.5, 8.8, 2.3 Hz, 1H), 5.08 (s, 2H).

Compound 10: 5- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole tert-butyl 4-in saturated HCl (20 mL) in 1,4-dioxane A solution of ((5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidine-1-carboxylate (Intermediate 15; 1.18 g; 2.63 mmol) And stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (DCM / MeOH = 8/1) to give 31 mg (33%) of the title compound as a yellow solid. It was. LC-MS for C ₂₁ H ₂₁ FN ₄ + H ⁺ [M + H] ⁺ : calculated 349.2; found:
349.0. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.42 (s, 1H), 8.60 (br s, 1H), 8.09 (s, 1H), 8.00 (s, 1H),
7.86 (dd, J = 8.8, 5.3 Hz, 1H), 7.79-7.65 (m, 3H), 7.30 (dd, J = 10.0, 2.4
Hz, 1H), 6.96 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 4.38 (d, J = 6.7 Hz, 2H), 3.26-
3.15 (m, 2H), 2.86-2.71 (m, 2H), 2.30-2.13 (m, 1H), 1.72-1.60 (m, 2H),
1.55-1.36 (m, 2H).

Compound 11: 1- (4-((5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone 5- (6-Fluoro- By preparative HPLC according to the general procedure outlined for compound 7, starting from 1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole (compound 10; 204 mg; 0.59 mmol) After purification, 65 mg (28%) of the title compound was obtained as a white solid. _{C 23 H 23 FN 4 O +} H + [M + H] + of LC-MS: calc 391.2; found:
390.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.38 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (dd, J =
8.9, 5.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.71-7.66 (m, 2H), 7.22 (dd, J =
10.0, 2.4 Hz, 1H), 6.96 (ddd, J = 9.6, 8.9, 2.3 Hz, 1H), 4.39-4.30 (m, 3H),
3.83-3.73 (m, 1H), 3.00-2.87 (m, 1H), 2.50-2.40 (m, 1H), 2.26-2.10 (m,
1H), 1.96 (s, 3H), 1.54-1.43 (m, 2H), 1.30-1.00 (m, 2H).

Compound 12: 3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanamide 3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H -Indol-3-yl) -1H-indazol-1-yl) propanamide and 3- (5- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazole-2 -Yl) propanamide (intermediate 16; 492 mg; 1.06 mmol) and after purification by preparative HPLC and chiral preparative HPLC according to the general procedure outlined in compound 1, 33.9 mg (10%) The title compound was obtained as a white solid. LC-MS for C ₁₈ H ₁₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 323.1; Found:
322.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.34 (s, 1H), 8.27 (d, J = 0.8 Hz, 1H), 7.93-7.91 (m,
1H), 7.88 (dd, J = 8.8, 5.4 Hz, 1H), 7.67-7.61 (m, 2H), 7.56 (dd, J = 9.0,
1.6 Hz, 1H), 7.43 (br s, 1H), 7.21 (dd, J = 10.0, 2.3 Hz, 1H), 6.95 (ddd, J =
9.6, 8.8, 2.3 Hz, 1H), 6.92 (br s, 1H), 4.62 (t, J = 6.8 Hz, 2H), 2.79 (t, J =
(6.9 Hz, 2H).

Compound 13: 5- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazole 1,4-dioxane (20 mL) in tert-butyl 4- (5- A solution of (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) piperidine-1-carboxylate (intermediate 18; 180 mg; 0.41 mmol) was saturated in 1,4-dioxane. HCl (10 mL) was added. The reaction mixture was stirred overnight. The resulting precipitate was collected by filtration and purified by preparative HPLC to give 56 mg (40%) of the title compound as a yellow solid. LC-MS for C ₂₀ H ₁₉ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 335.2; Found:
334.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.36 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.86 (dd, J =
8.8, 5.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 8.8, 1.6 Hz, 1H),
7.66 (d, J = 1.6 Hz, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.95 (ddd, J = 9.6,
8.8, 2.4 Hz, 1H), 4.73-4.60 (m, 1H), 3.14-3.04 (m, 2H), 2.76-2.64 (m,
2H), 2.20 (br s, 1H), 2.05-1.93 (m, 2H), 1.91-1.82 (m, 2H).

Compound 14: 1- (4- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) piperidin-1-yl) ethanone 5- (6-Fluoro-1H-indole Starting with -3-yl) -1- (piperidin-4-yl) -1H-indazole (compound 13; 53 mg; 0.16 mmol) and following purification by preparative HPLC according to the general procedure outlined in compound 7, 16 mg (27%) of the title compound were obtained as a yellow solid. _{C 22 H 21 FN 4 O +} H + [M + H] + of LC-MS: calc 377.2; found:
376.9. ¹ H NMR (300 MHz, MeOH-d ₄ ) δ [ppm]: 8.25 (s, 1H), 7.92-7.89 (m, 1H), 7.83 (dd, J = 8.8, 5.3 Hz,
1H), 7.66-7.63 (m, 2H), 7.46 (s, 1H), 7.12 (dd, J = 10.0, 2.3 Hz, 1H), 6.88
(ddd, J = 9.6, 8.8, 2.3 Hz, 1H), 4.86-4.66 (m, 2H), 4.16-4.06 (m, 1H), 3.42
-3.32 (m, 1H), 2.93-2.81 (m, 1H), 2.32-2.00 (m, 4H), 2.18 (s, 3H).

Compound 15: 2- (6- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) acetamide 6- (6-Fluoro-1- (phenyl) in DMF (16.5 mL) Sulfonyl) -1H-indol-3-yl) -1H-indazole (intermediate 4; 300 mg; 0.77 mmol), 2-bromoacetamide (1.05 g; 7.61 mmol), KI (290 mg; 1.75 mmol) and A mixture of K ₂ CO ₃ (986 mg; 7.13 mmol) was stirred at 60 ° C. for 48 hours under nitrogen. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), filtered, concentrated and purified by preparative HPLC to give 50 mg (21%) of the title compound as a yellow solid. LC-MS for C ₁₇ H ₁₃ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
308.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.42 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J = 8.8, 5.4 Hz, 1H),
7.80 (s, 1H), 7.81-7.72 (m, 2H), 7.66 (br s, 1H), 7.39 (dd, J = 8.7, 1.4 Hz,
1H), 7.35 (br s, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.97 (ddd, J = 9.6, 8.8,
2.4 Hz, 1H), 5.09 (s, 2H).

Compound 16: 1- (4-((6- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidin-1-yl) ethanone 1- (4-(( 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidin-1-yl) ethanone (Intermediate 19; 358 mg; 0.67 mmol ) And after purification by preparative HPLC, 10 mg (4%) of the title compound was obtained as a white solid according to the general procedure outlined for compound 1.
C ₂₃ H ₂₃ FN ₄ O + H ⁺
[M + H] ⁺ LC-MS: Calculated 389.9;
Found: 389.9. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.43 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J =
8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.77-7.71 (m, 2H), 7.39 (d, J = 8.6 Hz, 1H),
7.23 (dd, J = 10.0, 2.3 Hz, 1H), 6.97 (dd, J = 9.6, 8.8, 2.3 Hz, 1H), 4.40-
4.30 (m, 3H), 3.85-3.75 (m, 1H), 3.05-2.90 (m, 1H), 2.50-2.42 (m, 1H),
2.31-2.22 (m, 1H), 1.97 (s, 3H), 1.60-1.40 (m, 2H), 1.30-1.00 (m, 2H).

Compound 17: 3- (6- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) propanamide 3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H -Indol-3-yl) -2H-indazol-2-yl) propanamide (Intermediate 20; 75 mg; 0.16 mmol) and by preparative TLC (EtOAc) according to the general procedure outlined for compound 1 After purification, 20 mg (38%) of the title compound was obtained as a white solid. LC-MS for C ₁₈ H ₁₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 323.1; Found:
323.1. ¹ H NMR (300 MHz, MeOH-d ₄ ) δ [ppm]: 8.16 (s, 1H), 7.87 (dd, J = 8.8, 5.3 Hz, 1H), 7.81 (s, 1H),
7.70 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.13 (dd, J =
9.8, 2.3 Hz, 1H), 6.90 (ddd, J = 9.6, 8.8, 2.3 Hz, 1H), 4.73 (t, J = 6.7 Hz,
2H), 2.94 (t, J = 6.7 Hz, 2H).

Compound 18: 6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -2H-indazole During preparation of Compound 6, after purification by preparative HPLC, the title compound (26 mg, 5%) as a yellow solid. LC-MS for C ₂₀ H ₁₉ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 335.2; Found:
334.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.41 (s, 1H), 8.36 (s, 1H), 7.91 (dd, J = 8.6, 5.4 Hz, 1H),
7.83 (s, 1H), 7.75-7.70 (m, 2H), 7.39 (d, J = 8.6, 1.4 Hz, 1H), 7.24 (dd, J =
10.0, 2.4 Hz, 1H), 6.97 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 4.62-4.50 (m, 1H),
3.22-3.13 (m, 2H), 2.82-2.70 (m, 2H), 2.16-1.93 (m, 4H).

Compound 19: 1- (4- (6- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidin-1-yl) ethanone 6- (6-Fluoro-1H-indole Starting with -3-yl) -2- (piperidin-4-yl) -2H-indazole (compound 18; 300 mg; 0.90 mmol) and following purification by preparative HPLC according to the general procedure outlined in compound 7, 20 mg (6%) of the title compound were obtained as a yellow solid. _{C 22 H 21 FN 4 O +} H + [M + H] + of LC-MS: calc 377.2; found:
376.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.42 (s, 1H), 8.40 (s, 1H), 7.89 (dd, J = 8.7, 5.4 Hz, 1H),
7.80 (s, 1H), 7.75-7.71 (m, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.23 (dd, J =
10.0, 2.3 Hz, 1H), 6.96 (dd, J = 9.4, 8.7, 2.3 Hz, 1H), 4.81-4.71 (m, 1H),
4.56-4.43 (m, 1H), 4.02-3.94 (m, 1H), 3.32-3.22 (m, 1H), 2.82-2.73 (m,
1H), 2.21-1.86 (m, 4H), 2.07 (s, 3H).

Compound 20: 2- (5- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) acetamide After purification as a regioisomer of compound 9 by preparative HPLC and chiral preparative HPLC The title compound (71 mg, 29%) was obtained as a yellow solid. LC-MS for C ₁₇ H ₁₃ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
308.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.38 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.90 (dd, J =
8.7, 5.5 Hz, 1H), 7.70-7.55 (m, 4H), 7.37 (s, 1H), 7.22 (dd, J = 9.9, 2.3 Hz,
1H), 6.96 (ddd, J = 9.6, 8.7 2.3 Hz, 1H), 5.08 (s, 2H).

Compound 21: 1- (4-((5- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidin-1-yl) ethanone 5- (6-Fluoro- Preparative HPLC starting from 1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H-indazole (Intermediate 22; 100 mg; 0.29 mmol) and following the general procedure outlined for compound 7 After purification by 5 mg (4%) of the title compound was obtained as an off-white solid. _{C 23 H 23 FN 4 O +} H + [M + H] + of LC-MS: calc 391.2; found:
390.9. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ [ppm]: 8.14 (s, 1H), 7.90 (s, 1H), 7.84 (dd, J = 8.8, 5.4 Hz, 1H),
7.68-7.61 (m, 2H), 7.46 (s, 1H), 7.12 (dd, J = 9.8, 2.3 Hz, 1H), 6.89 (dd, J
= 9.7, 8.8, 2.3 Hz, 1H), 4.54-4.47 (m, 1H), 4.11 (d, J = 7.0 Hz, 2H), 3.92-
3.85 (m, 1H), 3.09-3.00 (m, 1H), 2.62-2.53 (m, 1H), 2.37-2.24 (m, 1H),
2.06 (s, 3H), 1.63-1.54 (m, 2H), 1.34-1.13 (m, 2H).

Compound 22: 3- (5- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) propanamide During preparation of compound 12, after purification by preparative HPLC and chiral preparative HPLC, The title compound (48 mg, 14%) was obtained as a white solid. LC-MS for C ₁₈ H ₁₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 323.1; Found:
322.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.39 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.87 (dd, J =
8.7, 5.4 Hz, 1H), 7.74-7.66 (m, 3H), 7.43 (s, 1H), 7.23 (dd, J = 10.0, 2.0
Hz, 1H), 6.96 (ddd, J = 9.3, 8.7 2.0 Hz, 1H), 6.89 (s, 1H), 4.61 (t, J = 6.8 Hz,
2H), 2.70 (t, J = 6.8 Hz, 2H).

Compound 23: 5- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -2H-indazole 1,4-dioxane (20 mL) in tert-butyl 4- (5- A solution of (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (intermediate 24; 180 mg; 0.41 mmol) was saturated in 1,4-dioxane. HCl (10 mL) was added. The reaction mixture was stirred at room temperature overnight, filtered and purified by preparative HPLC to give 59 mg (43%) of the title compound as a yellow solid. LC-MS for C ₂₀ H ₁₉ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 335.4; Found:
334.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.37 (s, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.87 (dd, J =
8.8, 5.4 Hz, 1H), 7.68-7.63 (m, 2H), 7.55 (dd, J = 9.0, 1.6 Hz, 1H), 7.22
(dd, J = 10.0, 2.4 Hz, 1H), 6.96 (ddd, J = 9.7, 8.8, 2.4 Hz, 1H), 4.59-4.43
(m, 1H), 3.11-3.02 (m, 2H), 2.70-2.59 (m, 2H), 2.26 (br s, 1H), 2.10-1.89
(m, 4H).

Compound 24: 1- (4- (5- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidin-1-yl) ethanone 5- (6-Fluoro-1H-indole Starting from -3-yl) -2- (piperidin-4-yl) -2H-indazole (compound 23; 53 mg; 0.16 mmol) and following purification by preparative HPLC according to the general procedure outlined in compound 7, 16 mg (27%) of the title compound were obtained as an off-white solid. _{C 22 H 21 FN 4 O +} H + [M + H] + of LC-MS: calc 377.4; found:
376.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 8.25 (s, 1H), 7.90 (s, 1H), 7.83 (dd, J = 8.8, 5.3 Hz, 1H),
7.65-7.61 (m, 2H), 7.45 (s, 1H), 7.11 (dd, J = 9.8, 2.4 Hz, 1H), 6.88 (ddd, J
= 9.6, 8.8, 2.4 Hz, 1H), 4.78-4.67 (m, 2H), 4.15-4.06 (m, 1H), 3.40-3.34
(m, 1H), 2.91-2.80 (m, 1H), 2.30-2.00 (m, 4H), 2.17 (s, 3H).

Compound 25: 5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazole 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H Starting from benzo [d] imidazole (intermediate 27; 550 mg crude; 0.46 mmol) and purifying by preparative HPLC according to the general procedure outlined in compound 1 5 mg (3%) of the title compound Obtained as a yellow solid. LC-MS for C ₁₅ H ₁₀ FN ₃ + H ⁺ [M + H] ⁺ : Calculated 252.1; Found:
252.0. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 12.44-12.33 (m, 1H), 11.38-11.30 (m, 1H), 8.22-8.17
(m, 1H), 7.88-7.72 (m, 2H), 7.71-7.44 (m, 3H), 7.25-7.18 (m, 1H), 7.01-
6.90 (m, 1H).

Compound 26: 5- (6-Fluoro-1H-indol-3-yl) -2-methyl-1H-benzo [d] imidazole 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indole-3- Yl) -2-methyl-1H-benzo [d] imidazole (Intermediate 30; 870 mg crude; 1.99 mmol) and 240 mg after purification by preparative HPLC according to the general procedure outlined in compound 1. (45%) of the title compound was obtained as an off-white solid. LC-MS for C ₁₆ H ₁₂ FN ₃ + H ⁺ [M + H] ⁺ : Calculated 266.1; Found:
265.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.16 (s, 1H), 11.34 (s, 1H), 7.82 (dd, J = 8.7, 5.5 Hz,
1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz,
1H), 7.22 (dd, J = 10.0, 1.9 Hz, 1H), 6.95 (ddd, J = 9.6, 8.7, 1.9 Hz, 1H),
2.50 (s, 3H).

Compound 27: (6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methanamine

ＴＨＦ（３０ｍＬ）中のｔｅｒｔ−ブチル（（６−（６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）メチル）カルバメート（中間体４８、４２９ｍｇ、１．１３ｍｍｏｌ）の溶液に、ＨＣｌ（１２Ｍ、３ｍＬ）を添加した。得られた混合物を５１℃で３時間撹拌した。反応混合物を室温に冷却し、濃縮した。残留物を水（８０ｍＬ）で希釈し、ＥｔＯＡｃ（３０ｍＬ×２）で抽出した。水相をＮＨ_４ＯＨでｐＨ＝１３に塩基性化し、ＥｔＯＡｃ（８０ｍＬ×３）で抽出した。合わせた有機層をブライン（３０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、７０ｍｇ（２２％）の表題化合物を白色固体として得た。C₁₆H₁₃FN₄+H⁺ [M+H]⁺のLC-MS:計算値281.1; 実測値:
280.9. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]:11.34 (s, 1H), 7.82 (dd, J = 8.8, 5.5 Hz, 1H), 7.70 (s, 1H),
7.61 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.22 (dd, J =
9.9, 2.3 Hz, 1H), 6.95 (td, J = 9.4, 2.1 Hz, 1H), 3.94 (s, 2H).

Tert-Butyl ((6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) carbamate (Intermediate 48, 429 mg, 1) in THF (30 mL) HCl (12 M, 3 mL) was added to the solution. The resulting mixture was stirred at 51 ° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (80 mL) and extracted with EtOAc (30 mL × 2). The aqueous phase was basified with NH ₄ OH to pH = 13 and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 70 mg (22%) of the title compound as a white solid. LC-MS for C ₁₆ H ₁₃ FN ₄ + H ⁺ [M + H] ⁺ : calculated 281.1; found:
280.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.34 (s, 1H), 7.82 (dd, J = 8.8, 5.5 Hz, 1H), 7.70 (s, 1H),
7.61 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.22 (dd, J =
9.9, 2.3 Hz, 1H), 6.95 (td, J = 9.4, 2.1 Hz, 1H), 3.94 (s, 2H).

Compound 28: 1- (6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-dimethylmethanamine

１−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）−Ｎ，Ｎ−ジメチルメタンアミン（中間体５０、３９１ｍｇ、０．８７ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、１０ｍｇ（４％）の表題化合物を白色固体として得た。C₁₈H₁₇FN₄+H⁺ [M+H]⁺のLC-MS: 計算値309.1; 実測値:
309.1. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 10.06- 9.46 (m, 1H), 8.31 (s, 1H), 7.86 (dd, J = 8.6, 5.3
Hz, 1H), 7.80 - 7.62 (m, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.35 (d, J = 2.3 Hz,
1H), 7.12 (dd, J = 9.5, 2.2 Hz, 1H), 6.96 (td, J = 9.3, 2.3 Hz, 1H), 3.80 (s,
2H), 2.38 (s, 6H).

1- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-dimethylmethanamine (Intermediate 50 391 mg, 0.87 mmol) to give 10 mg (4%) of the title compound as a white solid according to the general procedure outlined for compound 1. LC-MS for C ₁₈ H ₁₇ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
309.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 10.06- 9.46 (m, 1H), 8.31 (s, 1H), 7.86 (dd, J = 8.6, 5.3
Hz, 1H), 7.80-7.62 (m, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.35 (d, J = 2.3 Hz,
1H), 7.12 (dd, J = 9.5, 2.2 Hz, 1H), 6.96 (td, J = 9.3, 2.3 Hz, 1H), 3.80 (s,
2H), 2.38 (s, 6H).

Compound 30: N-((6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) acetamide

Ｎ−（（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）メチル）アセトアミド（中間体５３、４００ｍｇの粗製物、０．７４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、２０ｍｇ（９％）の表題化合物を白色固体として得た。C₁₈H₁₅FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値323.1; 実測値:
322.1. ¹H NMR (400 MHz, MeOH-d₄) δ [ppm]: 7.76 (dd, J = 8.8, 5.2 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J =
8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J = 9.6 Hz, 1H),
6.83 (td, J = 9.2, 2.4 Hz, 1H), 4.59 (s, 2H), 2.03 (s, 3H).

N-((6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) acetamide (Intermediate 53, 400 mg crude Product, 0.74 mmol) to give 20 mg (9%) of the title compound as a white solid after purification by preparative HPLC according to the general procedure outlined for compound 1. LC-MS for C ₁₈ H ₁₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 323.1; Found:
322.1. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ [ppm]: 7.76 (dd, J = 8.8, 5.2 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J =
8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J = 9.6 Hz, 1H),
6.83 (td, J = 9.2, 2.4 Hz, 1H), 4.59 (s, 2H), 2.03 (s, 3H).

Compound 31: 2-amino-N-((6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) acetamide

ＴＨＦ（２０ｍＬ）中のｔｅｒｔ−ブチル（２−（（（６−（６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）メチル）アミノ）−２−オキソエチル）カルバメート（中間体５１、６５０ｍｇ、１．４３ｍｍｏｌ）の撹拌溶液に、ＨＣｌ（１２Ｍ、３ｍＬ）を添加した。得られた混合物を室温で４０分間撹拌した。溶媒を減圧下で除去した。残留物を水（８０ｍＬ）で希釈し、ＥｔＯＡｃ（３０ｍＬ×２）で抽出した。水相をＮＨ_４ＯＨでｐＨ＝１３まで塩基性化し、ＥｔＯＡｃ（８０ｍＬ×３）で抽出した。合わせた有機層をブライン（３０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、７０ｍｇ（１５％）の表題化合物を白色固体として得た。C₁₈H₁₆FN₅O+H⁺ [M+H]⁺のLC-MS: 計算値338.1; 実測値:
337.9. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.36 (s, 1H), 8.55 (s, 1H), 7.83 (dd, J = 8.7, 5.4 Hz, 1H),
7.73 (s, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.45 (d, J =
8.3 Hz, 1H), 7.22 (dd, J = 10.0, 2.2 Hz, 1H), 6.95 (td, J = 9.5, 2.2 Hz, 1H),
4.55 (s, 2H), 3.22 (s, 2H).

Tert-Butyl (2-(((6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) amino) -2- in THF (20 mL) To a stirred solution of oxoethyl) carbamate (Intermediate 51, 650 mg, 1.43 mmol) was added HCl (12M, 3 mL). The resulting mixture was stirred at room temperature for 40 minutes. The solvent was removed under reduced pressure. The residue was diluted with water (80 mL) and extracted with EtOAc (30 mL × 2). The aqueous phase was basified with NH ₄ OH to pH = 13 and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 70 mg (15%) of the title compound as a white solid. LC-MS for C ₁₈ H ₁₆ FN ₅ O + H ⁺ [M + H] ⁺ : Calculated 338.1; Found:
337.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.36 (s, 1H), 8.55 (s, 1H), 7.83 (dd, J = 8.7, 5.4 Hz, 1H),
7.73 (s, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.45 (d, J =
8.3 Hz, 1H), 7.22 (dd, J = 10.0, 2.2 Hz, 1H), 6.95 (td, J = 9.5, 2.2 Hz, 1H),
4.55 (s, 2H), 3.22 (s, 2H).

Compound 32: N-((6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) methanesulfonamide

無水ＤＣＭ（２４ｍＬ）中のｃ−［６−（６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミダゾール−２−イル］−メチルアミン（化合物２７、３００ｍｇ、１．０７ｍｍｏｌ）およびＥｔ_３Ｎ（２７０ｍｇ、２．６８ｍｍｏｌ）の撹拌溶液に、ＭｓＣｌ（１２３ｍｇ、１．０７ｍｍｏｌ）を窒素下−１０℃で添加した。反応混合物を５℃で終夜撹拌した。反応混合物をＥｔＯＡｃ（８０ｍＬ）で希釈し、飽和Ｎａ_２ＣＯ_３水溶液で洗浄した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、２０ｍｇ（４４％）の表題化合物を黄色固体として得た。C₁₇H₁₅FN₄O₂S-H^-
[M-H]^-のLC-MS: 計算値357.1;
実測値: 356.9. ¹H NMR (400 MHz, MeOD) δ [ppm]:7.74 (dd, J = 8.8, 5.3 Hz, 1H), 7.70 (s, 1H), 7.52 (d, J =
8.4 Hz, 1H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.35 (s, 1H), 7.04 (dd, J = 9.8,
2.3 Hz, 1H), 6.80 (td, J = 9.3, 2.3 Hz, 1H), 4.46 (s, 2H), 2.92 (s, 3H).

C- [6- (6-Fluoro-1H-indol-3-yl) -1H-benzimidazol-2-yl] -methylamine (Compound 27, 300 mg, 1.07 mmol) and Et in anhydrous DCM (24 mL) _To a stirred solution of 3N (270 mg, 2.68 mmol), MsCl (123 mg, 1.07 mmol) was added at −10 ° C. under nitrogen. The reaction mixture was stirred at 5 ° C. overnight. The reaction mixture was diluted with EtOAc (80 mL) and washed with saturated aqueous Na ₂ CO ₃ solution. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 20 mg (44%) of the title compound as a yellow solid. _{C 17 H 15 FN 4 O 2} SH -
[MH] ^- the LC-MS: calc 357.1;
Found: 356.9. ¹ H NMR (400 MHz, MeOD) δ [ppm]: 7.74 (dd, J = 8.8, 5.3 Hz, 1H), 7.70 (s, 1H), 7.52 (d, J =
8.4 Hz, 1H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.35 (s, 1H), 7.04 (dd, J = 9.8,
2.3 Hz, 1H), 6.80 (td, J = 9.3, 2.3 Hz, 1H), 4.46 (s, 2H), 2.92 (s, 3H).

Compound 33: 6- (6-Fluoro-1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) -1H-benzo [d] imidazole

６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−（４−メチル−ピペラジン−１−イルメチル）−１Ｈ−ベンゾイミダゾール（中間体６０、２９０ｍｇ、０．４５ｍｍｏｌ、粗製）から出発し、化合物１で概説した一般的方法に従って、１８ｍｇ（１１％）の表題化合物を褐色固体として得た。C₂₁H₂₂FN₅+H⁺ [M+H]⁺のLC-MS: 計算値364.2; 実測値:
364.2. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.69 (br s, 1H), 11.10 (br s, 1H), 7.99 (s, 1H), 7.86 -
7.84 (m, 4H), 7.28 (dd, J = 9.8, 2.0 Hz, 1H), 7.02 (td, J = 9.6, 2.0 Hz, 1H),
4.26 (s, 2H), 3.43 - 3.40 (m, 2H), 3.18 - 3.10 (m, 4H), 2.84 - 2.76 (m, 5H).

6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2- (4-methyl-piperazin-1-ylmethyl) -1H-benzimidazole (Intermediate 60, 290 mg, 0.45 mmol, Starting from crude), following the general procedure outlined for compound 1, 18 mg (11%) of the title compound were obtained as a brown solid. LC-MS for C ₂₁ H ₂₂ FN ₅ + H ⁺ [M + H] ⁺ : calculated 364.2; found:
364.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.69 (br s, 1H), 11.10 (br s, 1H), 7.99 (s, 1H), 7.86-
7.84 (m, 4H), 7.28 (dd, J = 9.8, 2.0 Hz, 1H), 7.02 (td, J = 9.6, 2.0 Hz, 1H),
4.26 (s, 2H), 3.43-3.40 (m, 2H), 3.18-3.10 (m, 4H), 2.84-2.76 (m, 5H).

Compound 34: 5- (6-Fluoro-1H-indol-3-yl) -2-((4- (methylsulfonyl) piperazin-1-yl) methyl) -1H-benzo [d] imidazole

６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−（４−メタンスルホニル−ピペラジン−１−イルメチル）−１Ｈ−ベンゾイミダゾール（中間体６７、８０ｍｇ、０．１４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、１５ｍｇ（２５％）の表題化合物を白色固体として得た。C₂₁H₂₂FN₅O₂S+H⁺
[M+H]⁺のLC-MS: 計算値428.2;
実測値: 428.2. ¹H NMR (400 MHz, CD₃OD)
δ [ppm]: 7.72 (dd, J = 8.8, 5.2 Hz, 1H), 7.67 (s, 1H),
7.49 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.4, 0.9 Hz, 1H), 7.33 (s, 1H), 7.02
(dd, J = 9.6, 2.0 Hz, 1H), 7.78 (d, J = 8.8, 2.0 Hz, 1H), 3.77 (s, 2H),
3.28-3.20 (m, 4H), 2.75 (s, 3H), 2.62 - 2.52 (m, 4H).

6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2- (4-methanesulfonyl-piperazin-1-ylmethyl) -1H-benzimidazole (Intermediate 67, 80 mg, 0.14 mmol) ) To give 15 mg (25%) of the title compound as a white solid according to the general procedure outlined for compound 1. C ₂₁ H ₂₂ FN ₅ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: calc'd 428.2;
Found: 428.2. ¹ H NMR (400 MHz, CD ₃ OD)
δ [ppm]: 7.72 (dd, J = 8.8, 5.2 Hz, 1H), 7.67 (s, 1H),
7.49 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.4, 0.9 Hz, 1H), 7.33 (s, 1H), 7.02
(dd, J = 9.6, 2.0 Hz, 1H), 7.78 (d, J = 8.8, 2.0 Hz, 1H), 3.77 (s, 2H),
3.28-3.20 (m, 4H), 2.75 (s, 3H), 2.62-2.52 (m, 4H).

Compound 35: 2- (6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethanamine

２−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミダゾール−２−イル］−エチルアミン（中間体６４、４００ｍｇ、０．９２０ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（４０ｍｇ、１５％）を白色固体として得た。C₁₇H₁₅FN₄+H⁺ [M+H]⁺のLC-MS: 計算値295.1; 実測値:
295.1. ¹H NMR (400 MHz, CD₄O-d₄) δ [ppm]: 7.86 - 7.82 (m, 2H), 7.61 - 7.53 (m, 2H), 7.46 (s, 1H), 7.14
(dd, J = 10.0, 2.4 Hz, 1H), 6.91 (td, J = 9.2, 2.4 Hz, 1H), 3.28 - 3.22 (m,
2H), 3.16 - 3.08 (m, 2H).

Starting from 2- [6- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-benzimidazol-2-yl] -ethylamine (intermediate 64, 400 mg, 0.920 mmol); Following the general method outlined for compound 1, the title compound (40 mg, 15%) was obtained as a white solid. LC-MS for C ₁₇ H ₁₅ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 295.1; Found:
295.1. ¹ H NMR (400 MHz, CD ₄ Od ₄ ) δ [ppm]: 7.86-7.82 (m, 2H), 7.61-7.53 (m, 2H), 7.46 (s, 1H), 7.14
(dd, J = 10.0, 2.4 Hz, 1H), 6.91 (td, J = 9.2, 2.4 Hz, 1H), 3.28-3.22 (m,
2H), 3.16-3.08 (m, 2H).

Compound 36: N- (2- (6- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethyl) acetamide

Ｎ−｛２−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミド−アゾール−２−イル］−エチル｝−アセトアミド（中間体６６、４２４ｍｇ、０．８９０ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（８６ｍｇ、２９％）を白色固体として得た。C₁₉H₁₇FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値337.1; 実測値:
337.1. ¹H NMR (400 MHz, CD₄O-d₄) δ [ppm]: 7.70 (dd, J = 8.8, 5.6 Hz, 2H), 7.64 (s, 1H), 7.47 - 7.40
(m, 2H), 7.32 (s, 1H), 7.02 (dd, J = 9.6, 2.2 Hz, 1H), 6.77 (td, J = 9.2,
2.4Hz, 1H), 3.54 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H).

N- {2- [6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-benzoimido-azol-2-yl] -ethyl} -acetamide (Intermediate 66, 424 mg, 0 Starting from .890 mmol), the title compound (86 mg, 29%) was obtained as a white solid following the general procedure outlined for compound 1. LC-MS for C ₁₉ H ₁₇ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 337.1; Found:
337.1. ¹ H NMR (400 MHz, CD ₄ Od ₄ ) δ [ppm]: 7.70 (dd, J = 8.8, 5.6 Hz, 2H), 7.64 (s, 1H), 7.47-7.40
(m, 2H), 7.32 (s, 1H), 7.02 (dd, J = 9.6, 2.2 Hz, 1H), 6.77 (td, J = 9.2,
2.4Hz, 1H), 3.54 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H).

Compound 37: N- (2- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethyl) methanesulfonamide

Ｎ−｛２−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミダ−ゾール−２−イル］−エチル｝−メタンスルホンアミド（中間体６５、４３０ｍｇ、０．８４０ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（３６ｍｇ、１１％）を白色固体として得た。C₁₈H₁₇FN₄O₂S+H⁺
[M+H]⁺のLC-MS: 計算値373.1;
実測値: 373.1. ¹H NMR (400 MHz, CD₄O-d₄)
δ [ppm]: 7.73 - 7.66 (m, 2H), 7.51-7.44 (m, 2H), 7.34
(s, 1H), 7.02 (dd, J = 10.0, 2.0 Hz, 1H), 6.78 (td, J = 8.8, 2.0 Hz, 1H), 3.48
(t, J = 7.0 Hz, 2H), 3.11 (m, J = 7.0 Hz, 2H), 2.81 (s, 3H).

