JP5039268B2 - Benzimidazoles and analogs and their use as protein kinase inhibitors - Google Patents

Description

  The present invention relates to benzimidazoles of formula (Ix), their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states that can be modulated by inhibition of protein kinases. Such protein kinases are particularly in the following groups: EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-IR, KDR, PDGFR, tie2, VEGFR, ITK and SYK. Belongs.

  Protein kinases are a family of enzymes involved in signaling events that control cellular activation, growth and differentiation in response to changes in extracellular mediators and the environment. In general, these kinases preferentially catalyze the phosphorylation of the hydroxy group of serine and / or threonine residues and the phosphorylation of the hydroxy group of tyrosine residues. Classified as catalyzing [SK. Hanks and T. Hunter, FASEB, J., 1995, 9, p. 576-596]. Such phosphorylation greatly modifies the function of the protein, ie, protein kinases play an important role in various cellular processes including metabolism, cell proliferation, cell differentiation or cell survival.

  Of the various cellular functions involving kinase protein activity, certain processes are interesting targets for the treatment of certain diseases. Examples where kinase proteins can play an essential role include, in particular, angiogenesis and cell cycle control. Such a process is essential for solid tumor growth and other diseases.

  The formation of new blood vessels by angiogenesis or budding from existing blood vessels is paramount for embryonic development and organogenesis. If the need arises, the vasculature has the ability to create a network of new blood vessels to maintain the correct functioning of tissues and organs. Angiogenesis is a complex multi-step process involving endothelial cell activation, migration, proliferation and survival. In adults, angiogenesis is largely limited and occurs mainly only in the process of post-injury repair or intimal angiogenesis (Merenmies et al., Cell Growth & Differentiation, 8, 3 -10, 1997). However, uncontrolled angiogenesis has been observed in certain pathologies such as retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration or cancer (solid tumors) (Folkman, Nature Med, 1.17-31, 1995). Kinase proteins that have been shown to be involved in the angiogenesis process include three members of the family of growth factor receptor tyrosine kinases, namely VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR). , Kinase insert domain receptor, or FLK-1), FGF-R (gland fibroblast growth factor receptor) and TEK (also known as Tie-2).

  In the context of other systems, vascular endothelial growth factor receptor (VEGFR) transmits signals involved in endothelial cell migration, proliferation and survival. The VEGFR family includes the VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR3 (Flt4) families. The receptor VEGF-R2 is expressed only in endothelial cells and binds to the angiogenic growth factor VEGF, thereby functioning as a transduction signal mediator through its intracellular kinase domain. Thus, direct inhibition of the kinase activity of VEGF-R2 can reduce the reduction of angiogenesis in the presence of exogenous VEGF (Strawn et al., Cancer Research, 56, 3540-3545, 1996), a process that -Particularly revealed by using the R2 mutant (Millauer et al., Cancer Research, 56, 1615-1620, 1996). The VEGF-R2 receptor is thought to have no other functions in adults except those involved in the angiogenic activity of VEGF. Selective inhibition of the kinase activity of VEGF-R2 should show only slight toxicity.

  In addition to this central role in the dynamic angiogenesis process, recent studies have shown that VEGF expression contributes to tumor cell viability after chemotherapy and radiation therapy and is a KDR inhibitor with other drugs. Has been suggested (Lee CG, Heijn M. et al., (2000), Cancer Research, 60 (19), 5565-70). That is, KDR inhibitors constitute anti-angiogenic agents in particular, and such agents could be used as the first treatment to combat malignant tumor emergence or regenerative growth. Thus, inhibition or modulation of VEGFR-2 (KDR) provides a powerful and new mechanism of action for the treatment of many solid tumors.

Extensive research in the field of tumor angiogenesis over the past 20 years has identified a number of therapeutic targets such as kinases, proteases and integrins, resulting in the discovery of many new anti-angiogenic agents such as KDR inhibitors Some of them are currently under clinical evaluation (Jekunen et al., Cancer Treatment Rev., 1997, 23, p. 263-286).
That is, the invention of this application relates in particular to new inhibitors of the VEGFR-2 (KDR) receptor that may be used specifically for anti-angiogenesis in cancer.

  Protein kinases that preferentially catalyze phosphorylation of the hydroxy group of serine and / or threonine residues include, for example, protein kinase C isoforms [A.C. Newton, J.A. Biol. Chem., 1995, 270, p. 28495-28498] and a group of cyclin-dependent kinases such as cdk2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, p. 195-197]. For protein kinases that preferentially catalyze phosphorylation of the hydroxy group of serine and / or threonine residues, transmembrane growth factor receptors such as epidermal growth factor receptor [S. Iwashita and M. Kobayashi, Cellular Sognalling, 1992, 4, p. 123-132] and cytosolic non-receptor kinases such as p56lck, p59fYn, ZAP-70 and csk kinase [C. Chan et al., Ann. Rev. Immunol., 1994, 12, p. 555-592].

  Inappropriately high levels of protein kinase activity have been implicated in many diseases resulting from abnormal cellular function. This may be due to, for example, a disorder in the proper control mechanism for the kinase involved in enzyme mutation, overexpression or inappropriate activation, or a cytokine or growth factor that is also involved in the transmission of signals upstream or downstream of the kinase It is thought that it occurs directly or indirectly due to over or under production of. In all these examples, selective inhibition of the action of the kinase is expected to have a beneficial effect.

  SYK (spleen tyrosine kinase) is a 72 kDa protoplasmic protein tyrosine kinase that is expressed in various hematopoietic cells and is an essential element in several cascades that link antigen receptors to cellular responses. That is, SYK plays an important role in signaling the high affinity IgE receptor FcεR1 in mast cells and in receptor antigen signaling in T and B lymphocytes. Signal transduction pathways present in mast cells, T cells and B cells have common features. The ligand binding domain of the receptor lacks endogenous tyrosine kinase activity. However, they interact with transmission subunits that contain an immunoreceptor tyrosine-based activation motif (ITAM) [M. Reth, Nature, 1989, 338, p. 383-384]. These motifs are present in both the β and γ subunits of FcεR1, in the ζ-subunit of the T cell receptor (TCR), and in the IgGα and IgGβ subunits of the B cell receptor (BCR) [NS . van Oers and A. Weiss, Seminars in Immunology, 1995, 7, p. 227-236]. Upon antigen binding and multimerization, ITAM residues are phosphorylated by Src family protein tyrosine kinases. SYK belongs to a unique class of tyrosine kinases that have two tandem Src homology 2 (SH2) domains and a C-terminal catalytic domain. These SH2 domains bind with high affinity to ITAM, and this SH2-mediated association of SYK with activated receptors stimulates SYK kinase activity and localizes SYK to the plasma membrane.

In SYK-deficient mice, degranulation of mast cells is suppressed, suggesting that this is an important target for the development of mast cell stabilizers [PS. Costello, Oncogene, 1996,
13, p. 2595-2605]. Similar studies have revealed an important role for SYK in BCR and TCR signaling [AM. Cheng, Nature, 1995, 378, p. 303-306, (1995), DH. Chu et al., Immunological Reviews, 1998, 165, p. 167-180]. SYK is also thought to be involved in eosinophil survival in response to IL-5 and GM-CSF [S. Yousefi et al., J. Exp. Med., 1996, 183, p. 1407-1414]. Despite the important role of SYK in mast cells, BCR and T cells, little is known about the mechanism by which SYK transmits downstream effectors. Two adapter proteins, BLNK (B cell linker protein, SLP-65) and SLP-76, are known to be substrates of SYK in B cells and mast cells, respectively, presumed to be SYK interfaces to downstream effectors [M. Ishiai et al., Immunity, 1999, 10, p. 117-125, LR. Hendricks-Taylor et al., J.A. Biol. Chem., 1997, 272, p. 1363-1367]. Furthermore, SYK appears to play an important role in the CD40 signaling pathway, which plays an important role in B cell proliferation [M. Faris et al., J.A. Exp. Med., 1994, 179, p. 1923-1931].

  SYK is further stimulated via the low affinity IgG receptor (Fc gamma-RIIA) or by collagen [F. Yanaga et al., Biochem. J., 1995, 311, (pt.2), p. 471-478] Also involved in platelet activation.

  ITK is a T cell family T cell specific tyrosine kinase required for normal Th2 function. Asthma is a disease characterized by increased production of Th2 cytokines including IL-4. Thus, inhibition of ITK affects the progression of asthma disease through suppression of Th2 cytokine production.

  The present inventors have now discovered a new group of benzimidazoles with valuable pharmaceutical properties, in particular the ability to inhibit protein kinases, in particular the ability to inhibit protein kinase SYK, protein kinase KDR, protein kinase tie2 or protein kinase ITK. did.

｛式中、式（Ｉｘ)の目的のためには、
ＸはＣ−Ｒ²を示し、そして、Ｗ、ＹおよびＺは同じかまたは異なっていて、ＣＨまたはＣＲ³を示すか；または
ＷはＣＨを示し、ＸはＮを示し、ＹはＣＨまたはＣＲ³を示し、そして、ＺはＣＨまたはＣＲ³を示すか；または、
ＷはＮを示し、ＸはＣＨまたはＣＲ²を示し、ＹはＣＨまたはＣＲ³を示し、そして、ＺはＣＨまたはＣＲ³を示すか；または、
ＷはＮを示し、ＸはＣＨまたはＣＲ²を示し、ＹはＮを示し、そして、ＺはＣＨまたは
ＣＲ³を示すか；または、
ＷはＮを示し、ＸはＣＨまたはＣＲ²を示し、ＹはＣＨまたはＣＲ³を示し、そして、ＺはＮを示すか；または、
ＷはＮを示し、ＸはＮを示し、ＹはＣＨまたはＣＲ³を示し、そして、ＺはＣＨまたはＣＲ³を示し；
Ａ₅はＨまたはアルキルを示し；
Ｒ¹はアリールまたはヘテロアリールを示し、各々は場合により、カルボキシ、シアノ、ハロ、ハロアルキル、ヒドロキシ、ニトロ、Ｒ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂ＮＹ¹Ｙ²、−ＮＹ¹Ｙ²、−ＯＲ⁴、−ＯＣＦ₂Ｈ、−ＯＣＦ₃、−ＯＣ(＝Ｏ)Ｒ⁴、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²、−ＯＳ(Ｏ)_nＲ⁴、−Ｓ(Ｏ)_nＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²および−Ｓ(Ｏ)_nＯＲ⁴から選択される基１個または１個より多くで置換されており；
Ｒ²およびＲ³は下記の通り、即ち、
Ｒ²およびＲ³は同じかまたは異なっていて、Ｈ、カルボキシ、シアノ、ハロ、ハロアルキル、ヒドロキシ、ニトロ、Ｒ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂ＮＹ¹Ｙ²、−ＯＲ⁴、−ＯＣＦ₂Ｈ、−ＯＣＦ₃、−ＯＣ(＝Ｏ)Ｒ⁴、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²、−Ｓ(Ｏ)_nＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²または−Ｓ(Ｏ)_nＯＲ⁴であるか；または That is, in one aspect, the present invention provides the following formula (Ix):

{Wherein for the purpose of formula (Ix)
X represents C—R ² and W, Y and Z are the same or different and represent CH or CR ³ ; or W represents CH, X represents N and Y represents CH or CR ³ and Z represents CH or CR ³ ; or
W represents N, X represents CH or CR ² , Y represents CH or CR ³ , and Z represents CH or CR ³ ; or
W represents N, X represents CH or CR ² , Y represents N, and Z represents CH or CR ³ ; or
W represents N, X represents CH or CR ² , Y represents CH or CR ³ , and Z represents N; or
W represents N, X represents N, Y represents CH or CR ³ , and Z represents CH or CR ³ ;
A ₅ represents H or alkyl;
R ¹ represents aryl or heteroaryl, each optionally carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , ^{-C (= O) OR 4,} -N (R 6) C (= O) R 4, -N (R 6) C (= O) NY 1 Y 2, -N (R 6) C (= O) ^{OR 4, -N (R 6)} SO 2 R 4, -N (R 6) SO 2 NY 1 Y 2, -NY 1 Y 2, -OR 4, -OCF 2 H, -OCF 3, -OC (= O) R ⁴ , —OC (═O) NY ¹ Y ² , —OS (O) _n R ⁴ , —S (O) _n R ⁴ , —S (O) _n NY ¹ Y ² and —S (O) _n is substituted with one or more groups selected from OR ⁴ ;
R ² and R ³ are as follows:
R ² and R ³ are the same or different, and H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , ^{-C (= O) OR 4,} -NY 1 Y 2, -N (R 6) C (= O) R 4, -N (R 6) C (= O) NY 1 Y 2, -N (R 6 ) C (═O) OR ⁴ , —N (R ⁶ ) SO ₂ R ⁴ , —N (R ⁶ ) SO ₂ NY ¹ Y ² , —OR ⁴ , —OCF ₂ H, —OCF ₃ , —OC (= O) R ⁴ , —OC (═O) NY ¹ Y ² , —S (O) _n R ⁴ , —S (O) _n NY ¹ Y ² or —S (O) _n OR ⁴ ; or

R ² is H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR ⁴ , — NY ¹ Y ² , —N (R ⁶ ) C (═O) R ⁴ , —N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , − _{^{N (R 6) SO 2 R}} 4, -N (R 6) SO 2 NY 1 Y 2, -OR 4, -OCF 2 H, -OCF 3, -OC (= O) R 4, -OC (= O ) NY ¹ Y ² , —S (O) _n R ⁴ , —S (O) _n NY ¹ Y ² or —S (O) _n OR ⁴ , and R ³ is alkyl, haloalkyl, halogen and OR ^6. Indicate; or