N- {2- [6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -1H-benzimidazol-zol-2-yl] -ethyl} -methanesulfonamide (Intermediate 65, 430 mg The title compound (36 mg, 11%) was obtained as a white solid according to the general procedure outlined for compound 1 starting from 0.840 mmol). C ₁₈ H ₁₇ FN ₄ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: calcd 373.1;
Found: 373.1. ¹ H NMR (400 MHz, CD ₄ Od ₄ )
δ [ppm]: 7.73-7.66 (m, 2H), 7.51-7.44 (m, 2H), 7.34
(s, 1H), 7.02 (dd, J = 10.0, 2.0 Hz, 1H), 6.78 (td, J = 8.8, 2.0 Hz, 1H), 3.48
(t, J = 7.0 Hz, 2H), 3.11 (m, J = 7.0 Hz, 2H), 2.81 (s, 3H).

Compound 38: 5- (6-Fluoro-1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) -1H-benzo [d] imidazole 5- (6-Fluoro-1- (phenylsulfonyl) ) -1H-Indol-3-yl) -2- (2- (methylsulfonyl) ethyl) -1H-benzo [d] imidazole (Intermediate 34; 170 mg; 0.34 mmol) and outlined in compound 1 According to the general method, 20 mg (16%) of the title compound was obtained as a white solid after purification by preparative TLC (DCM / MeOH = 10/1) and preparative HPLC. C ₁₈ H ₁₆ FN ₃ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: calcd 358.1;
Found: 358.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 12.35 (s, 0.45H), 12.35 (s, 0.55H), 11.37 (s,
0.55H), 11.33 (s, 0.45H), 7.85-7.79 (m, 1H), 7.77 (s, 0.45H), 7.66-7.63 (m,
1H), 7.62-7.57 (m, 1H), 7.52-7.41 (m, 1.55H), 7.24-7.19 (m, 1H), 6.99-
6.91 (m, 1H), 3.71-3.65 (m, 2H), 3.32-3.27 (m, 2H), 2.32 (s, 3H), mixture of tautomers.

Compound 39: 6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -1H-benzo [d] imidazole

ＴＨＦ（５ｍＬ）中のｔｅｒｔ−ブチル４−（６−（６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−イル）ピペリジン−１−カルボキシレート（中間体５６、５５０ｍｇの粗製物、１．０５ｍｍｏｌ）の溶液に、濃ＨＣｌ水溶液（１ｍＬ）を添加した。反応混合物を５０℃で３時間撹拌した後、これを濃縮した。混合物をブラインに注ぎ入れ、ＥｔＯＡｃで抽出した。合わせた有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、２００ｍｇ（５７％）の表題化合物を黄色固体として得た。C₂₀H₁₉FN₄+H⁺ [M+H]⁺のLC-MS: 計算値335.2; 実測値:
335.1. ¹H NMR (400 MHz, MeOH-d₄) δ [ppm]: 7.84 (dd, J = 8.8, 5.2 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J =
8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.15 (dd, J = 9.8, 2.2 Hz,
1H), 6.91 (td, J = 9.2, 2.0 Hz, 1H), 3.54 - 3.51 (m, 2H), 3.31-3.28 (m, 1H),
3.21 - 3.15 (m, 2H), 2.38 - 2.35 (m, 2H), 2.20 - 2.13 (m, 2H).

Tert-Butyl 4- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) piperidine-1-carboxylate (intermediate 56) in THF (5 mL) To a solution of 550 mg crude, 1.05 mmol) was added concentrated aqueous HCl (1 mL). The reaction mixture was stirred at 50 ° C. for 3 hours before it was concentrated. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 200 mg (57%) of the title compound as a yellow solid. LC-MS for C ₂₀ H ₁₉ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 335.2; Found:
335.1. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ [ppm]: 7.84 (dd, J = 8.8, 5.2 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J =
8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.15 (dd, J = 9.8, 2.2 Hz,
1H), 6.91 (td, J = 9.2, 2.0 Hz, 1H), 3.54-3.51 (m, 2H), 3.31-3.28 (m, 1H),
3.21-3.15 (m, 2H), 2.38-2.35 (m, 2H), 2.20-2.13 (m, 2H).

Compound 40: 6- (6-Fluoro-1H-indol-3-yl) -2- (1- (methylsulfonyl) piperidin-4-yl) -1H-benzo [d] imidazole

ＤＣＭ（２ｍＬ）中の６−（６−フルオロ−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール（化合物３９、１００ｍｇ、０．３０ｍｍｏｌ）およびＥｔ_３Ｎ（２９０ｍｇ、２．９ｍｍｏｌ）の溶液に、ＭｓＣｌ（１６ｍｇ、０．１４ｍｍｏｌ）を滴下添加した。反応混合物を室温で２時間撹拌し、ブラインで洗浄し、濃縮し、分取ＨＰＬＣにより精製して、８ｍｇ（６％）の表題化合物を白色固体として得た。C₂₁H₂₁FN₄O₂S+H⁺
[M+H]⁺のLC-MS: 計算値413.1;
実測値: 413.1. ¹H NMR (400 MHz, MeOH-d₄)
δ [ppm]: 7.72 (dd, J = 8.4, 5.2 Hz, 1H), 7.65 (s, 1H),
7.47 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4, 1H), 7.33 (s, 1H), 7.02 (dd, J =
9.8, 2.4 Hz, 1H), 6.78 (td, J = 9.2, 2.0 Hz, 1H), 3.75 (d, J = 12.0 Hz, 2H),
3.02 (tt, J = 11.7, 3.6 Hz, 1H), 2.86 - 2.77 (m, 2H), 2.73 (s, 3H), 2.13 - 2.09
(m, 2H), 1.96 - 1.86 (m, 2H).

6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -1H-benzo [d] imidazole (Compound 39, 100 mg, 0.30 mmol) in DCM (2 mL) and To a solution of Et ₃ N (290 mg, 2.9 mmol), MsCl (16 mg, 0.14 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, washed with brine, concentrated and purified by preparative HPLC to give 8 mg (6%) of the title compound as a white solid. C ₂₁ H ₂₁ FN ₄ O ₂ S + H ⁺
[M + H] ⁺ LC-MS: calcd 413.1;
Found: 413.1. ¹ H NMR (400 MHz, MeOH-d ₄ )
δ [ppm]: 7.72 (dd, J = 8.4, 5.2 Hz, 1H), 7.65 (s, 1H),
7.47 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4, 1H), 7.33 (s, 1H), 7.02 (dd, J =
9.8, 2.4 Hz, 1H), 6.78 (td, J = 9.2, 2.0 Hz, 1H), 3.75 (d, J = 12.0 Hz, 2H),
3.02 (tt, J = 11.7, 3.6 Hz, 1H), 2.86-2.77 (m, 2H), 2.73 (s, 3H), 2.13-2.09
(m, 2H), 1.96-1.86 (m, 2H).

Compound 41: 6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-amine

６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−２−アミン（中間体８５、２６０ｍｇ、０．６４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、６０ｍｇ（３５％）の表題化合物を黄色固体として得た。C₁₅H₁₁FN₄+H⁺ [M+H]⁺のLC-MS: 計算値267.1; 実測値:
267.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.21 (br s, 1H), 10.61 (br s, 1H), 7.78 (dd, J = 8.8, 5.5
Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.34 (s, 1H), 7.18 (dd, J = 10.1, 2.2 Hz,
1H), 7.16 - 7.11 (m, 2H), 6.92 (ddd, J = 9.6, 8.6, 2.2 Hz, 1H), 6.11 (br s,
2H).

Starting from 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-amine (intermediate 85, 260 mg, 0.64 mmol), the compound Following purification by preparative HPLC, following the general method outlined in 1, 60 mg (35%) of the title compound was obtained as a yellow solid. LC-MS for C ₁₅ H ₁₁ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 267.1; Found:
267.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.21 (br s, 1H), 10.61 (br s, 1H), 7.78 (dd, J = 8.8, 5.5
Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.34 (s, 1H), 7.18 (dd, J = 10.1, 2.2 Hz,
1H), 7.16-7.11 (m, 2H), 6.92 (ddd, J = 9.6, 8.6, 2.2 Hz, 1H), 6.11 (br s,
2H).

Compound 44: 1- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) -N-methylmethanamine tert-butyl in THF (30 mL) ( To a solution of 5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl (methyl) carbamate (Intermediate 37; 470 mg crude; 0.87 mmol) Concentrated aqueous HCl (3 mL; 37%) was added. The reaction mixture was stirred at 51 ° C. for 3 h, concentrated in vacuo, diluted with water (80 mL) and extracted with EtOAc (50 mL × 3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with EtOAc (80 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (DCM / MeOH = 10/1) and preparative HPLC to give 40 mg (16%) of the title compound. Obtained as a white solid. LC-MS for C ₁₇ H ₁₅ FN ₄ + H ⁺ [M + H] ⁺ : Calculated 295.1; Found:
294.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.34 (s, 1H), 7.82 (dd, J = 8.7, 5.4 Hz, 1H), 7.70 (s, 1H),
7.61 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.22 (dd, J =
10.0, 2.3 Hz, 1H), 6.95 (ddd, J = 9.4, 8.7, 2.3 Hz, 1H), 3.87 (s, 2H), 2.34 (s,
3H).

Compound 45: 4-((5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) morpholine Step 1: 4-((5- (6- Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) morpholine 2- (chloromethyl) -5- (6 in DMF (2 mL) A solution of -fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazole (intermediate 39; 100 mg; 0.23 mmol) and morpholine (59 mg; 0.68 mmol) Stir at 80 ° C. for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H ₂ O (20 mL), brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and preparative TLC (DCM / MeOH = 20/1) to give 56 mg (50%) of the title compound as a brown solid. C ₂₆ H ₂₃ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
491.2; found: 490.9.
Step 2:
4-((5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) morpholine (Step 1; 56 mg; After purification by preparative TLC (DCM / MeOH = 20/1) according to the general procedure outlined for compound 1, 13 mg (32%) of the title compound was obtained as a white solid. LC-MS for C ₂₀ H ₁₉ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 351.2; Found:
351.2. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ [ppm]: 7.71 (dd, J = 8.4, 5.2 Hz, 1H), 7.67 (s, 1H), 7.49 (d, J =
8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.01 (dd, J = 10.0, 2.4
Hz, 1H), 6.78 (ddd, J = 9.2, 8.4, 2.4 Hz, 1H), 3.72 (s, 1H), 3.66-3.61 (m,
4H), 2.50-2.44 (m, 4H).

Compound 46: 3- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) propanamide Step 1: 3- (5- (6-Fluoro-1) -(Phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) propanamide 6- (6-Fluoro-1- (phenyl) in saturated NH ₃ (100 mL) in THF Sulfonyl) -1H-indol-3-yl) -2,3-dihydro-1H-benzo [d] pyrrolo [1,2-a] imidazol-1-one (Intermediate 41; 456 mg crude; 0.92 mmol) ) Was stirred in an autoclave at 137 ° C. for 24 hours. The reaction mixture was cooled to room temperature and concentrated to give 480 mg (100%) of the title compound as a yellow solid, which was used directly without further purification. C ₂₄ H ₁₉ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: Calculated
463.1; found: 462.8.
Step 2:
3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) propanamide in EtOH (10 mL) (Step 1; To a solution of 480 mg crude; 0.92 mmol) was added KOH (116 mg; 2.07 mmol). The reaction mixture was stirred at 50 ° C. for 4 hours. The mixture was neutralized with 2M aqueous HCl, concentrated and purified by preparative HPLC to give 50 mg (17%) of the title compound as a white solid. LC-MS for C ₁₈ H ₁₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 323.1; Found:
322.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.15 (s, 1H), 11.33 (s, 1H), 7.82 (dd, J = 8.7, 5.5 Hz,
1H), 7.67 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.48-
7.38 (m, 2H), 7.22 (dd, J = 10.0, 2.0 Hz, 1H), 6.95 (ddd, J = 9.6, 8.7, 2.0 Hz,
1H), 6.86 (s, 1H), 3.03 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H).

Compound 47: 5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazole 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (Intermediate 43; 423 mg; 1.08 mmol) and after purification by silica gel chromatography (petroleum ether / EtOAc = 100/1 to 6/1) according to the general procedure outlined for compound 1, 60 mg (22% ) Was obtained as a white solid. LC-MS for C ₁₅ H ₉ FN ₂ O + H ⁺ [M + H] ⁺ : Calculated 253.1; Found:
253.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.30 (br s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.84 (dd, J =
8.8, 5.2 Hz, 1H), 7.69-7.63 (m, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.14 (dd, J =
9.4, 2.2 Hz, 1H), 6.98 (ddd, J = 9.4, 8.8, 2.2 Hz, 1H).

Compound 48: 5- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] oxazole 5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2 Starting from methylbenzo [d] oxazole (intermediate 45; 718 mg; 1.77 mmol) and following purification by recrystallization in petroleum ether / EtOAc = 4/1 according to the general procedure outlined for compound 1, 184 mg ( 39%) of the title compound was obtained as a brown solid. LC-MS for C ₁₆ H ₁₁ FN ₂ O + H ⁺ [M + H] ⁺ : Calculated 267.1; Found:
267.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.45 (s, 1H), 7.87 (s, 1H), 7.83 (dd, J = 8.8, 5.2 Hz, 1H),
7.73-7.68 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 10.0, 2.4 Hz, 1H),
7.23 (ddd, J = 9.2, 8.8, 2.4 Hz, 1H), 2.63 (s, 3H).

Compound 53: 6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazole

オルトギ酸トリエチル（１５ｍＬ）中の２−アミノ−５−（６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体５７、５００ｍｇ、２．６６ｍｍｏｌ）の混合物を、１２０℃で０．５時間加熱した。混合物を濃縮し、水（２０ｍＬ）中に懸濁させ、濾過した。ケーキをＥｔＯＡｃ（５ｍＬ）と石油エーテル（２０ｍＬ）との混合物から再結晶して、１６０ｍｇ（３５％）の表題化合物を白色固体として得た。C₁₅H₉FN₂O+H⁺ [M+H]⁺のLC-MS: 計算値253.1; 実測値:
253.0. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.43 (s, 1H), 7.89 (s, 1H), 7.84 - 7.82 (m, 1H), 7.75 (d, J
= 8.0Hz, 1H), 7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.52 (s, 1H), 7.12 (dd, J = 10,
2.4 Hz, 1H), 6.90 (m, 1H).

A mixture of 2-amino-5- (6-fluoro-1H-indol-3-yl) -phenol (intermediate 57, 500 mg, 2.66 mmol) in triethylorthoformate (15 mL) Heated for hours. The mixture was concentrated, suspended in water (20 mL) and filtered. The cake was recrystallized from a mixture of EtOAc (5 mL) and petroleum ether (20 mL) to give 160 mg (35%) of the title compound as a white solid. LC-MS for C ₁₅ H ₉ FN ₂ O + H ⁺ [M + H] ⁺ : Calculated 253.1; Found:
253.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.43 (s, 1H), 7.89 (s, 1H), 7.84-7.82 (m, 1H), 7.75 (d, J
= 8.0Hz, 1H), 7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.52 (s, 1H), 7.12 (dd, J = 10,
2.4 Hz, 1H), 6.90 (m, 1H).

Compound 54: 6- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] oxazole

１，１，１−トリエトキシエタン（１５ｍＬ）中の２−アミノ−５−（６−フルオロ−１Ｈ−インドール−３−イル）−フェノール（中間体５７、５００ｍｇ；２．６６ｍｍｏｌ）の混合物を、１２０℃で０．５時間加熱した。混合物を濃縮し、水（２０ｍＬ）中に懸濁させ、濾過した。ケーキをＥｔＯＡｃ（５ｍＬ）と石油エーテル（２０ｍＬ）との混合物から再結晶して、１４０ｍｇ（３０％）の表題化合物を白色固体として得た。C₁₆H₁₁FN₂O+H⁺ [M+H]⁺のLC-MS: 計算値267.1; 実測値:
267.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.85 (dd, J = 8.8, 5.6 Hz, 1H), 7.82 (s, 1H), 7.66 (s, 2H),
7.53 (s, 1H), 7.16 (dd, J = 9.6, 2.4 Hz, 1H), 6.93 (td, J = 9.2, 2.0 Hz, 1H),
2.67 (s, 3H).

A mixture of 2-amino-5- (6-fluoro-1H-indol-3-yl) -phenol (intermediate 57, 500 mg; 2.66 mmol) in 1,1,1-triethoxyethane (15 mL) was Heated at 120 ° C. for 0.5 hour. The mixture was concentrated, suspended in water (20 mL) and filtered. The cake was recrystallized from a mixture of EtOAc (5 mL) and petroleum ether (20 mL) to give 140 mg (30%) of the title compound as a white solid. LC-MS for C ₁₆ H ₁₁ FN ₂ O + H ⁺ [M + H] ⁺ : Calculated 267.1; Found:
267.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.85 (dd, J = 8.8, 5.6 Hz, 1H), 7.82 (s, 1H), 7.66 (s, 2H),
7.53 (s, 1H), 7.16 (dd, J = 9.6, 2.4 Hz, 1H), 6.93 (td, J = 9.2, 2.0 Hz, 1H),
2.67 (s, 3H).

Compound 55: 6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole

ＨＣｌ／エーテル（４０ｍＬ）中のｔｅｒｔ−ブチル４−（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）ピペリジン−１−カルボキシレート（中間体１０６、１．２３ｇ、２．８２ｍｍｏｌ）の混合物を、室温で１時間撹拌した。混合物を濃縮し、飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブライン（５０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、再結晶により精製して、７８３ｍｇ（８３％）の表題化合物を灰色固体として得た。C₂₀H₁₈FN₃O+H⁺ [M+H]⁺のLC-MS: 計算値335.1; 実測値:
336.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.49 (br s, 1H), 7.91 (s, 1H), 7.89 (dd, J = 8.8, 3.2 Hz,
1H), 7.75 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.6, 1.4
Hz, 1H), 7.25 (dd, J = 9.8, 2.6 Hz, 1H), 6.97 (td, J =10.6, 2.5 Hz, 1H), 3.13 -
3.02 (m, 3H), 2.64 (t, J = 11.2 Hz, 2H), 2.03 (d, J = 10.8 Hz, 2H), 1.72 (td, J
= 12.2, 3.0 Hz, 2H).

Tert-Butyl 4- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidine-1-carboxylate (intermediate 106, in HCl / ether (40 mL) A mixture of 1.23 g, 2.82 mmol) was stirred at room temperature for 1 hour. The mixture was concentrated, diluted with saturated aqueous NaHCO ₃ (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by recrystallization to give 783 mg (83%) of the title compound as a gray solid. LC-MS for C ₂₀ H ₁₈ FN ₃ O + H ⁺ [M + H] ⁺ : Calculated 335.1; Found:
336.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.49 (br s, 1H), 7.91 (s, 1H), 7.89 (dd, J = 8.8, 3.2 Hz,
1H), 7.75 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.6, 1.4
Hz, 1H), 7.25 (dd, J = 9.8, 2.6 Hz, 1H), 6.97 (td, J = 10.6, 2.5 Hz, 1H), 3.13-
3.02 (m, 3H), 2.64 (t, J = 11.2 Hz, 2H), 2.03 (d, J = 10.8 Hz, 2H), 1.72 (td, J
= 12.2, 3.0 Hz, 2H).

Compound 56: 1- (4- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidin-1-yl) ethanone

室温のＤＣＭ（１０ｍＬ）中の６−（６−フルオロ−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イル）ベンゾ［ｄ］オキサゾール（化合物５５、２００ｍｇ、０．６０ｍｍｏｌ）およびＴＥＡ（１８２ｍｇ、１．８０ｍｍｏ）の撹拌溶液に、塩化アセチル（５７ｍｇ、０．７２ｍｍｏｌ）を滴下添加した。混合物を室温で終夜撹拌した。混合物をＤＣＭ（１０ｍＬ）で希釈し、水（２０ｍＬ×２）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、１２１ｍｇ（５４％）の表題化合物を黄色固体として得た。C₂₂H₂₀FN₃O₂+H⁺のLC-MS: [M+H]⁺: 計算値378.2;実測値: 378.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.48 (s, 1H), 7.92 (s, 1H), 7.89 (dd, J = 5.6, 8.8 Hz, 1H),
7.75 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.66 (dd, J = 1.6, 8.0 Hz,
1H), 7.23 (dd, J = 2.4, 10.0 Hz, 1H), 6.97 (td, J = 2.4, 9.6 Hz, 1H), 4.32 (d,
J = 13.6 Hz, 1H), 3.87 (d, J = 13.6 Hz, 1H), 3.35 - 3.27 (m, 2H), 2.88 (t, J =
11.2 Hz, 1H), 2.13 (t, J = 14.0 Hz, 2H), 2.04 (s, 3H), 1.88-1.77 (m, 1H), 1.72
- 1.62 (m, 1H).

6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole (Compound 55, 200 mg, 0.60 mmol) and TEA in DCM (10 mL) at room temperature To a stirred solution of (182 mg, 1.80 mmol), acetyl chloride (57 mg, 0.72 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (10 mL), washed with water (20 mL × 2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 121 mg (54%) of the title compound as a yellow solid. LC-MS for C ₂₂ H ₂₀ FN ₃ O ₂ + H ⁺ : [M + H] ⁺ : Calculated 378.2; Found: 378.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.48 (s, 1H), 7.92 (s, 1H), 7.89 (dd, J = 5.6, 8.8 Hz, 1H),
7.75 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.66 (dd, J = 1.6, 8.0 Hz,
1H), 7.23 (dd, J = 2.4, 10.0 Hz, 1H), 6.97 (td, J = 2.4, 9.6 Hz, 1H), 4.32 (d,
J = 13.6 Hz, 1H), 3.87 (d, J = 13.6 Hz, 1H), 3.35-3.27 (m, 2H), 2.88 (t, J =
11.2 Hz, 1H), 2.13 (t, J = 14.0 Hz, 2H), 2.04 (s, 3H), 1.88-1.77 (m, 1H), 1.72
-1.62 (m, 1H).

Compound 58: N- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanesulfonamide

エタノール（２０ｍＬ）中のＮ−［６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イル］−メタンスルホンアミド（中間体１２４、３５０ｍｇ、０．７２ｍｍｏｌ）の混合物に、水酸化カリウム（５５ｍｇ、２．８８ｍｍｏｌ）を添加した。混合物を５０℃で４時間撹拌した。溶媒を除去した。残留物をＥＡに再溶解し、水およびブラインで洗浄した。有機層を乾燥させ、濾過し、濃縮した。残留物を分取ＴＬＣ（ＤＣＭ／メタノール＝１０／１）により精製し、ＥＡとすり混ぜることによりさらに精製して、８ｍｇ（３％）の表題化合物を黒色固体として得た。C₁₆H₁₂FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値346.1;
実測値: 346.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 12.51(s, 1H), 11.44 (s, 1H), 7.86 (dd, J =
9.2, 5.6 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.0 Hz,
1H), 7.36 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.98 - 6.94 (m,
1H), 3.08 (s, 3H).

N- [6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazol-2-yl] -methanesulfonamide (Intermediate 124, 350 mg, 0. 1) in ethanol (20 mL) To a mixture of 72 mmol) potassium hydroxide (55 mg, 2.88 mmol) was added. The mixture was stirred at 50 ° C. for 4 hours. The solvent was removed. The residue was redissolved in EA and washed with water and brine. The organic layer was dried, filtered and concentrated. The residue was purified by preparative TLC (DCM / methanol = 10/1) and further purified by triturating with EA to give 8 mg (3%) of the title compound as a black solid. C ₁₆ H ₁₂ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 346.1;
Found: 346.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 12.51 (s, 1H), 11.44 (s, 1H), 7.86 (dd, J =
9.2, 5.6 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.0 Hz,
1H), 7.36 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.98-6.94 (m,
1H), 3.08 (s, 3H).

Compound 59: 6- (6-Fluoro-1H-indol-3-yl) -2- (piperazin-1-ylmethyl) -1H-benzo [d] imidazole

６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−ピペラジン−１−イルメチル−１Ｈ−ベンゾイミダゾール（中間体６２、８０ｍｇ、０．１６ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、３５ｍｇ（６２％）の表題化合物を白色固体として得た。C₂₀H₂₀FN5+H⁺ [M+H]⁺のLC-MS: 計算値350.2; 実測値:
350.1. ¹H NMR (400 MHz, CD₃OD) δ [ppm]: 7.73 (dd, J = 8.8, 5.2 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J =
8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.03 (dd, J = 9.6, 2.0 Hz,
1H), 7.79 (d, J = 8.8, 2.0 Hz, 1H), 3.74 (s, 2H), 2.89 (t, J = 4.8 Hz, 4H),
2.52 (t, J = 4.8 Hz, 4H).

Starting from 6- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-piperazin-1-ylmethyl-1H-benzimidazole (intermediate 62, 80 mg, 0.16 mmol), compound 1 35 mg (62%) of the title compound were obtained as a white solid according to the general method outlined in LC-MS for C ₂₀ H ₂₀ FN5 + H ⁺ [M + H] ⁺ : Calculated 350.2; Found:
350.1. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.73 (dd, J = 8.8, 5.2 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J =
8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.03 (dd, J = 9.6, 2.0 Hz,
1H), 7.79 (d, J = 8.8, 2.0 Hz, 1H), 3.74 (s, 2H), 2.89 (t, J = 4.8 Hz, 4H),
2.52 (t, J = 4.8 Hz, 4H).

Compound 60: 2- (6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) acetamide

０℃のＤＭＳＯ（５ｍＬ）中の［５−（６−フルオロ−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾイミダゾール−２−イル］−アセトニトリル（中間体６８、１８６ｍｇ、０．６２８ｍｍｏｌ）の撹拌溶液に、Ｋ_２ＣＯ_３（１７３ｍｇ、１．２６ｍｍｏｌ）、次いでＨ_２Ｏ_２水溶液（０．７ｍＬ、３０％ｗ／ｗ）を添加した。混合物を室温で１時間撹拌した後、これを水（５０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×２）で抽出した。合わせた有機層をブライン（３０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー（ＤＣＭ／ＭｅＯＨ＝２０／１から５／１）により精製して、固体を得た。固体をＤＣＭ／ＭｅＯＨ＝５／１（３ｍＬ）で懸濁させ、濾過した。濾過したケーキを蒸発乾固させて、４０ｍｇ（２１％）の表題化合物をオフホワイトの固体として得た。C₁₇H₁₁FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値309.1; 実測値:
309.3. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 12.19 (d, J = 24.0 Hz, 1H), 11.33 (d, J = 12.8 Hz, 1H), 7.82
(dd, J = 8.4, 5.2 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.61 (dd, J = 9.6, 2.4 Hz, 1H),
7.59 - 7.47 (m, 1H), 7.43 (td, J = 9.6, 2.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 6.99
- 6.91 (m, 1H), 3.73 (s, 2H).

Stirring of [5- (6-Fluoro-1H-indol-3-yl) -1H-benzimidazol-2-yl] -acetonitrile (Intermediate 68, 186 mg, 0.628 mmol) in DMSO (5 mL) at 0 ° C. To the solution was added K ₂ CO ₃ (173 mg, 1.26 mmol) followed by aqueous H ₂ O ₂ (0.7 mL, 30% w / w). After the mixture was stirred at room temperature for 1 hour, it was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH = 20/1 to 5/1) to give a solid. The solid was suspended in DCM / MeOH = 5/1 (3 mL) and filtered. The filtered cake was evaporated to dryness to give 40 mg (21%) of the title compound as an off-white solid. LC-MS for C ₁₇ H ₁₁ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
309.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.19 (d, J = 24.0 Hz, 1H), 11.33 (d, J = 12.8 Hz, 1H), 7.82
(dd, J = 8.4, 5.2 Hz, 1H), 7.76-7.66 (m, 2H), 7.61 (dd, J = 9.6, 2.4 Hz, 1H),
7.59-7.47 (m, 1H), 7.43 (td, J = 9.6, 2.4 Hz, 1H), 7.25-7.16 (m, 2H), 6.99
-6.91 (m, 1H), 3.73 (s, 2H).

Compound 61: 5- (6-Fluoro-1H-indol-3-yl) -2- (piperazin-1-ylmethyl) benzo [d] oxazole

ＭｅＯＨ（１０ｍＬ）中の５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−ピペラジン−１−イルメチル−ベンゾオキサゾール（中間体７２、８０ｍｇ、０．１６ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、３０ｍｇ（５２％）の表題化合物を白色固体として得た。C₂₀H₁₉FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値351.2; 実測値:
351.1. ¹H NMR (400 MHz, CD₃OD) δ [ppm]: 7.77 (s, 1H), 7.67 (dd, J = 8.8, 5.2 Hz, 1H), 7.54 (dd, J =
8.8, 1.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.03 (dd, J = 9.6,
2.0 Hz, 1H), 6.78 (td, J = 9.6, 2.0 Hz, 1H), 3.77 (s, 2H), 2.83 (t, J = 4.8 Hz,
4H), 2.56 (t, J = 4.8 Hz, 4H).

Starting from 5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-piperazin-1-ylmethyl-benzoxazole (Intermediate 72, 80 mg, 0.16 mmol) in MeOH (10 mL) According to the general method outlined for compound 1, 30 mg (52%) of the title compound were obtained as a white solid. LC-MS for C ₂₀ H ₁₉ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 351.2; Found:
351.1. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.77 (s, 1H), 7.67 (dd, J = 8.8, 5.2 Hz, 1H), 7.54 (dd, J =
8.8, 1.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.03 (dd, J = 9.6,
2.0 Hz, 1H), 6.78 (td, J = 9.6, 2.0 Hz, 1H), 3.77 (s, 2H), 2.83 (t, J = 4.8 Hz,
4H), 2.56 (t, J = 4.8 Hz, 4H).

Compound 62: 5- (6-Fluoro-1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) benzo [d] oxazole

５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−（４−メチル−ピペラジン−１−イルメチル）−ベンゾオキサゾール（中間体７３、１６０ｍｇ、０．３２ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、２７ｍｇ（２３％）の表題化合物を白色固体として得た。C₂₁H₂₁FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値365.2; 実測値:
365.1. ¹H NMR (400 MHz, CD₃OD) δ [ppm]: 7.89 (d, J = 0.8 Hz, 1H), 7.80 (dd, J = 8.8, 5.2 Hz, 1H),
7.67 (dd, J = 8.8, 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.13
(dd, J = 9.6, 2.0 Hz, 1H), 6.89 (td, J = 9.6, 2.0 Hz, 1H), 3.90 (s, 2H), 2.78 -
2.68 (m, 4H), 2.68 - 2.39 (m, 4H), 2.28 (s, 3H).

Starting from 5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2- (4-methyl-piperazin-1-ylmethyl) -benzoxazole (intermediate 73, 160 mg, 0.32 mmol) According to the general method outlined for compound 1, 27 mg (23%) of the title compound were obtained as a white solid. LC-MS for C ₂₁ H ₂₁ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 365.2; Found:
365.1. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.89 (d, J = 0.8 Hz, 1H), 7.80 (dd, J = 8.8, 5.2 Hz, 1H),
7.67 (dd, J = 8.8, 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.13
(dd, J = 9.6, 2.0 Hz, 1H), 6.89 (td, J = 9.6, 2.0 Hz, 1H), 3.90 (s, 2H), 2.78-
2.68 (m, 4H), 2.68-2.39 (m, 4H), 2.28 (s, 3H).

Compound 63: 5- (6-fluoro-1H-indol-3-yl) -2- (morpholinomethyl) benzo [d] oxazole

５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−モルホリン−４−イルメチル−ベンゾオキサゾール（中間体７４、１００ｍｇ、０．２０４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、３０ｍｇ（４２％）の表題化合物を白色固体として得た。C₂₀H₁₈FN₃O₂+H⁺
[M+H]⁺のLC-MS: 計算値352.1;
実測値: 352.1. ¹H NMR (400 MHz, CD₃OD)
δ [ppm]: 7.86 (s, 1H), 7.75 (dd, J = 8.8, 5.6 Hz, 1H),
7.62 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.12 (dd, J =
9.6, 1.6 Hz, 1H), 6.87 (td, J = 9.6, 2.0 Hz, 1H), 3.82 (s, 2H), 3.69 (t, J =
4.4 Hz, 4H), 2.59 (t, J = 4.4 Hz, 4H).

Starting with 5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-morpholin-4-ylmethyl-benzoxazole (intermediate 74, 100 mg, 0.204 mmol), outlined in compound 1 According to the general procedure, 30 mg (42%) of the title compound were obtained as a white solid. C ₂₀ H ₁₈ FN ₃ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 352.1;
Found: 352.1. ¹ H NMR (400 MHz, CD ₃ OD)
δ [ppm]: 7.86 (s, 1H), 7.75 (dd, J = 8.8, 5.6 Hz, 1H),
7.62 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.12 (dd, J =
9.6, 1.6 Hz, 1H), 6.87 (td, J = 9.6, 2.0 Hz, 1H), 3.82 (s, 2H), 3.69 (t, J =
4.4 Hz, 4H), 2.59 (t, J = 4.4 Hz, 4H).