R ² and R ³ on adjacent carbon atoms may be the same or different selected from O, N and S, and may contain one or more heteroatoms optionally substituted with alkyl. A 5- to 6-membered carbon-based ring may be formed [for example, R ² and R ³ are —O—CH ₂ —O—, —O—CH ₂ —CH ₂ —O—; —CH ₂ — _{O-CH 2 -, - CH} 2 -N (R 14) -CH 2 -, - CH 2 -CH 2 -CH 2 -, - CH 2 -C (CH 3) 2 -CH 2 -, - CH 2 - _{O-CH 2 -CH 2 -,} - CH 2 -N (R 14) -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -CH 2 -, - CH 2 -C (CH 3) 2 _{-CH 2 -CH 2 -, - CH} = CH-CH = CH -, - N = CH-CH = CH -, - CH = N-CH = CH -, - CH = CH-N = CH- and -CH = CH CH = N, provided that one R ¹⁴ is H or alkyl, to form a group selected encompassed from];

R ⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl,- ^{C (= O) NY 3 Y} 4, -C (= O) oR 6, -N (R 6) C (= O) NY 1 Y 2, -NY 1 Y 2, -OR 5 or -NY ³ Y, Substituted with one or more substituents selected from ^4- substituted alkyls ;
R ⁵ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R ⁶ is selected from the meaning of R ⁵ ;
n is zero or an integer of 1 or 2;
Y ¹ and Y ² are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or optionally cyano, aryl, heteroaryl, hydroxy, —C (═O) OR ⁶ , -C (= O) NY ³ Y ⁴ , -NY ³ Y ⁴ and -OR ⁵ is an alkyl substituted with one or more groups selected from, or the group -NY ¹ Y ² is May form a cyclic amine;
Y ³ and Y ⁴ are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —N
Y ³ Y ⁴ may form a cyclic amine;
here,
Any alkyl (or alk, i.e. alkyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups present in the above groups may optionally be halogen atoms and hydroxyl, cyano , Alkyl, alkoxy, acylamino (NH—COalk), —C (═O) OR ⁶ , —C (═O) R ⁶ , hydroxyalkyl, carboxyalkyl, S (O) _n -alk, S (O) _n — _{NH 2, S (O) n} -NH (alk), S (O) n -N (alk) 2, CF 3, OCF 3, NO 2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= O) -NY ³ Y is substituted ⁴ and NY ³ Y groups one selected from ^four or more than one, alkyl , The latter of which may be substituted with a halogen atom and an alkyl group optionally itself comprising aryl and heteroaryl, free, salt form or esterified carboxy group and an acylamino group NH-C (O) group selected from R ⁵ Substituted with one or more}
And the corresponding N-oxide, and prodrugs thereof, and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of such compounds, and the N-oxides thereof and It relates to a pharmaceutical composition comprising the prodrug and its acid biological equivalent; together with one or more pharmaceutically acceptable carriers or excipients.

であり、ここでＲ⁷は水素またはアルキルであり、そしてＲ⁸およびＲ⁹は独立して水素、カルボキシ、シアノ、ハロ、ハロアルキル、ヒドロキシ、ニトロ、Ｒ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂ＮＹ¹Ｙ²、−ＮＹ¹Ｙ²、−ＯＲ⁴、−ＯＣ(＝Ｏ)Ｒ⁴、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²、−Ｓ(Ｏ)_nＲ⁴および−Ｓ(Ｏ)₂ＮＹ¹Ｙ²から選択されるか；または、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になって（ｉ）場合により炭素環置換基１個または１個より多くで置換されている５〜８員の炭素環；（ii）場合によりアリール基置換基１個または１個より多くで置換されたフェニル環；（iii）環員の１個または１個より多くが窒素、酸素またはイオウであり（このような基の例にはフリル、イミダゾリル、イソキサゾリル、イソチアゾリル、オキサジアゾリル、ピラジニル、ピリダジニル、ピラゾリル、ピリジル、ピリミジニル、ピロリル、１,３,４−チアジアゾリル、チアゾリル、チエニルおよびトリアゾリル基が包含される)、そして、場合により、ハロアルキル、ヒドロキシ、ハロ、シアノ、ニトロ、Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−ＮＹ¹Ｙ²、−ＮＹ¹Ｙ²および−ＯＲ⁵から選択される基１個または１個より多くで置換されている５または６員の複素芳香族環；または（iv）場合によりアルキルまたはオキソで置換されており、そして、Ｏ、Ｓ、ＳＯ₂およびＮＹ⁵（ただしＹ⁵が水素、Ｒ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴または−ＳＯ₂Ｒ⁴であるもの)から選択されるヘテロ原子含有基を含む５または６員の複素環を形成する上記定義した式（Ｉｘ）の化合物、ただし、２−（２Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；２−（５−メチル−２Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；５−メチル−６−［２−（２Ｈ−ピラゾール−３−イル)−３Ｈ−ベンゾイミダゾール−５−イル］−４,５−ジヒドロ−２Ｈ−ピリダジン−３−オン；５−メチル−６−［２−（２Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール−４−イル］−４,５−ジヒドロ−２Ｈ−ピリダジン−３−オン；３,５−ビス（ベンゾイミダゾール−２−イル)−１Ｈ−ピラゾール；５,６−ジメチル−２−（５−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；６−メチル−２−（５−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；５,６−ジヒドロ−２−（５−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；５−ニトロ−２−（５−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；２−（５−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール−５−カルボン酸；２−（５−フェニル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；５,６−ジメチル−２−（５−フェニル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；５−メチル−２−（５−フェニル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；６−クロロ−２−（５−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；５−クロロ−２−（５−フェニル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダ
ゾール；５,６−ジクロロ−２−（５−フェニル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；Ｎ−［２−（５−イソキノリン−４−イル−１Ｈ−インダゾール−３−イル)−３Ｈ−ベンゾイミダゾール−５−イル］−メタンスルホンアミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−５−（１Ｈ−インダゾール−４−イル)−１Ｈ−インダゾール、３−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−５−イル］−２−メトキシフェノール；４−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾールー５−イル］イソキノリン；４−｛３−［６−（４−メチル−ピペラジン−１−イル)−１Ｈ−ベンゾイミダゾール−２−イル］−１Ｈ−インダゾール−５−イル｝−イソキノリン；４−［３−（４−クロロ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−５−イル］−イソキノリン；４−［２−（１Ｈ−インダゾール−３−イル)−１Ｈ−ベンゾイミダゾール−５−イル］−フェノール；３−［５−（４−メトキシ−フェニル)−１Ｈ−ベンゾイミダゾール−２−イル］−１Ｈ−インダゾール；３−［５−（４−メトキシ−フェニル)−１Ｈ−ベンゾイミダゾール−２−イル］−１Ｈ−インダゾール；３−［５−（３−メトキシ−フェニル)−１Ｈ−ベンゾイミダゾール−２−イル］−１Ｈ−インダゾール；３−（１Ｈ−ベンゾイミダゾール−２−イル)−５−フェニル−１Ｈ−インダゾール；２−（４−ブロモ−１−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；２−（５−ｔ−ブチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−ベンゾイミダゾール；３−（１Ｈ−ベンゾイミダゾール−２−イル)−６−（３−メトキシ−フェニル)−１Ｈ−インダゾール；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸；５−｛［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボニル］−アミノ｝−２−ヒドロキシ−安息香酸メチルエステル；５−｛［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボニル］−アミノ｝−フラン−２−カルボン酸メチルエステル；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（３−ヒドロキシ−４−メトキシ−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（５−ヒドロキシ−１Ｈ−ピラゾール−３−イル)アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（１Ｈ−ピラゾール−３−イル)アミド；［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−［４−（２−ヒドロキシ−エチル)−ピペリジン−１−イル］−メタノン；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（９Ｈ−プリン−６−イル)アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸ジメチルアミド；［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−モルホリン−４−イル−メタノン；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸ピラジン−２−イルアミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸シクロヘキシルアミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（１Ｈ−インダゾール−５−イル)−アミド；［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−ピロリジン−１−イル−メタノン；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（１Ｈ−インダゾール−５−イル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−［４−（フラン−２−カルボニル)−ピペラジン−１−イル］−メタノン；［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−（４−メチル−ピペラジン−１−イル)−メタノン；１−｛４−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボニル］−ピペラジン−１−イル｝−エタノン；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（６−メトキシ−ピリジン−３−イル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（３−ヒドロキシ−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸ピリジン−４−イルアミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（２−モルホリン−４−イル−エチル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（２−ヒドロキシ−エチル)−メチル−アミド；３−｛［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボニル］−アミノ｝−酪酸エチルエステル；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（３−ヒドロキシ−プロピル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸フェニルアミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸ピリジン−３−イルアミド；３−（６−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−６−ピリジン−４−イル−１Ｈ−インダゾール；３−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（５,６−ジメトキシ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（６−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；６−（ｔ−ブチル−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)アミド；３−（６,７−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（５,６−ジクロロ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（５,６−ジフルオロ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（３−フルオロ−４−ヒドロキシ−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−２,３−ジメチル−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−２−メチル−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸（４−ヒドロキシ−フェニル)−アミド；３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボン酸シクロプロピルアミド；２−［６−（４−ヒドロキシ−２−メトキシ−フェニル)−１Ｈ−インダゾール−３−イル］−３Ｈ−ベンゾイミダゾール−５−スルホン酸アミド；４−［３−（６−ジメチルアミノ−１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−３−メトキシ−フェノール；２−［６−（４−ヒドロキシ−２−メトキシ−フェニル)−１Ｈ−インダゾール−３−イル］−３Ｈ−ベンゾイミダゾール−５−カルボン酸メチルアミド；３−メトキシ−４−｛３−［６−（４−メチル−ピペラジン−１−イル)−１Ｈ−ベンゾイミダゾール−２−イル］−１Ｈ−インダゾール−６−イル｝−フェノール；２−［６−（４−ヒドロキシ−２−メトキシ−フェニル)−１Ｈ−インダゾール−３−イル］−３Ｈ−ベンゾイミダゾール−５−カルボン酸（２−モルホリン−４−イル−エチル)−アミド；４−［３−（１Ｈ−イミダゾ［４,５−ｃ］ピリジン−２−イル)−１Ｈ−インダゾール−６−イル］−３−メトキシ−フェノール；３−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−２−メトキシ−フェノール；３−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−フェノール；４−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−３,５−ジメチル−フェノール；４−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−３−フェノキシ−フェノール；４−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−ベンゼン−１,３−ジオール；４−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６
−イル］−３−メトキシ−フェノール；４−［３−（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−イル］−２−メトキシ−フェノール；Ｎ−｛３−［３−
（１Ｈ−ベンゾイミダゾール−２−イル)−１Ｈ−インダゾール−６−カルボニル］−フェニル｝−ベンズアミド；６−［２−（１,５−ジメチル−１Ｈ−ピラゾール−３−イル)−３Ｈ−ベンゾイミダゾール−５−イル］−５−メチル−４,５−ジヒドロ−２Ｈ−ピリダジン−３−オン；５−メチル−６−［２−（１−メチル−１Ｈ−ピラゾール−３−イル)−３Ｈ−ベンゾイミダゾール−５−イル｝−４,５−ジヒドロ−２Ｈ−ピリダジン−３−オン；８−（１,５−ジメチル−１Ｈ−ピラゾール−３−イル)−７Ｈ−プリン；２−（１,５−ジメチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−イミダゾ［４,５−ｂ］ピリジンおよび２−（５−メチル−１Ｈ−ピラゾール−３−イル)−１Ｈ−イミダゾ［４,５−ｂ］ピリジン以外のものに関する。 In another aspect, the invention provides that R ¹ is a pyrazolyl moiety:

Where R ⁷ is hydrogen or alkyl, and R ⁸ and R ⁹ are independently hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R ⁴ , —C (═O) R ⁴ , ^{-C (= O) NY 1 Y} 2, -C (= O) OR 4, -N (R 6) C (= O) R 4, -N (R 6) C (= O) NY 1 Y 2, ^{-N (R 6) C (=} O) OR 4, -N (R 6) SO 2 R 4, -N (R 6) SO 2 NY 1 Y 2, -NY 1 Y 2, -OR 4, -OC Selected from (═O) R ⁴ , —OC (═O) NY ¹ Y ² , —S (O) _n R ⁴ and —S (O) ₂ NY ¹ Y ² ; or R ⁸ and R ⁹ Are, together with the carbon atom to which they are attached, (i) a 5- to 8-membered carbocycle optionally substituted with one or more carbocyclic substituents; (ii) optionally an aryl group Phenyl substituted with one or more substituents (Iii) one or more than one ring member is nitrogen, oxygen or sulfur (examples of such groups are furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, Pyrimidinyl, pyrrolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups are included), and optionally haloalkyl, hydroxy, halo, cyano, nitro, R ⁴ , —C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) R ⁴ , —N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) SO ₂ R ⁴ , —NY ¹ Y ² , A 5- or 6-membered heteroaromatic ring substituted with one or more groups selected from —NY ¹ Y ² and —OR ⁵ ; or (iv) optionally substituted with alkyl or oxo And , O, S, SO ₂ and NY ⁵ (provided that Y ⁵ is ^{hydrogen, R 4, -C (= O} ) R 4, -C (= O) NY 1 Y 2, -C (= O) OR 4 or - A compound of formula (Ix) as defined above forming a 5- or 6-membered heterocycle containing a heteroatom-containing group selected from SO ₂ R ⁴ ), wherein 2- (2H-pyrazol-3-yl ) -1H-benzimidazole; 2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole; 5-methyl-6- [2- (2H-pyrazol-3-yl) -3H-benzo Imidazol-5-yl] -4,5-dihydro-2H-pyridazin-3-one; 5-methyl-6- [2- (2H-pyrazol-3-yl) -1H-benzimidazol-4-yl]- 4,5-dihydro-2H-pyridazin-3-one; 3,5-bis (benzimid Zol-2-yl) -1H-pyrazole; 5,6-dimethyl-2- (5-methyl-1H-pyrazol-3-yl) -1H-benzimidazole; 6-methyl-2- (5-methyl-1H) -Pyrazol-3-yl) -1H-benzimidazole; 5,6-dihydro-2- (5-methyl-1H-pyrazol-3-yl) -1H-benzimidazole; 5-nitro-2- (5-methyl) -1H-pyrazol-3-yl) -1H-benzimidazole; 2- (5-methyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid; 2- (5-phenyl-1H- Pyrazol-3-yl) -1H-benzimidazole; 5,6-dimethyl-2- (5-phenyl-1H-pyrazol-3-yl) -1H-benzimidazole; Nyl-1H-pyrazol-3-yl) -1H-benzimidazole; 6-chloro-2- (5-methyl-1H-pyrazol-3-yl) -1H-benzimidazole; 5-chloro-2- (5- Phenyl-1H-pyrazol-3-yl) -1H-benzimidazole; 5,6-Dichloro-2- (5-phenyl-1H-pyrazol-3-yl) -1H-benzimidazole; N- [2- (5 -Isoquinolin-4-yl-1H-indazol-3-yl) -3H-benzimidazol-5-yl] -methanesulfonamide; 3- (1H-benzimidazol-2-yl) -5- (1H-indazole- 4-yl) -1H-indazole, 3- [3- (1H-benzimidazol-2-yl) -1H-indazol-5-yl] -2-methoxyphenol; 4- [3 (1H-Benzimidazol-2-yl) -1H-indazol-5-yl] isoquinoline; 4- {3- [6- (4-methyl-piperazin-1-yl) -1H-benzimidazol-2-yl]- 1H-indazol-5-yl} -isoquinoline; 4- [3- (4-chloro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl] -isoquinoline; 4- [2- (1H- Indazol-3-yl) -1H-benzimidazol-5-yl] -phenol; 3- [5- (4-methoxy-phenyl) -1H-benzimidazol-2-yl] -1H-indazole; 3- [5 -(4-Methoxy-phenyl) -1H-benzimidazol-2-yl] -1H-indazole; 3- [5- (3-methoxy-phenyl) -1H-benzimidazo Ru-2-yl] -1H-indazole; 3- (1H-benzimidazol-2-yl) -5-phenyl-1H-indazole; 2- (4-bromo-1-methyl-1H-pyrazol-3-yl ) -1H-benzimidazole; 2- (5-t-butyl-1H-pyrazol-3-yl) -1H-benzimidazole; 3- (1H-benzimidazol-2-yl) -6- (3-methoxy- Phenyl) -1H-indazole; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid; 5-{[3- (1H-benzimidazol-2-yl) -1H-indazole- 6-carbonyl] -amino} -2-hydroxy-benzoic acid methyl ester; 5-{[3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carbo Nyl] -amino} -furan-2-carboxylic acid methyl ester; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (3-hydroxy-4-methoxy-phenyl) -amide; 3- (1H-Benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (5-hydroxy-1H-pyrazol-3-yl) amide; 3- (1H-benzimidazol-2-yl) -1H Indazole-6-carboxylic acid (1H-pyrazol-3-yl) amide; [3- (1H-benzoimidazol-2-yl) -1H-indazol-6-yl]-[4- (2-hydroxy-ethyl) ) -Piperidin-1-yl] -methanone; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (9H-purin-6- 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid dimethylamide; [3- (1H-benzimidazol-2-yl) -1H-indazol-6-yl] -Morpholin-4-yl-methanone; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid pyrazin-2-ylamide; 3- (1H-benzimidazol-2-yl) -1H Indazole-6-carboxylic acid cyclohexylamide; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (1H-indazol-5-yl) -amide; [3- (1H-benzoic acid Imidazol-2-yl) -1H-indazol-6-yl] -pyrrolidin-1-yl-methanone; 3- (1H-benzimidazo 2-yl) -1H-indazole-6-carboxylic acid (1H-indazol-5-yl) -amide; 3- (1H-benzimidazol-2-yl) -1H-indazol-6-yl]- [4- (furan-2-carbonyl) -piperazin-1-yl] -methanone; [3- (1H-benzoimidazol-2-yl) -1H-indazol-6-yl]-(4-methyl-piperazine- 1-yl) -methanone; 1- {4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-6-carbonyl] -piperazin-1-yl} -ethanone; 3- (1H-benzo Imidazol-2-yl) -1H-indazole-6-carboxylic acid (6-methoxy-pyridin-3-yl) -amide; 3- (1H-benzimidazol-2-yl) -1H-indazole- 6-carboxylic acid (3-hydroxy-phenyl) -amide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid pyridin-4-ylamide; 3- (1H-benzimidazole-2 -Yl) -1H-indazole-6-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (2- Hydroxy-ethyl) -methyl-amide; 3-{[3- (1H-benzimidazol-2-yl) -1H-indazole-6-carbonyl] -amino} -butyric acid ethyl ester; 3- (1H-benzimidazole- 2-yl) -1H-indazole-6-carboxylic acid (3-hydroxy-propyl) -amide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid phenylamide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid pyridin-3-ylamide; 3- (6-methoxy-1H-benzimidazole 2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1H-benzoimidazol-2-yl) -6-pyridin-4-yl-1H-indazole; 3 -(5-Chloro-1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-dimethoxy-1H-benzimidazol-2- Yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5-fluoro-1H-benzimidazo Ru-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (6-trifluoromethyl-1H-benzimidazol-2-yl) -1H-indazole-6 Carboxylic acid (4-hydroxy-phenyl) -amide; 6- (t-butyl-1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) amide; 3- (6 , 7-dimethyl-1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-dichloro-1H-benzimidazol-2-yl ) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-difluoro-1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (3-fluoro-4-hydroxy-phenyl ) -Amide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid amide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (4 -Hydroxy-2,3-dimethyl-phenyl) -amide; 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-2-methyl-phenyl) -amide; 3 -(1H-Benzimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1H- Nzoimidazol-2-yl) -1H-indazole-6-carboxylic acid cyclopropylamide; 2- [6- (4-hydroxy-2-methoxy-phenyl) -1H-indazol-3-yl] -3H-benzo Imidazole-5-sulfonic acid amide; 4- [3- (6-Dimethylamino-1H-benzoimidazol-2-yl) -1H-indazol-6-yl] -3-methoxy-phenol; 2- [6- ( 4-hydroxy-2-methoxy-phenyl) -1H-indazol-3-yl] -3H-benzimidazole-5-carboxylic acid methylamide; 3-methoxy-4- {3- [6- (4-methyl-piperazine- 1-yl) -1H-benzimidazol-2-yl] -1H-indazol-6-yl} -phenol; 2- [6- (4-hydroxy-2-methyl) Xyl-phenyl) -1H-indazol-3-yl] -3H-benzimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 4- [3- (1H-imidazo [4,5 -C] pyridin-2-yl) -1H-indazol-6-yl] -3-methoxy-phenol; 3- [3- (1H-benzimidazol-2-yl) -1H-indazol-6-yl]- 2-methoxy-phenol; 3- [3- (1H-benzimidazol-2-yl) -1H-indazol-6-yl] -phenol; 4- [3- (1H-benzimidazol-2-yl) -1H -Indazol-6-yl] -3,5-dimethyl-phenol; 4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-6-yl] -3-phenoxy-pheno 4- [3- (1H-benzoimidazol-2-yl) -1H-indazol-6-yl] -benzene-1,3-diol; 4- [3- (1H-benzimidazol-2-yl)- 1H-indazole-6
-Yl] -3-methoxy-phenol; 4- [3- (1H-benzimidazol-2-yl) -1H-indazol-6-yl] -2-methoxy-phenol; N- {3- [3-
(1H-Benzimidazol-2-yl) -1H-indazole-6-carbonyl] -phenyl} -benzamide; 6- [2- (1,5-dimethyl-1H-pyrazol-3-yl) -3H-benzimidazole -5-yl] -5-methyl-4,5-dihydro-2H-pyridazin-3-one; 5-methyl-6- [2- (1-methyl-1H-pyrazol-3-yl) -3H-benzo Imidazol-5-yl} -4,5-dihydro-2H-pyridazin-3-one; 8- (1,5-dimethyl-1H-pyrazol-3-yl) -7H-purine; 2- (1,5- Dimethyl-1H-pyrazol-3-yl) -1H-imidazo [4,5-b] pyridine and 2- (5-methyl-1H-pyrazol-3-yl) -1H-imidazo [4,5-b] pyridine Related to things other than

  As used herein, the term “compound of the invention” and equivalent expressions have the meaning encompassing the compounds of formula (Ix) described above, where this expression may be prodrugs, pharmaceutically, if possible. Including acceptable salts and solvates such as hydrates. Similarly, reference to an intermediate includes both salts and solvates thereof where possible, whether or not they are themselves recited in the claims. For clarity, specific examples are often described in the specification where possible, but these examples are purely illustrative and are not intended to exclude other examples where possible.

When used as described above with respect to compounds of formula (Ix) and throughout the following description of the invention, the following terms shall have the following meanings unless otherwise indicated.
“Patient” includes both humans and other mammals.

“Acid bioequivalent” means a group having chemical and physical similarities that give biological properties generally similar to a carboxy group [see (Non-patent Document 1)]. Examples of suitable acids bioisosteres -C (= O) -NHOH, -C (= O) -CH 2 OH, -C (= O) -CH 2 SH, -C (= O) -NH -CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2 , 4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.
Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283 “Bioisosterism In Drug Design”; Yun, Hwahak Sekye, 1993, 33, pages 576-579 “Application Of Bioisosterism To New Drug Design”; Zhao, Huaxue Tongbao, 1995, pages 34-38 “Bioisosteric Replacement And Development Of Lead Compounds In Drug Design”; Graham, Theochem, 1995, 343, pages 105-109 “Theoretical Studies Applied To Drug Design: ab initio Electronic Destributions In Bioisosteres”

  “Acyl” refers to the group R—C (═O) —, where R is a hydrogen atom, a linear or branched alkyl group containing no more than 6 carbon atoms; an optionally substituted amino group; Denotes an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, such as a phenyl or pyrrolidinyl group; that is, the term “acyl” is specifically exemplified by, for example, a formyl group and acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, benzoyl and pyrrolidinylcarbonyl Refers to the group.

“Acylamino” refers to the groups —C (═O) —NH ₂ , —C (O) —NH (alk) and —C (O) —N (alk) (alk), in which NH ( alk) and -NH (alk) (alk) have the meanings defined below.

  “Alkenyl” is a straight or branched chain containing carbon-carbon double bonds and having from about 2 to about 15 carbon atoms in the chain and containing one or more double bonds. Means an aliphatic hydrocarbon group. Preferred alkenyl groups have from 2 to about 12 carbon atoms in the chain, and more preferably from 2 to about 6 carbon atoms (eg, 2 to 4 carbon atoms) in the chain. "Branched chain" as used herein means that one or more lower alkyl groups such as methyl, ethyl or propyl are linear; here linked to a linear alkenyl chain Means. “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl. , 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, decenyl, and 3,7-dimethyl-octa-2,6-dienyl.

  “Alkoxy” means an alkyl-O— group in which the alkyl group is as described herein. Examples of alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, pentoxy, hexoxy and heptoxy, and straight or branched chains thereof The positional isomers are included.

  “Alkoxycarbonyl” means an alkyl-O—CO— group in which the alkyl group is as described herein. Examples of alkoxycarbonyl include methoxy- and ethoxycarbonyl.

“Alkyl” means a straight or branched chain having about 1 to about 15 carbon atoms in the chain, optionally substituted with one or more halogen atoms, unless otherwise specified. Means a good aliphatic hydrocarbon group, in particular an alkyl group having from 1 to about 6 carbon atoms, one group or "lower alkyl as part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group; “Unless otherwise stated, means an aliphatic hydrocarbon group that may be a straight chain or branched chain having from 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, hexyl, isohexyl, heptyl, octyl, Nonyl, decyl and dodecyl and their linear or branched positional isomers are included. Examples of alkyl groups substituted with one or more halogen atoms include trifluoromethyl, difluoromethyl, trifluoroethyl and difluoroethyl.

  “Alkylene” means an aliphatic divalent group derived from a straight or branched alkyl group wherein the alkyl group is as described herein. Examples of alkylene groups include methylene, ethylene and trimethylene.

  “Alkylenedioxy” means an —O-alkylene-O— group in which the alkyl group is as defined above. Examples of alkylenedioxy groups include methylenedioxy and ethylenedioxy.

“Alkylsulfinyl” means an alkyl-SO— group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is C _1-4 alkyl.

“Alkylsulfonyl” means an alkyl-SO ₂ — group in which the alkyl group is as previously described. Preferred alkylsulfonyl groups are those in which the alkyl group is C _1-4 alkyl.

“Alkylsulfonylcarbamoyl” means an alkyl-SO ₂ —NH—C (═O) — group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C _1-4 alkyl.

  “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Examples of alkylthio groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, hexylthio, isohexylthio and heptylthio, and their linear or branched positions Isomers are included. Preferred alkylthio groups have no more than 4 carbon atoms.

  “Alkynyl” means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain, more preferably 2 to about 6 carbon atoms (eg, 2 to 4 carbon atoms) in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl and n-pentynyl.

“Aroyl” means an aryl-CO— group in which the aryl group is as described herein. Examples of aroyl groups include benzyl and 1- and 2-naphthoyl.
“Aroylamino” means an aroyl-NH— group in which aroyl is as described herein.