Compound 64: 2- (6- (6-fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide

２−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−オキソベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）アセトアミド（中間体７６、１８３ｍｇ、０．４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、５０ｍｇ（３８％）の表題化合物を白色固体として得た。C₁₇H₁₂FN₃O₃+H]⁺
[M+H]⁺のLC-MS: 計算値326.1;
実測値: 325.8. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.43 (br s, 1H), 10.97 (br s, 1H), 9.81 (br
s, 1H), 7.81 (dd, J = 8.4, 5.2 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.31 (d, J =
8.0 Hz, 1H), 7.24 - 7.21 (m, 2H), 7.12 (dd, J = 8.0, 1.2 Hz, 1H), 6.97 (td, J =
9.2, 2.0 Hz, 1H), 4.28 (s, 2H).

2- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide (Intermediate 76, 183 mg, 0 Starting from 0.4 mmol), 50 mg (38%) of the title compound were obtained as a white solid according to the general procedure outlined for compound 1. C ₁₇ H ₁₂ FN ₃ O ₃ + H] ⁺
[M + H] ⁺ LC-MS: calcd 326.1;
Found: 325.8. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.43 (br s, 1H), 10.97 (br s, 1H), 9.81 (br
s, 1H), 7.81 (dd, J = 8.4, 5.2 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.31 (d, J =
8.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.12 (dd, J = 8.0, 1.2 Hz, 1H), 6.97 (td, J =
9.2, 2.0 Hz, 1H), 4.28 (s, 2H).

Compound 65: 5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2 (3H) -one

５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−，３−ジヒドロ−ベンゾイミダゾール−２−オン（中間体７７、１８５ｍｇ、０．４５ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、５２ｍｇ（４３％）の表題化合物を黄色固体として得た。C₁₅H₁₀FN₃O-H^- [M-H]のLC-MS: 計算値266.1; 実測値:
265.9. ¹H NMR (400 MHz, MeOD-d₄) δ [ppm]: 11.30 (s, 1H), 10.59 (s, 2H), 7.76 (dd, J₁ = 8.4
Hz, J₂ = 5.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.23 -
7.19 (m, 2H), 7.15 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.94 (td, J₁
= 9.2 Hz, J₂ = 2.0 Hz, 1H).

Starting from 5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl)-, 3-dihydro-benzimidazol-2-one (Intermediate 77, 185 mg, 0.45 mmol) Following the general method outlined, 52 mg (43%) of the title compound were obtained as a yellow solid. ^{_{C 15 H 10 FN 3 OH -}} [MH] of LC-MS: calc 266.1; found:
265.9. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ [ppm]: 11.30 (s, 1H), 10.59 (s, 2H), 7.76 (dd, J ₁ = 8.4
Hz, J ₂ = 5.6 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.23-
7.19 (m, 2H), 7.15 (s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.94 (td, J ₁
= 9.2 Hz, J ₂ = 2.0 Hz, 1H).

Compound 66: 6- (6-Fluoro-1H-indol-3-yl) -2- (morpholinomethyl) benzo [d] oxazole

６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（モルホリノメチル）ベンゾ［ｄ］オキサゾール（中間体８０、２４０ｍｇ、０．４８ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、６３ｍｇ（４４％）の表題化合物を黄褐色固体として得た。C₂₀H₁₈FN₃O₂+H⁺
[M+H]⁺のLC-MS: 計算値352.1;
実測値: 352.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.51 (s, 1H), 7.96 (s, 1H), 7.91 - 7.88 (m,
1H), 7.77 - 7.74 (m, 2H),7.69 - 7.67 (m, 1H), 7.24 (dd, J = 2.0, 9.6 Hz, 1H),
6.97 (td, J = 2.4, 9.6 Hz, 1H), 3.87 (s, 2H), 3.61 - 3.59 (m, 4H), 2.56 - 2.54
(m, 4H).

Starting from 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (morpholinomethyl) benzo [d] oxazole (intermediate 80, 240 mg, 0.48 mmol), the compound Following the general method outlined in 1, 63 mg (44%) of the title compound were obtained as a tan solid. C ₂₀ H ₁₈ FN ₃ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 352.1;
Found: 352.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.51 (s, 1H), 7.96 (s, 1H), 7.91-7.88 (m,
1H), 7.77-7.74 (m, 2H), 7.69-7.67 (m, 1H), 7.24 (dd, J = 2.0, 9.6 Hz, 1H),
6.97 (td, J = 2.4, 9.6 Hz, 1H), 3.87 (s, 2H), 3.61-3.59 (m, 4H), 2.56-2.54
(m, 4H).

Compound 67: 3- (6- (6-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propanamide

３−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−オキソベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）プロパンアミド（中間体８１、２８０ｍｇ、０．５８ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、５０ｍｇ（２５％）の表題化合物を白色固体として得た。C₁₈H₁₄FN₃O₃-H^-
[M-H]^-のLC-MS: 計算値338.1;
実測値: 337.9. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.40 (br s, 1H), 10.27 (br s, 1H), 9.60 (br
s, 1H), 7.81 (dd, J = 8.8, 5.4 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.24-7.19 (m,
3H), 7.11 (dd, J = 8.0, 1.6 Hz, 1H), 6.97 (td, J = 9.6, 2.0 Hz, 1H), 3.63 (t, J
= 6.6 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H).

3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propanamide (Intermediate 81,280 mg, Starting from 0.58 mmol), following the general method outlined for compound 1, 50 mg (25%) of the title compound were obtained as a white solid. _{C 18 H 14 FN 3 O 3} -H -
[MH] ^- the LC-MS: calc 338.1;
Found: 337.9. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.40 (br s, 1H), 10.27 (br s, 1H), 9.60 (br
s, 1H), 7.81 (dd, J = 8.8, 5.4 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.24-7.19 (m,
3H), 7.11 (dd, J = 8.0, 1.6 Hz, 1H), 6.97 (td, J = 9.6, 2.0 Hz, 1H), 3.63 (t, J
= 6.6 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H).

Compound 68: 6- (6-Fluoro-1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) benzo [d] oxazole

６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（（４−メチルピペラジン−１−イル）メチル）ベンゾ［ｄ］オキサゾール（中間体８２、２８５ｍｇ、０．５６ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、４５ｍｇ（２２％）の表題化合物を黄褐色固体として得た。C₂₁H₂₁FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値365.2 ; 実測値: 364.9. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.54 (s, 1H), 7.95 - 7.88 (m, 2H), 7.76 - 7.67 (m, 3H),
7.24 (dd, J = 9.6, 1.6 Hz, 1H), 6.99 - 6.95 (m, 1H), 3.84 (s, 2H), 2.55 (s,
4H), 2.34 (s, 4H), 2.15 (s,3H)

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) benzo [d] oxazole (Intermediate 82, 285 mg, Starting from 0.56 mmol), 45 mg (22%) of the title compound were obtained as a tan solid following the general procedure outlined for compound 1. LC-MS for C ₂₁ H ₂₁ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 365.2; Found: 364.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.54 (s , 1H), 7.95-7.88 (m, 2H), 7.76-7.67 (m, 3H),
7.24 (dd, J = 9.6, 1.6 Hz, 1H), 6.99-6.95 (m, 1H), 3.84 (s, 2H), 2.55 (s,
4H), 2.34 (s, 4H), 2.15 (s, 3H)

Compound 69: 2- (5- (6-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide

２−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−オキソベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）アセトアミド（中間体８４、６００ｍｇの粗製物、１．２９ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、１３ｍｇ（３％）の表題化合物を白色固体として得た。C₁₇H₁₂FN₃O₃-H^-
[M-H]^-のLC-MS: 計算値324.1;
実測値: 323.9. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.31 (br s, 1H), 10.95 (br s, 1H), 9.74 (br
s, 1H), 7.80 (dd, J = 8.7, 5.4 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.54 (d, J =
2.0 Hz, 1H), 7.46 -7.43 (m, 1H), 7.19 (dd, J = 10.0, 2.0 Hz, 1H), 6.99 - 6.90
(m, 2H), 4.32 (s, 2H).

2- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide (Intermediate 84, 600 mg crude) Product, 1.29 mmol) to give 13 mg (3%) of the title compound as a white solid after purification by preparative HPLC according to the general procedure outlined for compound 1. _{C 17 H 12 FN 3 O 3} -H -
[MH] ^- the LC-MS: calc 324.1;
Found: 323.9. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.31 (br s, 1H), 10.95 (br s, 1H), 9.74 (br
s, 1H), 7.80 (dd, J = 8.7, 5.4 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.54 (d, J =
2.0 Hz, 1H), 7.46 -7.43 (m, 1H), 7.19 (dd, J = 10.0, 2.0 Hz, 1H), 6.99-6.90
(m, 2H), 4.32 (s, 2H).

Compound 70: N-((5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide

Ｎ−［５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イルメチル］−メタンスルホンアミド（中間体８７、８３ｍｇ、０．１７ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、３０ｍｇ（５０％）の表題化合物を白色固体として得た。C₁₇H₁₄FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値360.1;
実測値: 360.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.45 (br s, 1H), 8.01 (br s, 1H), 7.95 (s,
1H), 7.89-7.81 (m, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H),
7.70 (d, J = 8.8 Hz, 1H), 7.23 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 8.8,
2.0 Hz, 1H), 4.54 (s, 2H), 3.04 (s, 3H).

Starting from N- [5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazol-2-ylmethyl] -methanesulfonamide (Intermediate 87, 83 mg, 0.17 mmol) Following the general method outlined for Compound 1, 30 mg (50%) of the title compound was obtained as a white solid. C ₁₇ H ₁₄ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 360.1;
Found: 360.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.45 (br s, 1H), 8.01 (br s, 1H), 7.95 (s,
1H), 7.89-7.81 (m, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H),
7.70 (d, J = 8.8 Hz, 1H), 7.23 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 8.8,
2.0 Hz, 1H), 4.54 (s, 2H), 3.04 (s, 3H).

Compound 71: 3- (5- (6-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propanamide)

３−［５−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−オキソ−ベンゾオキサゾール−３−イル］−プロピオンアミド（中間体８８、２７０ｍｇ、０．５６ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（４８ｍｇ、２５％）を白色固体として得た。C₁₈H₁₄FN₃O₃-H^-
[M-H]^-のLC-MS: 計算値338.1;
実測値: 338.0. ¹H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 10.31 (s, 1H), 9.56 (s, 1H), 7.78 (dd, J = 8.8, 5.6
Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.4,
2.2 Hz, 1H), 7.19 (dd, J = 9.9, 1.9 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.99 -
6.90 (m, 2H), 3.67 (t, J = 6.6 Hz, 2H), 2.72 (t, J = 6.6 Hz, 2H).

From 3- [5- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-oxo-benzoxazol-3-yl] -propionamide (Intermediate 88, 270 mg, 0.56 mmol) Starting and following the general method outlined for compound 1, the title compound (48 mg, 25%) was obtained as a white solid. _{C 18 H 14 FN 3 O 3} -H -
[MH] ^- the LC-MS: calc 338.1;
Found: 338.0. ¹ H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 10.31 (s, 1H), 9.56 (s, 1H), 7.78 (dd, J = 8.8, 5.6
Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.4,
2.2 Hz, 1H), 7.19 (dd, J = 9.9, 1.9 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.99-
6.90 (m, 2H), 3.67 (t, J = 6.6 Hz, 2H), 2.72 (t, J = 6.6 Hz, 2H).

Compound 72: 3- (benzo [b] thiophen-5-yl) -6-fluoro-1H-indole

３−（ベンゾ［ｂ］チオフェン−５−イル）−６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール（中間体９０、３００ｍｇ、０．７４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、３−ベンゾ［ｂ］チオフェン−５−イル−６−フルオロ−１Ｈ−インドール（７０ｍｇ、３６％）を白色固体として得た。C₁₆H₁₀FNS-H^- [M-H]^-のLC-MS: 計算値266.1; 実測値:
265.9. ¹H NMR (400 MHz, DMSO) δ 11.44
(s, 1H), 8.18 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 8.8, 5.2 Hz,
1H), 7.77 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.51 (d,
J = 5.6 Hz, 1H), 7.23 (dd, J = 9.8, 2.0 Hz, 1H), 6.97 (td, J = 9.2, 2.4 Hz,
1H).

General starting from 3- (benzo [b] thiophen-5-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole (intermediate 90, 300 mg, 0.74 mmol) and outlined in compound 1 According to the method, 3-benzo [b] thiophen-5-yl-6-fluoro-1H-indole (70 mg, 36%) was obtained as a white solid. ^{_{C 16 H 10 FNS-H -}} [MH] - the LC-MS: calc 266.1; found:
265.9. ¹ H NMR (400 MHz, DMSO) δ 11.44
(s, 1H), 8.18 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 (dd, J = 8.8, 5.2 Hz,
1H), 7.77 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.51 (d,
J = 5.6 Hz, 1H), 7.23 (dd, J = 9.8, 2.0 Hz, 1H), 6.97 (td, J = 9.2, 2.4 Hz,
1H).

Compound 73: N-((5- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) acetamide

室温のＤＣＭ（６ｍＬ）中のＣ−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イル］−メチルアミン塩酸塩（化合物８１、４０ｍｇ、０．１２６ｍｍｏｌ）の撹拌混合物に、ＴＥＡ（２５ｍｇ、０．２５２ｍｍｏｌ）およびＡｃＣｌ（４９ｍｇ、０．６３ｍｍｏｌ）を添加した。混合物をさらに３０分間撹拌した後、これを氷水（２０ｍＬ）でクエンチし、ＥｔＯＡｃ（２０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＴＬＣ（ＤＣＭ／ＭｅＯＨ＝２０／１）により精製して、１３ｍｇ（３２％）の表題化合物を黄色固体として得た。C₁₈H₁₄FN₃O₂+H⁺
[M+H]⁺のLC-MS: 計算値324.1;
実測値: 324.1. ¹H NMR (400 MHz, CD₃OD)
δ [ppm]: 7.90 (s, 1H), 7.82 (dd, J = 8.8, 1.6 Hz, 1H),
7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.16
(dd, J = 9.6, 2.0 Hz, 1H), 6.92 (td, J = 9.6, 2.4 Hz, 1H), 4.70 (s, 2H), 2.10
(s, 3H).

Of C- [5- (6-Fluoro-1H-indol-3-yl) -benzoxazol-2-yl] -methylamine hydrochloride (Compound 81, 40 mg, 0.126 mmol) in DCM (6 mL) at room temperature. To the stirred mixture was added TEA (25 mg, 0.252 mmol) and AcCl (49 mg, 0.63 mmol). After the mixture was stirred for an additional 30 minutes, it was quenched with ice water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative TLC (DCM / MeOH = 20/1) to give 13 mg (32%) of the title compound as a yellow solid. C ₁₈ H ₁₄ FN ₃ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 324.1;
Found: 324.1. ¹ H NMR (400 MHz, CD ₃ OD)
δ [ppm]: 7.90 (s, 1H), 7.82 (dd, J = 8.8, 1.6 Hz, 1H),
7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.16
(dd, J = 9.6, 2.0 Hz, 1H), 6.92 (td, J = 9.6, 2.4 Hz, 1H), 4.70 (s, 2H), 2.10
(s, 3H).

Compound 74: N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide

ＨＣｌ／１，４−ジオキサン（１５ｍＬ）中のｔｅｒｔ−ブチルｔｅｒｔ−ブチル（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）（メチルスルホニル）カルバメート（中間体９２、１１４ｍｇ、０．２５ｍｍｏｌ）の混合物を、室温で０．５時間撹拌した。反応混合物を濃縮し、分取ＨＰＬＣにより精製して、２２ｍｇ（２４％）の表題化合物を黄色固体として得た。C₁₇H₁₄FN₃O₃S+H⁺
[M + H]⁺のLC-MS: 計算値360.1;
実測値: 360.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.51 (s, 1H), 8.03 - 7.99 (m, 1H), 7.97 (s,
1H), 7.90 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.70 (dd, J = 8.3,
1.3 Hz, 1H), 7.24 (dd, J = 10.2, 2.2 Hz, 1H), 6.97 (td, J = 9.2, 2.1 Hz, 1H),
4.54 (d, J = 4.4 Hz, 2H), 3.04 (s, 3H).

Tert-Butyl tert-butyl ((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) (methylsulfonyl) in HCl / 1,4-dioxane (15 mL) ) A mixture of carbamate (Intermediate 92, 114 mg, 0.25 mmol) was stirred at room temperature for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC to give 22 mg (24%) of the title compound as a yellow solid. C ₁₇ H ₁₄ FN ₃ O ₃ S + H ⁺
LC-MS of [M + H] ⁺ : calculated 360.1;
Found: 360.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.51 (s, 1H), 8.03-7.99 (m, 1H), 7.97 (s,
1H), 7.90 (dd, J = 8.8, 5.4 Hz, 1H), 7.80-7.75 (m, 2H), 7.70 (dd, J = 8.3,
1.3 Hz, 1H), 7.24 (dd, J = 10.2, 2.2 Hz, 1H), 6.97 (td, J = 9.2, 2.1 Hz, 1H),
4.54 (d, J = 4.4 Hz, 2H), 3.04 (s, 3H).

Compound 75: N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) acetamide

ＤＣＭ（２０ｍＬ）中の（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メタンアミン塩酸塩（化合物７６、１２０ｍｇ、０．３８ｍｍｏｌ）およびＴＥＡ（１１５ｍｇ、１．１４ｍｍｏｌ）の溶液に、塩化アセチル（３６ｍｇ、０．４５ｍｍｏｌ）を窒素下で添加した。混合物を窒素下室温で１時間撹拌した。反応物をＨＣｌ（１２Ｍ）でｐＨ＝５まで酸性化した。混合物を水（６０ｍＬ）で希釈し、ＤＣＭ（３０ｍＬ）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、５５ｍｇ（３９％）の表題化合物を白色固体として得た。C₁₈H₁₄FN₃O₂+H⁺
[M+H]⁺のLC-MS: 計算値324.1;
実測値: 324.5. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.50 (s, 1H), 8.69 (t, J = 5.6 Hz, 1H), 7.94
(s, 1H), 7.89 (dd, J = 9.0, 5.4 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.74 (d, J =
8.2 Hz, 1H), 7.69 - 7.67 (m, 1H), 7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J =
9.2, 2.0 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 1.93 (s, 3H).

(6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine hydrochloride (Compound 76, 120 mg, 0.38 mmol) and TEA (115 mg, in DCM (20 mL)) To a solution of 1.14 mmol) acetyl chloride (36 mg, 0.45 mmol) was added under nitrogen. The mixture was stirred at room temperature for 1 hour under nitrogen. The reaction was acidified with HCl (12M) to pH = 5. The mixture was diluted with water (60 mL) and extracted with DCM (30 mL). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 55 mg (39%) of the title compound as a white solid. C ₁₈ H ₁₄ FN ₃ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 324.1;
Found: 324.5. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.50 (s, 1H), 8.69 (t, J = 5.6 Hz, 1H), 7.94
(s, 1H), 7.89 (dd, J = 9.0, 5.4 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.74 (d, J =
8.2 Hz, 1H), 7.69-7.67 (m, 1H), 7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J =
9.2, 2.0 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 1.93 (s, 3H).

Compound 76: (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine

ＨＣｌ／１，４−ジオキサン（２０ｍＬ）中のｔｅｒｔ−ブチルＮ−［（ｔｅｒｔ−ブトキシ）カルボニル］−Ｎ−｛［６−（６−フルオロ−１Ｈ−インドール−３−イル）−１，３−ベンゾオキサゾール−２−イル］メチル｝カルバメート（中間体９４；３７６ｍｇ、０．７８ｍｍｏｌ）の混合物を、室温で０．５時間撹拌した。反応混合物を濃縮して、２１９ｍｇ（１００％）の表題化合物を黄色固体として得た。C₁₆H₁₃ClFN₃O+H⁺ [M+H]⁺のLC-MS:計算値282.1; 実測値:
281.9. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.51 (br s, 1H), 7.92 (s, 1H), 7.90 - 7.87 (m, 1H), 7.77
(s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 9.6
Hz, 1H), 6.98 (t, J = 9.0 Hz, 1H), 3.99 (s, 2H).

Tert-Butyl N-[(tert-butoxy) carbonyl] -N-{[6- (6-fluoro-1H-indol-3-yl) -1,3- in HCl / 1,4-dioxane (20 mL) A mixture of benzoxazol-2-yl] methyl} carbamate (Intermediate 94; 376 mg, 0.78 mmol) was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated to give 219 mg (100%) of the title compound as a yellow solid. LC-MS for C ₁₆ H ₁₃ ClFN ₃ O + H ⁺ [M + H] ⁺ : calculated 282.1; found:
281.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.51 (br s, 1H), 7.92 (s, 1H), 7.90-7.87 (m, 1H), 7.77
(s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 9.6
Hz, 1H), 6.98 (t, J = 9.0 Hz, 1H), 3.99 (s, 2H).

Compound 77: 5- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H-indazole

ＨＣｌ／１，４−ジオキサン（１０ｍＬ）中の４−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−２−イルメチル］−ピペリジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体５−２、１８９ｍｇ、０．４２ｍｍｏｌ）の混合物を、室温で１時間撹拌した。混合物を濃縮し、残留物を分取ＴＬＣ（ジクロロメタン／ＭｅＯＨ＝１０／１）により精製して、１３６ｍｇ（９３％）の表題化合物を黄色固体として得た。C₂₁H₂₁FN₄+H⁺ [M+H]⁺のLC-MS: 計算値349.2; 実測値:
348.9
¹H NMR
(400 MHz, MeOD-d₄) δ [ppm]: 11.35 (s, 1H),
8.31 (s, 1H), 7.92-7.86 (m, 2H), 7.66-7.63 (m, 2H), 7.55 (dd, J = 9.2, 1.6 Hz,
1H), 7.21 (dd, J = 9.6, 2.4 Hz, 1H), 6.95 (td, J = 9.6, 2.4 Hz, 1H), 4.28 (d, J
= 7.2 Hz, 2H), 2.91-2. 89 (m, 2H), 2.41-2.36 (m, 2H), 1.39 (d, J = 10.8 Hz,
2H), 1.12 (td, J = 12.2, 3.4 Hz, 2H).

4- [5- (6-Fluoro-1H-indol-3-yl) -indazol-2-ylmethyl] -piperidine-1-carboxylic acid tert-butyl ester (intermediate) in HCl / 1,4-dioxane (10 mL) 5-2, 189 mg, 0.42 mmol) was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by preparative TLC (dichloromethane / MeOH = 10/1) to give 136 mg (93%) of the title compound as a yellow solid. LC-MS for C ₂₁ H ₂₁ FN ₄ + H ⁺ [M + H] ⁺ : calculated 349.2; found:
348.9
¹ H NMR
(400 MHz, MeOD-d ₄ ) δ [ppm]: 11.35 (s, 1H),
8.31 (s, 1H), 7.92-7.86 (m, 2H), 7.66-7.63 (m, 2H), 7.55 (dd, J = 9.2, 1.6 Hz,
1H), 7.21 (dd, J = 9.6, 2.4 Hz, 1H), 6.95 (td, J = 9.6, 2.4 Hz, 1H), 4.28 (d, J
= 7.2 Hz, 2H), 2.91-2. 89 (m, 2H), 2.41-2.36 (m, 2H), 1.39 (d, J = 10.8 Hz,
2H), 1.12 (td, J = 12.2, 3.4 Hz, 2H).

Compound 78: 6- (6-Fluoro-1H-indol-3-yl) -2- (piperazin-1-ylmethyl) benzo [d] oxazole

６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（ピペラジン−１−イルメチル）ベンゾ［ｄ］オキサゾール（中間体９５、２７７ｍｇ、０．５６ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、８４ｍｇ（４３％）の表題化合物を白色固体として得た。C₂₀H₁₉FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値351.2; 実測値:
351.1. ¹H NMR (400 MHz, MeOD) δ [ppm]:
7.89 - 7.84 (m, 2H), 7.74 - 7.73 (m, 2H), 7.56 (s, 1H), 7.16 (dd, J = 10, 2.4
Hz, 1H), 6.94 (td, J = 9.2, 2.4 Hz, 1H), 3.96 - 3.95 (m, 2H), 2.97 (br s, 4H),
2.71 (br s, 4H)

Starting from 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperazin-1-ylmethyl) benzo [d] oxazole (Intermediate 95, 277 mg, 0.56 mmol) In accordance with the general method outlined for Compound 1, 84 mg (43%) of the title compound were obtained as a white solid. LC-MS for C ₂₀ H ₁₉ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 351.2; Found:
351.1. ¹ H NMR (400 MHz, MeOD) δ [ppm]:
7.89-7.84 (m, 2H), 7.74-7.73 (m, 2H), 7.56 (s, 1H), 7.16 (dd, J = 10, 2.4
Hz, 1H), 6.94 (td, J = 9.2, 2.4 Hz, 1H), 3.96-3.95 (m, 2H), 2.97 (br s, 4H),
2.71 (br s, 4H)

Compound 79: 3- (benzo [b] thiophen-6-yl) -6-fluoro-1H-indole

ＭｅＯＨ（２０ｍＬ）中の３−（ベンゾ［ｂ］チオフェン−６−イル）−６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール（中間体９７、３３８ｍｇ、０．８３ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、８９ｍｇ（４０％）の表題化合物を黄色固体として得た。C₁₆H₁₀FNS- H⁺ [M - H]⁺のLC-MS: 計算値266.1; 実測値:
266.0. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.47 (s, 1H), 8.29 (s, 1H), 7.97 - 7.91 (m, 2H), 7.78 (d, J
= 2.4 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.45 (d, J = 5.2 Hz, 1H), 7.24 (dd, J =
10.0, 2.0 Hz, 1H), 6.98 (td, J = 9.2, 2.4 Hz, 1H).

Starting from 3- (benzo [b] thiophen-6-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole (intermediate 97, 338 mg, 0.83 mmol) in MeOH (20 mL) Following the general procedure outlined in 1, 89 mg (40%) of the title compound was obtained as a yellow solid. LC-MS for C ₁₆ H ₁₀ FNS- H ⁺ [M-H] ⁺ : Calculated 266.1; Found:
266.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.47 (s, 1H), 8.29 (s, 1H), 7.97-7.91 (m, 2H), 7.78 (d, J
= 2.4 Hz, 1H), 7.73-7.68 (m, 2H), 7.45 (d, J = 5.2 Hz, 1H), 7.24 (dd, J =
10.0, 2.0 Hz, 1H), 6.98 (td, J = 9.2, 2.4 Hz, 1H).

Compound 80: 5- (6-Fluoro-1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) benzo [d] oxazole

ＭｅＯＨ（１ｍＬ）中の６−フルオロ−３−［２−（２−メタンスルホニル−エチル）−ベンゾオキサゾール−５−イル］−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１０１、４５ｍｇ、０．０９８ｍｍｏｌ）の溶液に、ＨＣｌ／Ｅｔ_２Ｏ（５ｍＬ、４Ｍ）を０℃で添加した。混合物を室温で１６時間撹拌した後、これを濃縮した。残留物をＭｅＯＨ（５ｍＬ）で希釈し、ＮＨ_３／ＴＨＦでｐＨ＝８に塩基性化した。混合物を濃縮し、分取ＴＬＣ（ＤＣＭ／ＭｅＯＨ＝２０／１）により精製して、６ｍｇ（１７％）の表題化合物をオフホワイトの固体として得た。C₁₈H₁₅FN₂O3S+H⁺ [M+H]⁺のLC-MS: 計算値359.1; 実測値:
359.0. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.26 (brs, 1H), 7.91 (s, 1H), 7.82 (dd, J = 8.8, 5.2 Hz,
1H), 7.61 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz,
1H), 7.14 (d, J = 9.6, 2.0 Hz, 1H), 6.97 (td, J = 8.8, 2.0 Hz, 1H), 3.70 (t, J
= 7.6 Hz, 2H), 3.54 (t, J = 7.6 Hz, 2H), 3.02 (s, 3H).

6-Fluoro-3- [2- (2-methanesulfonyl-ethyl) -benzoxazol-5-yl] -indole-1-carboxylic acid tert-butyl ester (Intermediate 101, 45 mg, 0) in MeOH (1 mL). HCl / Et ₂ O (5 mL, 4M) was added at 0 ° C. to a solution of. After the mixture was stirred at room temperature for 16 hours, it was concentrated. The residue was diluted with MeOH (5 mL) and basified to pH = 8 with NH ₃ / THF. The mixture was concentrated and purified by preparative TLC (DCM / MeOH = 20/1) to give 6 mg (17%) of the title compound as an off-white solid. LC-MS for C ₁₈ H ₁₅ FN ₂ O3S + H ⁺ [M + H] ⁺ : Calculated 359.1; Found:
359.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.26 (brs, 1H), 7.91 (s, 1H), 7.82 (dd, J = 8.8, 5.2 Hz,
1H), 7.61 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz,
1H), 7.14 (d, J = 9.6, 2.0 Hz, 1H), 6.97 (td, J = 8.8, 2.0 Hz, 1H), 3.70 (t, J
= 7.6 Hz, 2H), 3.54 (t, J = 7.6 Hz, 2H), 3.02 (s, 3H).

Compound 81: (5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine

ＭｅＯＨ（３ｍＬ）中の［５−（６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イルメチル］−カルバミン酸ｔｅｒｔ−ブチルエステル（中間体１０３、６３ｍｇ、０．１６５ｍｍｏｌ）の溶液に、ＨＣｌ／Ｅｔ_２Ｏ（３ｍＬ、８Ｍ）を０℃で添加した。混合物を室温で１時間撹拌した。混合物を蒸発乾固させて、２０ｍｇ（４３％）の表題化合物を黄色固体として得た。C₁₆H₁₂FN₃O+H⁺ [M+H]⁺のLC-MS: 計算値282.1; 実測値:
282.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.53 (br s, 1H), 8.83 (br s, 3H), 8.00 (s, 1H), 7.86 - 7.82
(m, 2H), 7.77 - 7.75 (m, 2H), 7.25 (dd, J = 10.0, 2.4 Hz, 1H), 6.98 (td, J =
8.8, 2.0 Hz, 1H), 4.54 - 4.52 (m, 2H).

A solution of [5- (6-Fluoro-1H-indol-3-yl) -benzoxazol-2-ylmethyl] -carbamic acid tert-butyl ester (Intermediate 103, 63 mg, 0.165 mmol) in MeOH (3 mL) HCl / Et ₂ O (3 mL, 8M) was added at 0 ° C. The mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to give 20 mg (43%) of the title compound as a yellow solid. LC-MS for C ₁₆ H ₁₂ FN ₃ O + H ⁺ [M + H] ⁺ : Calculated 282.1; Found:
282.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.53 (br s, 1H), 8.83 (br s, 3H), 8.00 (s, 1H), 7.86-7.82
(m, 2H), 7.77-7.75 (m, 2H), 7.25 (dd, J = 10.0, 2.4 Hz, 1H), 6.98 (td, J =
8.8, 2.0 Hz, 1H), 4.54-4.52 (m, 2H).

Compound 82: 3- (benzofuran-5-yl) -6-fluoro-1H-indole

３−（ベンゾフラン−５−イル）−６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール（中間体１０４、３００ｍｇ、０．７７ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、シリカゲルクロマトグラフィー（石油エーテル／ＥｔＯＡｃ＝５／１、ｖ／ｖ）による精製後に、４０ｍｇ（２１％）の表題化合物を黄色固体として得た。C₁₆H₁₀FNO-H^- [M-H]^-のLC-MS: 計算値250.1; 実測値:
250.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.39 (br s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.8
Hz, 1H), 7.85 (dd, J = 8.8, 5.5 Hz, 1H), 7.66 (s, 1H), 7.60 (dd, J = 8.4, 2.0
Hz, 2H), 7.23 (dd, J = 9.6, 2.4 Hz, 1H), 6.70 - 6.93 (m, 2H).

Silica gel according to the general procedure outlined for compound 1, starting from 3- (benzofuran-5-yl) -6-fluoro-1- (phenylsulfonyl) -1H-indole (intermediate 104, 300 mg, 0.77 mmol). After purification by chromatography (petroleum ether / EtOAc = 5/1, v / v), 40 mg (21%) of the title compound were obtained as a yellow solid. ^{_{C 16 H 10 FNO-H -}} [MH] - the LC-MS: calc 250.1; found:
250.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.39 (br s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.8
Hz, 1H), 7.85 (dd, J = 8.8, 5.5 Hz, 1H), 7.66 (s, 1H), 7.60 (dd, J = 8.4, 2.0
Hz, 2H), 7.23 (dd, J = 9.6, 2.4 Hz, 1H), 6.70-6.93 (m, 2H).