“Aryl” as a group or part of a group means (i) an optionally substituted mono- or polycyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms such as phenyl or naphthyl; or (Ii) an optionally substituted partially saturated polycyclic ring wherein a monocyclic aromatic carbocyclic moiety and a cycloalkyl or cycloalkenyl group are fused to form a cyclic structure such as a tetrahydronaphthyl, indenyl or indanyl ring. Refers to the aromatic carbocyclic moiety. Unless otherwise defined, aryl groups may be substituted with one or more of the same or different aryl groups, where “aryl group substituent” includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl , Alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or acid Biological equivalents), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hete Rocycloalkyl, hydroxy, nitro, trifluoromethyl, —C (═O) NY ¹ Y ² , —NY ¹ —C (═O) alkyl, —NY ¹ SO ₂ alkyl, —NY ¹ Y ² , —SO ₂ NY ¹ Y ² or each optionally aryl, cycloalkyl, heteroaryl, hydroxy, —C (═O) OR ⁶ , —C (═O) NY ¹ Y ² , —NY ¹ Y ² or —OR ^5. Including alkyl, alkenyl or alkynyl substituted with.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C _1-4 alkyl moiety. Examples of arylalkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.

  “Arylalkyloxy” means an arylalkyl-O— group in which the arylalkyl group is as previously described. Examples of arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

  “Arylalkyloxycarbonyl” means an arylalkyl-O—CO— group in which the arylalkyl group is as previously described. Examples of arylalkyloxycarbonyl groups include benzyloxycarbonyl.

“Arylalkylthio” means an arylalkyl-S— group in which the arylalkyl group is as previously described. Examples of arylalkylthio groups include benzylthio.
“Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Examples of aryloxy groups include phenoxy and naphthoxy, each optionally substituted.

  “Aryloxycarbonyl” means an aryl-O—C (═O) — group in which the aryl group is as previously described. Examples of aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

“Arylsulfinyl” means an aryl-SO— group in which the aryl group is as previously described.
“Arylsulfonyl” means an aryl-SO ₂ — group in which the aryl group is as previously described.

“Arylsulfonylcarbamoyl” means an aryl-SO ₂ —NH—C (═O) — group in which the aryl group is as previously described.
“Arylthio” means an aryl-S— group in which the aryl group is as previously described. Examples of arylthio groups include phenylthio and naphthylthio.
“Carbocycle” means a saturated ring system containing carbon atoms.

“Carbocyclic group substituent” includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, Aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or acid biological equivalent), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryl Oxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, —C (═O) NY ¹ Y ² , —NY ¹ —C (═O) alkyl, —NY ¹ SO ₂ alkyl, —NY ¹ Y ² , —SO ₂ NY ¹ Y ² , or each optionally aryl, cycloalkyl, heteroaryl, hydroxy, —C (═O) OR ⁶ , —C (═O) NY Alkyl, alkenyl or alkynyl substituted with ¹ Y ² , —NY ¹ Y ² or —OR ⁵ is included.

“Cyclic amine” means that one of the ring carbon atoms is replaced by nitrogen and (i) is replaced with O, S, SO ₂ or NY ⁶ (where Y ⁶ is hydrogen, alkyl, aryl, arylalkyl, — Another heteroatom-containing group selected from C (═O) R ⁵ , —C (═O) OR ⁵ , —C (═O) NY ¹ Y ² , —SO ₂ R ⁵ ). And (ii) a 3-8 member that may be condensed with another aryl (eg phenyl), heteroaryl (eg pyridyl), heterocycloalkyl or cycloalkyl ring to form a bicyclic or tricyclic system A monocyclic cycloalkyl ring system. Examples of cyclic amines include groups such as pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindrine, tetrahydroquinoline and the like.

  “Cycloalkenyl” means a non-aromatic mono- or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Examples of monocyclic alkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.

“Cycloalkyl” means a saturated mono- or bicyclic ring system having about 3 to about 10 carbon atoms, optionally substituted with oxo. Examples of monocyclic cycloalkyl rings include C _3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

  “Cycloalkylalkyl” means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl moieties are as previously described. Examples of monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

“Halo” or “halogen” means fluoro, chloro, bromo or iodo. Preference is given to fluoro, bromo and chloro.
“Haloalkyl” means an alkyl group having about 1 to about 6 carbon atoms in the chain and being substituted with one or more halogen atoms. Examples of haloalkyl groups include trifluoromethyl.

“Heteroaroyl” means a heteroaryl- (C═O) — group in which the heteroaryl group is as previously described. Examples of heteroaryl include pyridylcarbonyl.
“Heteroaroylamino” means a heteroaroyl-NH— group in which the heteroaryl moiety is as previously described.

“Heteroaryl” as a group or part of a group means (i) about 5 to about 10 ring members in which one or more of the ring members is an element other than carbon, such as nitrogen, oxygen or sulfur. Optionally substituted aromatic monocyclic or polycyclic organic moieties (examples of such groups include benzimidazole, benzotriazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, Pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally, unless otherwise defined, one aryl group substituent as defined above or Includes those substituted with more than one (Ii) an optionally substituted partially saturated polycyclic heterocarbocyclic ring in which a monocyclic heteroaromatic moiety and a cycloalkyl, cycloalkenyl or heterocycloalkyl group are fused together to form a cyclic structure Moieties (examples of such groups include tetrahydro-indazole, tetrahydro-pyrazolopyridine, 5-oxo-1,4,5,6,7,8,9,9a-octahydro-1,2,4,5a -Tetraazacyclopenta [a] naphthyl, optionally including those substituted with one or more aryl group substituents as defined above unless otherwise defined). Optional substituents include one or more aryl group substituents as defined above, unless otherwise defined. When R ¹ is heteroaryl, this is in particular pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, phenyl, pyridinyl, oxodihydropyridinyl, pyrimidinyl, indolyl, indazolyl, thieno Pyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or oxodihydropyridinopyzolyl Show.

“Heteroarylalkyl” means a heteroaryl-alkyl-group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C _1-4 alkyl moiety. Examples of heteroarylalkyl groups include pyridylmethyl.

  “Heteroarylalkyloxy” means a heteroarylalkyl-O— group in which the heteroarylalkyl group is as previously described. Examples of heteroaryloxy groups include optionally substituted pyridylmethoxy.

“Heteroaryloxy” means a heteroaryl-O— group in which the heteroaryl group is as previously described. Examples of heteroaryloxy groups include optionally substituted pyridyloxy.
“Heteroarylsulfonylcarbamoyl” means a heteroaryl-SO ₂ —NH—C (═O) — group in which the heteroaryl group is as previously described.

  “Heterocycloalkyl” means (i) about 3 to about 10 rings containing one or more heteroatoms or heteroatom-containing groups selected from O, S and NY6 and optionally substituted with oxo. Membered cycloalkyl groups (examples of such groups include hexahydropyran, pyrrolidinyl, piperidinyl, tetrahydropyranyl and octahydropyrido [1,2-c] pyrimidin-1-one); (ii A partially saturated polycyclic ring, each optionally substituted with one or more “aryl group substituents” and the arylaryl (or heteroaryl) ring and heterocycloalkyl group are fused together to form a cyclic structure. Heterocarbocyclic moieties (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups ) Means.

“Heterocycloalkylalkyl” means a heterocycloalkyl-alkyl-group in which the heterocycloalkyl and alkyl moieties are as previously described.
“Hydroxyalkyl” means an alkyl group substituted with one or more hydroxy groups.

“NH (alk)” and “NH (alk) (alk)” each refer to an amino group substituted with one or two alkyl groups, the alkyl group being linear or branched, and the alkyl It is selected from the group and preferably contains no more than 4 carbon atoms.

  “Prodrug” means a compound that is converted in vivo by metabolic means (eg, hydrolysis) to a compound of formula (Ix) containing an N-oxide. For example, an ester of a compound of formula (Ix) containing a hydroxy group is converted to the parent molecule by in vivo hydrolysis. Alternatively, an ester of a compound of formula (Ix) containing a carboxy group is converted to the parent molecule by in vivo hydrolysis.

  Suitable esters of compounds of formula (Ix) containing hydroxy groups are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene bis beta hydroxynaphthoate, gentisate, isethionate, di- p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.

  Suitable esters of compounds of formula (Ix) containing a carboxy group are for example F.J. Leinweber, Drug Metab. Res., 1987, 18, p. 379.

  A particularly useful class of esters of compounds of formula (Ix) containing a hydroxy group is Bundgaard et al., J. MoI. Med. Chem., 1989, 32, p. May be formed from an acid moiety selected from those described in 2503-2507, and substituted (aminomethyl) -benzoates, eg, two alkyl groups together and / or by an oxygen atom Or dialkylaminomethylbenzoates, in particular (morpholino-methyl) benzoates, such as 3- or 4- (morpholinomethyl) -benzoates and (4), which may be interrupted by optionally substituted nitrogen atoms, for example alkylated nitrogen atoms -Alkylpiperazin-1-yl) benzoates, such as 3- or 4- (4-alkylpiperazin-1-yl) benzoates may be included.

  If a compound of the invention of formula (Ix) contains a carboxy group or a sufficiently acidic bioequivalent, it may form a base addition salt, which is simply a more convenient form of use, indeed Use of the form is comparable to use of the free acid form. The base that can be used for the preparation of the base addition salt is preferably a pharmaceutically acceptable salt when mixed with the free acid, i.e. its cation is non-toxic to the patient at the pharmaceutical dose of the salt. And thereby those that produce salts in which the beneficial inhibitory action inherent to free bases is not impaired by side effects due to cations. The pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metals included within the scope of the present invention, include the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide , Aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine , N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide and the like.

  Some of the compounds of the invention of formula (Ix) are basic and such compounds are useful in the form of the free base or in the form of their pharmaceutically acceptable acid addition salts. It is.

  Acid addition salts are a more convenient form for use; indeed the use of the salt form is comparable to the use of the free base form. The acids that can be used for the preparation of the acid addition salts are preferably pharmaceutically acceptable salts when mixed with the free base, i.e. their anions are non-toxic to the patient at the pharmaceutical dose of the salt. This includes those that produce salts such that the beneficial inhibitory action inherent to free bases is not impaired by side effects due to anions. Pharmaceutically acceptable salts of the basic compounds are preferred, but for example when a particular salt itself forms a salt only for purification and identification purposes, for example, or by ionic exchange methods. All acid addition salts are useful as starting materials for free bases, even when the specific salt itself is only desired as an intermediate product, such as when used as an intermediate in the production of salts. It is. Pharmaceutically acceptable salts included within the scope of the present invention include those derived from inorganic and organic acids, and hydrohalides, such as hydrochloride and hydrobromide, sulfuric acid Salt, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleic acid Salt, methylenebis-b-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl Sulfamates and quinates are included.

  In addition to being useful as active compounds per se, the salts of the compounds of the invention of formula (Ix) can be prepared, for example, by a method known to those skilled in the art, between the salt and the parent compound, by-products and / or starting materials. Is useful for the purpose of purification of the compounds.

  The compounds of the invention of formula (Ix) may contain asymmetric centers. These asymmetric centers may independently be either in R configuration or S configuration. As one skilled in the art knows, certain compounds of the present invention may exhibit geometric isomerism. The present invention is also intended to include the individual geometric isomers and stereoisomers of the compounds of formula (Ix) described above and mixtures thereof, eg racemic mixtures. Such isomers can be separated from the mixture by applying known methods, for example by chromatographic and recrystallization methods, or they can be separated from the appropriate isomers of the intermediates individually. Manufactured. Furthermore, tautomers of the compound of formula (Ix) are also contemplated and the present invention is intended to include all tautomers of the compound.

［式中、
ＸはＣ−Ｒ²を示し、そして、Ｗ、ＹおよびＺは同じかまたは異なっていて、ＣＨまた
はＣＲ³を示し；
Ｒ¹はアリールまたはピラゾリル、トリアゾリル、イミダゾリル、インドリル、インダゾリル、チエノピラゾリル、テトラヒドロインダゾリル、テトラヒドロシクロペンタピラゾリル、ジヒドロフロピラゾリル、オキソジヒドロピリダジニル、テトラヒドロピロロピラゾリル、オキソテトラヒドロピロロピラゾリル、テトラヒドロピラノピラゾリル、テトラヒドロピリジノピラゾリルおよびオキソジヒドロピリジノピラゾリル基から選択されるヘテロアリールを示し、これらの基は全て、場合によりＨ、ハロゲン、ハロアルキル、ＯＨ、Ｒ⁴、ＮＯ₂、ＣＮ、Ｓ(Ｏ)_nＲ⁴、ＯＲ⁴、ＮＹ¹Ｙ²、ＣＯＲ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｃ(＝Ｏ)ＯＨ、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｓ(Ｏ)_nＯＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²、−ＯＳ(Ｏ)_nＲ⁴、−ＯＣ(＝Ｏ)Ｒ⁴および場合により置換されたチエニルから選択される基Ｘ¹、Ｘ²またはＸ³の１個または１個より多くで置換されており；
Ｒ²およびＲ³は下記の通り、即ち、
Ｒ²およびＲ³は同じかまたは異なっていて、Ｈ、Ｒ⁴、ハロゲン、ハロアルキル、ＯＨ、ＮＯ₂、ＣＮ、ＯＲ⁴、ＣＯＲ⁴、Ｓ(Ｏ)_nＲ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｃ(＝Ｏ)ＯＨ、−ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｓ(Ｏ)_nＯＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²および−ＯＣ(＝Ｏ)Ｒ⁴を示すか、
またはＲ²がＨ、Ｒ⁴、ハロゲン、ハロアルキル、ＯＨ、ＮＯ₂、ＣＮ、ＯＲ⁴、ＣＯＲ⁴、Ｓ(Ｏ)_nＲ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｃ(＝Ｏ)ＯＨ、−ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｓ(Ｏ)_nＯＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²および−ＯＣ(＝Ｏ)Ｒ⁴を示し、
そしてＲ³がアルキル、ハロアルキル、ハロゲンまたはＯＲ⁶を示すか、
またはＲ²とＲ³は一緒になってＯ、ＮおよびＳから選択される同じかまたは異なっていてもよいヘテロ原子１個または１個より多くを含む５〜６員の炭素系の環を形成し；
Ｒ⁴はアルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、ヘテロアリールアルキルまたはアリールアルキルを示し、これらの基は全て、アリール（場合により置換されている)、ハロゲン、アルキル、ヒドロキシアルキル、ＯＨ、ＯＲ⁵、Ｃ(＝Ｏ)ＮＹ³Ｙ⁴、ＮＹ³Ｙ⁴、ａｌｋ−ＮＹ³Ｙ⁴および−Ｃ(＝Ｏ)ＯＲ⁶から選択される置換基１個または１個より多くで場合により置換されており； That is, one requirement of the present invention is the following formula (I):