Compound 83: 3- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) propanamide

無水ＴＨＦ中の３−［６−（６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イル］−プロピオン酸（中間体１０８、５２ｍｇ、０．１７ｍｍｏｌ）およびＮＨ_４Ｃｌ（２７ｍｇ、０．５０ｍｍｏｌ）の混合物に、ＨＡＴＵ（１２７ｍｇ、０．３３ｍｍｏｌ）およびＴＥＡ（３４ｍｇ、０．３３ｍｍｏｌ）を０℃で添加した。混合物を窒素下室温で１．５時間撹拌した後、これを氷水（３０ｍＬ）でクエンチし、ＥｔＯＡｃ（３０ｍＬ×２）で抽出した。合わせた有機層を１Ｍ ＮａＯＨ（１０ｍＬ×２）およびブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を蒸発させ、分取ＴＬＣ（ＤＣＭ）および分取ＨＰＬＣ（添加剤としてＮＨ_３／Ｈ_２Ｏ）により精製して、１０ｍｇ（２０％）の表題化合物を白色固体として得た。C₁₈H₁₄FN₃O₂+H⁺
[M+H]⁺のLC-MS: 計算値324.1;
実測値: 324.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.48 (brs, 1H), 7.92-7.86 (m, 2H), 7.75(d, J
= 2.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 1.6 Hz, 1H), 7.47
(brs, 1H), 7.24 (dd, J = 9.6, 2.0 Hz, 1H), 6.96 (td, J = 8.4, 2.0 Hz, 1H),
6.91(brs, 1H), 3.14 (t J = 7.2 Hz, 2H), 2.68 (t J = 7.2 Hz, 2H).

3- [6- (6-Fluoro-1H-indol-3-yl) -benzoxazol-2-yl] -propionic acid (intermediate 108, 52 mg, 0.17 mmol) and NH ₄ Cl (27 mg) in anhydrous THF , 0.50 mmol) was added HATU (127 mg, 0.33 mmol) and TEA (34 mg, 0.33 mmol) at 0 ° C. After the mixture was stirred at room temperature under nitrogen for 1.5 hours, it was quenched with ice water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with 1M NaOH (10 mL × 2) and brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was evaporated and purified by preparative TLC (DCM) and preparative HPLC (NH ₃ / H ₂ O as additive) to give 10 mg (20%) of the title compound as a white solid. C ₁₈ H ₁₄ FN ₃ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 324.1;
Found: 324.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.48 (brs, 1H), 7.92-7.86 (m, 2H), 7.75 (d, J
= 2.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 1.6 Hz, 1H), 7.47
(brs, 1H), 7.24 (dd, J = 9.6, 2.0 Hz, 1H), 6.96 (td, J = 8.4, 2.0 Hz, 1H),
6.91 (brs, 1H), 3.14 (t J = 7.2 Hz, 2H), 2.68 (t J = 7.2 Hz, 2H).

Compound 84: 2- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide

２−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−イル）アセトアミド（中間体１０９Ａ、１００ｍｇ、０．２２ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、分取ＴＬＣ（ＤＣＭ／ＭｅＯＨ＝１０／１、ｖ／ｖ）による精製後に、１４ｍｇ（２１％）の表題化合物を白色固体として得た。C₁₇H₁₃FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値309.1; 実測値:
309.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.48 (br s, 1H), 8.14 (s, 1H), 7.88 (dd, J = 8.8, 5.5 Hz,
1H), 7.87 (br s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.65
(d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.37 (br s, 1H), 7.23 (dd,
J = 9.9, 2.4 Hz, 1H), 6.95 (m, 1H), 4.98 (s, 2H).

2- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide (Intermediate 109A, 100 mg, 0.22 mmol) After purification by preparative TLC (DCM / MeOH = 10/1, v / v) according to the general method outlined in compound 1, 14 mg (21%) of the title compound were obtained as a white solid. LC-MS for C ₁₇ H ₁₃ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
309.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.48 (br s, 1H), 8.14 (s, 1H), 7.88 (dd, J = 8.8, 5.5 Hz,
1H), 7.87 (br s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.65
(d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.37 (br s, 1H), 7.23 (dd,
J = 9.9, 2.4 Hz, 1H), 6.95 (m, 1H), 4.98 (s, 2H).

Compound 85: 2- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide

２−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−イル）アセトアミド（中間体１０９Ｂ、６０ｍｇ、０．１３ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、１３ｍｇ（３１％）の表題化合物を白色固体として得た。C₁₇H₁₃FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値309.1; 実測値:
309.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.35 (br s, 1H), 8.16 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H),
7.84 (dd, J = 8.8, 5.5 Hz, 1H), 7.76 (br s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.56
(dd, J = 8.4, 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.37 (br s, 1H), 7.22 (dd,
J = 10.0, 2.4 Hz, 1H), 6.95 (m, 1H), 4.93 (s, 2H).

2- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide (Intermediate 109B, 60 mg, 0.13 mmol) Starting from, 13 mg (31%) of the title compound was obtained as a white solid after purification by preparative HPLC according to the general procedure outlined for compound 1. LC-MS for C ₁₇ H ₁₃ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 309.1; Found:
309.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.35 (br s, 1H), 8.16 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H),
7.84 (dd, J = 8.8, 5.5 Hz, 1H), 7.76 (br s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.56
(dd, J = 8.4, 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.37 (br s, 1H), 7.22 (dd,
J = 10.0, 2.4 Hz, 1H), 6.95 (m, 1H), 4.93 (s, 2H).

Compound 86: 3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -1-morpholinopropan-1-one

５ｍＬのＤＭＦ中の３−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオン酸（中間体１１１、１８０ｍｇ、粗製、０．５６ｍｍｏｌ）、モルホリン（４８ｍｇ、０．５６ｍｍｏｌ）、ＨＡＴＵ（３１９ｍｇ、０．８４ｍｍｏｌ）およびＤＩＥＡ（２１７ｍｇ、１．６８ｍｍｏｌ）の混合物を、室温で２時間撹拌した。次いで、混合物を水に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を分取ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ＝３０％〜７５％、ＮＨ_４ＨＣＯ_３）により精製して、１０ｍｇ（５％）の表題化合物を白色固体として得た。C₂₂H₂₁FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値393.1;
実測値: 393.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.37 (br s, 1H), 8.08 (br s, 1H), 7.98 (br s,
1H), 7.86 (dd, J = 8.8, 5.6 Hz, 1H), 7.74 - 7.67 (m, 3H), 7.22 (dd, J = 9.6,
2.4 Hz, 1H), 6.96 (td, J = 9.4, 2.4 Hz, 1H), 4.65 (t, J = 6.8 Hz, 2H), 3.47 -
3.38 (m, 6H), 3.34 - 3.30 (m, 2H), 2.96 (t, J = 6.8 Hz, 2H).

3- [5- (6-Fluoro-1H-indol-3-yl) -indazol-1-yl] -propionic acid (intermediate 111, 180 mg, crude, 0.56 mmol), morpholine (48 mg) in 5 mL DMF. , 0.56 mmol), HATU (319 mg, 0.84 mmol) and DIEA (217 mg, 1.68 mmol) were stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O = 30% -75%, NH ₄ HCO ₃ ) to give 10 mg (5%) of the title compound as a white solid. C ₂₂ H ₂₁ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 393.1;
Found: 393.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.37 (br s, 1H), 8.08 (br s, 1H), 7.98 (br s,
1H), 7.86 (dd, J = 8.8, 5.6 Hz, 1H), 7.74-7.67 (m, 3H), 7.22 (dd, J = 9.6,
2.4 Hz, 1H), 6.96 (td, J = 9.4, 2.4 Hz, 1H), 4.65 (t, J = 6.8 Hz, 2H), 3.47-
3.38 (m, 6H), 3.34-3.30 (m, 2H), 2.96 (t, J = 6.8 Hz, 2H).

Compound 87: 3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -1- (4-methylpiperazin-1-yl) propan-1-one

５ｍＬのＤＭＦ中の３−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオン酸（中間体１１１、３００ｍｇ、粗製、０．９３ｍｍｏｌ）、１−メチル−ピペラジン（９３ｍｇ、０．９３ｍｍｏｌ）、ＨＡＴＵ（５３０ｍｇ、１．４ｍｍｏｌ）およびＤＩＥＡ（３６０ｍｇ、２．８ｍｍｏｌ）の混合物を、室温で２時間撹拌した。次いで、混合物を水に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を分取ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ＝３０％〜７５％、ＮＨ_４ＨＣＯ_３）により精製して、７６ｍｇ（２０％）の表題化合物を白色固体として得た。C₂₃H₂₄FN₅O+H⁺ [M+H]⁺のLC-MS: 計算値406.2; 実測値:
406.2. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.36 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.88 - 7.84 (m,
1H), 7.73 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (td, J = 8.8,
2.4 Hz, 1H), 4.64 (t, J = 6.8 Hz, 2H), 3.40-3.38 (m, 2H), 3.32 - 3.29 (m, 2H),
2.94 (t, J = 6.8 Hz, 2H), 2.14 - 2.09 (m, 7H).

3- [5- (6-Fluoro-1H-indol-3-yl) -indazol-1-yl] -propionic acid (intermediate 111, 300 mg, crude, 0.93 mmol), 1-methyl in 5 mL DMF A mixture of piperazine (93 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) was stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative _{HPLC (CH 3 CN / H 2} O = 30% ~75%, NH 4 HCO 3) to give the title compound 76 mg (20%) as a white solid. LC-MS for C ₂₃ H ₂₄ FN ₅ O + H ⁺ [M + H] ⁺ : Calculated 406.2; Found:
406.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.36 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.88-7.84 (m,
1H), 7.73-7.66 (m, 3H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (td, J = 8.8,
2.4 Hz, 1H), 4.64 (t, J = 6.8 Hz, 2H), 3.40-3.38 (m, 2H), 3.32-3.29 (m, 2H),
2.94 (t, J = 6.8 Hz, 2H), 2.14-2.09 (m, 7H).

Compound 88: N- (2- (dimethylamino) ethyl) -3- (5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanamide

５ｍＬのＤＭＦ中の３−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオン酸（中間体１１１、３００ｍｇ、粗製、０．９３ｍｍｏｌ）、（２−アミノエチル）ジメチルアミン（８２ｍｇ、０．９３ｍｍｏｌ）、ＨＡＴＵ（５３０ｍｇ、１．４ｍｍｏｌ）およびＤＩＥＡ（３６０ｍｇ、２．８ｍｍｏｌ）の混合物を、室温で２時間撹拌した。次いで、混合物を水に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を分取ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ＝３０％〜７５％、ＮＨ_４ＨＣＯ_３）により精製して、６０ｍｇ（１６％）の表題化合物を白色固体として得た。C₂₂H₂₄FN₅O+H⁺ [M+H]⁺のLC-MS: 計算値394.2; 実測値:
394.2. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.37 (br s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.88 - 7.84
(m, 2H), 7.72 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 1.6 Hz, 1H), 6.96 (t, J = 5.2
Hz, 1H), 4.62 (t, J = 6.4 Hz, 2H), 3.06 (q, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4
Hz, 2H), 2.11 (t, J = 6.4 Hz, 2H), 2.04 (s, 6H).

3- [5- (6-Fluoro-1H-indol-3-yl) -indazol-1-yl] -propionic acid (intermediate 111, 300 mg, crude, 0.93 mmol) in 5 mL of DMF, (2- A mixture of aminoethyl) dimethylamine (82 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) was stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative _{HPLC (CH 3 CN / H 2} O = 30% ~75%, NH 4 HCO 3) to give the title compound 60 mg (16%) as a white solid. LC-MS for C ₂₂ H ₂₄ FN ₅ O + H ⁺ [M + H] ⁺ : Calculated 394.2; Found:
394.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.37 (br s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.88-7.84
(m, 2H), 7.72-7.66 (m, 3H), 7.22 (dd, J = 10.0, 1.6 Hz, 1H), 6.96 (t, J = 5.2
Hz, 1H), 4.62 (t, J = 6.4 Hz, 2H), 3.06 (q, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4
Hz, 2H), 2.11 (t, J = 6.4 Hz, 2H), 2.04 (s, 6H).

Compound 89: 3- (5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -N- (2-hydroxyethyl) propanamide

５ｍＬのＤＭＦ中の３−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオン酸（中間体１１１、３００ｍｇ、粗製、０．９３ｍｍｏｌ）、２−アミノ−エタノール（５７ｍｇ、０．９３ｍｍｏｌ）、ＨＡＴＵ（５３０ｍｇ、１．４ｍｍｏｌ）およびＤＩＥＡ（３６０ｍｇ、２．８ｍｍｏｌ）の混合物を、室温で２時間撹拌した。次いで、混合物を水に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を分取ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ＝３０％〜７５％、ＮＨ_４ＨＣＯ_３）により精製して、５３ｍｇ（１６％）の表題化合物を白色固体として得た。C₂₀H₁₉FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値367.2;
実測値: 367.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.37 (br s, 1H), 8.07 (br s, 1H), 7.98 - 7.94
(m, 2H), 7.88 - 7.85 (m, 1H), 7.70 - 7.67 (m, 3H), 7.22 (d, J = 10.0 Hz, 1H),
6.96 (t, J = 9.2 Hz, 1H), 4.63 - 4.61 (m, 3H), 3.36 - 3.30 (m, 2H), 3.08 - 3.07
(m, 2H), 2.71 (t, J = 6.0 Hz, 2H).

3- [5- (6-Fluoro-1H-indol-3-yl) -indazol-1-yl] -propionic acid (intermediate 111, 300 mg, crude, 0.93 mmol), 2-amino in 5 mL DMF A mixture of ethanol (57 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) was stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O = 30% -75%, NH ₄ HCO ₃ ) to give 53 mg (16%) of the title compound as a white solid. C ₂₀ H ₁₉ FN ₄ O ₂ + H ⁺
LC-MS for [M + H] ⁺ : calculated 367.2;
Found: 367.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.37 (br s, 1H), 8.07 (br s, 1H), 7.98-7.94
(m, 2H), 7.88-7.85 (m, 1H), 7.70-7.67 (m, 3H), 7.22 (d, J = 10.0 Hz, 1H),
6.96 (t, J = 9.2 Hz, 1H), 4.63-4.61 (m, 3H), 3.36-3.30 (m, 2H), 3.08-3.07
(m, 2H), 2.71 (t, J = 6.0 Hz, 2H).

Compound 90: 3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -N- (2- (methylsulfonyl) ethyl) propanamide

５ｍＬのＤＭＦ中の３−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオン酸（中間体１１１、３００ｍｇ、粗製、０．９３ｍｍｏｌ）、２−メタンスルホニル−エチルアミンＨＣｌ塩（１４８ｍｇ、０．９３ｍｍｏｌ）、ＨＡＴＵ（５３０ｍｇ、１．４ｍｍｏｌ）およびＤＩＥＡ（３６０ｍｇ、２．８ｍｍｏｌ）の混合物を、室温で２時間撹拌した。次いで、混合物を水に注ぎ入れ、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残留物を分取ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ＝３０％〜７５％、ＮＨ_４ＨＣＯ_３）により精製して、６４ｍｇ（１６％）の表題化合物を白色固体として得た。C₂₁H₂₁FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値429.1;
実測値: 429.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.37 (br s, 1H), 8.25 (t, J = 5.6 Hz, 1H),
8.07 (s, 1H), 7.98 (s, 1H), 7.89 - 7.85 (m, 1H), 7.70 (s, 2H), 7.67 (s, 1H),
7.22 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 9.2, 2.0 Hz, 1H), 4.63 (t, J =
6.8 Hz, 2H), 3.40 (q, J = 6.4 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H), 2.89 (s, 3H),
2.72 (t, J = 6.8 Hz, 2H).

3- [5- (6-Fluoro-1H-indol-3-yl) -indazol-1-yl] -propionic acid (intermediate 111, 300 mg, crude, 0.93 mmol), 2-methane in 5 mL DMF A mixture of sulfonyl-ethylamine HCl salt (148 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) was stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative _{HPLC (CH 3 CN / H 2} O = 30% ~75%, NH 4 HCO 3) to give the title compound 64 mg (16%) as a white solid. C ₂₁ H ₂₁ FN ₄ O ₃ S + H ⁺
LC-MS for [M + H] ⁺ : calc'd 429.1;
Found: 429.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.37 (br s, 1H), 8.25 (t, J = 5.6 Hz, 1H),
8.07 (s, 1H), 7.98 (s, 1H), 7.89-7.85 (m, 1H), 7.70 (s, 2H), 7.67 (s, 1H),
7.22 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 9.2, 2.0 Hz, 1H), 4.63 (t, J =
6.8 Hz, 2H), 3.40 (q, J = 6.4 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H), 2.89 (s, 3H),
2.72 (t, J = 6.8 Hz, 2H).

Compound 91: 3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -1- (piperazin-1-yl) propan-1-one

ＨＣｌ／ＥｔＯＡｃ（２５％、１０ｍＬ）中の４−｛３−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−インダゾール−１−イル］−プロピオニル｝−ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１１２、９８ｍｇ、０．２ｍｍｏｌ）の溶液を、室温で２時間撹拌した。次いで、混合物を濃縮した。残留物を分取ＨＰＬＣ（ＣＨ_３ＣＮ／Ｈ_２Ｏ＝３０％〜７５％、ＮＨ_４ＨＣＯ_３）により精製して、３４ｍｇ（４３％）の表題化合物を白色固体として得た。C₂₂H₂₂FN₅O+H⁺ [M+H]⁺のLC-MS: 計算値392.2; 実測値:
392.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.37 (br s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.88 - 7.85
(m, 1H), 7.74 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (td, J =
9.2, 2.4 Hz, 1H), 4.63 (t, J = 6.8 Hz, 2H), 3.32 - 3.30 (m, 2H), 3.25 - 3.23
(m, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.55 - 2.47 (m, 4H).

4- {3- [5- (6-Fluoro-1H-indol-3-yl) -indazol-1-yl] -propionyl} -piperazine-1-carboxylic acid tert in HCl / EtOAc (25%, 10 mL) A solution of butyl ester (Intermediate 112, 98 mg, 0.2 mmol) was stirred at room temperature for 2 hours. The mixture was then concentrated. The residue was purified by preparative HPLC (CH ₃ CN / H ₂ O = 30% -75%, NH ₄ HCO ₃ ) to give 34 mg (43%) of the title compound as a white solid. LC-MS for C ₂₂ H ₂₂ FN ₅ O + H ⁺ [M + H] ⁺ : Calculated 392.2; Found:
392.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.37 (br s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.88-7.85
(m, 1H), 7.74-7.66 (m, 3H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (td, J =
9.2, 2.4 Hz, 1H), 4.63 (t, J = 6.8 Hz, 2H), 3.32-3.30 (m, 2H), 3.25-3.23
(m, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.55-2.47 (m, 4H).

Compound 92: 6- (6-Fluoro-1H-indol-3-yl) indoline-2-one

ＴＨＦ（２ｍＬ）およびＭｅＯＨ（８ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）インドリン−２−オン（中間体１１３、４００ｍｇ、０．９８ｍｍｏｌ）、Ｍｇ削り屑（２００ｍｇ、８．２ｍｍｏｌ）およびＮＨ_４Ｃｌ（１０６ｍｇ、２．０ｍｍｏｌ）の混合物を、室温で２時間撹拌した。反応混合物をセライトに通して濾過し、濃縮し、分取ＴＬＣ（石油エーテル／ＥｔＯＡｃ＝３／１）により精製して、２６ｍｇ（１０％）の表題化合物を黄色固体として得た。C₁₆H₁₁FN₂O-H^- [M-H]^-のLC-MS: 計算値265.1; 実測値:
265.1. ¹H NMR (400 MHz, MeOH-d₄) δ [ppm]: 7.68 (dd, J = 8.8, 5.2 Hz, 1H), 7.33 (s, 1H), 7.18 (s, 1H),
7.07 (s, 2H), 7.01 (dd, J = 9.8, 2.2 Hz, 1H), 6.77 (td, J = 9.1, 2.4 Hz, 1H),
3.45 (s, 2H).

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) indoline-2-one (Intermediate 113, 400 mg, 0.98 mmol) in THF (2 mL) and MeOH (8 mL), A mixture of Mg shavings (200 mg, 8.2 mmol) and NH ₄ Cl (106 mg, 2.0 mmol) was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, concentrated and purified by preparative TLC (petroleum ether / EtOAc = 3/1) to give 26 mg (10%) of the title compound as a yellow solid. ^{_{C 16 H 11 FN 2 OH -}} [MH] - the LC-MS: calc 265.1; found:
265.1. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ [ppm]: 7.68 (dd, J = 8.8, 5.2 Hz, 1H), 7.33 (s, 1H), 7.18 (s, 1H),
7.07 (s, 2H), 7.01 (dd, J = 9.8, 2.2 Hz, 1H), 6.77 (td, J = 9.1, 2.4 Hz, 1H),
3.45 (s, 2H).

Compound 93: 3- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide

３−（６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−イル）プロパンアミド（中間体１１４Ａ、１４０ｍｇ、０．３０ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、３０ｍｇ（３１％）の表題化合物を白色固体として得た。C₁₈H₁₅FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値323.1; 実測値:
323.2. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.51 (br s, 1H), 8.13 (s, 1H), 7.96 (dd, J = 8.8, 5.6 Hz,
1H), 7.85 (s, 1H), 7.69 -7.67(m, 2H). 7.51 (d, J = 8.0 Hz, 1H), 7.47 (br s,
1H), 7.24 (dd, J = 9.8, 2.2 Hz, 1H), 6.97 (td, J = 9.2, 2.0 Hz, 2H), 4.52 (t, J
= 6.4 Hz, 2H), 2.68 (t, J = 6.6 Hz, 2H).

3- (6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide (Intermediate 114A, 140 mg, 0.30 mmol ) And after purification by preparative HPLC, 30 mg (31%) of the title compound was obtained as a white solid following the general procedure outlined for compound 1. LC-MS for C ₁₈ H ₁₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 323.1; Found:
323.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.51 (br s, 1H), 8.13 (s, 1H), 7.96 (dd, J = 8.8, 5.6 Hz,
1H), 7.85 (s, 1H), 7.69 -7.67 (m, 2H) .7.51 (d, J = 8.0 Hz, 1H), 7.47 (br s,
1H), 7.24 (dd, J = 9.8, 2.2 Hz, 1H), 6.97 (td, J = 9.2, 2.0 Hz, 2H), 4.52 (t, J
= 6.4 Hz, 2H), 2.68 (t, J = 6.6 Hz, 2H).

Compound 94: 3- (5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide

３−（５−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−ベンゾ［ｄ］イミダゾール−１−イル）プロパンアミド（中間体１１４Ｂ、１８０ｍｇ、０．３９ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、５１ｍｇ（４１％）の表題化合物を白色固体として得た。C₁₈H₁₅FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値323.1; 実測値:
323.2. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.37 (br s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.84 (dd, J =
8.4, 5.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.57 (d,
J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.95 (m, 2H),
4.48 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H).

3- (5- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide (Intermediate 114B, 180 mg, 0.39 mmol) ) And after purification by preparative HPLC, 51 mg (41%) of the title compound was obtained as a white solid following the general procedure outlined for compound 1. LC-MS for C ₁₈ H ₁₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 323.1; Found:
323.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.37 (br s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.84 (dd, J =
8.4, 5.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.57 (d,
J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.95 (m, 2H),
4.48 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H).

Compound 95: 1- (4- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidin-1-yl) ethanone

室温のＤＣＭ（１０ｍＬ）中の６−（６−フルオロ−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イル）ベンゾ［ｄ］オキサゾール（化合物５５、２００ｍｇ、０．６０ｍｍｏｌ）およびＴＥＡ（１８２ｍｇ、１．８０ｍｍｏ）の撹拌溶液に、塩化アセチル（５７ｍｇ、０．７２ｍｍｏｌ）を滴下添加した。混合物を室温で終夜撹拌した。混合物をＤＣＭ（１０ｍＬ）で希釈し、水（２０ｍＬ×２）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、１２１ｍｇ（５４％）の表題化合物を黄色固体として得た。C₂₂H₂₀FN₃O₂+H⁺:
[M+H]⁺のLC-MS: 計算値378.2;実測値: 378.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.48 (s, 1H), 7.92 (s, 1H), 7.89 (dd, J = 5.6, 8.8 Hz, 1H),
7.75 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.66 (dd, J = 1.6, 8.0 Hz,
1H), 7.23 (dd, J = 2.4, 10.0 Hz, 1H), 6.97 (td, J = 2.4, 9.6 Hz, 1H), 4.32 (d,
J = 13.6 Hz, 1H), 3.87 (d, J = 13.6 Hz, 1H), 3.35 - 3.27 (m, 2H), 2.88 (t, J =
11.2 Hz, 1H), 2.13 (t, J = 14.0 Hz, 2H), 2.04 (s, 3H), 1.88-1.77 (m, 1H), 1.72
- 1.62 (m, 1H).

6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole (Compound 55, 200 mg, 0.60 mmol) and TEA in DCM (10 mL) at room temperature To a stirred solution of (182 mg, 1.80 mmol), acetyl chloride (57 mg, 0.72 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (10 mL), washed with water (20 mL × 2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 121 mg (54%) of the title compound as a yellow solid. C ₂₂ H ₂₀ FN ₃ O ₂ + H ⁺ :
LC-MS of [M + H] ⁺ : Calculated 378.2; Found: 378.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.48 (s, 1H), 7.92 (s, 1H) , 7.89 (dd, J = 5.6, 8.8 Hz, 1H),
7.75 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.66 (dd, J = 1.6, 8.0 Hz,
1H), 7.23 (dd, J = 2.4, 10.0 Hz, 1H), 6.97 (td, J = 2.4, 9.6 Hz, 1H), 4.32 (d,
J = 13.6 Hz, 1H), 3.87 (d, J = 13.6 Hz, 1H), 3.35-3.27 (m, 2H), 2.88 (t, J =
11.2 Hz, 1H), 2.13 (t, J = 14.0 Hz, 2H), 2.04 (s, 3H), 1.88-1.77 (m, 1H), 1.72
-1.62 (m, 1H).

Compound 96: 6- (6-Fluoro-1H-indol-3-yl) -2- (1- (methylsulfonyl) piperidin-4-yl) benzo [d] oxazole

ＤＣＭ（１０ｍＬ）中の６−（６−フルオロ−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イル）ベンゾ［ｄ］オキサゾール（化合物５５、２００ｍｇ、０．６０ｍｍｏｌ）およびＴＥＡ（１８２ｍｇ、１．８０ｍｍｏ）の溶液を、室温で１０分間撹拌した後、これを０℃に冷却した。次いで、メタンスルホニルクロリド（８２ｍｇ、０．７２ｍｍｏｌ）を滴下添加した。反応物を室温で１時間撹拌した。混合物をＤＣＭ（１０ｍＬ）で希釈し、水（２０ｍＬ×２）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。残留物を分取ＨＰＬＣにより精製して、１５９ｍｇ（６４％）の表題化合物を桃色固体として得た。C₂₁H₂₀FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値414.12;
実測値: 414.10. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.48 (s, 1H), 7.93 (s, 1H), 7.88 (dd, J =
5.6, 8.8 Hz, 1H), 7.75 (s, 1H), 7.74 (d, J = 11.2 Hz, 2H), 7.66 (dd, J = 1.6,
8.0 Hz, 1H), 7.24 (dd, J = 2.4, 10.0 Hz, 1H), 6.97 (td, J = 2.4, 10.0 Hz, 1H),
3.62 - 3.58 (m, 2H), 3.26-3.19 (m, 1H), 3.00 (td, J = 2.4, 12.0 Hz, 2H), 2.91 (s,
3H), 2.24 (dd, J = 13.6, 3.6 Hz, 2H), 1.93 - 1.89 (m, 2H).

6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole (Compound 55, 200 mg, 0.60 mmol) and TEA (182 mg) in DCM (10 mL). , 1.80 mmol) was stirred at room temperature for 10 minutes and then cooled to 0 ° C. Methanesulfonyl chloride (82 mg, 0.72 mmol) was then added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was diluted with DCM (10 mL), washed with water (20 mL × 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give 159 mg (64%) of the title compound as a pink solid. C ₂₁ H ₂₀ FN ₃ O ₃ S + H ⁺
LC-MS for [M + H] ⁺ : calculated 414.12;
Found: 414.10. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.48 (s, 1H), 7.93 (s, 1H), 7.88 (dd, J =
5.6, 8.8 Hz, 1H), 7.75 (s, 1H), 7.74 (d, J = 11.2 Hz, 2H), 7.66 (dd, J = 1.6,
8.0 Hz, 1H), 7.24 (dd, J = 2.4, 10.0 Hz, 1H), 6.97 (td, J = 2.4, 10.0 Hz, 1H),
3.62-3.58 (m, 2H), 3.26-3.19 (m, 1H), 3.00 (td, J = 2.4, 12.0 Hz, 2H), 2.91 (s,
3H), 2.24 (dd, J = 13.6, 3.6 Hz, 2H), 1.93-1.89 (m, 2H).

Compound 97: 5- (6-fluoro-1H-indol-3-yl) indoline-2-one

ＭｅＯＨ中の１−ベンゼンスルホニル−６−フルオロ−１’，３’−ジヒドロ−１Ｈ−［３，５’］ビインドリル−２’−オン（中間体１１６、３００ｍｇ、０．７４ｍｍｏｌ）、Ｍｇ（１７８ｍｇ、７．４ｍｍｏｌ）およびＮＨ_４Ｃｌ（１２ｍｇ、０．２２ｍｍｏｌ）の混合物を、窒素下室温で約５時間撹拌した。撹拌が終わった後、混合物をセライトのパッドに通して濾過し、濃縮した。残留物を分取ＴＬＣ（ＤＣＭ／メタノール＝２０／１）により精製して、表題化合物（６０ｍｇ、３０％）を黄色固体として得た。C₁₆H₁₁FN₂O-H^- [M-H]^-のLC-MS: 計算値265.1; 実測値:
265.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.31 (s, 1H), 10.38 (s, 1H), 7.78 (dd, J = 8.8, 5.6 Hz,
1H), 7.56 (d, J = 2.4 Hz, 1H), 7.50 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.19
(dd, J = 10.0, 2.3 Hz, 1H), 6.93 (td, J = 9.5, 2.4 Hz, 1H), 6.88 (d, J = 8.0
Hz, 1H), 3.53 (s, 2H).

1-benzenesulfonyl-6-fluoro-1 ′, 3′-dihydro-1H- [3,5 ′] biindolyl-2′-one (Intermediate 116, 300 mg, 0.74 mmol), Mg (178 mg, in MeOH) 7.4 mmol) and NH ₄ Cl (12 mg, 0.22 mmol) were stirred at room temperature under nitrogen for about 5 hours. After stirring was complete, the mixture was filtered through a pad of celite and concentrated. The residue was purified by preparative TLC (DCM / methanol = 20/1) to give the title compound (60 mg, 30%) as a yellow solid. ^{_{C 16 H 11 FN 2 OH -}} [MH] - the LC-MS: calc 265.1; found:
265.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.31 (s, 1H), 10.38 (s, 1H), 7.78 (dd, J = 8.8, 5.6 Hz,
1H), 7.56 (d, J = 2.4 Hz, 1H), 7.50 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.19
(dd, J = 10.0, 2.3 Hz, 1H), 6.93 (td, J = 9.5, 2.4 Hz, 1H), 6.88 (d, J = 8.0
Hz, 1H), 3.53 (s, 2H).

Compound 98: 6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-amine

ＭｅＯＨ中の６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イルアミン（中間体１１８、３００ｍｇ、０．７４ｍｍｏｌ）、Ｍｇ（１７８ｍｇ、７．４ｍｍｏｌ）およびＮＨ_４Ｃｌ（１２ｍｇ、０．２２ｍｍｏｌ）の混合物を、窒素下室温で約５時間撹拌した。撹拌が終わった後、混合物をセライトのパッドに通して濾過し、濃縮した。残留物を分取ＴＬＣ（ＤＣＭ／メタノール＝２０／１）により精製して、表題化合物（４０ｍｇ、２５％）を黄色固体として得た。C₁₅H₁₀FN₃O+H⁺ [M+H]⁺のLC-MS: 計算値268.1; 実測値:
268.0. ¹H NMR (400 MHz, DMSO) δ 11.33
(s, 1H), 7.82 (dd, J = 8.8, 5.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.56 (d, J =
1.2 Hz, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.36 (s, 2H), 7.24 (d, J = 8.1 Hz,
1H), 7.20 (dd, J = 10.0, 2.4 Hz, 1H), 6.93 (td, J = 9.6, 2.4 Hz, 1H).

6- (1-Benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazol-2-ylamine (Intermediate 118, 300 mg, 0.74 mmol), Mg (178 mg, 7.4 mmol) in MeOH And a mixture of NH ₄ Cl (12 mg, 0.22 mmol) was stirred at room temperature under nitrogen for about 5 hours. After stirring was complete, the mixture was filtered through a pad of celite and concentrated. The residue was purified by preparative TLC (DCM / methanol = 20/1) to give the title compound (40 mg, 25%) as a yellow solid. LC-MS for C ₁₅ H ₁₀ FN ₃ O + H ⁺ [M + H] ⁺ : Calculated 268.1; Found:
268.0. ¹ H NMR (400 MHz, DMSO) δ 11.33
(s, 1H), 7.82 (dd, J = 8.8, 5.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.56 (d, J =
1.2 Hz, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.36 (s, 2H), 7.24 (d, J = 8.1 Hz,
1H), 7.20 (dd, J = 10.0, 2.4 Hz, 1H), 6.93 (td, J = 9.6, 2.4 Hz, 1H).

Compound 99: N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2-methoxyethanesulfonamide

ＤＣＭ（３０ｍＬ）中の（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メタンアミン塩酸塩（化合物７６、１９６ｍｇ、０．６２ｍｍｏｌ）およびＴＥＡ（０．２５ｍＬ、１．８６ｍｍｏｌ）の撹拌溶液に、２−メトキシエタンスルホニルクロリド（１２８ｍｇ、０．８ｍｍｏｌ）を窒素下０℃で添加した。混合物を０℃で１時間撹拌した後、これをＤＣＭ（２０ｍＬ）で希釈した。有機層を水（５０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、１５ｍｇ（５％）の表題化合物を黄色固体として得た。C₁₉H₁₈FN₃O₄S+H⁺
[M+H]⁺のLC-MS: 計算値404.1;
実測値: 403.8. ¹H NMR (400 MHz, MeOD ) δ [ppm]: 7.77 - 7.71 (m, 2H), 7.63 - 7.58 (m, 2H), 7.43 (s, 1H), 7.04
(dd, J = 10.0, 2.4 Hz, 1H), 6.82 (td, J = 9.2, 2.4 Hz, 1H), 4.49 (s, 2H), 3.68
(t, J = 6.0 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 3.22 (s, 3H).

(6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine hydrochloride (Compound 76, 196 mg, 0.62 mmol) and TEA (0. To a stirred solution of 25 mL, 1.86 mmol) was added 2-methoxyethanesulfonyl chloride (128 mg, 0.8 mmol) at 0 ° C. under nitrogen. After the mixture was stirred at 0 ° C. for 1 h, it was diluted with DCM (20 mL). The organic layer was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 15 mg (5%) of the title compound as a yellow solid. C ₁₉ H ₁₈ FN ₃ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: calcd 404.1;
Found: 403.8. ¹ H NMR (400 MHz, MeOD) δ [ppm]: 7.77-7.71 (m, 2H), 7.63-7.58 (m, 2H), 7.43 (s, 1H), 7.04
(dd, J = 10.0, 2.4 Hz, 1H), 6.82 (td, J = 9.2, 2.4 Hz, 1H), 4.49 (s, 2H), 3.68
(t, J = 6.0 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 3.22 (s, 3H).

Compound 100: 2- (dimethylamino) -N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) ethanesulfonamide

ＭｅＣＮ（１０ｍＬ）中のＮ−（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）エテンスルホンアミド（中間体１１９、１４７ｍｇ、０．３９６ｍｍｏｌ）の撹拌溶液に、ＴＨＦ中ジメチルアミン（０．９９ｍＬ、２Ｍ）を添加した。混合物を室温で０．５時間撹拌した後、これをＨＣｌ（１２Ｍ）で中和した。混合物を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、２０ｍｇ（１２％）の表題化合物を黄色固体として得た。C₂₀H₂₁FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値417.1;
実測値: 417.5. ¹H NMR (400 MHz, CDCl₃
) δ [ppm]: 8.33 (s, 1H), 7.82 (dd, J = 8.8, 5.2 Hz,
1H), 7.76 (d, J = 0.9 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.2, 1.4
Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 9.4, 2.2 Hz, 1H), 6.99 (td, J
= 9.2, 2.3 Hz, 1H), 4.67 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.86 (t, J = 6.3
Hz, 2H), 2.27 (s, 6H).

N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) ethenesulfonamide (Intermediate 119, 147 mg, 0.396 mmol in MeCN (10 mL) ) Was added to the stirred solution of dimethylamine in THF (0.99 mL, 2M). After the mixture was stirred at room temperature for 0.5 h, it was neutralized with HCl (12M). The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 20 mg (12%) of the title compound as a yellow solid. C ₂₀ H ₂₁ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calc'd 417.1;
Found: 417.5. ¹ H NMR (400 MHz, CDCl ₃
) δ [ppm]: 8.33 (s, 1H), 7.82 (dd, J = 8.8, 5.2 Hz,
1H), 7.76 (d, J = 0.9 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.2, 1.4
Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 9.4, 2.2 Hz, 1H), 6.99 (td, J
= 9.2, 2.3 Hz, 1H), 4.67 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.86 (t, J = 6.3
Hz, 2H), 2.27 (s, 6H).

Compound 101: 6- (6-Fluoro-1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) benzo [d] oxazole

ＨＣｌ／ＥｔＯＡｃ（５ｍＬ、２Ｍ）中の６−フルオロ−３−［２−（２−メタンスルホニル−エチル）−ベンゾオキサゾール−６−イル］−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１２３、３９０ｍｇ、０．８５２ｍｍｏｌ）の混合物を、室温で３時間撹拌した。混合物をＥｔＯＡｃ（５０ｍＬ）で希釈し、ＮａＨＣＯ_３水溶液（２０ｍＬ）およびブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を蒸発させ、分取ＨＰＬＣにより精製して、１３２ｍｇ（４３％）の表題化合物を白色固体として得た。C₁₈H₁₅FN₂O₃S+H⁺
[M+H]⁺のLC-MS: 計算値359.1;
実測値: 359.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.49 (br s, 1H), 7.93 (d, J = 1.2 Hz, 1H),
7.88 (dd, J = 8.8, 1.6 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.0 Hz,
1H), 7.68 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (dd, J = 9.6, 2.4 Hz, 1H), 6.97 (td,
J = 9.6, 2.4 Hz, 1H), 3.73 (t, J = 7.6 Hz, 2H), 3.44 (t, J = 7.8 Hz, 2H), 3.11
(s, 3H).

6-Fluoro-3- [2- (2-methanesulfonyl-ethyl) -benzoxazol-6-yl] -indole-1-carboxylic acid tert-butyl ester (Intermediate 123) in HCl / EtOAc (5 mL, 2M) 390 mg, 0.852 mmol) was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (50 mL), washed with aqueous NaHCO ₃ (20 mL) and brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was evaporated and purified by preparative HPLC to give 132 mg (43%) of the title compound as a white solid. C ₁₈ H ₁₅ FN ₂ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 359.1;
Found: 359.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.49 (br s, 1H), 7.93 (d, J = 1.2 Hz, 1H),
7.88 (dd, J = 8.8, 1.6 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.0 Hz,
1H), 7.68 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (dd, J = 9.6, 2.4 Hz, 1H), 6.97 (td,
J = 9.6, 2.4 Hz, 1H), 3.73 (t, J = 7.6 Hz, 2H), 3.44 (t, J = 7.8 Hz, 2H), 3.11
(s, 3H).

Compound 102: 1-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) urea

ＤＣＭ（１０ｍＬ）中の（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メタンアミン塩酸塩（化合物７６、１５８ｍｇ、０．５０ｍｍｏｌ）およびＥｔ_３Ｎ（１７６ｍｇ、１．７４ｍｍｏｌ）の溶液に、トリメチルシリルイソシアネート（１３８ｍｇ、１．２０ｍｍｏｌ）を添加した。混合物を室温で１２時間撹拌した。次いで、これを濃縮し、分取ＨＰＬＣにより精製して、１５ｍｇ（９％）の表題化合物を白色固体として得た。C₁₇H₁₃FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値325.1;
実測値: 325.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.48 (br s, 1H), 7.92 (s, 1H), 7.89 (dd, J =
8.8, 5.5 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.67 (dd,
J = 8.4, 1.8 Hz, 1H), 7.24 (dd, J = 9.9, 2.2 Hz, 1H), 6.97 (t, J = 2.0 Hz, 1H),
6.69 (t, J = 6.0 Hz, 1H), 5.77 (br s, 2H), 4.50 (d, J = 6.0 Hz, 2H).

(6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine hydrochloride (compound 76, 158 mg, 0.50 mmol) and Et ₃ N (10 mL) in DCM (10 mL) Trimethylsilyl isocyanate (138 mg, 1.20 mmol) was added to a solution of 176 mg, 1.74 mmol). The mixture was stirred at room temperature for 12 hours. It was then concentrated and purified by preparative HPLC to give 15 mg (9%) of the title compound as a white solid. C ₁₇ H ₁₃ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 325.1;
Found: 325.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.48 (br s, 1H), 7.92 (s, 1H), 7.89 (dd, J =
8.8, 5.5 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.67 (dd,
J = 8.4, 1.8 Hz, 1H), 7.24 (dd, J = 9.9, 2.2 Hz, 1H), 6.97 (t, J = 2.0 Hz, 1H),
6.69 (t, J = 6.0 Hz, 1H), 5.77 (br s, 2H), 4.50 (d, J = 6.0 Hz, 2H).

Compound 103: 1-carbamoyl-1-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) urea

化合物１０２について記載した合成中に、表題化合物（５ｍｇ、３％）を副産物として得た。C₁₈H₁₄FN₅O₃+H⁺
[M+H]⁺のLC-MS: 計算値368.1;
実測値: 368.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.49 (br s, 1H), 8.92 (s, 1H), 8.30 (br t,
1H), 7.95 (s, 1H), 7.90 (dd, J = 8.8, 5.5 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H),
7.74 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 10.0, 2.2 Hz,
1H), 6.96 (m, 1H), 6.7d (br s, 2H), 4.66 (d, J = 5.7 Hz, 2H).

During the synthesis described for compound 102, the title compound (5 mg, 3%) was obtained as a byproduct. C ₁₈ H ₁₄ FN ₅ O ₃ + H ⁺
[M + H] ⁺ LC-MS: calcd 368.1;
Found: 368.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.49 (br s, 1H), 8.92 (s, 1H), 8.30 (br t,
1H), 7.95 (s, 1H), 7.90 (dd, J = 8.8, 5.5 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H),
7.74 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 10.0, 2.2 Hz,
1H), 6.96 (m, 1H), 6.7d (br s, 2H), 4.66 (d, J = 5.7 Hz, 2H).

Compound 104: 5- (1H-indol-3-yl) -1H-indazole

化合物８で概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、表題化合物を黄色固体として得た。C₁₅H₁₁N₃+H⁺ [M+H]⁺のLC-MS: 計算値234.1; 実測値:
234.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 13.01 (br s, 1H), 11.27 (br s, 1H), 8.09 (s, 1H), 8.01 (s,
1H), 7.90 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 2.3 Hz,
1H), 7.59 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.18-7.08 (m, 2H).

The title compound was obtained as a yellow solid after purification by preparative HPLC according to the general procedure outlined for compound 8. LC-MS for C ₁₅ H ₁₁ N ₃ + H ⁺ [M + H] ⁺ : Calculated 234.1; Found:
234.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.01 (br s, 1H), 11.27 (br s, 1H), 8.09 (s, 1H), 8.01 (s,
1H), 7.90 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 2.3 Hz,
1H), 7.59 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.18-7.08 (m, 2H).

Compound 105: 6- (6-Fluoro-1H-indol-3-yl) -2- (2- (4-methylpiperazin-1-yl) ethyl) benzo [d] oxazole

メタノール（１０ｍＬ）中の２−（２−クロロエチル）−６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体１２５、１００ｍｇ、０．２２ｍｍｏｌ）、水酸化ナトリウム（４４ｍｇ、１．１０ｍｍｏｌ）およびＮ−メチルピペラジン（４４ｍｇ、０．４４ｍｍｏｌ）の溶液を、５０℃で終夜撹拌した。反応混合物を室温に冷却した後、これを濃縮した。残留物を水（２０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×３）で抽出した。有機層を濃縮し、分取ＨＰＬＣ（ＮＨ_４ＨＣＯ_３）により精製して、４４ｍｇ（５３％）の表題化合物を白色固体として得た。C₂₂H₂₃FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値379.2;実測値:
379.2. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.28 (s, 1H), 7.86 - 7.82 (m 1H), 7.76 - 7.67 (m, 2H), 7.58
(d, J = 8.1 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 9.5, 2.1 Hz, 1H),
7.01 - 6.96 (m, 1H), 3.19 - 3.15 (m, 2H), 3.01 - 2.97 (m, 2H), 2.66 - 2.47 (m,
8H), 2.32 (s, 3H).

2- (2-Chloroethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole in methanol (10 mL) (Intermediate 125, 100 mg,. 22 mmol), sodium hydroxide (44 mg, 1.10 mmol) and N-methylpiperazine (44 mg, 0.44 mmol) were stirred at 50 ° C. overnight. After the reaction mixture was cooled to room temperature, it was concentrated. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL × 3). The organic layer was concentrated and purified by preparative HPLC (NH ₄ HCO ₃ ) to give 44 mg (53%) of the title compound as a white solid. _{C 22 H 23 FN 4 O +} H + [M + H] + of LC-MS: calc 379.2; found:
379.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.28 (s, 1H), 7.86-7.82 (m 1H), 7.76-7.67 (m, 2H), 7.58
(d, J = 8.1 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 9.5, 2.1 Hz, 1H),
7.01-6.96 (m, 1H), 3.19-3.15 (m, 2H), 3.01-2.97 (m, 2H), 2.66-2.47 (m,
8H), 2.32 (s, 3H).

Compound 106: N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2-hydroxyethanesulfonamide

ＤＣＭ（２０ｍＬ）中のＮ−（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）−２−メトキシエタンスルホンアミド（化合物９９、１２０ｍｇ、０．３ｍｍｏｌ）の溶液に、トリブロモボラン（０．３８ｍＬ、４．１７ｍｍｏｌ）を窒素下０℃で滴下添加した。混合物を窒素下室温で１時間撹拌した後、これをＤＣＭ（３０ｍＬ）で希釈した。ＮａＨＣＯ_３の水溶液（１５ｍＬ）を０℃で反応混合物中に滴下添加し、２０分間撹拌した。反応混合物をＥｔＯＡｃ（３０ｍＬ×２）および水（２０ｍＬ×２）で抽出した。合わせた有機層をブライン（６０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、２０ｍｇ（１７％）の表題化合物を黄色固体として得た。C₁₈H₁₆FN₃O₄S+H⁺
[M+H]⁺のLC-MS: 計算値390.1;
実測値: 390.5. ¹H NMR (400 MHz, CD₃OH
) δ [ppm]: 7.77 (s, 1H), 7.74 (dd, J = 8.8, 5.3 Hz,
1H), 7.640 - 7.58 (m, 2H), 7.43 (s, 1H), 7.04 (dd, J = 9.7, 2.3 Hz, 1H), 6.81
(td, J = 9.2, 2.3 Hz, 1H), 4.52 (s, 2H), 3.88 (t, J = 6.2 Hz, 2H), 3.29 (t, J =
6.2 Hz, 2H).

N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2-methoxyethanesulfonamide (Compound 99, 120 mg, in DCM (20 mL), To the 0.3 mmol) solution, tribromoborane (0.38 mL, 4.17 mmol) was added dropwise at 0 ° C. under nitrogen. The mixture was stirred at room temperature under nitrogen for 1 hour before it was diluted with DCM (30 mL). An aqueous solution of NaHCO ₃ (15 mL) was added dropwise to the reaction mixture at 0 ° C. and stirred for 20 minutes. The reaction mixture was extracted with EtOAc (30 mL × 2) and water (20 mL × 2). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 20 mg (17%) of the title compound as a yellow solid. C ₁₈ H ₁₆ FN ₃ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: calcd 390.1;
Found: 390.5. ¹ H NMR (400 MHz, CD ₃ OH
) δ [ppm]: 7.77 (s, 1H), 7.74 (dd, J = 8.8, 5.3 Hz,
1H), 7.640-7.58 (m, 2H), 7.43 (s, 1H), 7.04 (dd, J = 9.7, 2.3 Hz, 1H), 6.81
(td, J = 9.2, 2.3 Hz, 1H), 4.52 (s, 2H), 3.88 (t, J = 6.2 Hz, 2H), 3.29 (t, J =
6.2 Hz, 2H).

Compound 107: N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2-morpholinoethanesulfonamide

ＭｅＣＮ（２０ｍＬ）中のＮ−（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）エテンスルホンアミド（中間体１１９、４３３ｍｇ、１．１６ｍｍｏｌ）の溶液に、モルホリン（０．５ｍＬ、５．８３ｍｍｏｌ）を添加した。混合物を室温で０．５時間撹拌した。混合物を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、１３ｍｇ（２％）の表題化合物を黄色固体として得た。C₂₂H₂₃FN₄O₄S+H⁺
[M+H]⁺のLC-MS: 計算値459.1;
実測値: 458. 8. ¹H NMR (400 MHz, CD₃OH
) δ [ppm]: 7.90 (s, 1H), 7.86 (dd, J = 8.7, 5.4 Hz,
1H), 7.78 - 7.71 (m, 2H), 7.56 (s, 1H), 7.17 (dd, J = 9.7, 2.3 Hz, 1H), 6.94
(td, J = 9.1, 2.2 Hz, 1H), 4.66 (s, 2H), 3.65 (t, J = 4.6 Hz, 4H), 3.39 (t, J =
7.2 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.48 - 2.47 (m, 4H).

N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) ethenesulfonamide (Intermediate 119, 433 mg, 1.16 mmol) in MeCN (20 mL) ) Was added morpholine (0.5 mL, 5.83 mmol). The mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 13 mg (2%) of the title compound as a yellow solid. C ₂₂ H ₂₃ FN ₄ O ₄ S + H ⁺
[M + H] ⁺ LC-MS: calcd 459.1;
Found: 458. 8. ¹ H NMR (400 MHz, CD ₃ OH
) δ [ppm]: 7.90 (s, 1H), 7.86 (dd, J = 8.7, 5.4 Hz,
1H), 7.78-7.71 (m, 2H), 7.56 (s, 1H), 7.17 (dd, J = 9.7, 2.3 Hz, 1H), 6.94
(td, J = 9.1, 2.2 Hz, 1H), 4.66 (s, 2H), 3.65 (t, J = 4.6 Hz, 4H), 3.39 (t, J =
7.2 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.48-2.47 (m, 4H).

Compound 108: 6- (1H-indol-3-yl) -1H-indazole

ＭｅＯＨ（２０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−１Ｈ−インダゾール（中間体４、１４８ｍｇ、０．４ｍｍｏｌ）の溶液に、ＮａＯＨ（１５８ｍｇ、４．０ｍｍｏｌ）の溶液を室温で添加した。反応物を８０℃で１時間撹拌した。混合物を室温に冷却し、濃縮した。残留物を分取ＴＬＣ（ＰＥ／ＥｔＯＡｃ＝１／１）により精製して、３２ｍｇ（３６％）の表題化合物を黄色固体として得た。C₁₅H₁₁N₃+H⁺ [M + H]⁺のLC-MS: 計算値234.1; 実測値:
234.0. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 12.93 (s, 1H), 11.40 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 7.6
Hz, 1H), 7.80 - 7.76 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.20 - 7.10 (m, 2H).

To a solution of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -1H-indazole (Intermediate 4, 148 mg, 0.4 mmol) in MeOH (20 mL) was added NaOH (158 mg 4.0 mmol) was added at room temperature. The reaction was stirred at 80 ° C. for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative TLC (PE / EtOAc = 1/1) to give 32 mg (36%) of the title compound as a yellow solid. LC-MS for C ₁₅ H ₁₁ N ₃ + H ⁺ [M + H] ⁺ : Calculated 234.1; Found:
234.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.93 (s, 1H), 11.40 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 7.6
Hz, 1H), 7.80-7.76 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.20-7.10 (m, 2H).

Compound 109: 6- (1H-indol-3-yl) benzo [d] oxazole

６−（１−ベンゼンスルホニル−１Ｈ−インドール−３−イル）−ベンゾオキサゾール（中間体１２７、３３０ｍｇ、０．８８ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、６−（１Ｈ−インドール−３−イル）−ベンゾオキサゾール（１００ｍｇ、４９％）を白色固体として得た。C₁₅H₁₀N₂O+H⁺ [M+H]⁺のLC-MS: 計算値235.1; 実測値:
235.5. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.45 (s, 1H), 8.71 (s, 1H), 8.01 (d, J = 1.1 Hz, 1H), 7.93
(d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.75
(dd, J = 8.3, 1.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.20 - 7.09 (m, 2H).

Starting from 6- (1-benzenesulfonyl-1H-indol-3-yl) -benzoxazole (Intermediate 127, 330 mg, 0.88 mmol) and following the general procedure outlined for compound 1, 6- (1H-indole -3-yl) -benzoxazole (100 mg, 49%) was obtained as a white solid. LC-MS for C ₁₅ H ₁₀ N ₂ O + H ⁺ [M + H] ⁺ : Calculated 235.1; Found:
235.5. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ [ppm]: 11.45 (s, 1H), 8.71 (s, 1H), 8.01 (d, J = 1.1 Hz, 1H), 7.93
(d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.75
(dd, J = 8.3, 1.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.20-7.09 (m, 2H).

Compound 110: 6- (6-Fluoro-1H-indol-3-yl) -2- (2- (piperazin-1-yl) ethyl) benzo [d] oxazole

メタノール（２０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１．００ｇ、２．３９ｍｍｏｌ）、水酸化ナトリウム（４７８ｍｇ、１１．９６ｍｍｏｌ）およびピペラジン（６１７ｍｇ、７．１７ｍｍｏｌ）の溶液を、５０℃で終夜撹拌した。反応混合物を室温に冷却し、濃縮し、水で希釈し、ＥｔＯＡｃで抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣ（ＮＨ_４ＨＣＯ_３）により精製して、６０９ｍｇ（７０％）の表題化合物を白色固体として得た。C₂₁H₂₁FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値365.1; 実測値:
365.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.46 (br s, 1H), 7.90-7.86 (m, 2H), 7.74 (d, J = 2.4 Hz,
1H), 7.70 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 8.3, 1.5 Hz, 1H), 7.23 (dd, J =
9.9, 2.4 Hz, 1H), 6.96 (td, J = 9.5, 2.4 Hz, 1H), 3.11 (t, J = 7.2 Hz, 2H),
2.80 (t, J = 7.4 Hz, 2H), 2.70 - 2.62 (m, 4H), 2.38 (m, 4H).

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (Intermediate 128, 1.00 g, 2.39 mmol) in methanol (20 mL), A solution of sodium hydroxide (478 mg, 11.96 mmol) and piperazine (617 mg, 7.17 mmol) was stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC (NH ₄ HCO ₃ ) to give 609 mg (70%) of the title compound as a white solid. LC-MS for C ₂₁ H ₂₁ FN ₄ O + H ⁺ [M + H] ⁺ : calculated 365.1; found:
365.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.46 (br s, 1H), 7.90-7.86 (m, 2H), 7.74 (d, J = 2.4 Hz,
1H), 7.70 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 8.3, 1.5 Hz, 1H), 7.23 (dd, J =
9.9, 2.4 Hz, 1H), 6.96 (td, J = 9.5, 2.4 Hz, 1H), 3.11 (t, J = 7.2 Hz, 2H),
2.80 (t, J = 7.4 Hz, 2H), 2.70-2.62 (m, 4H), 2.38 (m, 4H).

Compound 111: 5- (6-chloro-1H-indol-3-yl) benzo [d] oxazole

５−（６−クロロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体１２９、３３０ｍｇ、０．０８ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、１１５ｍｇ（５３％）の表題化合物を白色固体として得た。C₁₅H₉ClN₂O+H⁺ [M+H]⁺のLC-MS: 計算値269.0; 実測値:
269.3. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.52 (s, 1H), 8.75 (s, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.88
(d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.74
(dd, J = 8.6, 1.7 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.12 (dd, J = 8.6, 2.0 Hz,
1H).

General method outlined for compound 1 starting from 5- (6-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (intermediate 129, 330 mg, 0.08 mmol) To give 115 mg (53%) of the title compound as a white solid. LC-MS for C ₁₅ H ₉ ClN ₂ O + H ⁺ [M + H] ⁺ : Calculated 269.0; Found:
269.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.52 (s, 1H), 8.75 (s, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.88
(d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.74
(dd, J = 8.6, 1.7 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.12 (dd, J = 8.6, 2.0 Hz,
1H).

Compound 112: 6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazole-2-thiol

６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−チオール（中間体１３０、４５０ｍｇ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（２ステップで８０ｍｇ、３６％）を黄色固体として得た。C₁₅H₉FN₂OS-H^- [M-H]^-のLC-MS: 計算値283.0; 実測値:
283.0. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 13.85 (s, 1H), 11.48 (s, 1H), 7.86 (dd, J = 9.2, 5.2 Hz,
1H), 7.77 (d, J = 1.1 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.4, 1.6
Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 9.6, 2.4 Hz, 1H), 6.97 (td, J
= 9.6, 2.4 Hz, 1H).

Starting from 6- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -benzoxazol-2-thiol (intermediate 130, 450 mg), the title compound was prepared according to the general procedure outlined for compound 1. (80 mg, 36% over 2 steps) was obtained as a yellow solid. _{C 15 H 9 FN 2 OS-} H - [MH] - the LC-MS: calc 283.0; found:
283.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.85 (s, 1H), 11.48 (s, 1H), 7.86 (dd, J = 9.2, 5.2 Hz,
1H), 7.77 (d, J = 1.1 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.4, 1.6
Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 9.6, 2.4 Hz, 1H), 6.97 (td, J
= 9.6, 2.4 Hz, 1H).

Compound 113: 6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-ylmethyl) benzo [d] oxazole

６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（ピペリジン−４−イルメチル）ベンゾ［ｄ］オキサゾール（中間体１３２、２９０ｍｇ、０．５９ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（１５ｍｇ、７％）を白色固体として得た。C₂₁H₂₀FN₃O+H⁺ [M+H]⁺のLC-MS: 計算値350.2; 実測値:
350.1. ¹H NMR (400 MHz, MeOD) δ [ppm]:
7.73 -7.69 (m, 2H), 7.54 (d, J = 0.8 Hz, 2H), 7.40 (s, 1H), 7.03 (dd, J = 10.0,
2.0 Hz, 1H), 6.80 (td, J = 9.2, 2.0 Hz, 1H), 2.99 (d, J = 12.4Hz, 2H), 2.80 (d,
J = 7.2 Hz ,2H), 2.57 (td, J = 12.4, 2.4 Hz, 2H), 2.06 - 2.00 (m, 1H), 1.70 (d,
J = 12.8 Hz, 2H), 1.31 - 1.20 (m,2H).

Starting from 6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2- (piperidin-4-ylmethyl) benzo [d] oxazole (Intermediate 132, 290 mg, 0.59 mmol) The title compound (15 mg, 7%) was obtained as a white solid according to the general method outlined for compound 1. LC-MS for C ₂₁ H ₂₀ FN ₃ O + H ⁺ [M + H] ⁺ : Calculated 350.2; Found:
350.1. ¹ H NMR (400 MHz, MeOD) δ [ppm]:
7.73 -7.69 (m, 2H), 7.54 (d, J = 0.8 Hz, 2H), 7.40 (s, 1H), 7.03 (dd, J = 10.0,
2.0 Hz, 1H), 6.80 (td, J = 9.2, 2.0 Hz, 1H), 2.99 (d, J = 12.4Hz, 2H), 2.80 (d,
J = 7.2 Hz, 2H), 2.57 (td, J = 12.4, 2.4 Hz, 2H), 2.06-2.00 (m, 1H), 1.70 (d,
J = 12.8 Hz, 2H), 1.31-1.20 (m, 2H).

Compound 114: N-((6- (1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide

ＭｅＯＨ（３０ｍＬ）中のｔｅｒｔ−ブチルメチルスルホニル（（６−（１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）カルバメート（中間体１３３、１．２５ｇ、２．１５ｍｍｏｌ）の撹拌溶液に、ＮａＯＨ（４２０ｍｇ、１０．７５ｍｍｏｌ）を添加した。混合物を８５℃で２時間撹拌した。反応物をＨＣｌ（１２Ｍ）で中和した。混合物を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層をブライン（３０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、２１５ｍｇ（３０％）の表題化合物を黄色固体として得た。C₁₇H₁₅N₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値342.1;
実測値: 341.9. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.44 (s, 1H), 8.00 (s, 1H), 7.98 (d, J = 0.9
Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 7.0, 5.5 Hz, 2H), 7.72 (dd, J
= 8.3, 1.5 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.14 - 7.09
(m, 1H), 4.54 (s, 2H), 3.04 (s, 3H).

Tert-Butylmethylsulfonyl ((6- (1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) carbamate (Intermediate 133, 1) in MeOH (30 mL) NaOH (420 mg, 10.75 mmol) was added to a stirred solution of .25 g, 2.15 mmol). The mixture was stirred at 85 ° C. for 2 hours. The reaction was neutralized with HCl (12M). The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 215 mg (30%) of the title compound as a yellow solid. C ₁₇ H ₁₅ N ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 342.1;
Found: 341.9. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.44 (s, 1H), 8.00 (s, 1H), 7.98 (d, J = 0.9
Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 7.0, 5.5 Hz, 2H), 7.72 (dd, J
= 8.3, 1.5 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.20-7.15 (m, 1H), 7.14-7.09
(m, 1H), 4.54 (s, 2H), 3.04 (s, 3H).

Compound 115: (S) -N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -1-methylpyrrolidine-2-carboxamide

室温のＴＨＦ／ＤＭＦ（２０ｍＬ／２ｍＬ）中の（２Ｓ）−１−メチルピロリジン−２−カルボン酸（２５８ｍｇ、２．０ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（７６０ｍｇ、２．０ｍｍｏｌ）、ＤＩＰＥＡ（３８７ｍｇ、３．０ｍｍｏｌ）およびｃ−［５−（６−フルオロ−１Ｈ−インドール−３−イル）−ベンゾオキサゾール−２−イル］−メチルアミン塩酸塩（化合物８１、３１７ｍｇ、１．０ｍｍｏｌ）を添加した。混合物を室温で２時間撹拌し、濃縮し、ＥｔＯＡＣ（１００ｍＬ）で希釈し、水（１０ｍＬ×４）で洗浄した。有機相を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、２９ｍｇの表題化合物を得た。C₂₂H₂₁FN₄O₂+H⁺
[M+H]⁺のLC-MS: 計算値393.2;
実測値: 393.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.48 (br s, 1H), 8.49 (t, J = 5.6 Hz, 1H),
7.91-7.87 (m, 2H), 7.76 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H)),7.66
(dd,J = 8.0, 1.2 Hz, 1H), 7.24 (dd, J = 10, 2.4 Hz, 1H), 6.98 (m, 1H), 4.62 -
4.57 (m, 2H), 3.08 - 3.07 (m, 1H), 2.83 - 2.80 (m, 1H), 2.36 (s, 3H), 2.30 -
2.28 (m, 1H), 2.11 - 2.07 (m, 1H), 1.78 - 1.74 (m, 3H).

To a stirred solution of (2S) -1-methylpyrrolidine-2-carboxylic acid (258 mg, 2.0 mmol) in THF / DMF (20 mL / 2 mL) at room temperature was added HATU (760 mg, 2.0 mmol), DIPEA (387 mg, 3.0 mmol) and c- [5- (6-Fluoro-1H-indol-3-yl) -benzoxazol-2-yl] -methylamine hydrochloride (Compound 81, 317 mg, 1.0 mmol) were added. The mixture was stirred at room temperature for 2 hours, concentrated, diluted with EtOAC (100 mL) and washed with water (10 mL × 4). The organic phase was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 29 mg of the title compound. C ₂₂ H ₂₁ FN ₄ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 393.2;
Found: 393.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.48 (br s, 1H), 8.49 (t, J = 5.6 Hz, 1H),
7.91-7.87 (m, 2H), 7.76 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H)), 7.66
(dd, J = 8.0, 1.2 Hz, 1H), 7.24 (dd, J = 10, 2.4 Hz, 1H), 6.98 (m, 1H), 4.62-
4.57 (m, 2H), 3.08-3.07 (m, 1H), 2.83-2.80 (m, 1H), 2.36 (s, 3H), 2.30-
2.28 (m, 1H), 2.11-2.07 (m, 1H), 1.78-1.74 (m, 3H).

Compound 116: 6- (6-Fluoro-1H-indol-3-yl) -2-methoxybenzo [d] oxazole

６−（１−ベンゼンスルホニル−６−フルオロ−１Ｈ−インドール−３−イル）−２−メトキシ−ベンゾオキサゾール（中間体１３４、１１０ｍｇ、０．２６ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、２０ｍｇ（２７％）の表題化合物を白色固体として得た。C₁₆H₁₁FN₂O₂+H⁺
[M+H]⁺のLC-MS: 計算値283.1;
実測値: 283.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.43 (brs, 1H), 7.86 (dd, J = 8.8, 5.6 Hz,
1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (d, J =
8.0 Hz, 1H), 7.22 (dd, J = 9.6, 2.0 Hz, 1H), 6.98 - 6.93 (m, 1H), 4.19 (s, 3H).

General procedure outlined for compound 1 starting from 6- (1-benzenesulfonyl-6-fluoro-1H-indol-3-yl) -2-methoxy-benzoxazole (intermediate 134, 110 mg, 0.26 mmol) To give 20 mg (27%) of the title compound as a white solid. C ₁₆ H ₁₁ FN ₂ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 283.1;
Found: 283.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.43 (brs, 1H), 7.86 (dd, J = 8.8, 5.6 Hz,
1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (d, J =
8.0 Hz, 1H), 7.22 (dd, J = 9.6, 2.0 Hz, 1H), 6.98-6.93 (m, 1H), 4.19 (s, 3H).