[Where:
X represents C—R ² and W, Y and Z are the same or different and represent CH or CR ³ ;
R ¹ is aryl or pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyrazyl Heteroaryl selected from nopyrazolyl, tetrahydropyridinopyrazolyl and oxodihydropyridinopyrazolyl groups, all of which are optionally H, halogen, haloalkyl, OH, R ⁴ , NO ₂ , CN, S (O _{^{) n R 4, OR 4,}} NY 1 Y 2, COR 4, -C (= O) NY 1 Y 2, -C (= O) OR 4, -C (= O) OH, -N (R 6) ^{C (= O) R 4,} -N (R 6) SO 2 R 4, -N (R 6) C (= O) NY 1 ^{2, -N (R 6) C} (= O) OR 4, -S (O) n OR 4, -S (O) n NY 1 Y 2, -OC (= O) NY 1 Y 2, -OS ( Substituted with one or more of the groups X ¹ , X ² or X ³ selected from O) _n R ⁴ , —OC (═O) R ⁴ and optionally substituted thienyl;
R ² and R ³ are as follows:
R ² and R ³ are the same or different, and H, R ⁴ , halogen, haloalkyl, OH, NO ₂ , CN, OR ⁴ , COR ⁴ , S (O) _n R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR ⁴ , —C (═O) OH, —NY ¹ Y ² , —N (R ⁶ ) C (═O) R ⁴ , —N (R ⁶ ) SO ₂ R ⁴ , —N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , —S (O) _n OR ⁴ , —S (O) _n NY ¹ Y ² , —OC (═O) NY ¹ Y ² and —OC (═O) R ⁴ ,
Or R ² is H, R ⁴ , halogen, haloalkyl, OH, NO ₂ , CN, OR ⁴ , COR ⁴ , S (O) _n R ⁴ , —C (═O) NY ¹ Y ² , —C (═O ) OR ⁴ , —C (═O) OH, —NY ¹ Y ² , —N (R ⁶ ) C (═O) R ⁴ , —N (R ⁶ ) SO ₂ R ⁴ , —N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , —S (O) _n OR ⁴ , —S (O) _n NY ¹ Y ² , —OC (═O) NY ^{1 represents} Y ² and —OC (═O) R ⁴ ,
And R ³ represents alkyl, haloalkyl, halogen or OR ⁶ ,
Or R ² and R ³ together form a 5- to 6-membered carbon-based ring containing one or more heteroatoms selected from O, N and S, which may be the same or different. And
R ⁴ represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all of these groups being aryl (optionally substituted), halogen, alkyl, ^{hydroxyalkyl, OH, oR 5, C (} = O) NY 3 Y 4, NY 3 Y 4, alk-NY 3 Y 4 and -C (= O) 1 or substituents selected from oR ⁶ Or optionally substituted with more than one;

R ⁵ represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl;
Y ¹ and Y ² are as follows: Y ¹ and Y ² are the same or different and are H or optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl Represents alkyl, heteroaryl and heteroarylalkyl,
Or Y ¹ and Y ² together with the nitrogen atom to which they are linked form a cyclic amino group;
Y ³ and Y ⁴ are as follows: Y ³ and Y ⁴ are the same or different and represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y ³ and Y ⁴ together with the nitrogen atom to which they are attached form an optionally substituted cyclic amino group;
A ₅ represents H or alkyl;
R ⁶ is selected from the meaning of R ⁵ ;
here,
Any alkyl (or alk representing alkyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups present in the above groups may optionally further be halogen atoms and hydroxyl, cyano, alkyl , Alkoxy, acylamino (NH—COalk), —C (═O) OR ⁶ , acyl-C (═O) R ⁶ , hydroxyalkyl, carboxyalkyl, S (O) _n -alk, S (O) _n —NH ₂ , S (O) _n —NH (alk), S (O) _n —N (alk) ₂ , CF ₃ , OCF ₃ , NO ₂ , arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, − Substituted with one or more groups selected from C (═O) —NY ³ Y ⁴ and NY ³ Y ⁴ groups;
The latter groups, including alkyl, aryl and heteroaryl, are themselves selected from halogen atoms and alkyl groups, free, salt-formated or esterified carboxyl groups and acylamino groups NH-C (O) R ⁵ Substituted with one or more groups,
The phenyl group is optionally further substituted with a dioxole group;
n represents an integer of 0 to 2,

の化合物を与える場合は、Ｗは必然的にＨまたは未置換のアルキルを示す］の化合物であり、
式（Ｉ）の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオマーの異性体、および無機または有機の酸との、または無機の塩基との付加塩である。 However, when R ¹ represents an imidazole group, X is H, and R ² and R ³ are defined as follows:

Wherein W necessarily represents H or unsubstituted alkyl]
The compounds of formula (I) are any possible racemates, enantiomers or diastereomeric isomers and addition salts with inorganic or organic acids or with inorganic bases.

［式中、
ＸａはＣ−Ｒ²ａを示し、そして、Ｗａ、ＹａおよびＺａは同じかまたは異なっていて、ＣＨまたはＣＲ³ａを示し；
Ｒ₁ａは、アリールまたはピラゾリル、トリアゾリルおよびインダゾリル基から選択されるヘテロアリールを示し、これらの基は全て、場合によりＨ、ハロゲン、ＯＨ、Ｒ⁴ａ、ＯＲ⁴ａ、ＮＹ¹ａＹ²ａ、−Ｓ(Ｏ)_nＲ⁴ａ、−Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｃ(＝Ｏ)ＯＲ⁴ａ、−Ｎ(Ｒ⁶ａ)Ｃ(＝Ｏ)Ｒ⁴ａ、−Ｎ(Ｒ⁶ａ)ＳＯ₂Ｒ⁴ａ、−Ｎ(Ｒ⁶ａ)Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｎ(Ｒ⁶ａ)Ｃ(＝Ｏ)ＯＲ⁴ａ、−ＯＣ(＝Ｏ)ＮＹ¹ａＹ²ａ、−ＯＣ(＝Ｏ)Ｒ⁴ａ、−ＯＳ(Ｏ)_nＲ⁴ａおよび場合によりアルキル基で置換されたチエニルから選択される基Ｘ¹ａ、Ｘ²ａまたはＸ³ａの１個または１個より多くで置換されており；
Ｒ²ａおよびＲ³ａは下記の通り、即ち、
Ｒ²ａおよびＲ³ａは同じかまたは異なっていて、Ｈ、Ｒ⁴ａ、ハロゲン、ＯＨ、ＯＲ⁴ａ、−Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｃ(＝Ｏ)ＯＲ⁴ａまたは−Ｃ(＝Ｏ)ＯＨを示し、そしてＲ³ａはアルキル、ハロゲンまたはＯＲ⁶ａを示すか、
またはＲ²ａがＨ、Ｒ⁴ａ、ハロゲン、ＯＨ、ＯＲ⁴ａ、−Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｃ(＝Ｏ)ＯＲ⁴ａまたは−Ｃ(＝Ｏ)ＯＨを示し、そしてＲ³ａはアルキル、ハロゲンまたはＯＲ⁶ａを示すか、
またはＲ²ａとＲ³ａは一緒になって−Ｏ−ＣＨ₂−Ｏ−または−Ｏ−ＣＨ₂−ＣＨ₂−Ｏ−環を形成し、
Ｒ⁴ａはアルキル、アルケニル、アルキニル、シクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、ヘテロアリールアルキルまたはアリールアルキルを示し、これらの基は全て、場合により置換されたアリール、ハロゲン、アルキル、ヒドロキシアルキル、ＯＨ、ＯＲ⁵ａ、Ｃ(＝Ｏ)ＮＹ³ａＹ⁴ａ、ＮＹ³ａＹ⁴ａ、ａｌｋ−ＮＹ³ａＹ⁴ａおよび−Ｃ(＝Ｏ)ＯＲ⁶ａから選択される置換基１個または１個より多くで場合により置換されており； That is, one requirement of the present invention is the following formula (Ia):

[Where:
Xa represents C—R ² a and Wa, Ya and Za are the same or different and represent CH or CR ³ a;
R ₁ a represents aryl or heteroaryl selected from pyrazolyl, triazolyl and indazolyl groups, all of which optionally are H, halogen, OH, R ⁴ a, OR ⁴ a, NY ¹ aY ² a, ^{_{-S (O) n R 4 a}} , -C (= O) NY 1 aY 2 a, -C (= O) OR 4 a, -N (R 6 a) C (= O) R 4 a, -N _{^{(R 6 a) SO 2 R}} 4 a, -N (R 6 a) C (= O) NY 1 aY 2 a, -N (R 6 a) C (= O) OR 4 a, -OC (= O A group X ¹ a, X ² a or X selected from: NY ¹ aY ² a, —OC (═O) R ⁴ a, —OS (O) _n R ⁴ a and thienyl optionally substituted with an alkyl group ³ is substituted with one or more of a;
R ² a and R ³ a are as follows:
R ² a and R ³ a are the same or different, and H, R ⁴ a, halogen, OH, OR ⁴ a, —C (═O) NY ¹ aY ² a, —C (═O) OR ⁴ a Or —C (═O) OH and R ³ a represents alkyl, halogen or OR ⁶ a,
Or R ² a represents H, R ⁴ a, halogen, OH, OR ⁴ a, —C (═O) NY ¹ aY ² a, —C (═O) OR ⁴ a or —C (═O) OH. And R ³ a represents alkyl, halogen or OR ⁶ a,
Or R ² a and R ³ a together form an —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O— ring;
R ⁴ a represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all of which groups are optionally substituted aryl, halogen, alkyl, ^{hydroxyalkyl, OH, oR 5 a, C} (= O) NY 3 aY 4 a, NY 3 aY 4 a, are selected from the alk-NY ³ aY ⁴ a and -C (= O) oR ⁶ a substituted Optionally substituted with one or more groups;

R ⁵ a is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, shown aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted optionally all these groups;
Y ¹ a and Y ² a are as follows, ie, Y ¹ a and Y ² a are the same or different, and H, alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl , Cycloalkyl, aryl or heteroaryl, these groups are all optionally substituted or Y ¹ a and Y ² a are optionally substituted together with the nitrogen atom to which they are attached. Forming a cyclic amino group;
Y ³ a and Y ⁴ a are as follows: Y ³ a and Y ⁴ a are the same or different and represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl;
Or Y ³ a and Y ⁴ a together with the nitrogen atom to which they are linked form a cyclic amino group;
A ₅ represents H or alkyl;
All alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups present in the above groups are further optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH— ^{C (O) R 6 a)} , - C (= O) OR 6 a, acyl ^{-C (= O) R 6 a} , hydroxyalkyl, _{carboxyalkyl, S (O) n -alk,} S (O) n - _{NH 2, S (O) n} -NH (alk), S (O) n -N (alk) 2, CF 3, OCF 3, NO 2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, Substituted with one or more groups selected from —C (═O) —NY ³ aY ⁴ a and NY ³ aY ⁴ a groups;
The latter groups including alkyl, aryl and heteroaryl are themselves optionally halogen atoms and alkyl groups, alkoxy groups, free, salt-formated or esterified carboxyl groups and acylamino groups NH—C (O) R ⁶ a Substituted with one or more than one group selected from
The phenyl group is optionally further substituted with a dioxole group;
R ⁶ a is selected from the meaning of R ⁵ a;
n represents an integer of 0 to 2]
A compound of formula (I) as defined above corresponding to
The compounds of formula (Ia) are any possible racemates, enantiomers or diastereoisomers and addition salts with inorganic or organic acids or with inorganic bases.