Compound 117: amino {[6- (6-fluoroindol-3-yl) benzoxazol-2-yl] methyl} sulfonamide

ＴＨＦ（５ｍＬ）中のｔｅｒｔ−ブトキシカルボニルアミノ｛［６−（６−フルオロインドール−３−イル）ベンゾオキサゾール−２−イル］メチル｝スルホンアミド（中間体１３５、１８０ｍｇ、０．３９ｍｍｏｌ）の溶液に、ＥＡ／ＨＣｌ（３ｍＬ、５Ｎ）を添加した。混合物を室温で終夜撹拌した。混合物をＴＨＦ／ＮＨ_３（１０Ｎ）で中和し、濾過した。溶媒を除去し、残留物を分取ＴＬＣ（ＤＣＭ／メタノール＝１０／１）により精製して、表題化合物（５０ｍｇ、３４％）を白色固体として得た。C₁₆H₁₃FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値361.1;
実測値: 361.0. ¹H NMR (400 MHz, DMSO) δ 11.49 (br s, 1H), 7.94 (s, 1H), 7.89 (dd, J = 8.8, 5.2 Hz, 1H),
7.77 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.0, 1.2 Hz,
1H), 7.46 (t, J = 6.0 Hz, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.97 (td, J =
9.6, 2.4 Hz, 1H), 6.77 (s, 2H), 4.40 (d, J = 6.4 Hz, 2H).

To a solution of tert-butoxycarbonylamino {[6- (6-fluoroindol-3-yl) benzoxazol-2-yl] methyl} sulfonamide (Intermediate 135, 180 mg, 0.39 mmol) in THF (5 mL) EA / HCl (3 mL, 5N) was added. The mixture was stirred at room temperature overnight. The mixture was neutralized with THF / NH ₃ (10N) and filtered. The solvent was removed and the residue was purified by preparative TLC (DCM / methanol = 10/1) to give the title compound (50 mg, 34%) as a white solid. C ₁₆ H ₁₃ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 361.1;
Found: 361.0. ¹ H NMR (400 MHz, DMSO) δ 11.49 (br s, 1H), 7.94 (s, 1H), 7.89 (dd, J = 8.8, 5.2 Hz, 1H),
7.77 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.0, 1.2 Hz,
1H), 7.46 (t, J = 6.0 Hz, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.97 (td, J =
9.6, 2.4 Hz, 1H), 6.77 (s, 2H), 4.40 (d, J = 6.4 Hz, 2H).

Compound 118: 5- (1H-indol-3-yl) benzo [d] oxazole

５−（１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体１３６、５２５ｍｇ、１．４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、５６ｍｇ（３６％）の表題化合物を白色固体として得た。C₁₅H₁₀N₂O+H⁺ [M+H]⁺のLC-MS: 計算値235.1; 実測値:
235.1. ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 8.30 (br s, 1H), 8.13 (s, 1H), 8.06 (d, J = 1.1 Hz, 1H),
7.95 (d, J = 7.9 Hz, 1H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 7.65 (dd, J = 8.5,
0.5 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.30-7.20 (m, 2H).

Starting from 5- (1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole (intermediate 136, 525 mg, 1.4 mmol), following the general procedure outlined for compound 1, 56 mg ( 36%) of the title compound was obtained as a white solid. LC-MS for C ₁₅ H ₁₀ N ₂ O + H ⁺ [M + H] ⁺ : Calculated 235.1; Found:
235.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]: 8.30 (br s, 1H), 8.13 (s, 1H), 8.06 (d, J = 1.1 Hz, 1H),
7.95 (d, J = 7.9 Hz, 1H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 7.65 (dd, J = 8.5,
0.5 Hz, 1H), 7.47-7.45 (m, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.30-7.20 (m, 2H).

Compound 119: 6- (6-Fluoro-1H-indol-3-yl) -2-((1- (methylsulfonyl) piperidin-4-yl) methyl) benzo [d] oxazole

６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（（１−（メチルスルホニル）ピペリジン−４−イル）メチル）ベンゾ［ｄ］オキサゾール（中間体１３７、２２０ｍｇ、０．３８８ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（４０ｍｇ、２４％）を白色固体として得た。C₂₂H₂₂FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値428.1;
実測値: 428.1. 1H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.47(s, 1H), 7.90 - 7.86 (m, 2H),7.75 - 7.70 (m, 2H), 7.66
- 7.64 (m, 1H), 7.23 (dd, J = 10, 2.4 Hz, 1H), 6.96 (td, J = 9.6, 2.4 Hz, 1H),
3.56 (d, J= 12.0 Hz, 2H), 2.95 (d, J= 6.8 Hz, 2H), 2.85 (s, 3H), 2.74 (td, J=
12.4, 2.4 Hz, 2H), 2.07 - 2.01(m, 1H), 1.84 (dd, J= 12.4, 2.0 Hz, 2H) 1.37(qd,
J= 12.4, 4.0 Hz, 2H).

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((1- (methylsulfonyl) piperidin-4-yl) methyl) benzo [d] oxazole (intermediate 137) 220 mg, 0.388 mmol) and the title compound (40 mg, 24%) was obtained as a white solid according to the general procedure outlined for compound 1. C ₂₂ H ₂₂ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calc'd 428.1;
Found: 428.1. 1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.47 (s, 1H), 7.90-7.86 (m, 2H), 7.75-7.70 (m, 2H), 7.66
-7.64 (m, 1H), 7.23 (dd, J = 10, 2.4 Hz, 1H), 6.96 (td, J = 9.6, 2.4 Hz, 1H),
3.56 (d, J = 12.0 Hz, 2H), 2.95 (d, J = 6.8 Hz, 2H), 2.85 (s, 3H), 2.74 (td, J =
12.4, 2.4 Hz, 2H), 2.07-2.01 (m, 1H), 1.84 (dd, J = 12.4, 2.0 Hz, 2H) 1.37 (qd,
J = 12.4, 4.0 Hz, 2H).

Compound 120: 6- (6-Fluoro-1H-indol-3-yl) -2- (2- (4- (methylsulfonyl) piperazin-1-yl) ethyl) benzo [d] oxazole

メタノール（１０ｍＬ）中の２−（２−クロロエチル）−６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール（中間体１２５、１１０ｍｇ、０．２４ｍｍｏｌ）、水酸化ナトリウム（４８ｍｇ、１．２９ｍｍｏｌ）および１−（メチルスルホニル）ピペラジン（８０ｍｇ、０．４８ｍｍｏｌ）の溶液を、５０℃で終夜撹拌した。反応混合物を室温に冷却し、濃縮した。残留物を水（２０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ）で抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、７３ｍｇ（６８％）の表題化合物を白色固体として得た。C₂₂H₂₃FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値443.2;
実測値: 443.2. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.47 (s, 1H), 7.90-7.86 (m, 2H), 7.75 (d, J =
2.5 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 8.2, 1.5 Hz, 1H), 7.23
(dd, J = 10.1, 2.4 Hz, 1H), 6.97 (td, J = 9.6, 2.6 Hz, 1H), 3.15 (t, J = 7.2
Hz, 2H), 3.11 - 3.03 (m, 4H), 2.91 (t, J = 7.2 Hz, 2H), 2.85 (s, 3H), 2.63 -
2.55 (m, 4H).

2- (2-Chloroethyl) -6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) benzo [d] oxazole in methanol (10 mL) (intermediate 125, 110 mg,. 24 mmol), sodium hydroxide (48 mg, 1.29 mmol) and 1- (methylsulfonyl) piperazine (80 mg, 0.48 mmol) were stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 73 mg (68%) of the title compound as a white solid. C ₂₂ H ₂₃ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 443.2;
Found: 443.2. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.47 (s, 1H), 7.90-7.86 (m, 2H), 7.75 (d, J =
2.5 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 8.2, 1.5 Hz, 1H), 7.23
(dd, J = 10.1, 2.4 Hz, 1H), 6.97 (td, J = 9.6, 2.6 Hz, 1H), 3.15 (t, J = 7.2
Hz, 2H), 3.11-3.03 (m, 4H), 2.91 (t, J = 7.2 Hz, 2H), 2.85 (s, 3H), 2.63-
2.55 (m, 4H).

Compound 121: 5- (5-chloro-1H-indol-3-yl) benzo [d] oxazole

化合物４７について概説した一般的方法に従って、分取ＨＰＬＣによる精製後に、表題化合物を黄色固体として得た。C₁₅H₉ClN₂O+H⁺ [M+H]⁺のLC-MS: 計算値269.0; 実測値:
268.9. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.60 (br s, 1H), 8.76 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H),
7.85 - 7.81 (m, 3H), 7.73 (dd, J = 8.4, 1.8 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H),
7.18 (dd, J = 8.6, 2.0 Hz, 1H).

The title compound was obtained as a yellow solid after purification by preparative HPLC following the general method outlined for compound 47. LC-MS for C ₁₅ H ₉ ClN ₂ O + H ⁺ [M + H] ⁺ : Calculated 269.0; Found:
268.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.60 (br s, 1H), 8.76 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H),
7.85-7.81 (m, 3H), 7.73 (dd, J = 8.4, 1.8 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H),
7.18 (dd, J = 8.6, 2.0 Hz, 1H).

Compound 122: N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (4-methylpiperazin-1-yl) ethanesulfonamide

ＭｅＣＮ／ＴＨＦ（５ｍＬ／２０ｍＬ）中のＮ−（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）エテンスルホンアミド（中間体１１９、８６ｍｇ、０．２３ｍｍｏｌ）の溶液に、１−メチルピペラジン（４７ｍｇ、０．４６ｍｍｏｌ）を添加した。混合物を室温で７２時間撹拌した。混合物を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層をブライン（６０ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、５０ｍｇ（４６％）の表題化合物を白色固体として得た。C₂₃H₂₆FN₅O₃S+H⁺
[M+H]⁺のLC-MS: 計算値472.2;
実測値: 472.8. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.50 (s, 1H), 8.02 (t, J = 6.0 Hz, 1H), 7.96
(d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.78 - 7.75 (m, 2H), 7.70
(dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J = 9.6,
2.4 Hz, 1H), 4.55 (d, J = 5.8 Hz, 2H), 3.29 (d, J = 7.8 Hz, 2H), 2.70 - 2.64
(m, 2H), 2.44 - 2.23 (m, 7H), 2.13 (s, 3H).

N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) ethenesulfonamide (Intermediate 119, 86 mg in MeCN / THF (5 mL / 20 mL) , 0.23 mmol) was added 1-methylpiperazine (47 mg, 0.46 mmol). The mixture was stirred at room temperature for 72 hours. The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 50 mg (46%) of the title compound as a white solid. C ₂₃ H ₂₆ FN ₅ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 472.2;
Found: 472.8. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.50 (s, 1H), 8.02 (t, J = 6.0 Hz, 1H), 7.96
(d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.78-7.75 (m, 2H), 7.70
(dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J = 9.6,
2.4 Hz, 1H), 4.55 (d, J = 5.8 Hz, 2H), 3.29 (d, J = 7.8 Hz, 2H), 2.70-2.64
(m, 2H), 2.44-2.23 (m, 7H), 2.13 (s, 3H).

Compound 123: N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (piperazin-1-yl) ethanesulfonamide

ＭｅＣＮ／ＴＨＦ（５ｍＬ／３０ｍＬ）中のピペラジン（７５２ｍｇ、８．７３ｍｍｏｌ）の溶液に、Ｎ−（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）エテンスルホンアミド（中間体１１９、１８０ｍｇ、０．４８５ｍｍｏｌ）を添加した。混合物を室温で５時間撹拌した。ＮＨ_４Ｃｌの水溶液（２０ｍＬ）を添加した。混合物をＥＡ（６０ｍＬ×３）で抽出した。有機相をブライン（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、８５ｍｇ（３５％）の表題化合物を黄色固体として得た。C₂₂H₂₄FN₅O₃S+H⁺
[M+H]⁺のLC-MS: 計算値458.2;
実測値: 457.8. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.50 (s, 1H), 7.96 (d, J = 1.0 Hz, 1H), 7.89
(dd, J = 8.8, 5.4 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.70 (dd, J = 8.3, 1.5 Hz, 1H),
7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J = 9.5, 2.4 Hz, 1H), 4.55 (s, 2H),
3.29 (t, J = 7.6 Hz, 2H), 2.66 - 2.61 (m, 6H), 2.33 - 2.24 (m, 4H).

To a solution of piperazine (752 mg, 8.73 mmol) in MeCN / THF (5 mL / 30 mL) was added N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl. ) Methyl) ethenesulfonamide (Intermediate 119, 180 mg, 0.485 mmol) was added. The mixture was stirred at room temperature for 5 hours. An aqueous solution of NH ₄ Cl (20 mL) was added. The mixture was extracted with EA (60 mL × 3). The organic phase was washed with brine (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 85 mg (35%) of the title compound as a yellow solid. C ₂₂ H ₂₄ FN ₅ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 458.2;
Found: 457.8. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.50 (s, 1H), 7.96 (d, J = 1.0 Hz, 1H), 7.89
(dd, J = 8.8, 5.4 Hz, 1H), 7.80-7.74 (m, 2H), 7.70 (dd, J = 8.3, 1.5 Hz, 1H),
7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J = 9.5, 2.4 Hz, 1H), 4.55 (s, 2H),
3.29 (t, J = 7.6 Hz, 2H), 2.66-2.61 (m, 6H), 2.33-2.24 (m, 4H).

Compound 124: N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (pyrrolidin-1-yl) ethanesulfonamide

ＭｅＣＮ／ＴＨＦ（５ｍＬ／３０ｍＬ）中のピロリジン（７５２ｍｇ、８．７３ｍｍｏｌ）の溶液に、Ｎ−（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）エテンスルホンアミド（中間体１１９、１８０ｍｇ、０．４８５ｍｍｏｌ）を添加した。混合物を室温で６時間撹拌した。反応混合物を濃縮し、分取ＨＰＬＣにより精製して、１２０ｍｇ（５０％）の表題化合物を白色固体として得た。C₂₂H₂₃FN₄O₃S+H⁺
[M+H]⁺のLC-MS: 計算値443.2;
実測値: 443.6. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.50 (s, 1H), 8.03 (s, 1H), 7.95 (d, J = 1.0
Hz, 1H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.70 (dd, J =
8.3, 1.4 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 6.97 (td, J = 9.4, 2.4 Hz,
1H), 4.54 (s, 2H), 3.31 - 3.28 (m, 2H), 2.79 - 2.75 (m, 2H), 2.41 (s, 4H), 1.64
(dt, J = 6.3, 3.0 Hz, 4H).

To a solution of pyrrolidine (752 mg, 8.73 mmol) in MeCN / THF (5 mL / 30 mL) was added N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl. ) Methyl) ethenesulfonamide (Intermediate 119, 180 mg, 0.485 mmol) was added. The mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and purified by preparative HPLC to give 120 mg (50%) of the title compound as a white solid. C ₂₂ H ₂₃ FN ₄ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 443.2;
Found: 443.6. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.50 (s, 1H), 8.03 (s, 1H), 7.95 (d, J = 1.0
Hz, 1H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.79-7.74 (m, 2H), 7.70 (dd, J =
8.3, 1.4 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 6.97 (td, J = 9.4, 2.4 Hz,
1H), 4.54 (s, 2H), 3.31-3.28 (m, 2H), 2.79-2.75 (m, 2H), 2.41 (s, 4H), 1.64
(dt, J = 6.3, 3.0 Hz, 4H).

Compound 125: 6- (6-Fluoro-1H-indol-3-yl) -2-((1-methylpiperidin-4-yl) methyl) benzo [d] oxazole

６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−（（１−メチルピペリジン−４−イル）メチル）ベンゾ［ｄ］オキサゾール（中間体１３８、２００ｍｇ、０．４ｍｍｏｌ）から出発し、化合物１で概説した一般的方法に従って、表題化合物（９０ｍｇ、６２％）を黄色固体として得た。C₂₂H₂₂FN₃O+H⁺ [M+H]⁺のLC-MS: 計算値364.2; 実測値:
364.1. 1H NMR (400 MHz, DMSO-d₆) δ [ppm]:
11.47(s, 1H), 7.89 - 7.86(m, 2H), 7.74(d, J=2.4Hz,1H), 7.70 (d, J=8.4Hz, 1H),
7.64 (dd, J=1.6Hz, J=8.8Hz, 1H), 7.23(dd, J = 2.4Hz, J=9.6Hz, 1H), 6.96 (td, J
= 2.4Hz, J=9.6Hz, 1H), 2.87 (d, J=8.8Hz, 2H), 2.73 (d, J=11.6Hz, 2H), 2.13(s,
3H), 1.88 - 1.81 (m, 3H), 1.68 (d, J=12.8Hz, 2H) 1.36 - 1.28 (m, 2H),

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-((1-methylpiperidin-4-yl) methyl) benzo [d] oxazole (intermediate 138, 200 mg, Starting from 0.4 mmol), the title compound (90 mg, 62%) was obtained as a yellow solid following the general procedure outlined for compound 1. LC-MS for C ₂₂ H ₂₂ FN ₃ O + H ⁺ [M + H] ⁺ : Calculated 364.2; Found:
364.1. 1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]:
11.47 (s, 1H), 7.89-7.86 (m, 2H), 7.74 (d, J = 2.4Hz, 1H), 7.70 (d, J = 8.4Hz, 1H),
7.64 (dd, J = 1.6Hz, J = 8.8Hz, 1H), 7.23 (dd, J = 2.4Hz, J = 9.6Hz, 1H), 6.96 (td, J
= 2.4Hz, J = 9.6Hz, 1H), 2.87 (d, J = 8.8Hz, 2H), 2.73 (d, J = 11.6Hz, 2H), 2.13 (s,
3H), 1.88-1.81 (m, 3H), 1.68 (d, J = 12.8Hz, 2H) 1.36-1.28 (m, 2H),

Compound 126: N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (4- (methylsulfonamido) piperidin-1-yl ) Ethanesulfonamide

ＭｅＣＮ／ＴＨＦ（５ｍＬ／３０ｍＬ）中のＮ−（ピペリジン−４−イル）メタンスルホンアミド塩酸塩（８３３ｍｇ、３．８８ｍｍｏｌ）およびＤＢＵ（５９１ｍｇ、３．８８ｍｍｏｌ）の撹拌溶液に、Ｎ−（（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）メチル）エテンスルホンアミド（中間体１１９、１６０ｍｇ、０．４３ｍｍｏｌ）を添加した。混合物を室温で３時間撹拌した後、これをＮＨ_４Ｃｌ水溶液（３０ｍＬ）でクエンチした。混合物をＥＡ（６０ｍＬ×３）で抽出し、ブライン（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、１１０ｍｇ（４７％）の表題化合物を白色固体として得た。C₂₄H₂₈FN₅O₅S₂+H⁺
[M+H]⁺のLC-MS: 計算値550.2;
実測値: 550.7. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.51 (br s, 1H), 8.06 - 8.01 (m, 1H), 7.96
(d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.70
(dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 7.03 - 6.95 (m, 2H),
4.54 (d, J = 5.6 Hz, 2H), 3.30 (s, 2H), 3.08 (br s, 1H), 2.86 (s, 3H), 2.76 -
2.74 (m, 2H), 2.69 - 2.67 (m, 2H), 2.03 - 1.98 (m, 2H), 1.77 - 1.75 (m, 2H),
1.45 -1.40 (m, 2H).

To a stirred solution of N- (piperidin-4-yl) methanesulfonamide hydrochloride (833 mg, 3.88 mmol) and DBU (591 mg, 3.88 mmol) in MeCN / THF (5 mL / 30 mL) was added N-((6 -(6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) ethenesulfonamide (Intermediate 119, 160 mg, 0.43 mmol) was added. After the mixture was stirred at room temperature for 3 h, it was quenched with aqueous NH ₄ Cl (30 mL). The mixture was extracted with EA (60 mL × 3), washed with brine (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 110 mg (47%) of the title compound as a white solid. C ₂₄ H ₂₈ FN ₅ O ₅ S ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 550.2;
Found: 550.7. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.51 (br s, 1H), 8.06-8.01 (m, 1H), 7.96
(d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.80-7.75 (m, 2H), 7.70
(dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 7.03-6.95 (m, 2H),
4.54 (d, J = 5.6 Hz, 2H), 3.30 (s, 2H), 3.08 (br s, 1H), 2.86 (s, 3H), 2.76-
2.74 (m, 2H), 2.69-2.67 (m, 2H), 2.03-1.98 (m, 2H), 1.77-1.75 (m, 2H),
1.45 -1.40 (m, 2H).

Compound 127: N-((6- (6-chloro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide

化合物７４について概説した一般的方法に従って、分取ＴＬＣ（ＤＣＭ／ＭｅＯＨ＝１０／１、ｖ／ｖ）による精製後に、表題化合物を黄色固体として得た。C₁₇H₁₄ClN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値376.0;
実測値: 376.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.58 (br s, 1H), 7.98 - 7.95 (m, 2H), 7.92
(d, J = 8.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.70
(dd, J = 8.3, 1.6 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.6, 2.0 Hz,
1H), 4.54 (s, 2H), 3.03 (s, 3H).

The title compound was obtained as a yellow solid after purification by preparative TLC (DCM / MeOH = 10/1, v / v) according to the general method outlined for compound 74. C ₁₇ H ₁₄ ClN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calc. 376.0;
Found: 376.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.58 (br s, 1H), 7.98-7.95 (m, 2H), 7.92
(d, J = 8.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.70
(dd, J = 8.3, 1.6 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.6, 2.0 Hz,
1H), 4.54 (s, 2H), 3.03 (s, 3H).

Compound 128: N-((6- (5-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide

化合物７４について概説した一般的方法に従って、分取ＴＬＣ（ＤＣＭ／ＭｅＯＨ＝１０／１、ｖ／ｖ）による精製後に、表題化合物を黄色固体として得た。C₁₇H₁₄FN₃O₃S+H⁺
[M+H]⁺のLC-MS: 計算値360.1;
実測値: 360.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.59 (br s, 1H), 8.02 (br t, J = 6.1 Hz, 1H),
7.98 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H),
7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.64 (dd, J = 10.6, 2.4 Hz, 1H), 7.47 (dd, J =
8.8, 4.8 Hz, 1H), 7.03 (ddd, J = 9.5, 8.8, 2.4 Hz, 1H), 4.54 (d, J = 6.0 Hz,
2H), 3.04 (s, 3H).

The title compound was obtained as a yellow solid after purification by preparative TLC (DCM / MeOH = 10/1, v / v) according to the general method outlined for compound 74. C ₁₇ H ₁₄ FN ₃ O ₃ S + H ⁺
[M + H] ⁺ LC-MS: calcd 360.1;
Found: 360.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.59 (br s, 1H), 8.02 (br t, J = 6.1 Hz, 1H),
7.98 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H),
7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.64 (dd, J = 10.6, 2.4 Hz, 1H), 7.47 (dd, J =
8.8, 4.8 Hz, 1H), 7.03 (ddd, J = 9.5, 8.8, 2.4 Hz, 1H), 4.54 (d, J = 6.0 Hz,
2H), 3.04 (s, 3H).

Compound 129: 5-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) imidazolidine-2,4-dione

ＤＣＭ（１．５ｍＬ）中のｔｅｒｔ−ブチル３−（２−（（２，５−ジオキソイミダゾリジン−４−イル）メチル）ベンゾ［ｄ］オキサゾール−６−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート（中間体１４１、５０ｍｇ、０．１１ｍｍｏｌ）の溶液に、ＴＦＡ（１．０ｍＬ）を添加した。反応混合物を室温で２時間撹拌し、濃縮した。残留物をＥｔＯＡｃで希釈し、飽和ＮａＨＣＯ_３水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＴＬＣ（ＤＣＭ／ＭｅＯＨ＝５／１、ｖ／ｖ）により精製して、９ｍｇ（２３％）の表題化合物を黄色固体として得た。C₁₉H₁₃FN₄O₃-H^-
[M-H]^-のLC-MS: 計算値363.1;
実測値: 363.1. ¹H NMR (400 MHz, MeOH-d₄)
δ [ppm]: 7.74-7.71 (m, 2H), 7.60-7.58 (m, 2H), 7.42 (s,
1H), 7.09 (dd, J = 9.6, 2.0 Hz, 1H), 6.81 (td, J = 8.8, 2.4 Hz, 1H), 4.59 (dd,
J = 7.2, 4.8 Hz, 1H), 3.43 (dd, J = 16.4, 4.8 Hz, 1H), 3.27-3.25 (m, 1H).

Tert-Butyl 3- (2-((2,5-dioxoimidazolidin-4-yl) methyl) benzo [d] oxazol-6-yl) -6-fluoro-1H- in DCM (1.5 mL) To a solution of indole-1-carboxylate (intermediate 141, 50 mg, 0.11 mmol) was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative TLC (DCM / MeOH = 5/1, v / v) to give 9 mg (23%) of the title compound as a yellow solid. _{C 19 H 13 FN 4 O 3} -H -
[MH] ^- the LC-MS: calc 363.1;
Found: 363.1. ¹ H NMR (400 MHz, MeOH-d ₄ )
δ [ppm]: 7.74-7.71 (m, 2H), 7.60-7.58 (m, 2H), 7.42 (s,
1H), 7.09 (dd, J = 9.6, 2.0 Hz, 1H), 6.81 (td, J = 8.8, 2.4 Hz, 1H), 4.59 (dd,
J = 7.2, 4.8 Hz, 1H), 3.43 (dd, J = 16.4, 4.8 Hz, 1H), 3.27-3.25 (m, 1H).

Compound 130: 5- (6-Fluoro-1H-indol-3-yl) benzo [d] isothiazol-3 (2H) -one 1,1-dioxide

ステップ１：ｔｅｒｔ−ブチル３−（１，１−ジオキシド−３−オキソ−２，３−ジヒドロベンゾ［ｄ］イソチアゾール−５−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート

Step 1: tert-Butyl 3- (1,1-dioxide-3-oxo-2,3-dihydrobenzo [d] isothiazol-5-yl) -6-fluoro-1H-indole-1-carboxylate

ジオキサン（２０ｍＬ）および水（２ｍＬ）中の５−ブロモベンゾ［ｄ］イソチアゾール−３（２Ｈ）−オン１，１−ジオキシド（３１０ｍｇ、１．１８ｍｍｏｌ、Ｔｅｔｒａｈｅｄｒｏｎ ２００６、６２、７９０２に記載されている通りに調製した）、ｔｅｒｔ−ブチル６−フルオロ−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インドール−１−カルボキシレート（中間体２、５１４ｍｇ、１．４２ｍｍｏｌ）およびＫ_２ＣＯ_３（４８９ｍｇ、３．５４ｍｍｏｌ）の混合物に、Ｐｄ（ＰＰｈ_３）_４（６９ｍｇ、０．０６ｍｍｏｌ）を添加した。混合物を１１０℃で２時間撹拌した後、これを濃縮した。残留物をＥｔＯＡｃで希釈し、飽和ＮａＨＣＯ_３水溶液で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮して、３００ｍｇ（６１％）の表題化合物を黄色固体として得、これをさらに精製することなく直接使用した。
ステップ２：
ＨＣｌ／ＥｔＯＡｃ（１０ｍＬ、２Ｍ）中のｔｅｒｔ−ブチル３−（１，１−ジオキシド−３−オキソ−２，３−ジヒドロベンゾ［ｄ］イソチアゾール−５−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート（ステップ１、３００ｍｇ、０．７２ｍｍｏｌ）の溶液を、６０℃で２時間撹拌した。反応混合物をアンモニアでクエンチし、濃縮し、シリカゲルクロマトグラフィー（ＤＣＭ）により精製して、３１ｍｇ（１４％）の表題化合物を黄色固体として得た。C₁₅H₉FN₂O₃S-H^-
[M-H]^-のLC-MS: 計算値315.0;
実測値: 315.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.80 (br s, 1H), 8.26 (dd, J = 8.4, 1.6 Hz,
1H), 8.17 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.4 Hz,
1H), 7.93 (dd, J = 8.8, 5.3 Hz, 1H), 7.28 (dd, J = 9.8, 2.4 Hz, 1H), 7.05 (m,
1H).

5-Bromobenzo [d] isothiazol-3 (2H) -one 1,1-dioxide (310 mg, 1.18 mmol, Tetrahedron 2006, 62, 7902 as described in dioxane (20 mL) and water (2 mL). ), Tert-butyl 6-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylate (intermediate) To a mixture of 2,514 mg, 1.42 mmol) and K ₂ CO ₃ (489 mg, 3.54 mmol) was added Pd (PPh ₃ ) ₄ (69 mg, 0.06 mmol). After the mixture was stirred at 110 ° C. for 2 hours, it was concentrated. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 300 mg (61%) of the title compound as a yellow solid, which was used directly without further purification.
Step 2:
Tert-Butyl 3- (1,1-dioxide-3-oxo-2,3-dihydrobenzo [d] isothiazol-5-yl) -6-fluoro-1H-indole in HCl / EtOAc (10 mL, 2M) A solution of -1-carboxylate (Step 1, 300 mg, 0.72 mmol) was stirred at 60 ° C. for 2 hours. The reaction mixture was quenched with ammonia, concentrated and purified by silica gel chromatography (DCM) to give 31 mg (14%) of the title compound as a yellow solid. _{C 15 H 9 FN 2 O 3} SH -
[MH] ^- the LC-MS: calc 315.0;
Found: 315.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.80 (br s, 1H), 8.26 (dd, J = 8.4, 1.6 Hz,
1H), 8.17 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.4 Hz,
1H), 7.93 (dd, J = 8.8, 5.3 Hz, 1H), 7.28 (dd, J = 9.8, 2.4 Hz, 1H), 7.05 (m,
1H).

Compound 131: 2- (6- (5-fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide

ＭｅＯＨ（３０ｍＬ）中の２−（６−（５−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−オキソベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）アセトアミド（中間体１４３、２８１ｍｇ、０．６ｍｍｏｌ）の溶液に、ＮａＯＨ（２４１ｍｇ、６．０４ｍｍｏｌ）を添加した。混合物を８５℃で１時間撹拌した。反応物をＨＣｌ（１２Ｍ）で中和した。混合物を水（６０ｍＬ）で希釈し、ＥｔＯＡｃ（６０ｍＬ×３）で抽出した。合わせた有機層を水（６０ｍＬ×３）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、１００ｍｇ（４３％）の表題化合物を白色固体として得た。C₁₇H₁₂FN₃O₃-H^-
[M-H]^-のLC-MS: 計算値324.1;
実測値: 324.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.48 (s, 1H), 11.00 (s, 1H), 9.78 (s, 1H),
7.74 (d, J = 2.6 Hz, 1H), 7.54 (dd, J = 10.4, 2.4 Hz, 1H), 7.45 (dd, J = 8.9,
4.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.12 (dd, J =
8.1, 1.9 Hz, 1H), 7.01 (td, J = 9.1, 2.4 Hz, 1H), 4.28 (s, 2H).

2- (6- (5-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide (intermediate) in MeOH (30 mL) To a solution of body 143, 281 mg, 0.6 mmol) was added NaOH (241 mg, 6.04 mmol). The mixture was stirred at 85 ° C. for 1 hour. The reaction was neutralized with HCl (12M). The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with water (60 mL × 3), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 100 mg (43%) of the title compound as a white solid. _{C 17 H 12 FN 3 O 3} -H -
[MH] ^- the LC-MS: calc 324.1;
Found: 324.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.48 (s, 1H), 11.00 (s, 1H), 9.78 (s, 1H),
7.74 (d, J = 2.6 Hz, 1H), 7.54 (dd, J = 10.4, 2.4 Hz, 1H), 7.45 (dd, J = 8.9,
4.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.12 (dd, J =
8.1, 1.9 Hz, 1H), 7.01 (td, J = 9.1, 2.4 Hz, 1H), 4.28 (s, 2H).

Compound 132: 5- (6-fluoro-1H-indol-3-yl) isoindoline-1,3-dione

４−（６−フルオロ−１Ｈ−インドール−３−イル）−フタル酸（中間体１４５、１３６ｍｇ、０．４５ｍｍｏｌ）、イミダゾール（４６ｍｇ、０．６８ｍｍｏｌ）および尿素（５４ｍｇ、０．９０ｍｍｏｌ）の混合物をよくすり混ぜ、フラスコに入れ、続いて４滴のＤＭＦを添加した。混合物を油浴中１５０℃で３時間加熱した。混合物を冷却し、１０％ｖ／ｖ ＨＣｌ水溶液に注ぎ入れ、１０分間撹拌した。固体を濾別し、分取ＨＰＬＣにより精製して、９０ｍｇ（５８％）の表題化合物を黄色固体として得た。C₁₆H₉FN₂O₂-H^-
[M-H]^-のLC-MS: 計算値279.1;
実測値: 279.0. ¹H NMR (400 MHz, DMSO-d₆)
δ[ppm]: 11.75 (br s, 1H), 11.25 (br s, 1H), 8.14 (d, J
= 8.0 Hz, 1H), 8.06 (s, 1H), 8.05 (s, 1H),7.92 (dd, J = 8.8, 5.2 Hz, 1H), 7.85
(d, J = 7.6 Hz, 1H), 7.27 (dd, J = 9.8, 2.8 Hz, 1H), 7.03 (td, J = 9.3, 2.4 Hz,
1H).