［式中、
ＸはＣ−Ｒ²を示し、そして、Ｗ、ＹおよびＺは同じかまたは異なっていて、ＣＨまたはＣＲ³を示し；
Ｒ¹はアリールまたはピラゾリル、トリアゾリル、イミダゾリル、インドリル、インダゾリル、チエノピラゾリル、テトラヒドロインダゾリル、テトラヒドロシクロペンタピラゾリル、ジヒドロフロピラゾリル、オキソジヒドロピリダジニル、テトラヒドロピロロピラゾリル、オキソテトラヒドロピロロピラゾリル、テトラヒドロピラノピラゾリル、テトラヒドロピリジノピラゾリルおよびオキソジヒドロピリジノピラゾリル基から選択されるヘテロアリールを示し、これらの基は全て、場合によりＨ、ハロゲン、ハロアルキル、ＯＨ、Ｒ⁴、ＮＯ₂、ＣＮ、Ｓ(Ｏ)_nＲ⁴、ＯＲ⁴、ＮＹ¹Ｙ²、ＣＯＲ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｃ(＝Ｏ)ＯＨ、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｓ(Ｏ)_nＯＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²、−ＯＳ(Ｏ)_nＲ⁴、−ＯＣ(＝Ｏ)Ｒ⁴および場合により置換されたチエニルから選択される基Ｘ¹、Ｘ²またはＸ³の１個または１個より多くで置換されており；
Ｒ²およびＲ³は下記の通り、即ち、
Ｒ²およびＲ³は同じかまたは異なっていて、Ｈ、Ｒ⁴、ハロゲン、ハロアルキル、ＯＨ、ＮＯ₂、ＣＮ、ＯＲ⁴、ＣＯＲ⁴、Ｓ(Ｏ)_nＲ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｃ(＝Ｏ)ＯＨ、−ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｓ(Ｏ)_nＯＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²または−ＯＣ(＝Ｏ)Ｒ⁴を示すか、
またはＲ²がＨ、Ｒ⁴、ハロゲン、ハロアルキル、ＯＨ、ＮＯ₂、ＣＮ、ＯＲ⁴、ＣＯＲ⁴、Ｓ(Ｏ)_nＲ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｃ(＝Ｏ)ＯＨ、−ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｓ(Ｏ)_nＯＲ⁴、−Ｓ(Ｏ)_nＮＹ¹Ｙ²、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²または−ＯＣ(＝Ｏ)Ｒ⁴を示し、
そしてＲ³がアルキル、ハロアルキル、ハロゲンまたはＯＲ⁶を示すか、
またはＲ²とＲ³は一緒になってＯ、ＮおよびＳから選択される同じかまたは異なっていてよいヘテロ原子１個または１個より多くを含む５〜６員の炭素系の環を形成し；
Ｒ⁴はアルキル、アルケニル、シクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、ヘテロアリールアルキルまたはアリールアルキルを示し、これらの基は全て、アリール、ＯＨ、ＯＲ⁵、Ｃ(＝Ｏ)ＮＹ³Ｙ⁴、ＮＹ³Ｙ⁴およびＣ(＝Ｏ)ＯＲ⁶から選択される置換基１個または１個より多くで場合により置換されており；
Ｒ⁵はアルキル、アルケニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、シクロアルキルアルキル、ヘテロアリールアルキルまたはヘテロシクロアルキルアルキルを示し；
Ｒ⁶はＨおよびＣ１−Ｃ４アルキルを示し；
ｎは０〜２の整数を示し、
Ｙ¹およびＹ²は以下の通り、即ちＹ¹およびＹ²は同じかまたは異なっていて、Ｈ、アルキル、アルケニル、シクロアルキル、アリール、アリールアルキル、ヘテロアリールおよびヘテロアリールアルキルを示し、これらの基全ては場合によりヒドロキシル、−Ｃ(＝Ｏ)ＮＹ³Ｙ⁴、−Ｃ(＝Ｏ)ＯＲ⁶およびＮＹ³Ｙ⁴から選択される基１個または１個より多くで置換されているか、
またはＹ¹およびＹ²はそれらが連結している窒素原子と一緒になって環状アミノ基を形成し；
Ｙ³およびＹ⁴は以下の通り、即ちＹ³およびＹ⁴は同じかまたは異なっていて、水素、アルケニル、アルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリールまたはヘテロアリールアルキルを示すか、またはＹ³およびＹ⁴はそれらが連結している窒素原子と一緒になって環状アミノ基を形成し；
Ａ₅はＨまたはアルキルを示すが、 That is, one requirement of the present invention is the following formula (I):

[Where:
X represents C—R ² and W, Y and Z are the same or different and represent CH or CR ³ ;
R ¹ is aryl or pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyrazyl Heteroaryl selected from nopyrazolyl, tetrahydropyridinopyrazolyl and oxodihydropyridinopyrazolyl groups, all of which are optionally H, halogen, haloalkyl, OH, R ⁴ , NO ₂ , CN, S (O _{^{) n R 4, OR 4,}} NY 1 Y 2, COR 4, -C (= O) NY 1 Y 2, -C (= O) OR 4, -C (= O) OH, -N (R 6) ^{C (= O) R 4,} -N (R 6) SO 2 R 4, -N (R 6) C (= O) NY 1 ^{2, -N (R 6) C} (= O) OR 4, -S (O) n OR 4, -S (O) n NY 1 Y 2, -OC (= O) NY 1 Y 2, -OS ( Substituted with one or more of the groups X ¹ , X ² or X ³ selected from O) _n R ⁴ , —OC (═O) R ⁴ and optionally substituted thienyl;
R ² and R ³ are as follows:
R ² and R ³ are the same or different, and H, R ⁴ , halogen, haloalkyl, OH, NO ₂ , CN, OR ⁴ , COR ⁴ , S (O) _n R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR ⁴ , —C (═O) OH, —NY ¹ Y ² , —N (R ⁶ ) C (═O) R ⁴ , —N (R ⁶ ) SO ₂ R ⁴ , —N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , —S (O) _n OR ⁴ , —S (O) _n NY ¹ Y ² , —OC (═O) NY ¹ Y ² or —OC (═O) R ⁴ ,
Or R ² is H, R ⁴ , halogen, haloalkyl, OH, NO ₂ , CN, OR ⁴ , COR ⁴ , S (O) _n R ⁴ , —C (═O) NY ¹ Y ² , —C (═O ) OR ⁴ , —C (═O) OH, —NY ¹ Y ² , —N (R ⁶ ) C (═O) R ⁴ , —N (R ⁶ ) SO ₂ R ⁴ , —N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , —S (O) _n OR ⁴ , —S (O) _n NY ¹ Y ² , —OC (═O) NY ^{1 represents} Y ² or —OC (═O) R ⁴ ,
And R ³ represents alkyl, haloalkyl, halogen or OR ⁶ ,
Or R ² and R ³ together form a 5-6 membered carbon-based ring containing one or more heteroatoms selected from O, N and S, which may be the same or different. ;
R ⁴ represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all of these groups being aryl, OH, OR ⁵ , C (═O) Optionally substituted with one or more substituents selected from NY ³ Y ⁴ , NY ³ Y ⁴ and C (═O) OR ⁶ ;
R ⁵ represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl;
R ⁶ represents H and C1-C4 alkyl;
n represents an integer of 0 to 2,
Y ¹ and Y ² are as follows: Y ¹ and Y ² are the same or different and represent H, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, and these groups All optionally substituted with one or more groups selected from hydroxyl, —C (═O) NY ³ Y ⁴ , —C (═O) OR ⁶ and NY ³ Y ⁴ ,
Or Y ¹ and Y ² together with the nitrogen atom to which they are linked form a cyclic amino group;
Y ³ and Y ⁴ are as follows: Y ³ and Y ⁴ are the same or different and represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y ³ and Y ⁴ together with the nitrogen atom to which they are attached form a cyclic amino group;
A ₅ represents H or alkyl,

の化合物を与える場合は、Ｗは必然的にＨまたは未置換のアルキルを示す］
の化合物であり、
式（Ｆ）の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオマーの異性体、および無機または有機の酸との、または無機の塩基との付加塩である。 However, when R ¹ represents an imidazole group, X is H, and R ² and R ³ are defined as follows:

Where W necessarily represents H or unsubstituted alkyl]
A compound of
The compounds of formula (F) are any possible racemates, enantiomers or diastereomeric isomers and addition salts with inorganic or organic acids or with inorganic bases.

［式中、
ＸａはＣ−Ｒ²ａを示し、そして、Ｗａ、ＹａおよびＺａは同じかまたは異なっていて、ＣＨまたはＣＲ³ａを示し；
Ｒ₁ａはアリールまたはピラゾリル、トリアゾリルおよびインダゾリル基から選択されるヘテロアリールを示し、これらの基は全て、場合によりＨ、ハロゲン、ＯＨ、Ｒ⁴ａ、ＯＲ⁴ａ、ＮＹ¹ａＹ²ａ、−Ｓ(Ｏ)_nＲ⁴ａ、−Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｃ(＝Ｏ)ＯＲ⁴ａ、−Ｎ(Ｒ⁶ａ)Ｃ(＝Ｏ)Ｒ⁴ａ、−Ｎ(Ｒ⁶ａ)ＳＯ₂Ｒ⁴ａ、−Ｎ(Ｒ⁶ａ)Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｎ(Ｒ⁶ａ)Ｃ(＝Ｏ)ＯＲ⁴ａ、−ＯＣ(＝Ｏ)ＮＹ¹ａＹ²ａおよび−ＯＣ(＝Ｏ)Ｒ⁴ａ、−ＯＳ(Ｏ)_nＲ⁴ａおよび場合によりアルキル基で置換されたチエニルから選択される基Ｘ¹ａ、Ｘ²ａまたはＸ³ａの１個または１個より多くで置換されており；
Ｒ²ａおよびＲ³ａは下記の通り、即ち、
Ｒ²ａおよびＲ³ａは同じかまたは異なっていて、Ｈ、Ｒ⁴ａ、ハロゲン、ＯＨ、ＯＲ⁴ａ、−Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｃ(＝Ｏ)ＯＲ⁴ａ、−Ｃ(＝Ｏ)ＯＨを示し、そしてＲ³ａはアルキル、ハロゲンまたはＯＲ⁶ａを示すか、
またはＲ²ａがＨ、Ｒ⁴ａ、ハロゲン、ＯＨ、ＯＲ⁴ａ、−Ｃ(＝Ｏ)ＮＹ¹ａＹ²ａ、−Ｃ(＝Ｏ)ＯＲ⁴ａまたは−Ｃ(＝Ｏ)ＯＨを示し、そしてＲ³ａはアルキル、ハロゲンまたはＯＲ⁶ａを示すか、
またはＲ²ａとＲ³ａは一緒になって−Ｏ−ＣＨ₂−Ｏ−または−Ｏ−ＣＨ₂−ＣＨ₂−Ｏ−環を形成し、
Ｒ⁴ａはアルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、ヘテロアリールアルキルまたはアリールアルキルを示し、これらの基は全て場合によりアリール、ＯＨ、ＯＲ⁵ａ、Ｃ(＝Ｏ)ＮＹ³ａＹ⁴ａ、ＮＹ³ａＹ⁴ａおよび−Ｃ(＝Ｏ)Ｏ
Ｒ⁶ａから選択される置換基１個または１個より多くで置換されており；
Ｒ⁵ａはアルキル、アルケニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキル、シクロアルキルアルキル、ヘテロアリールアルキルまたはヘテロシクロアルキルアルキルを示し；
Ｒ⁶ａはＨおよびＣ１−Ｃ４アルキルを示し；
ｎは０〜２の整数であり；
Ｙ¹ａおよびＹ²ａは以下の通り、即ちＹ¹ａおよびＹ²ａは同じかまたは異なっていて、Ｈ、アルキル、シクロアルキル、アリールまたはヘテロアリールを示し、これらの基は全て場合によりヒドロキシル、−Ｃ(＝Ｏ)−ＮＹ³Ｙ⁴、−Ｃ(＝Ｏ)ＯＲ⁶およびＮＹ³Ｙ⁴から選択される置換基１個または１個より多くで置換されているか、または、Ｙ¹ａおよびＹ²ａはそれらが連結している窒素原子と一緒になって環状アミノ基を形成し；
Ｙ³ａおよびＹ⁴ａは以下の通り、即ちＹ³ａおよびＹ⁴ａは同じかまたは異なっていて、水素、アルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリールまたはヘテロアリールアルキルを示すか、またはＹ³ａおよびＹ⁴ａはそれらが連結している窒素原子と一緒になって環状アミノ基を形成し；
Ａ₅はＨまたはアルキルを示す］に相当する上記定義した式（Ｉ）の化合物であり、
式（Ｉａ）の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオマーの異性体、および無機または有機の酸との、または無機の塩基との付加塩である。 That is, one requirement of the present invention is the following formula (Ia):

[Where:
Xa represents C—R ² a and Wa, Ya and Za are the same or different and represent CH or CR ³ a;
R ₁ a represents aryl or heteroaryl selected from pyrazolyl, triazolyl and indazolyl groups, all of which are optionally H, halogen, OH, R ⁴ a, OR ⁴ a, NY ¹ aY ² a, − S (O) _n R ⁴ a, —C (═O) NY ¹ aY ² a, —C (═O) OR ⁴ a, —N (R ⁶ a) C (═O) R ⁴ a, —N ( _{^{R 6 a) SO 2 R 4}} a, -N (R 6 a) C (= O) NY 1 aY 2 a, -N (R 6 a) C (= O) OR 4 a, -OC (= O) A group X ¹ a, X ² a or X ³ selected from NY ¹ aY ² a and —OC (═O) R ⁴ a, —OS (O) _n R ⁴ a and thienyl optionally substituted with an alkyl group substituted with one or more of a;
R ² a and R ³ a are as follows:
R ² a and R ³ a are the same or different, and H, R ⁴ a, halogen, OH, OR ⁴ a, —C (═O) NY ¹ aY ² a, —C (═O) OR ⁴ a , -C (= O) indicates OH, and R ³ a is either represents an alkyl, halogen or oR ⁶ a,
Or R ² a represents H, R ⁴ a, halogen, OH, OR ⁴ a, —C (═O) NY ¹ aY ² a, —C (═O) OR ⁴ a or —C (═O) OH. And R ³ a represents alkyl, halogen or OR ⁶ a,
Or R ² a and R ³ a together form an —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O— ring;
R ⁴ a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all of these groups optionally being aryl, OH, OR ⁵ a, C (═O) NY ³ aY ⁴ a, NY ³ aY ⁴ a and —C (═O) O
More than one substituent or one selected from R ⁶ a is substituted with;
R ⁵ a represents an alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl;
R ⁶ a represents H and C1-C4 alkyl;
n is an integer from 0 to 2;
Y ¹ a and Y ² a are as follows: Y ¹ a and Y ² a are the same or different and represent H, alkyl, cycloalkyl, aryl or heteroaryl, all these groups optionally hydroxyl , —C (═O) —NY ³ Y ⁴ , —C (═O) OR ⁶ and NY ³ Y ⁴ or substituted with one or more substituents selected from Y ¹ a And Y ² a together with the nitrogen atom to which they are attached form a cyclic amino group;
Y ³ a and Y ⁴ a are as follows: Y ³ a and Y ⁴ a are the same or different and represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; Or Y ³ a and Y ⁴ a together with the nitrogen atom to which they are linked form a cyclic amino group;
A ₅ represents H or alkyl] and is a compound of formula (I) as defined above,
The compounds of formula (Ia) are any possible racemates, enantiomers or diastereoisomers and addition salts with inorganic or organic acids or with inorganic bases.

［式中、Ａは５または６員の単環の基または１０員より多くない２環の基のいずれかである飽和の複素環基を示し、これらの環員は、その少なくとも２つが窒素原子１個と他の原子を示しそして該他の原子は同じかまたは異なっていてもよく、炭素環員またはＯ、ＮおよびＳから選択されるヘテロ原子の環員を示し、この複素環Ａは場合により基Ｘ¹、Ｘ²またはＸ³に関して上記した意味から選択される基ＸＡ¹、ＸＡ²またはＸＡ³の１個または１個より多くで置換されており；
Ａ₁、Ａ₂、Ａ₃およびＡ₄は同じかまたは異なっていて、水素原子、ハロゲン原子およびヒドロキシル、アルキル、アルケニル、アルコキシ、ニトロ、シアノ、アリール、ヘテロアリールおよびアリールオキシ基、遊離、塩形態化またはアルキル基でエステル化または基ＮＡ⁶Ａ⁷でアミド化されたカルボキシル基から選択され、ここでＡ⁶およびＡ⁷は同じかまたは異なっていて、水素および場合により置換されたアルキル、アルコキシアルキル、フェノキシアルキル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクロアルキルアルキルおよびヘテロアリールアルキル基から選択されるか、または、Ａ⁶およびＡ⁷はそれらが連結している窒素原子と一緒になって場合により置換された５または６員の環状の基を形成し、
ここでＡ₁、Ａ₂、Ａ₃およびＡ₄のうちの２つの連続する基はそれらが連結しているベン
ゾイミダゾール基と一緒になってＯ、ＮおよびＳから選択される同じかまたは異なっていてよいヘテロ原子１個または１個より多くを含む５〜６員の炭素系の環を形成し得るものと解され；
Ａ₅は水素原子またはアルキル基を示し；
Ｒ⁶ｂは水素、アルキル、アルケニル、シクロアルキル、フェニル、フェニルアルキルおよびシクロアルキルアルキルを示し、
上記基内に存在する全てのアルキル、アルケニル、アリール、ヘテロアリール、アリールオキシ、シクロアルキルおよびヘテロシクロアルキル基は場合によりハロゲン原子およびヒドロキシル、シアノ、アルキル、アルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、フェニルアミノ、フェニルアルキルアミノ、アシルアミノ（ＮＨ−ＣＯＲ⁶)、−Ｃ(＝Ｏ)ＯＲ⁶ｂ、アシル−Ｃ(＝Ｏ)Ｒ⁶ｂ、ヒドロキシアルキル、カルボキシアルキル、フェノキシアルキル、Ｓ(Ｏ)_n−ａｌｋ、Ｓ(Ｏ)_n−ＮＨ₂、Ｓ(Ｏ)_n−ＮＨ(ａｌｋ)、Ｓ(Ｏ)_n−Ｎ(ａｌｋ)₂、ＣＦ₃、ＯＣＦ₃、ＮＯ₂、ＣＮ、フェニル、それ自体が場合によりハロゲン原子１個または１個より多くで置換されているもの、チエニル、フェノキシ、フェニルアルコキシ、−Ｃ(＝Ｏ)−ＮＨ₂、−Ｃ(＝Ｏ)−ＮＨ(ａｌｋ)およびＣ(＝Ｏ)−Ｎ(ａｌｋ)₂基から選択される基１個または１個より多くで置換されており、
全て上記したアルキル、アルケニル、アルコキシおよびアルキルチオ基は直鎖または分枝鎖であり、そして４個より多くない炭素原子を含み、
フェニル基は更に場合によりジオキソール基で置換されており；
ｎは０〜２の整数を示す］
に相当する上記定義した式（Ｉ）の化合物であり、
式（ＩＡ）の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオマーの異性体、および式（ＩＡ）の該化合物の無機または有機の酸との、または無機の塩基との付加塩である。 That is, one requirement of the present invention is the following formula (IA):

[Wherein A represents a saturated heterocyclic group which is either a 5- or 6-membered monocyclic group or a bicyclic group not more than 10-membered, at least two of which are nitrogen atoms. One and other atoms, which may be the same or different, represent carbon ring members or ring members of a heteroatom selected from O, N and S, this heterocycle A being Substituted by one or more of the groups XA ¹ , XA ² or XA ³ selected from the meanings given above for the groups X ¹ , X ² or X ³ ;
A ₁ , A ₂ , A ₃ and A ₄ are the same or different and are hydrogen atom, halogen atom and hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy groups, free, salt form Or a carboxyl group esterified with an alkyl group or amidated with the group NA ⁶ A ⁷ , wherein A ⁶ and A ⁷ are the same or different and are hydrogen and optionally substituted alkyl, alkoxyalkyl , Phenoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl groups, or A ⁶ and A ⁷ together with the nitrogen atom to which they are attached 5 or 6 member optionally replaced Forming a Jo groups,
Wherein two consecutive groups of A ₁ , A ₂ , A ₃ and A ₄ are the same or different selected from O, N and S together with the benzimidazole group to which they are linked. It is understood that it may form a 5-6 membered carbon-based ring containing one or more heteroatoms that may be present;
A ₅ represents a hydrogen atom or an alkyl group;
R ⁶ b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl;
All alkyl, alkenyl, aryl, heteroaryl, aryloxy, cycloalkyl and heterocycloalkyl groups present in the above groups are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenyl Amino, phenylalkylamino, acylamino (NH—COR ⁶ ), —C (═O) OR ⁶ b, acyl-C (═O) R ⁶ b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) _n — _{alk, S (O) n -NH} 2, S (O) n -NH (alk), S (O) n -N (alk) 2, CF 3, OCF 3, NO 2, CN, phenyl, itself Optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= _{) -NH 2, -C (= O} ) -NH (alk) and C (= O) -N (alk ) is substituted with one or more than one group selected from the ₂ groups,
All alkyl, alkenyl, alkoxy and alkylthio groups mentioned above are straight-chain or branched and contain no more than 4 carbon atoms,
The phenyl group is optionally further substituted with a dioxole group;
n represents an integer of 0 to 2]
A compound of formula (I) as defined above corresponding to
The compounds of formula (IA) are any possible racemates, enantiomers or diastereoisomers, and addition salts of the compounds of formula (IA) with inorganic or organic acids or with inorganic bases It is.

［式中、Ａａはピラゾリル、トリアゾリルまたはインダゾリル基を示し、この複素環Ａａは場合により基Ｘ¹、Ｘ²またはＸ³に関して上記した意味から選択される基ＸＡ¹、ＸＡ²またはＸＡ³の１個または１個より多くで置換されており；
Ａ₁ａ、Ａ₂ａ、Ａ₃ａおよびＡ₄ａは同じかまたは異なっていて、水素原子、ハロゲン原子、ヒドロキシル、アルキル、アルコキシ、ニトロ、シアノ、フェニルおよびフェノキシ基、および、遊離、塩形態化またはアルキル基でエステル化または基ＮＡ⁶ａＡ⁷ａでアミド化されたカルボキシル基から選択され、ここでＡ⁶ａおよびＡ⁷ａは同じかまたは異なっていて、水素原子およびアルキル、フェニル、フェニルアルキル、シクロアルキルアルキル、シクロアルキル、フリルアルキル、チエニルアルキルおよびピリジルアルキル基から選択されるか、または、Ａ⁶ａおよびＡ⁷ａはそれらが連結している窒素原子と一緒になっ
てそれ自体場合により置換されているアルキルまたはフェニル基で第２窒素原子上で場合により置換されているピロリジニル、ピラゾリジニル、ピラゾリニル、ピペリジニル、モルホリノまたはピペラジニル基を形成し、
ここでＡ₁ａ、Ａ₂ａ、Ａ₃ａおよびＡ₄ａのうちの２つの連続する基はそれらが連結しているベンゾイミダゾール基と一緒になって酸素原子１個または２個を含む場合により置換されていてもよい５〜６員の炭素系の環を形成してよく、
Ａ₅ａは水素原子またはアルキル基を示し；
上記したフェニルおよびフェノキシ基は場合によりハロゲン原子およびヒドロキシル、シアノ、トリフルオロメチル、トリフルオロメトキシ、アルキル、アルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、フェニルアミノ、フェニルアルキルアミノ、遊離、塩形態化またはエステル化されたカルボキシルおよびジオキソール基から選択される基１個または１個より多くで置換されており；
全て上記したアルキル、アルコキシおよびアルキルチオ基は直鎖または分枝鎖であり、そして６個より多くない炭素原子を含む］に相当する上記定義した式（Ｉ）の化合物であり、
式（ＩＡａ）の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオマーの異性体、および、式（ＩＡａ）の該化合物の無機または有機の酸との、または無機の塩基との付加塩である。 That is, one requirement of the present invention is the following formula (IAa):

[Wherein Aa represents a pyrazolyl, triazolyl or indazolyl group, and this heterocyclic ring Aa is optionally selected from the group XA ¹ , XA ² or XA ³ selected from the meanings given above for the group X ¹ , X ² or X ^3. Or more than one is substituted;
A ₁ a, A ₂ a, A ₃ a and A ₄ a are the same or different and are hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, and free, salt form Selected from carboxyl groups esterified or esterified with an alkyl group or amidated with the group NA ⁶ aA ⁷ a, wherein A ⁶ a and A ⁷ a are the same or different and are hydrogen atoms and alkyl, phenyl, phenyl Selected from alkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl groups, or when A ⁶ a and A ⁷ a are themselves together with the nitrogen atom to which they are attached Optionally substituted on the second nitrogen atom with an alkyl or phenyl group substituted by Pyrrolidinyl, formed pyrazolidinyl, pyrazolinyl, piperidinyl, morpholino or piperazinyl group,
Where two consecutive groups of A ₁ a, A ₂ a, A ₃ a and A ₄ a together with the benzimidazole group to which they are linked contain one or two oxygen atoms May form a 5-6 membered carbon-based ring optionally substituted by
A ₅ a represents a hydrogen atom or an alkyl group;
The phenyl and phenoxy groups mentioned are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salt form or ester Substituted with one or more groups selected from activated carboxyl and dioxole groups;
All of the above-mentioned alkyl, alkoxy and alkylthio groups are straight-chain or branched and contain not more than 6 carbon atoms] corresponding to the compounds of formula (I) defined above,
The compound of formula (IAa) may be any possible racemate, enantiomer or diastereoisomer, and addition of the compound of formula (IAa) with an inorganic or organic acid or with an inorganic base Salt.

The substituents X ¹ , X ² or X ³ defined above are in particular one hydrogen atom and the other two are the same or different halogen atoms and OH, R ⁴ a, OR ⁴ a, CF ₃ , OCF ₃ , NO _2. CN, NY ¹ aY ² a, acylamino (NH—COR ⁶ b), S (O) _n -alk, S (O) _n —NH ₂ , S (O) _n —NH (alk), S (O) _{n -N (alk) 2, -C} (= O) -NH 2, -C (= O) -NH (alk), C (= O) -N (alk) 2, C (= O) OR 4 a ^{, -N (R 6 b) C} (= O) R 4 a, -N (R 6 b) SO 2 R 4 a, -N (R 6 b) C (= O) NY 1 aY 2 a, -N (R ⁶ b) C (═O) OR ⁴ a, —OC (═O) NY ¹ aY ² a and a thienyl group, the thienyl group optionally substituted with an alkyl group;
R ⁴ a, Y ¹ a, Y ² a and R ⁶ b have the above meanings, and alk contains no more than 6 carbon atoms and is optionally substituted as described above Represents an alkyl group.

  All alkylthio groups are those in which the sulfur atom is optionally oxidized with one or two oxygen atoms to give a sulfone or sulfoxide.

Tables I, II and III below show examples of compounds illustrating the invention having substituents selected in particular from the meaning of X ¹ , X ² or X ³ as described above.

  That is, the requirement of the present invention is that the substituent of the compound of formula (I) has any of the meanings defined above, and the aryl group represents phenyl and naphthyl groups; the heteroaryl group is furyl, thienyl, benzothienyl. , Thiantenyl, pyridyl, pyrazolyl, benzimidazolyl, benzofuran, isobenzofuran and dihydrobenzofuran groups; a cycloalkyl group represents a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; a heterocycloalkyl group represents a hexahydropyran, piperidyl or morpholino group A heterocycloalkylalkyl group represents hexahydropyranylalkyl, piperidylalkyl and morpholinoalkyl groups; an arylalkyl group represents phenylalkyl, ethylenedioxyphenylalkyl and A heteroarylalkyl group represents thienylalkyl, pyridylalkyl, furylalkyl, pyrazolylalkyl, benzothienylalkyl, dihydrobenzofuranylalkyl and benzimidazolylalkyl groups; aryloxy groups represent phenoxy and naphthyloxy groups An arylalkoxy group represents a phenylalkoxy and naphthylalkoxy group; and an aryloxyalkyl group represents a phenoxyalkyl group; all of these groups are optionally substituted as defined above (I ).