A mixture of 4- (6-fluoro-1H-indol-3-yl) -phthalic acid (intermediate 145, 136 mg, 0.45 mmol), imidazole (46 mg, 0.68 mmol) and urea (54 mg, 0.90 mmol). Mix well and place in a flask followed by the addition of 4 drops of DMF. The mixture was heated in an oil bath at 150 ° C. for 3 hours. The mixture was cooled and poured into 10% v / v aqueous HCl and stirred for 10 minutes. The solid was filtered off and purified by preparative HPLC to give 90 mg (58%) of the title compound as a yellow solid. _{C 16 H 9 FN 2 O 2} -H -
[MH] ^- the LC-MS: calc 279.1;
Found: 279.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.75 (br s, 1H), 11.25 (br s, 1H), 8.14 (d, J
= 8.0 Hz, 1H), 8.06 (s, 1H), 8.05 (s, 1H), 7.92 (dd, J = 8.8, 5.2 Hz, 1H), 7.85
(d, J = 7.6 Hz, 1H), 7.27 (dd, J = 9.8, 2.8 Hz, 1H), 7.03 (td, J = 9.3, 2.4 Hz,
1H).

Compound 133: 6-Fluoro-3- (isoindoline-5-yl) -1H-indole

ＤＣＭ（２０ｍＬ）中のｔｅｒｔ−ブチル３−（２−（ｔｅｒｔ−ブトキシカルボニル）イソインドリン−５−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート（中間体１４６、５２５ｍｇ、１．４ｍｍｏｌ）およびＣＦ_３ＣＯＯＨ（８ｍＬ）の溶液を、室温で終夜撹拌した。混合物を濃縮した。残留物を水（１００ｍＬ）で希釈し、ＥｔＯＡｃ（３００ｍＬ）で抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣにより精製して、１７ｍｇ（１５％）の表題化合物を白色固体として得た。C₁₆H₁₃FN₂+H]⁺ [M+H]⁺のLC-MS: 計算値253.1; 実測値:
253.1. ¹H NMR (400 MHz, MeOD) δ [ppm]:
7.81 - 7.78 (m, 1H), 7.58 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.35
(d, J = 7.8 Hz, 1H), 7.13 (dd, J = 9.9, 2.4 Hz, 1H), 6.89 (td, J =9.6, 2.4 Hz,
1H), 4.27 (d, J = 10.0 Hz, 4H).

Tert-Butyl 3- (2- (tert-butoxycarbonyl) isoindoline-5-yl) -6-fluoro-1H-indole-1-carboxylate (Intermediate 146, 525 mg, 1.4 mmol) in DCM (20 mL) ) And CF ₃ COOH (8 mL) were stirred at room temperature overnight. The mixture was concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (300 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC to give 17 mg (15%) of the title compound as a white solid. LC-MS for C ₁₆ H ₁₃ FN ₂ + H] ⁺ [M + H] ⁺ : Calculated 253.1; Found:
253.1. ¹ H NMR (400 MHz, MeOD) δ [ppm]:
7.81-7.78 (m, 1H), 7.58 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.35
(d, J = 7.8 Hz, 1H), 7.13 (dd, J = 9.9, 2.4 Hz, 1H), 6.89 (td, J = 9.6, 2.4 Hz,
1H), 4.27 (d, J = 10.0 Hz, 4H).

Compound 134: 6- (6-Fluoro-1H-indol-3-yl) benzo [d] isothiazol-3 (2H) -one 1,1-dioxide

室温のＤＣＭ（１０．０ｍＬ）中の３−（１，１−ジオキソ−２，３−ジヒドロ−１Ｈ−１ｌ６−ベンゾ［ｄ］イソチアゾール−６−イル）−６−フルオロ−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１４７、５０ｍｇ、０．１１ｍｍｏｌ）の撹拌混合物に、ＴＦＡ（１．０ｍＬ）を添加した。混合反応物を２時間撹拌し、次いでこれを真空下で濃縮した。残留物を分取ＨＰＬＣにより精製して、１４ｍｇ（３１％）の表題化合物を黄色固体として得た。C₁₅H₁₁FN₂O₂S-H^-
[M-H]^-のLC-MS: 計算値301.1;
実測値: 301.0. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.60 (s, 1H), 8.03-8.00 (m, 2H), 7.92 (d, J =
2.4 Hz, 1H), 7.88 - 7.86 (m, 2H), 7.86 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.26
(dd, J = 9.6, 2.0 Hz, 1H), 7.03 - 6.99 (m, 1H), 4.44 (s, 2H).

3- (1,1-Dioxo-2,3-dihydro-1H-11-benzo [d] isothiazol-6-yl) -6-fluoro-indole-1-carvone in DCM (10.0 mL) at room temperature To a stirred mixture of acid tert-butyl ester (Intermediate 147, 50 mg, 0.11 mmol) was added TFA (1.0 mL). The mixed reaction was stirred for 2 hours, then it was concentrated in vacuo. The residue was purified by preparative HPLC to give 14 mg (31%) of the title compound as a yellow solid. _{C 15 H 11 FN 2 O 2} SH -
[MH] ^- the LC-MS: calc 301.1;
Found: 301.0. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.60 (s, 1H), 8.03-8.00 (m, 2H), 7.92 (d, J =
2.4 Hz, 1H), 7.88-7.86 (m, 2H), 7.86 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.26
(dd, J = 9.6, 2.0 Hz, 1H), 7.03-6.99 (m, 1H), 4.44 (s, 2H).

Compound 135: 5- (6-Fluoro-1H-indol-3-yl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide

ステップ１：ｔｅｒｔ−ブチル３−（１，１−ジオキシド−２，３−ジヒドロベンゾ［ｄ］イソチアゾール−５−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート

Step 1: tert-Butyl 3- (1,1-dioxide-2,3-dihydrobenzo [d] isothiazol-5-yl) -6-fluoro-1H-indole-1-carboxylate

２０ｍＬのジオキサンおよび２ｍＬの水中の５−ブロモ−２，３−ジヒドロベンゾ［ｄ］イソチアゾール１，１−ジオキシド（２００ｍｇ、０．８ｍｍｏｌ）、ｔｅｒｔ−ブチル６−フルオロ−３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インドール−１−カルボキシレート（中間体２、２９２ｍｇ、０．８ｍｍｏｌ）、Ｐｄ（ＰＰｈ_３）_４（４６ｍｇ、０．０８ｍｍｏｌ）およびＫ_２ＣＯ_３（２２１ｍｇ、２．４ｍｍｏｌ）の溶液を、１１０℃で２時間撹拌した。混合物を濾過し、濾液を真空中で蒸発させた。残留物を分取ＴＬＣ（ＥｔＯＡｃ／石油エーテル＝１／３）により精製して、２４０ｍｇ（７４％）の表題化合物を白色固体として得た。
ステップ２：
ｔｅｒｔ−ブチル３−（１，１−ジオキシド−２，３−ジヒドロベンゾ［ｄ］イソチアゾール−５−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート（２４０ｍｇ、０．５９ｍｍｏｌ）の溶液を、１０ｍＬのＥＡ／ＨＣｌに溶解した。溶液を６０℃未満で２時間撹拌した。混合物を濾過し、濾液を真空中で蒸発させた。残留物を分取ＴＬＣ（ＥｔＯＡｃ／石油エーテル＝１／３）により精製して、３２ｍｇ（１７％）の最終生成物を黄色固体として得た。C₁₅H₁₁FN₂O₂S-H^- [M-H]^-のLC-MS: 計算値301.0; 実測値:
301.0. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.64 (br s, 1H), 7.95 (dd, J = 8.4, 5.6 Hz, 1H), 7.90 -
7.80 (m, 4H), 7.74 (s, 1H), 7.27-7.25 (m, 1H), 7.03 - 6.98 (m, 1H), 4.45 (d, J
= 4.3 Hz, 2H).

5-bromo-2,3-dihydrobenzo [d] isothiazole 1,1-dioxide (200 mg, 0.8 mmol), tert-butyl 6-fluoro-3- (4,4,4) in 20 mL dioxane and 2 mL water. 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylate (Intermediate 2, 292 mg, 0.8 mmol), Pd (PPh ₃ ) ₄ (46 mg, 0 0.08 mmol) and K ₂ CO ₃ (221 mg, 2.4 mmol) were stirred at 110 ° C. for 2 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC (EtOAc / petroleum ether = 1/3) to give 240 mg (74%) of the title compound as a white solid.
Step 2:
A solution of tert-butyl 3- (1,1-dioxide-2,3-dihydrobenzo [d] isothiazol-5-yl) -6-fluoro-1H-indole-1-carboxylate (240 mg, 0.59 mmol) Was dissolved in 10 mL of EA / HCl. The solution was stirred at less than 60 ° C. for 2 hours. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC (EtOAc / petroleum ether = 1/3) to give 32 mg (17%) of the final product as a yellow solid. _{C 15 H 11 FN 2 O 2} SH - [MH] - the LC-MS: calc 301.0; found:
301.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.64 (br s, 1H), 7.95 (dd, J = 8.4, 5.6 Hz, 1H), 7.90-
7.80 (m, 4H), 7.74 (s, 1H), 7.27-7.25 (m, 1H), 7.03-6.98 (m, 1H), 4.45 (d, J
= 4.3 Hz, 2H).

Compound 136: 6- (6-Fluoro-1H-indol-3-yl) -3- (piperidin-4-yl) benzo [d] oxazol-2 (3H) -one

ＤＣＭ（５ｍＬ）中の３−［３−（１−ｔｅｒｔ−ブトキシカルボニル−ピペリジン−４−イル）−２−オキソ−２，３−ジヒドロ−ベンゾオキサゾール−６−イル］−６−フルオロ−インドール−１−カルボン酸ｔｅｒｔ−ブチルエステル（中間体１５０、１２５ｍｇ、０．２２７ｍｍｏｌ）の撹拌溶液に、ＴＦＡ（１ｍＬ）を−６０℃で滴下添加した。混合物をゆっくりと室温に加温し、さらに１６時間撹拌した後、これを−７８℃に再冷却した。反応物をＴＥＡ（１．５ｍＬ）でクエンチした。混合物をゆっくりと室温に加温し、水（３０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×２）で抽出した。合わせた有機層をブライン（２０ｍＬ×２）で洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣ（添加剤としてＮＨ_４ＨＣＯ_３）により精製して、５０ｍｇ（６３％）の表題化合物をオフホワイトの固体として得た。C₂₀H₁₈FN₃O₂+H⁺
[M+H]⁺のLC-MS: 計算値352.1;
実測値: 352.1. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.42 (br s, 1H), 7.81 (dd, J = 8.8, 5.6 Hz,
1H), 7.68 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.53 - 7.45 (m, 2H), 7.22 (dd, J =
10.0, 2.4 Hz, 1H), 6.95 (td, J = 9.2, 2.4 Hz, 1H), 4.21 - 4.15 (m, 1H), 3.08
(d, J = 12.0 Hz, 2H), 2.59 (t, J = 12.0 Hz, 2H), 2.19 - 2.07 (m, 3H), 1.76 -
1.72 (m, 2H).

3- [3- (1- (tert-Butoxycarbonyl-piperidin-4-yl) -2-oxo-2,3-dihydro-benzoxazol-6-yl] -6-fluoro-indole- in DCM (5 mL) To a stirred solution of 1-carboxylic acid tert-butyl ester (intermediate 150, 125 mg, 0.227 mmol) was added TFA (1 mL) dropwise at -60 ° C. The mixture was slowly warmed to room temperature and stirred for an additional 16 hours before it was re-cooled to -78 ° C. The reaction was quenched with TEA (1.5 mL). The mixture was slowly warmed to room temperature, diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC (NH ₄ HCO ₃ as additive) to give 50 mg (63%) of the title compound as an off-white solid. C ₂₀ H ₁₈ FN ₃ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 352.1;
Found: 352.1. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.42 (br s, 1H), 7.81 (dd, J = 8.8, 5.6 Hz,
1H), 7.68 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.53-7.45 (m, 2H), 7.22 (dd, J =
10.0, 2.4 Hz, 1H), 6.95 (td, J = 9.2, 2.4 Hz, 1H), 4.21-4.15 (m, 1H), 3.08
(d, J = 12.0 Hz, 2H), 2.59 (t, J = 12.0 Hz, 2H), 2.19-2.07 (m, 3H), 1.76-
1.72 (m, 2H).

Compound 137: (6- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] oxazol-5-yl) methanol

ＴＨＦ（１０ｍＬ）中の６−（６−フルオロ−１Ｈ−インドール−３−イル）−２−メチル−ベンゾオキサゾール−５−カルボン酸メチルエステル（中間体１５４、２２０ｍｇ、０．６８ｍｍｏｌ）の溶液に、水素化ジイソブチルアルミニウム（１．０２ｍＬ、１．０２ｍｍｏｌ、ＴＨＦ中１Ｍ）を添加した。混合物を０℃で１時間撹拌した。別のバッチの水素化ジイソブチルアルミニウム（１．０２ｍＬ、１．０２ｍｍｏｌ）を添加し、混合物を室温でさらに４時間撹拌した後、これを飽和ＮＨ_４Ｃｌでクエンチした。混合物をＥｔＯＡｃ（３０ｍＬ×３）で抽出した。合わせた有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させた。溶媒を除去し、残留物を分取ＴＬＣ（ＤＣＭ／メタノール＝２０／１）および分取ＨＰＬＣにより精製して、表題化合物（２３ｍｇ、１１％）を白色固体として得た。C₁₇H₁₃FN₂O₂+H⁺
[M+H]⁺のLC-MS: 計算値297.1;
実測値: 297.1. ¹H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.55 (d, J = 2.0 Hz,
1H), 7.41 (dd, J = 8.4, 5.4 Hz, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.89 (td,
J = 9.6, 2.4 Hz, 1H), 5.19 (t, J = 5.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 2.63
(s, 3H).

To a solution of 6- (6-fluoro-1H-indol-3-yl) -2-methyl-benzoxazole-5-carboxylic acid methyl ester (intermediate 154, 220 mg, 0.68 mmol) in THF (10 mL) was added. Diisobutylaluminum hydride (1.02 mL, 1.02 mmol, 1M in THF) was added. The mixture was stirred at 0 ° C. for 1 hour. Another batch of diisobutylaluminum hydride (1.02 mL, 1.02 mmol) was added and the mixture was stirred at room temperature for an additional 4 hours before it was quenched with saturated NH ₄ Cl. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The solvent was removed and the residue was purified by preparative TLC (DCM / methanol = 20/1) and preparative HPLC to give the title compound (23 mg, 11%) as a white solid. C ₁₇ H ₁₃ FN ₂ O ₂ + H ⁺
[M + H] ⁺ LC-MS: calcd 297.1;
Found: 297.1. ¹ H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.55 (d, J = 2.0 Hz,
1H), 7.41 (dd, J = 8.4, 5.4 Hz, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.89 (td,
J = 9.6, 2.4 Hz, 1H), 5.19 (t, J = 5.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 2.63
(s, 3H).

Compound 138: 5- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] isothiazol-3 (2H) -one 1,1-dioxide

ＨＣｌ／ＥｔＯＡｃ（１０ｍＬ、２Ｍ）中のｔｅｒｔ−ブチル６−フルオロ−３−（２−メチル−１，１−ジオキシド−３−オキソ−２，３−ジヒドロベンゾ［ｄ］イソチアゾール−５−イル）−１Ｈ−インドール−１−カルボキシレート（中間体１５１、６０ｍｇ、０．１４ｍｍｏｌ）の溶液を、６０℃で２時間撹拌した。反応混合物をアンモニアでクエンチし、濃縮し、シリカゲルクロマトグラフィー（ＤＣＭ）により精製して、３５ｍｇ（３２％）の表題化合物を黄色固体として得た。C₁₆H₁₁FN₂O₃S-H^-
[M-H]^-のLC-MS: 計算値329.0;
実測値: 329.0.
¹H NMR
(400 MHz, DMSO-d₆) δ [ppm]: 11.86 (br s,
1H), 8.35-8.29 (m, 3H), 8.16 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.6, 5.0 Hz,
1H), 7.29 (dd, J = 9.6, 2.0 Hz, 1H), 7.06-7.05 (m, 1H), 3.19 (s, 3H).

Tert-Butyl 6-fluoro-3- (2-methyl-1,1-dioxide-3-oxo-2,3-dihydrobenzo [d] isothiazol-5-yl) in HCl / EtOAc (10 mL, 2M) A solution of -1H-indole-1-carboxylate (Intermediate 151, 60 mg, 0.14 mmol) was stirred at 60 ° C for 2 hours. The reaction mixture was quenched with ammonia, concentrated and purified by silica gel chromatography (DCM) to give 35 mg (32%) of the title compound as a yellow solid. _{C 16 H 11 FN 2 O 3} SH -
[MH] ^- the LC-MS: calc 329.0;
Actual value: 329.0.
¹ H NMR
(400 MHz, DMSO-d ₆ ) δ [ppm]: 11.86 (br s,
1H), 8.35-8.29 (m, 3H), 8.16 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.6, 5.0 Hz,
1H), 7.29 (dd, J = 9.6, 2.0 Hz, 1H), 7.06-7.05 (m, 1H), 3.19 (s, 3H).

Compound 139: 2- (2- (cis-3,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazole

メタノール（２０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１００ｍｇ、０．２４ｍｍｏｌ）、水酸化ナトリウム（４７．８ｍｇ、１．１９ｍｍｏｌ）およびｃｉｓ−２，６−ジメチル−ピペラジン（１３３ｍｇ、１．１６ｍｍｏｌ）の溶液を、５０℃で終夜撹拌した。反応混合物を室温に冷却し、濃縮した。残留物を水（１００ｍＬ）で希釈し、ＥｔＯＡｃ（１００ｍＬ×３）で抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣ（ＮＨ_４ＨＣＯ_３）により精製して、３０ｍｇ（３２％）の表題化合物を白色固体として得た。C₂₃H₂₅FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値393.2; 実測値:
393.2. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.46 (br s, 1H), 7.89 - 7.86 (m, 2H), 7.74 (s, 1H), 7.70
(d, J = 8.3 Hz, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.2 Hz,
1H), 6.96 (td, J = 9.3, 2.4 Hz, 1H), 3.11 (t, J = 7.3 Hz, 2H), 2.85 - 2.73 (m,
4H), 2.67 (s, 2H), 1.82 (s, 1H), 1.54 (t, J = 10.3 Hz, 2H), 0.91 (d, J = 6.3
Hz, 6H).

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (intermediate 128, 100 mg, 0.24 mmol), hydroxylated in methanol (20 mL) A solution of sodium (47.8 mg, 1.19 mmol) and cis-2,6-dimethyl-piperazine (133 mg, 1.16 mmol) was stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC (NH ₄ HCO ₃ ) to give 30 mg (32%) of the title compound as a white solid. LC-MS for C ₂₃ H ₂₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated 393.2; Found:
393.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.46 (br s, 1H), 7.89-7.86 (m, 2H), 7.74 (s, 1H), 7.70
(d, J = 8.3 Hz, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.23 (dd, J = 9.9, 2.2 Hz,
1H), 6.96 (td, J = 9.3, 2.4 Hz, 1H), 3.11 (t, J = 7.3 Hz, 2H), 2.85-2.73 (m,
4H), 2.67 (s, 2H), 1.82 (s, 1H), 1.54 (t, J = 10.3 Hz, 2H), 0.91 (d, J = 6.3
Hz, 6H).

Compound 140: 1- (2- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) ethyl) piperidin-4-ol

メタノール（２０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１００ｍｇ、０．２４ｍｍｏｌ）、水酸化ナトリウム（４８ｍｇ、１．１９ｍｍｏｌ）およびピペリジン−４−オール（１２５ｍｇ、１．２３ｍｍｏｌ）の溶液を、５０℃で終夜撹拌した。反応混合物を室温に冷却し、濃縮した。残留物を水（１００ｍＬ）で希釈し、ＥｔＯＡｃ（３００ｍＬ）で抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣ（ＮＨ_４ＨＣＯ_３）により精製して、３３ｍｇ（３６％）の表題化合物を白色固体として得た。C₂₂H₂₂FN₃O₂+H]⁺
[M + H]⁺のLC-MS: 計算値380.2;
実測値: 380.2. ¹H NMR (400 MHz, DMSO-d₆)
δ [ppm]: 11.46 (br s 1H), 7.90-7.86 (m, 2H), 7.74 (d, J
= 2.5 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.23
(dd, J = 10.0, 2.4 Hz, 1H), 6.96-6.93 (m, 1H), 4.51 (s,1H), 3.34 - 3.29 (m,
1H), 3.12 - 3.08 (m, 2H), 2.83 - 2.75 (m, 4H), 2.14 - 2.11 (m, 2H), 1.71
- 1.62 (m, 2H), 1.39 - 1.30 (m, 2H).

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (intermediate 128, 100 mg, 0.24 mmol), hydroxylated in methanol (20 mL) A solution of sodium (48 mg, 1.19 mmol) and piperidin-4-ol (125 mg, 1.23 mmol) was stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (300 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC (NH ₄ HCO ₃ ) to give 33 mg (36%) of the title compound as a white solid. C ₂₂ H ₂₂ FN ₃ O ₂ + H] ⁺
LC-MS for [M + H] ⁺ : calculated 380.2;
Found: 380.2. ¹ H NMR (400 MHz, DMSO-d ₆ )
δ [ppm]: 11.46 (br s 1H), 7.90-7.86 (m, 2H), 7.74 (d, J
= 2.5 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.23
(dd, J = 10.0, 2.4 Hz, 1H), 6.96-6.93 (m, 1H), 4.51 (s, 1H), 3.34-3.29 (m,
1H), 3.12-3.08 (m, 2H), 2.83-2.75 (m, 4H), 2.14-2.11 (m, 2H), 1.71
-1.62 (m, 2H), 1.39-1.30 (m, 2H).

Compound 141: 2- (2- (trans-2,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazole

メタノール（２０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１１０ｍｇ、０．２６ｍｍｏｌ）、水酸化ナトリウム（５３ｍｇ、１．３１ｍｍｏｌ）およびｔｒａｎｓ−２，５−ジメチル−ピペラジン（１５０ｍｇ、１．３１ｍｍｏｌ）の溶液を、５０℃で終夜撹拌した。反応混合物を室温に冷却し、濃縮した。残留物を水（１００ｍＬ）で希釈し、ＥｔＯＡｃで抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣ（ＮＨ_４ＨＣＯ_３）により精製して、６ｍｇ（６％）の表題化合物を白色固体として得た。C₂₃H₂₅FN₄O+H⁺ [M+H]⁺のLC-MS: 計算値: 393.2; 実測値: 393.2. ¹H NMR (400 MHz, MeOD) δ [ppm]: 7.71-7.68 (m, 2H), 7.52 (s, 2H), 7.38 (s, 1H), 6.99 (dd, J =
10.0, 2.4 Hz, 1H), 6.77 (td, J = 9.2, 2.4 Hz, 1H), 3.25-3.19 (m, 1H), 3.05-3.00
(m, 2H), 2.85-2.79 (m, 2H), 2.78-2.67 (m, 2H), 2.36-2.21 (m, 1H), 2.20 (s, 1H),
2.04 (t, J = 10.9 Hz, 1H), 1.10 (m, 6H).

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (intermediate 128, 110 mg, 0.26 mmol), hydroxylated in methanol (20 mL) A solution of sodium (53 mg, 1.31 mmol) and trans-2,5-dimethyl-piperazine (150 mg, 1.31 mmol) was stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC (NH ₄ HCO ₃ ) to give 6 mg (6%) of the title compound as a white solid. LC-MS for C ₂₃ H ₂₅ FN ₄ O + H ⁺ [M + H] ⁺ : Calculated: 393.2; Found: 393.2. ¹ H NMR (400 MHz, MeOD) δ [ppm]: 7.71-7.68 (m , 2H), 7.52 (s, 2H), 7.38 (s, 1H), 6.99 (dd, J =
10.0, 2.4 Hz, 1H), 6.77 (td, J = 9.2, 2.4 Hz, 1H), 3.25-3.19 (m, 1H), 3.05-3.00
(m, 2H), 2.85-2.79 (m, 2H), 2.78-2.67 (m, 2H), 2.36-2.21 (m, 1H), 2.20 (s, 1H),
2.04 (t, J = 10.9 Hz, 1H), 1.10 (m, 6H).

Compound 142: (+)-2- (2-((3R, 5R) -3,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [ d] oxazole

ＭｅＯＨ（１０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１００ｍｇ、０．２４ｍｍｏｌ）の撹拌溶液に、（２Ｒ，６Ｒ）−２，６−ジメチルピペラジン（２７３ｍｇ、２．３９ｍｍｏｌ；Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９５、６０、４１７７により報告されている手順に従って作製した）およびＮａＯＨ（４８ｍｇ、１．２０ｍｍｏｌ）を室温で添加した。混合物をＮ_２下５０℃で１６時間撹拌した。混合物を濃縮し、残留物をＥｔＯＡｃ（５０ｍＬ）で懸濁させた。懸濁液を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、分取ＨＰＬＣ（添加剤としてＮＨ_４ＯＨ）により精製して、表題化合物、３０ｍｇ（３２％）を白色固体として得た。
C₂₃H₂₅FN₄O
+H⁺ [M+H]⁺のLC-MS: 計算値: 393.2; 実測値: 393.2
¹H NMR
(300 MHz, DMSO-d₆) δ [ppm]: 11.46 (br s,
1H), 7.90-7.85 (m, 2H), 7.74 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H),
7.64 (dd, J = 8.1, 1.8 Hz, 1H), 7.23 (dd, J = 9.6, 2.4 Hz, 1H), 6.96 (td, J =
9.6, 2.4 Hz, 1H), 3.12-3.00 (m, 2H), 2.99-2.95 (m, 2H), 2.81-2.68 (m, 2H),
2.43-2.38 (m, 2H), 2.11-2.08 (m, 2H), 1.68 (brs, 1H), 0.95 (d, J = 6.6 Hz, 6H).
[α]²⁰ _D
+10.9° (c=0.2,MeOH).

A stirred solution of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (Intermediate 128, 100 mg, 0.24 mmol) in MeOH (10 mL). (2R, 6R) -2,6-dimethylpiperazine (273 mg, 2.39 mmol; made according to the procedure reported by J. Org. Chem. 1995, 60, 4177) and NaOH (48 mg, 1.20 mmol). ) Was added at room temperature. The mixture was stirred at 50 ° C. under N ₂ for 16 hours. The mixture was concentrated and the residue was suspended in EtOAc (50 mL). The suspension was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC (NH ₄ OH as additive) to give the title compound, 30 mg (32%) as a white solid.
C ₂₃ H ₂₅ FN ₄ O
+ H ⁺ [M + H] ⁺ LC-MS: Calculated: 393.2; Found: 393.2
¹ H NMR
(300 MHz, DMSO-d ₆ ) δ [ppm]: 11.46 (br s,
1H), 7.90-7.85 (m, 2H), 7.74 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H),
7.64 (dd, J = 8.1, 1.8 Hz, 1H), 7.23 (dd, J = 9.6, 2.4 Hz, 1H), 6.96 (td, J =
9.6, 2.4 Hz, 1H), 3.12-3.00 (m, 2H), 2.99-2.95 (m, 2H), 2.81-2.68 (m, 2H),
2.43-2.38 (m, 2H), 2.11-2.08 (m, 2H), 1.68 (brs, 1H), 0.95 (d, J = 6.6 Hz, 6H).
[α] ²⁰ _D
+ 10.9 ° (c = 0.2, MeOH).

Compound 143: 2- (2- (2,6-diazaspiro [3.3] heptan-2-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazole

ＤＣＭ（３ｍＬ）中のｔｅｒｔ−ブチル６−（２−（６−（６−フルオロ−１Ｈ−インドール−３−イル）ベンゾ［ｄ］オキサゾール−２−イル）エチル）−２，６−ジアザスピロ［３．３］ヘプタン−２−カルボキシレート（中間体１５２、１７０ｍｇ、０．３５ｍｍｏｌ）の溶液に、ＴＦＡ（１ｍＬ）を添加した。混合物を室温で２時間撹拌した後、これを濃縮した。残留物を分取ＨＰＬＣにより精製して、生成物、６６ｍｇ（４９％）を白色固体として得た。C₂₂H₂₁FN₄O [M+ H]⁺のLC-MS: 計算値376.2; 実測値:
376.8. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.50 (br s, 1H), 7.90-7.86 (m, 2H), 7.75 (s, 1H), 7.71-7.63
(m, 2H), 7.23 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (td, J = 18.8, 2.0 Hz, 1H), 3.82
(s, 2H), 3.48 (s, 2H), 3.20 (s, 4H), 2.94-2.90 (m, 2H), 2.83-2.81 (m, 2H).

Tert-Butyl 6- (2- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) ethyl) -2,6-diazaspiro [3 in DCM (3 mL) .3] To a solution of heptane-2-carboxylate (intermediate 152, 170 mg, 0.35 mmol) was added TFA (1 mL). After the mixture was stirred at room temperature for 2 hours, it was concentrated. The residue was purified by preparative HPLC to give the product, 66 mg (49%) as a white solid. _{C 22 H 21 FN 4 O [} M + H] + of LC-MS: calc 376.2; found:
376.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.50 (br s, 1H), 7.90-7.86 (m, 2H), 7.75 (s, 1H), 7.71-7.63
(m, 2H), 7.23 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (td, J = 18.8, 2.0 Hz, 1H), 3.82
(s, 2H), 3.48 (s, 2H), 3.20 (s, 4H), 2.94-2.90 (m, 2H), 2.83-2.81 (m, 2H).

Compound 144: (−)-2- (2-((3S, 5S) -3,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [ d] oxazole

ＭｅＯＨ（１０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１００ｍｇ、０．２４ｍｍｏｌ）の撹拌溶液に、（２Ｓ，６Ｓ）−２，６−ジメチルピペラジン（１３６ｍｇ、１．１９ｍｍｏｌ；Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９５、６０、４１７７により報告されている手順に従って作製した）およびＮａＯＨ（４８ｍｇ、１．２０ｍｍｏｌ）を室温で添加した。混合物をＮ_２下５０℃で１６時間撹拌した。ＭｅＯＨを真空下で除去し、残留物をＥＡ（５０ｍＬ）で懸濁させた。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮し、分取ＨＰＬＣ（添加剤としてＮＨ_４ＯＨ）により精製して、４５ｍｇ（４９％）の表題化合物を白色粉末として得た。
C₂₃H₂₅FN₄O+H⁺
[M+H]⁺のLC-MS: 計算値: 393.2; 実測値: 393.2
¹H NMR
(400 MHz, DMSO-d₆) δ [ppm]: 11.48 (br s,
1H), 7.89-7.86 (m, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 13.6 Hz, 2H),
7.24 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 9.6, 2.4 Hz, 1H), 3.12-3.00 (m,
2H), 3.00-2.98 (m, 2H), 2.80-2.77 (m, 2H), 2.43-2.40 (m, 2H), 2.12-2.10 (m,
2H), 1.68 (brs, 1H), 0.97 (d, J = 6.4 Hz, 6H).

A stirred solution of 6- (6-fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (Intermediate 128, 100 mg, 0.24 mmol) in MeOH (10 mL). (2S, 6S) -2,6-dimethylpiperazine (136 mg, 1.19 mmol; made according to the procedure reported by J. Org. Chem. 1995, 60, 4177) and NaOH (48 mg, 1.20 mmol). ) Was added at room temperature. The mixture was stirred at 50 ° C. under N ₂ for 16 hours. MeOH was removed under vacuum and the residue was suspended in EA (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC (NH ₄ OH as additive) to give 45 mg (49%) of the title compound as a white powder.
C ₂₃ H ₂₅ FN ₄ O + H ⁺
LC-MS for [M + H] ⁺ : calcd: 393.2; found: 393.2
¹ H NMR
(400 MHz, DMSO-d ₆ ) δ [ppm]: 11.48 (br s,
1H), 7.89-7.86 (m, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 13.6 Hz, 2H),
7.24 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 9.6, 2.4 Hz, 1H), 3.12-3.00 (m,
2H), 3.00-2.98 (m, 2H), 2.80-2.77 (m, 2H), 2.43-2.40 (m, 2H), 2.12-2.10 (m,
2H), 1.68 (brs, 1H), 0.97 (d, J = 6.4 Hz, 6H).

Compound 145: 4- (2- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) ethyl) piperazine-2-carboxylic acid

メタノール（２０ｍＬ）中の６−（６−フルオロ−１−（フェニルスルホニル）−１Ｈ−インドール−３−イル）−２−ビニルベンゾ［ｄ］オキサゾール（中間体１２８、１２０ｍｇ、０．２８ｍｍｏｌ）、水酸化ナトリウム（５７ｍｇ、１．４３ｍｍｏｌ）およびピペラジン−２−カルボン酸（４３８ｍｇ、３．４ｍｍｏｌ）の溶液を、５０℃で終夜撹拌した。反応混合物を室温に冷却し、濃縮した。残留物を水（１００ｍＬ）で希釈し、ＥｔＯＡｃ（２００ｍＬ）で抽出した。有機層を無水Ｎａ_２ＳＯ_４で乾燥させ、濾過した。濾液を濃縮し、分取ＨＰＬＣ（ＮＨ_４ＨＣＯ_３）により精製して、１２ｍｇ（１０％）の表題化合物を白色固体として得た。C₂₂H₂₁FN₄O₃+H⁺
[M + H]⁺のLC-MS: 計算値:
409.2; 実測値: 408.8. ¹H NMR (400 MHz,
DMSO-d₆) δ [ppm]: 11.51 (br s, 1H), 7.90 -
7.87 (m, 2H), 7.75 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H),
7.24 (d, J = 10.4 Hz, 1H), 6.96 (t, J = 9.6 Hz, 1H), 3.34-3.09 (m, 5H), 3.05
(d, J = 11.6 Hz, 1H), 2.92-2.87 (m, 3H), 2.78 (t, J = 11.6 Hz, 1H), 2.27 -2.18
(m, 2H).

6- (6-Fluoro-1- (phenylsulfonyl) -1H-indol-3-yl) -2-vinylbenzo [d] oxazole (intermediate 128, 120 mg, 0.28 mmol), hydroxylated in methanol (20 mL) A solution of sodium (57 mg, 1.43 mmol) and piperazine-2-carboxylic acid (438 mg, 3.4 mmol) was stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by preparative HPLC (NH ₄ HCO ₃ ) to give 12 mg (10%) of the title compound as a white solid. C ₂₂ H ₂₁ FN ₄ O ₃ + H ⁺
[M + H] ⁺ LC-MS: Calculated:
409.2; Found: 408.8. ¹ H NMR (400 MHz,
DMSO-d ₆ ) δ [ppm]: 11.51 (br s, 1H), 7.90-
7.87 (m, 2H), 7.75 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H),
7.24 (d, J = 10.4 Hz, 1H), 6.96 (t, J = 9.6 Hz, 1H), 3.34-3.09 (m, 5H), 3.05
(d, J = 11.6 Hz, 1H), 2.92-2.87 (m, 3H), 2.78 (t, J = 11.6 Hz, 1H), 2.27 -2.18
(m, 2H).

Compound 146: 3- (benzofuran-6-yl) -6-fluoro-1H-indole

ＤＣＭ（２．０ｍＬ）中のｔｅｒｔ−ブチル３−（ベンゾフラン−６−イル）−６−フルオロ−１Ｈ−インドール−１−カルボキシレート（中間体１５３、５８ｍｇ、０．３２ｍｍｏｌ）の撹拌溶液に、アニソール（０．２ｍＬ）およびＴＦＡ（１ｍＬ）を添加した。混合物を室温で終夜撹拌した。反応混合物を濃縮した。残留物を分取ＴＬＣ（ＥｔＯＡｃ／石油エーテル＝１／５）および分取ＨＰＬＣで精製して、１６ｍｇの表題化合物を得た。C₁₆H₁₀FNO+H⁺ [M+H]⁺のLC-MS: 計算値: 252.1; 実測値: 251.9. ¹H NMR (400 MHz, DMSO- d₆) δ [ppm]: 11.47 (br s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.90 (dd, J
=8.8, 5.2 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 8.0 Hz,
1H), 7.59 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 9.8, 2.4 Hz, 1H), 6.97 (td,
J = 9.2, 2.4 Hz, 2H).

To a stirred solution of tert-butyl 3- (benzofuran-6-yl) -6-fluoro-1H-indole-1-carboxylate (intermediate 153, 58 mg, 0.32 mmol) in DCM (2.0 mL) was added anisole. (0.2 mL) and TFA (1 mL) were added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified by preparative TLC (EtOAc / petroleum ether = 1/5) and preparative HPLC to give 16 mg of the title compound. LC-MS for C ₁₆ H ₁₀ FNO + H ⁺ [M + H] ⁺ : Calculated: 252.1; Found: 251.9. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ [ppm]: 11.47 (br s , 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.90 (dd, J
= 8.8, 5.2 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 8.0 Hz,
1H), 7.59 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 9.8, 2.4 Hz, 1H), 6.97 (td,
J = 9.2, 2.4 Hz, 2H).

II. Biology Example II. 1. Assay for TDO2 Enzyme Activity Compounds of formula I inhibit the enzyme activity of human TDO2.

  To measure TDO2 activity, Dolusic et al. Med. Chem. 2011, 54, 5320-533 were adapted. The reaction mixture consists of potassium phosphate buffer (50 mM, pH 7.5), ascorbic acid (0.25 M), methylene blue (0.125 μM), catalase (40 units / mL, from bovine liver, Sigma), and human recombinant TDO2 enzyme (prepared as described in Dolusic et al., J. Med. Chem., 2011, 54, 5320-5334, 0.9 μg) without or at the indicated concentration of the compound of the invention. (Final concentration) (total volume 112.5 μL). The reaction was started by adding 37.5 μL L-Trp (final concentration 1 mM) at room temperature. The reaction was carried out at room temperature for 1 hour and stopped by adding 30 μL of 30% (w / v) trichloroacetic acid.

  To convert N-formylkynurenine to kynurenine, the reaction mixture was incubated at 65 ° C. for 30 minutes. 150 μL of the reaction mixture was then mixed with 120 μL of 2.5% (w / v) 4- (dimethylamino) -benzaldehyde in acetic acid and incubated at room temperature for 5 minutes. The kynurenine concentration was determined by measuring the absorbance at 480 nm. Calibration curves were made with pure kynurenine. TDO activity was measured as described above using 10 concentrations of the compounds of the invention. The data was fitted using standard parameters using Prism ™ software (GraphPad Software, Inc.).

  The biological activity of representative compounds is summarized in the table below.

  In one embodiment, a compound is selected that has an IC50 of less than 2000 nm, preferably an IC50 of less than 1000 nm.

II. 2. Cell assay for TDO2 activity II. 2. a P815 cells overexpressing hTDO2 Compounds of formula I inhibit the activity of human TDO2 in cells.

Murine mastocytoma P815 cells overexpressing hTDO2 (prepared as described in Pilotte et al., PNAS, 2012, 109 (7), 2497-2502) were transferred to 5 × 10 ⁴ cells / well in a final volume of 200 μL. The assay (Pilotte L et al., Proc Natl Acad Sci USA, 2012, 109 (7), 2497-502 adapted) was performed in 96 well flat bottom plates seeded at a concentration of To determine TDO or IDO activity, cells were cultured in IMDM (Invitrogen) supplemented with 2% FBS and 2% penicillin / streptomycin in the presence of different concentrations of the compounds of the invention at 37 ° C., 5% CO _2. Incubated overnight. The cells can be obtained from [ATCC® TIB-64 ™, or commercially available from, for example, Sigma-Aldrich or Life Technologies, from the American Cultured Cell Line Conservation Organization.

  The plate was then centrifuged at 1000 rpm for 5 minutes and 100 μL of the supernatant was collected on a conical plate, 30 uL TCA 30% was added and further centrifuged at 3000 × g for 10 minutes. 100 μL of the supernatant was collected in a flat bottom plate containing 100 μL of 2% (w / v) 4- (dimethylamino) -benzaldehyde in acetic acid and incubated for 5 minutes at room temperature. The kynurenine concentration was determined by measuring the absorbance at 480 nm. Calibration curves were made with pure kynurenine. TDO activity was measured as described above using 10 concentrations of the compounds of the invention. The data was fitted using standard parameters using Prism ™ software (GraphPad Software, Inc.).

  The biological activity of representative compounds is summarized in the table below.

In one embodiment, compounds with an IC ₅₀ of less than 2000 nm are selected. In another embodiment, compounds with an IC ₅₀ of less than 1000 nm are selected.

II. 2. b A172 cells Compounds of formula I inhibit the activity of human TDO2 in cells that constitutively express TDO2, such as A172 cells. A172 is a cell line derived from human brain glioblastoma cells. This cell is available as CRL-1620 ™ from the American Cultured Cell Line Conservation Organization (ATCC®).

Human glioblastoma A172 cells spontaneously expressing hTDO2 (prepared as described in Tilman et al., Mol Cancer, 2007, 17 (6), 80) were 1.25 × 10 ⁴ cells in a final volume of 200 μL. The assay (Pilotte L et al., Proc Natl Acad Sci USA, 2012, 109 (7), 2497-502 adapted) was performed in 96 well flat bottom plates seeded at a concentration of / well. To determine TDO, cells are incubated overnight at 37 ° C., 5% CO ₂ in IMDM (Invitrogen) supplemented with 2% FBS and 2% penicillin / streptomycin in the presence of different concentrations of the compounds of the invention. did.

  The plate was then centrifuged at 1000 rpm for 5 minutes and 100 μL of the supernatant was collected on a conical plate, 30 uL TCA 30% was added and further centrifuged at 3000 × g for 10 minutes. 100 μL of the supernatant was collected in a flat bottom plate and 100 μL of 2% (w / v) 4- (dimethylamino) -benzaldehyde in acetic acid and incubated at room temperature for 5 minutes. The kynurenine concentration was determined by measuring the absorbance at 480 nm. Calibration curves were made with pure kynurenine. TDO activity was measured as described above using 10 concentrations of the compounds of the invention. The data was fitted using standard parameters using Prism ™ software (GraphPad Software, Inc.).

  The biological activity of representative compounds is summarized in the table below.

In one embodiment, compounds with an IC ₅₀ of less than 2000 nm are selected. In another embodiment, compounds with an IC ₅₀ of less than 1000 nm are selected.

II. 3. Pharmacodynamic assay for in vivo activity of TDO2: Increasing blood tryptophan levels in mice Compounds of the invention increase the amount of tryptophan in mouse blood. Briefly, female BALB / c mice (7-8 weeks of age) were treated with 0.5% hydroxypropylmethylcellulose (1%) of one of the compounds of the present invention at different doses (30, 60, and 100 mg / kg). HPMC) Suspension suspended in K4M (4000 mPa · s (cPs), Methocell ™, Dow chemical) /0.25% Tween® 20 (Signa Aldrich), or vehicle control (0.5 % HPMC K4M / 0.25% Tween 20) were treated by oral route by gavage (dosing volume 5 mL / kg, 10 mice per group). Two hours later, blood was collected, plasma was prepared, and the amount of tryptophan present was measured using LC-MS-MS (HPLC column Unison UK-Phenyl, 75 × 4.6, 3 μm, flow rate 0.8 mL / min, 95 1. 8% gradient from 5% water + 0.1% formic acid / 5% acetonitrile + 0.1% formic acid to 5% water + 0.1% formic acid / 95% acetonitrile + 0.1% formic acid, retention time 4 min; determined by AB Sciex API 4000 MS-MS system, ESI + mode, parent ion 205.1, daughter ion 146.1).

  As shown in the table below, Compound 110 has 46% (p <0.0001) circulating tryptophan at 30 mg / kg and 52% at 60 mg / kg (p <0. 0001), 100 mg / kg, increased by 78% (p <0.0001).

Tryptophan concentration in plasma (mean ± standard error of mean, nM):

  All publications cited herein, as well as priority applications, including US Provisional Patent Application No. 61 / 996,975, filed March 18, 2014, are incorporated herein by reference. Although the invention has been described in connection with specific embodiments, it will be understood that modifications may be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims (30)

Compound of formula I

Or a pharmaceutically acceptable enantiomer, salt, or solvate thereof, wherein
X ¹ and X ² each independently represent H, halogen, alkyl, or haloalkyl,
R ¹ , R ² , and R ³ each independently represent H, halogen, C1-C6 alkyl, alkoxy, or haloalkyl, which are halogen, hydroxyl, OR ⁴ , COOR ⁴ , CONR ⁴ R ⁵ , NR ⁴ COR ⁵ , NR ⁴ R ⁵ , SO ₂ R ⁴ , SO ₂ NR ⁴ R ⁵ , NR ⁴ SO ₂ R ⁵ , SO ₂ R ⁴ , aryl, CO-alkyl, or selected from halogen, hydroxyl, amino or COOH Optionally substituted with one or more substituents selected from C1-C6 alkyl optionally substituted with one or more groups wherein R ⁴ and R ⁵ are each independently hydrogen Atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl Represents an optionally substituted group selected from: alkylheteroaryl, or amino;
A ¹ , A ² , and A ³ each independently represent C, N, S, or O, and when A ¹ , A ² , or A ³ is S, A ¹ -Y ¹ , A ^2- Y ² or A ³ -Y ³ may be SO ₂ ,
Each of Y ¹ , Y ² , and Y ³ is absent or, independently,
e) a hydrogen atom,
f) Oxo,
g) SH,
^{h) CR 6 R 7 R 8} , NR 6 R 7, and OR ⁶
R ⁶ , R ⁷ , and R ⁸ are each independently
i) a hydrogen atom,
ii) halogen,
iii) hydroxyl,
iv) OR ⁹ or NR ⁹ R ¹⁰ [R ⁹ and R ¹⁰ are each independently a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino Represents an optionally substituted group selected from CO ₂ , CO-alkyl, or SO ₂ R ¹¹ , wherein R ¹¹ is a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl Represents an optionally substituted group selected from alkyl, alkylheteroaryl, hydroxyl, or amino],
v) straight or branched C1~C10 alkyl [with halogen, ^{hydroxyl, OR 9, COOR 9, CONR} 9 R 10, NR 9 COR 10, NR 9 R 10, SO 2 R 9, SO 2 NR 9 R 10, NR 9 Optionally substituted with up to three substituents selected from SO ₂ R ¹⁰ , SOR ⁹ , aryl, or CO-alkyl, wherein R ⁹ and R ¹⁰ are each independently a hydrogen atom or C ¹ -C 6. Represents an optionally substituted group selected from alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino],
vi) heterocyclyl or C1~C2 alkyl - heterocyclyl [heterocyclyl substituent halogen, up to three, hydroxyl, ^{oxo, OR 9, COOR 9, CONR} 9 R 10, NR 9 COR 10, NR 9 R 10, SO 2 R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ , aryl, CO-alkyl, or alkyl, the alkyl group is from halogen, hydroxyl, amino, or COOH R ⁹ and R ¹⁰ may each independently be a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl, optionally substituted with one or more selected groups Alkyl, alkylheteroaryl, or amino It represents the optionally substituted group selected,
vii) —CO—R ¹¹ or —SO ₂ R ¹¹ [R ¹¹ represents a group selected from hydroxy, amine, alkyl, heterocyclyl, halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SOR ⁹ , aryl, CO-alkyl, or 1 selected from halogen, hydroxyl, amino or COOH R ⁹ and R ¹⁰ are each independently a hydrogen atom, optionally substituted with up to three substituents selected from the group comprising C1-C6 alkyl optionally substituted with one or more groups Or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroaryl Ruarukiru, alkyl heteroaryl or group which may be substituted are selected from amino,]
Represents
viii) when Y 1, Y 2, or Y 3 is CR ⁶ R ⁷ R ⁸ , R ⁶ , R ⁷ , and the carbon atom to which they are attached together,
Cycloalkyl [halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , SO ₂ R ⁹ substituted with up to 3 substituents selected from aryl, CO-alkyl, or C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino Represents an optionally substituted group] or heterocyclyl [Halogen, ^{hydroxyl, OR 9, COOR 9, CONR} 9 R 10, NR 9 COR 10, NR 9 R 10, SO 2 R 9, SO 2 NR 9 R 10, NR 9 SO 2 R 10, SO 2 R 9, With up to three substituents selected from the group comprising aryl, CO-alkyl, or C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH Optionally substituted, R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, or C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino Represents an optionally substituted group]
Or ix) when Y 1, Y 2, or Y 3 is NR ⁶ R ⁷ , R ⁶ , R ⁷ , and the nitrogen atom to which they are attached together And may form a ring, and the ring is halogen, hydroxyl, OR ⁹ , COOR ⁹ , CONR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ R ¹⁰ , SO ₂ R ⁹ , SO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ R ¹¹ , SO ₂ R ⁹ , aryl, CO-alkyl, or C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxyl, amino or COOH may be substituted with up to three substituents selected from, R ⁹ and R ¹⁰ each independently represent a hydrogen atom, or a C1~C6 alkyl, Le represents arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkyl heteroaryl or optionally substituted group selected from amino, R ¹¹ is a hydrogen atom or an aryl, arylalkyl, alkylaryl Represents an optionally substituted group selected from:, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino, or R ¹¹ is halogen, hydroxyl, OR ¹² , COOR ¹² , CONR ¹² R ¹³ , NR ¹² Substituted with up to three substituents selected from COR ¹³ , NR ¹² R ¹³ , SO ₂ R ¹² , SO ₂ NR ¹² R ¹³ , NR ¹² SO ₂ R ¹³ , SO ₂ R ¹² , or aryl Represents a good alkyl group, R ¹² and R ¹³ are each independently a hydrogen atom or a substituted group selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino. Represents a group,
The dotted line represents a single bond or a double bond,
However, A ¹ , A ² and A ³ are not all C,
However, if ^one of A ¹ and A ³ is N, the other two are not both C, provided that ^one of A ¹ , A ² , and A ³ is S Where only one S is present, at least one C is present and the other is C or N;
However, the compound of formula I is not 3- (benzofuran-5-yl) -6-chloro-1H-indole or 3- (benzo [d] [1,3] dioxol-5-yl) -1H-indole. ]. The compound of claim 1, wherein X ¹ and X ² are independently H or F. The compound according to claim ² , wherein R ¹ , R ² and R ³ each independently represent H, halogen or methyl. The compound according to claim 1 or ² , wherein R ¹ , R ² , and R ³ are each H. If R ^{6, R} 7 or when R ^8, represents halogen, halogen is F, the compound according to any one of claims 1 to 4. When R ⁶ , R ⁷ , or R ⁸ is heterocyclyl or C1-heterocyclyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or 2,6-diazaspiro [3.3] heptane, both of which are , C1 to C3 alkyl, amino, hydroxyl, halogen, COCH3, COOH, or optionally substituted with one or more of _SO 2 CH _3, a compound according to any one of claims 1 to 4, . The compound according to any one of claims 1 to 4, wherein when R ⁶ , R ⁷ , or R ⁸ is C1-C10 alkyl, the alkyl is methyl, ethyl, or propyl. The compound according to claim 1, wherein when R ¹¹ is a heterocycle, the heterocycle is piperidine, pyrrolidine, piperazine, or tetrahydrothiopyran dioxide. When R ⁶ , R ⁷ and the carbon atom to which they are attached form a ring that is a heterocycle, the heterocycle is morpholine, piperazine, or piperidine, both of which are substituted The compound of claim 1, which may be   The compound according to claim 1, wherein R6, R7 and the nitrogen atom to which they are bonded form a heterocyclyl ring.   The compound according to claim 10, wherein the heterocycle is morpholine, piperazine, or piperidine, any of which may be substituted. The ^{first one of} A ¹ , A ² , and A ³ is N, the ^{second of} A ¹ , A ² , and A ³ is C, and A ¹ , A ² , and A 12. A compound according to any one of claims 1 to 11 wherein the ^third of ³ is N or O. The compound according to any one of claims 1 to 12, wherein A ² is N, one of A ¹ and A ³ is N or S, and the other is C. When A ¹ or ^{A 3} is ^S, A 1 -Y ¹ or ^A 3 -Y ³ is SO _2, A compound according to claim 13. The compound according to any one of claims 1 to 11, wherein A ² is C, one of A ¹ and A ³ is N, and the other is N or O. A ¹ or A ³ is O, and another of A ¹ , A ² , or A ³ is C substituted with CR ⁶ R ⁷ R ⁸ , R ⁶ , R ⁷ , or R ⁸ is heterocyclyl or C1-C2 alkyl-heterocyclyl, where heterocyclyl is azetidine substituted with piperidine, pyrrolidine, piperazine, morpholine, or azetidine, any of which are C1-C3 alkyl, amino, hydroxyl , halogen, COCH3, COOH, or optionally substituted with one or more of _SO 2 CH _3, the compound according to claim 15. One of A ¹ , A ² , or A ³ is S, or A ¹ -Y ¹ , A ² -Y ² , or A ³ -Y ³ is SO ₂ , and A ¹ , A ² , or one of a ³ is N or ^{C, a 1,} a ^2, and one of ^{a 3} but is C, a compound according to any one of claims 1 to 11. 6- (6-Fluoro-1H-indol-3-yl) -1H-indazole;
-2- (6- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) acetamide;
6- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole;
1- (4-((6- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone;
-3- (6- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanamide;
6- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazole;
1- (4- (6- (6- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) piperidin-1-yl) ethanone;
-5- (6-Fluoro-1H-indol-3-yl) -1H-indazole;
-2- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) acetamide;
-5- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-ylmethyl) -1H-indazole;
1- (4-((5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) methyl) piperidin-1-yl) ethanone;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanamide;
-5- (6-Fluoro-1H-indol-3-yl) -1- (piperidin-4-yl) -1H-indazole;
1- (4- (5- (6- (fluoro-1H-indol-3-yl) -1H-indazol-1-yl) piperidin-1-yl) ethanone;
-2- (6- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) acetamide;
1- (4-((6- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidin-1-yl) ethanone;
-3- (6- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) propanamide;
6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -2H-indazole;
1- (4- (6- (6- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidin-1-yl) ethanone;
-2- (5- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) acetamide;
1- (4-((5- (6-fluoro-1H-indol-3-yl) -2H-indazol-2-yl) methyl) piperidin-1-yl) ethanone;
-3- (5- (6-Fluoro-1H-indol-3-yl) -2H-indazol-2-yl) propanamide;
-5- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -2H-indazole;
1- (4- (5- (6- (fluoro-1H-indol-3-yl) -2H-indazol-2-yl) piperidin-1-yl) ethanone;
-5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazole;
-5- (6-Fluoro-1H-indol-3-yl) -2-methyl-1H-benzo [d] imidazole;
-(5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methanamine;
1- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) -N, N-dimethylmethanamine;
2-((((5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) amino) ethanol;
-N-((5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) acetamide;
-2-amino-N-((5- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) acetamide;
-N-((5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) methanesulfonamide;
-5- (6-Fluoro-1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) -1H-benzo [d] imidazole;
-5- (6-Fluoro-1H-indol-3-yl) -2-((4- (methylsulfonyl) piperazin-1-yl) methyl) -1H-benzo [d] imidazole;
-2- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethanamine;
N- (2- (5- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethyl) acetamide;
-N- (2- (5- (6- (6-fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) ethyl) methanesulfonamide;
-5- (6-Fluoro-1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) -1H-benzo [d] imidazole;
-5- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) -1H-benzo [d] imidazole;
-5- (6-Fluoro-1H-indol-3-yl) -2- (1- (methylsulfonyl) piperidin-4-yl) -1H-benzo [d] imidazole;
-5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-amine;
-N- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) acetamide;
-N- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methanesulfonamide;
1- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) -N-methylmethanamine;
-4-((5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) methyl) morpholine;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) propanamide;
-5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazole;
-5- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] oxazole;
-5- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole;
1- (4- (5- (6- (fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidin-1-yl) ethanone;
-N- (5- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) acetamide;
-N- (5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanesulfonamide;
6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazole;
6- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] oxazole;
6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-yl) benzo [d] oxazole;
1- (4- (6- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidin-1-yl) ethanone;
-N- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) acetamide;
-N- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanesulfonamide;
6- (6-Fluoro-1H-indol-3-yl) -2- (piperazin-1-ylmethyl) -1H-benzo [d] imidazole;
-2- (6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2-yl) acetamide;
-5- (6-Fluoro-1H-indol-3-yl) -2- (piperazin-1-ylmethyl) benzo [d] oxazole;
-5- (6-Fluoro-1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) benzo [d] oxazole;
-5- (6-Fluoro-1H-indol-3-yl) -2- (morpholinomethyl) benzo [d] oxazole;
-2- (6- (6-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide;
-5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-2 (3H) -one;
6- (6-Fluoro-1H-indol-3-yl) -2- (morpholinomethyl) benzo [d] oxazole;
-3- (6- (6-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propanamide;
6- (6-Fluoro-1H-indol-3-yl) -2-((4-methylpiperazin-1-yl) methyl) benzo [d] oxazole;
-2- (5- (6-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide;
-N-((5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide;
-3- (5- (6-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propanamide;
-3- (benzo [b] thiophen-5-yl) -6-fluoro-1H-indole;
-N-((5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) acetamide;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) acetamide;
-(6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine;
-5- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-ylmethyl) -2H-indazole;
6- (6-Fluoro-1H-indol-3-yl) -2- (piperazin-1-ylmethyl) benzo [d] oxazole;
-3- (benzo [b] thiophen-6-yl) -6-fluoro-1H-indole;
-5- (6-Fluoro-1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) benzo [d] oxazole;
-(5- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methanamine;
-3- (benzofuran-5-yl) -6-fluoro-1H-indole;
-3- (6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) propanamide;
-2- (6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide;
-2- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) acetamide;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -1-morpholinopropan-1-one;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -1- (4-methylpiperazin-1-yl) propan-1-one;
-N- (2- (dimethylamino) ethyl) -3- (5- (6-fluoro-1H-indol-3-yl) -1H-indazol-1-yl) propanamide;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -N- (2-hydroxyethyl) propanamide;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -N- (2- (methylsulfonyl) ethyl) propanamide;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-indazol-1-yl) -1- (piperazin-1-yl) propan-1-one;
6- (6-Fluoro-1H-indol-3-yl) indoline-2-one;
-3- (6- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide;
-3- (5- (6-Fluoro-1H-indol-3-yl) -1H-benzo [d] imidazol-1-yl) propanamide;
1- (4- (6- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) piperidin-1-yl) ethanone;
6- (6-Fluoro-1H-indol-3-yl) -2- (1- (methylsulfonyl) piperidin-4-yl) benzo [d] oxazole;
-5- (6-Fluoro-1H-indol-3-yl) indoline-2-one;
6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-amine;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2-methoxyethanesulfonamide;
2- (dimethylamino) -N-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) ethanesulfonamide;
6- (6-Fluoro-1H-indol-3-yl) -2- (2- (methylsulfonyl) ethyl) benzo [d] oxazole;
1-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) urea;
1-carbamoyl-1-((6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) urea;
-5- (1H-indol-3-yl) -1H-indazole;
6- (6-Fluoro-1H-indol-3-yl) -2- (2- (4-methylpiperazin-1-yl) ethyl) benzo [d] oxazole;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2-hydroxyethanesulfonamide;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2-morpholinoethanesulfonamide;
6- (1H-indol-3-yl) -1H-indazole;
6- (1H-indol-3-yl) benzo [d] oxazole;
6- (6-Fluoro-1H-indol-3-yl) -2- (2- (piperazin-1-yl) ethyl) benzo [d] oxazole;
-5- (6-Chloro-1H-indol-3-yl) benzo [d] oxazole;
6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazole-2-thiol;
6- (6-Fluoro-1H-indol-3-yl) -2- (piperidin-4-ylmethyl) benzo [d] oxazole;
-N-((6- (1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide;
-(S) -N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -1-methylpyrrolidine-2-carboxamide;
6- (6-Fluoro-1H-indol-3-yl) -2-methoxybenzo [d] oxazole;
-Amino {[6- (6-fluoroindol-3-yl) benzoxazol-2-yl] methyl} sulfonamide;
-5- (1H-indol-3-yl) benzo [d] oxazole;
6- (6-Fluoro-1H-indol-3-yl) -2-((1- (methylsulfonyl) piperidin-4-yl) methyl) benzo [d] oxazole;
6- (6-Fluoro-1H-indol-3-yl) -2- (2- (4- (methylsulfonyl) piperazin-1-yl) ethyl) benzo [d] oxazole;
-5- (5-chloro-1H-indol-3-yl) benzo [d] oxazole;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (4-methylpiperazin-1-yl) ethanesulfonamide;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (piperazin-1-yl) ethanesulfonamide;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (pyrrolidin-1-yl) ethanesulfonamide;
6- (6-Fluoro-1H-indol-3-yl) -2-((1-methylpiperidin-4-yl) methyl) benzo [d] oxazole;
-N-((6- (6-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) -2- (4- (methylsulfonamido) piperidin-1-yl) ethane Sulfonamide;
-N-((6- (6-chloro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide;
N-((6- (5-Fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) methyl) methanesulfonamide-5-((6- (6-fluoro-1H-indole -3-yl) benzo [d] oxazol-2-yl) methyl) imidazolidine-2,4-dione;
-5- (6-Fluoro-1H-indol-3-yl) benzo [d] isothiazol-3 (2H) -one 1,1-dioxide;
-2- (6- (5-Fluoro-1H-indol-3-yl) -2-oxobenzo [d] oxazol-3 (2H) -yl) acetamide;
-5- (6-Fluoro-1H-indol-3-yl) isoindoline-1,3-dione;
6-fluoro-3- (isoindoline-5-yl) -1H-indole;
6- (6-Fluoro-1H-indol-3-yl) benzo [d] isothiazol-3 (2H) -one 1,1-dioxide;
-5- (6-Fluoro-1H-indol-3-yl) -2,3-dihydrobenzo [d] isothiazole 1,1-dioxide;
6- (6-Fluoro-1H-indol-3-yl) -3- (piperidin-4-yl) benzo [d] oxazol-2 (3H) -one;
-(6- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] oxazol-5-yl) methanol;
-5- (6-Fluoro-1H-indol-3-yl) -2-methylbenzo [d] isothiazol-3 (2H) -one 1,1-dioxide;
2- (2- (cis-3,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazole;
1- (2- (6- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) ethyl) piperidin-4-ol;
2- (2- (2- (trans-2,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazole;
-(+)-2- (2-((3R, 5R) -3,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] Oxazole;
2- (2- (2,6-diazaspiro [3.3] heptan-2-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazole;
-(-)-2- (2-((3S, 5S) -3,5-dimethylpiperazin-1-yl) ethyl) -6- (6-fluoro-1H-indol-3-yl) benzo [d] Oxazole;
4- (2- (6- (6- (6-fluoro-1H-indol-3-yl) benzo [d] oxazol-2-yl) ethyl) piperazine-2-carboxylic acid; or -3- (benzofuran-6 Yl) -6-fluoro-1H-indole, or a pharmaceutically acceptable enantiomer, salt or solvate thereof according to claim 1 selected from the group consisting of:   19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable enantiomer, salt, or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, pharmaceutical additive. And / or a pharmaceutical composition comprising an adjuvant.   A medicament comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable enantiomer, salt or solvate thereof.   Claims 1-18 for use in the treatment and / or prevention of cancer, Parkinson's disease, Alzheimer's disease, neurodegenerative disorders such as Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity. A compound according to any one or a pharmaceutically acceptable enantiomer, salt or solvate thereof.   The cancer is bladder cancer, liver cancer, melanoma, mesothelioma, neuroblastoma, sarcoma, breast cancer, leukemia, renal cell cancer, colorectal cancer, head and neck cancer, lung cancer, brain tumor, glioblastoma, 24. The compound of claim 21, selected from the group consisting of astrocytoma, myeloma, pancreatic cancer.   19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable enantiomer, salt or solvate thereof for use as a TDO2 inhibitor.   A method of treating and / or preventing cancer, Parkinson's disease, Alzheimer's disease, neurodegenerative disorders such as Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity or inhibiting TD02, 19. A method comprising administering a compound according to any of claims 1 to 18 to a subject in need thereof.   The cancer is bladder cancer, liver cancer, melanoma, mesothelioma, neuroblastoma, sarcoma, breast cancer, leukemia, renal cell cancer, colorectal cancer, head and neck cancer, lung cancer, brain tumor, glioblastoma, 25. The method of claim 24, selected from the group consisting of astrocytoma, myeloma, and pancreatic cancer. A process for the preparation of a compound of formula I according to claims 1 to 18 or a pharmaceutically acceptable enantiomer, salt or solvate thereof,
(A1) Compound of formula (i)

[Where:
X ¹ and X ² each independently represent H, halogen, alkyl, haloalkyl,
Z ¹ represents H or an amino protecting group,
Y represents halogen, alkylsulfonyloxy having 1 to 6 carbon atoms, or arylsulfonyloxy having 6 to 10 carbon atoms].
Compound of formula (ii)

[Where:
R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are defined in claim 1,
Z ² and Z ³ represent H or an alkyl group, or Z ² and Z ³ may form a ring]
Compound of formula (iii)

Wherein Z ¹ , X ¹ , X ² , R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , Y ¹ , Y ² , and Y ³ are as described above; ,
(B1) when Z ¹ is not H, deprotecting the indoleamine of the compound of formula (iii) to obtain a compound of formula I.   27. The method of claim 26, wherein the amino protecting group for Z1 is arylsulfonyl, tert-butoxycarbonyl, methoxymethyl, paramethoxybenzyl, or benzyl.   28. A method according to claim 26 or claim 27, wherein when Y is halogen, Y is iodine, bromine or chlorine.   28. A method according to claim 26 or claim 27, wherein when Y is alkylsulfonyl, Y is methylsulfonyloxy or trifluoromethylsulfonyloxy.   28. The method of claim 26 or claim 27, wherein when Y is arylsulfonyl, Y is phenyl- or p-tolylsulfonyloxy.