［式中、Ａは５または６員の単環の基または１０員より多くない２環の基のいずれかである飽和の複素環基を示し、これらの環員は、その少なくとも２つが窒素原子１個と他の原子を示しそして該他の原子は同じかまたは異なっていて、炭素環員またはＯ、ＮおよびＳから選択されるヘテロ原子の環員を示し、この複素環Ａは場合によりハロゲン原子、アルキル、アルコキシまたはアルキルチオ基または場合によりアルキル基で置換されたチエニルから選択される基ＸＡ¹、ＸＡ²またはＸＡ³の１個または１個より多くで置換されており；
Ａ₁、Ａ₂、Ａ₃およびＡ₄は同じかまたは異なっていて、水素原子、ハロゲン原子およびヒドロキシル、アルキル、アルコキシ、ニトロ、シアノ、フェニルおよびフェノキシ基、遊離、塩形態化またはアルキル基でエステル化または基ＮＡ⁶Ａ⁷でアミド化されたカルボキシル基から選択され、ここでＡ⁶およびＡ⁷は同じかまたは異なっていて、水素原子およびアルキル、フェニル、フェニルアルキル、シクロアルキルアルキル、シクロアルキルおよびヘテロアリールアルキル基から選択されるか、または、Ａ⁶およびＡ⁷はそれらが連結している窒素原子と一緒になって５または６員の環状の基を形成し、
ここでＡ₁、Ａ₂、Ａ₃およびＡ₄のうちの２つの連続する基はそれらが連結しているベンゾイミダゾール基と一緒になってＯ、ＮおよびＳから選択される同じかまたは異なってい
てよいヘテロ原子１個または１個より多くを含む５〜６員の炭素系の環を形成してよく；
Ａ₅は水素原子またはアルキル基を示し；
上記基内に存在する全てのフェニル、フェノキシ、シクロアルキルおよびヘテロアリールアルキル基は場合によりハロゲン原子およびヒドロキシル、シアノ、トリフルオロメチル、トリフルオロメトキシ、アルキル、アルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、フェニルアミノ、フェニルアルキルアミノ、遊離、塩形態化またはエステル化されたカルボキシルおよびジオキソール基から選択される基１個または１個より多くで置換されており；
全て上記したアルキル、アルコキシおよびアルキルチオ基は直鎖または分枝鎖であり、そして６個より多くない炭素原子を含む］
に相当する上記定義した式（Ｉ)の化合物であり、
式（ＩＡ)の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオ
マーの異性体、および式（ＩＡ)の該化合物の無機または有機の酸との、または無機の塩基との付加塩である。 In particular, one requirement of the present invention is the following formula (IA):

[Wherein A represents a saturated heterocyclic group which is either a 5- or 6-membered monocyclic group or a bicyclic group not more than 10-membered, at least two of which are nitrogen atoms. One and the other atom and the other atom is the same or different and represents a carbon ring member or a heteroatom ring member selected from O, N and S, the heterocycle A optionally halogenated Substituted with one or more of the groups XA ¹ , XA ² or XA ³ selected from atoms, alkyl, alkoxy or alkylthio groups or thienyl optionally substituted with alkyl groups;
A ₁ , A ₂ , A ₃ and A ₄ are the same or different and are hydrogen, halogen and hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy groups, free, salted or alkylated with an ester Or a carboxyl group amidated with the group NA ⁶ A ⁷ , wherein A ⁶ and A ⁷ are the same or different and are hydrogen and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and Selected from heteroarylalkyl groups, or A ⁶ and A ⁷ together with the nitrogen atom to which they are attached form a 5- or 6-membered cyclic group;
Wherein two consecutive groups of A ₁ , A ₂ , A ₃ and A ₄ are the same or different selected from O, N and S together with the benzimidazole group to which they are linked. May form a 5-6 membered carbon-based ring containing one or more heteroatoms, which may be
A ₅ represents a hydrogen atom or an alkyl group;
All phenyl, phenoxy, cycloalkyl and heteroarylalkyl groups present in the above groups are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenyl Substituted with one or more groups selected from amino, phenylalkylamino, free, salt-formated or esterified carboxyl and dioxole groups;
All the alkyl, alkoxy and alkylthio groups described above are straight or branched and contain no more than 6 carbon atoms]
A compound of formula (I) as defined above corresponding to
The compounds of formula (IA) are any possible racemates, enantiomers or diastereoisomers, and addition salts of the compounds of formula (IA) with inorganic or organic acids or with inorganic bases It is.

［式中、Ａｂはハロゲン原子およびＯＨ、アルキル、アルキニル、−ＯＲ⁶ｂ、例えばアルコキシ、−ＣＯＲ⁶ｂ、−Ｏ−ＣＯＲ⁶ｂ、−ＯＳ(Ｏ)_nＲ⁶ｂ、−Ｏ(ＣＨ₂)_n−ＣＯ−Ｒ⁶ｂ、フェニル、フェニルアルキル、ＣＦ₃、ＯＣＦ₃、ＮＯ₂、ＣＮ、ＮＹ¹ｂＹ²ｂ、−ＮＨ−Ｃ(＝Ｏ)ＮＹ¹ｂＹ²ｂ、アシルアミノ(ＮＨ−ＣＯ−Ｒ⁶ｂ)、Ｓ(Ｏ)_n−ａｌｋ、Ｓ(Ｏ)_n−ＮＹ¹ｂＹ²ｂ、−Ｃ(＝Ｏ)−ＮＹ¹ｂＹ²ｂ、−Ｃ(＝Ｏ)ＯＲ⁶ｂ、−ＮＨ−Ｃ(＝Ｏ)Ｒ⁶ｂ、−ＮＨ−Ｓ(Ｏ)_nＲ⁶ｂ、−ＮＨ−Ｃ(＝Ｏ)ＯＲ⁶ｂ、−Ｎ(Ｒ⁶ｂ)Ｃ(＝Ｏ)ＮＹ¹ｂＹ²ｂ、−ＯＣ(＝Ｏ)ＮＹ¹ｂＹ²ｂおよびチエニル基、ただしこれら全ての基は場合により置換されているものから選択される基１個または１個より多くで場合により置換されているピラゾリルまたはインダゾリル基を示し、
ここでＮＹ¹ｂＹ²ｂは以下の通り、即ちＹ¹ｂおよびＹ²ｂは同じかまたは異なっていて、水素および場合により置換されたアルキル、シクロアルキル、シクロアルキルアルキル、フェニル、ナフチル、フェノキシ、フェニルアルキル、フェニルアルキルチオおよびナフチルアルキルから選択されるか、またはＹ¹ｂおよびＹ²ｂはそれらが連結している窒素原子と一緒になってピペリジル、ヘキサヒドロフラン、モルホリニルまたはモルホリニルアルキル基を形成し；
Ａ₁ｂ、Ａ₂ｂ、Ａ₃ｂおよびＡ₄ｂは同じかまたは異なっていて、水素原子、ハロゲン原子、ヒドロキシル、アルキル、アルケニル、−ＯＲ⁶ｂ、例えばアルコキシ、−ＣＯＲ⁶ｂ、−Ｏ−ＣＯＲ⁶ｂ、−ＯＳ(Ｏ)_nＲ⁶ｂ、−Ｏ(ＣＨ₂)_n−ＣＯ−Ｒ⁶ｂ、ニトロ、シアノ、フリル、チエニル、ベンゾチエニル、ナフチル、チアントレニル、フェニルおよびフェノキシ基および遊離、塩形態化、アルキル基でエステル化または基ＮＡ⁶ｂＡ⁷ｂでアミド化されたカルボキシル基から選択され、ここでＡ⁶ｂおよびＡ⁷ｂは同じかまたは異なっていて、水素およびアルキル、アルコキシアルキル、フェノキシアルキル、フェニル、フェニルアルキル、シクロアルキルアルキル、シクロアルキル、フリルアルキル、ナフチルアルキル、チエニルアルキル、ピペリジニルアルキル、ピリジルアルキル、ベンゾチエニルアルキル、ピラゾリルアルキル、ジヒドロベンゾフラニルアルキル、ヘキサヒドロピラニルアルキル、エチレンジオキシフェニルアルキルおよびベンズイミダゾリルアルキル基から選択され、全てこれらの基は場合により置換されているか、または、Ａ⁶ｂおよびＡ⁷ｂはそれらが連結している窒素原子と一緒になってピロリジニル、モルホリノまたはピペラジニル基を形成し、ピペラジニル基は場合によりそれ自体場合により置換されているアルキル基で第２窒素原子上で置換されており、
ここでＡ₁ｂ、Ａ₂ｂ、Ａ₃ｂおよびＡ₄ｂのうちの２つの連続する基はそれらが連結しているベンゾイミダゾール基と一緒になって場合により置換された４,５−エチレンジオキ
シベンゾイミダゾール基または場合により置換された４,５−メチレンジオキシベンゾイ
ミダゾール基を形成し；
Ａ₅ｂは水素原子を示し； One requirement of the present invention is still more particularly the following formula (IAb):

[In the formula, Ab represents a halogen atom and OH, alkyl, alkynyl, —OR ⁶ b, such as alkoxy, —COR ⁶ b, —O—COR ⁶ b, —OS (O) _n R ⁶ b, —O (CH ₂ ) _n -CO-R ⁶ b, phenyl, _{phenylalkyl, CF 3, OCF 3, NO} 2, CN, NY 1 bY 2 b, -NH-C (= O) NY 1 bY 2 b, acylamino (NH-CO ^{-R 6 b), S (O} ) n -alk, S (O) n -NY 1 bY 2 b, -C (= O) -NY 1 bY 2 b, -C (= O) OR 6 b, - NH—C (═O) R ⁶ b, —NH—S (O) _n R ⁶ b, —NH—C (═O) OR ⁶ b, —N (R ⁶ b) C (═O) NY ¹ bY ² b, —OC (═O) NY ¹ bY ² b and thienyl groups, all of which are optionally substituted with one or more groups selected from those optionally substituted Pi Represents a lazolyl or indazolyl group,
Where NY ¹ bY ² b is as follows: Y ¹ b and Y ² b are the same or different and are hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, Selected from phenylalkyl, phenylalkylthio and naphthylalkyl, or Y ¹ b and Y ² b together with the nitrogen atom to which they are attached a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group; Forming;
A ₁ b, A ₂ b, A ₃ b and A ₄ b are the same or different and are a hydrogen atom, a halogen atom, hydroxyl, alkyl, alkenyl, —OR ⁶ b, such as alkoxy, —COR ⁶ b, —O ^{-COR 6 b, -OS (O)} n R 6 b, -O (CH 2) n -CO-R 6 b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy groups and free Selected from carboxylate groups, esterified with alkyl groups, esterified with alkyl groups or amidated with groups NA ⁶ bA ⁷ b, wherein A ⁶ b and A ⁷ b are the same or different, hydrogen and alkyl, alkoxy Alkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienyl Selected from alkyl, piperidinylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl groups, all of which are optionally Are substituted or A ⁶ b and A ⁷ b together with the nitrogen atom to which they are linked form a pyrrolidinyl, morpholino or piperazinyl group, the piperazinyl group is optionally substituted by itself Substituted on the second nitrogen atom with an alkyl group
Wherein two consecutive groups of A ₁ b, A ₂ b, A ₃ b and A ₄ b are optionally substituted 4,5-ethylene together with the benzimidazole group to which they are linked. Forming a dioxybenzimidazole group or an optionally substituted 4,5-methylenedioxybenzimidazole group;
A ₅ b represents a hydrogen atom;

All the above groups including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenyl Amino, phenylalkylamino, acylamino (NH-C
^{OR 6 b), - C (} = O) OR 6 b, acyl ^{-C (= O) R 6 b} , hydroxyalkyl, carboxyalkyl, _{phenoxyalkyl, S (O) n -alk,} S (O) n -NH ₂ , S (O) _n —NH (alk), S (O) _n —N (alk) ₂ , CF ₃ , OCF ₃ , NO ₂ , CN, phenyl, itself optionally one or one halogen atom which is substituted by more, thienyl, phenoxy, _{phenylalkoxy, -C (= O) -NH 2} , -C (= O) -NH (alk) and C (= O) -N (alk ) 2 radical Substituted with one or more than one group selected from:
n represents an integer of 0 to 2;
R ⁶ b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamantyl, quinoline, quinolone, dihydroquinolone, —NH-phenyl, phenylalkyl or cycloalkyl, and all these groups morpholino optionally include piperidyl or phenyl group, a halogen atom and a cyano optionally itself, CF _3, OCF _3, alkyl, phenyl -S (O) _n -alk- phenyl, _{alkoxy, NH 2, NHalk, H (} alk ) ₂ , substituted with one or more groups selected from the group SO ₂ NH ₂ , SO ₂ Nalk or SO ₂ N (alk) ₂ ;
All the alkyl, alkenyl, alkoxy and alkylthio groups described above are straight or branched and contain no more than 10 carbon atoms;
All the phenyl groups described above are optionally further substituted with a dioxole group]
A compound of formula (I) as defined above corresponding to
The compounds of formula (IAb) are any possible racemates, enantiomers or diastereoisomers and addition salts of the compounds of formula (IAb) with inorganic or organic acids or with inorganic bases It is.

That is, one requirement of the present invention is that Ab is a halogen atom and OH, alkyl, alkynyl, alkoxy, phenyl, phenylalkyl, CF ₃ , OCF ₃ , NO ₂ , CN, NY ¹ bY ² b, —NH—C ( = O) NY ¹ bY ² b, acylamino (NH—CO—R ⁶ b), S (O) _n -alk, S (O) _n —NY ¹ bY ² b, —C (═O) —NY ¹ bY ^{2 b, -C (= O)} OR 6 b, -NH-C (= O) R 6 b, -NH-S (O) n R 6 b, -NH-C (= O) OR 6 b, - In the case of one or more groups selected from N (R ⁶ b) C (═O) NY ¹ bY ² b, —OC (═O) NY ¹ bY ² b and optionally substituted thienyl groups A pyrazolyl or indazolyl group substituted by
Where NY ¹ bY ² b is as follows: Y ¹ b and Y ² b are the same or different and are hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, Selected from phenylalkyl, phenylalkylthio and naphthylalkyl, or Y ¹ b and Y ² b together with the nitrogen atom to which they are attached a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group; Forming;
A ₁ b, A ₂ b, A ₃ b and A ₄ b are the same or different and are hydrogen atom, halogen atom, hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, Selected from thiantenyl, phenyl and phenoxy groups and free, salt form, carboxyl group esterified with alkyl group or amidated with group NA ⁶ bA ⁷ b, wherein A ⁶ b and A ⁷ b are the same or different Hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidinylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihy B benzofuranyl alkyl, hexa tetrahydropyranyl alkyl is selected from ethylene dioxy phenyl alkyl and benzimidazolyl alkyl group, or all of these groups being optionally substituted with, or, A ⁶ b and A ⁷ b are they Together with the linking nitrogen atom forms a pyrrolidinyl, morpholino or piperazinyl group, the piperazinyl group itself being optionally substituted on the second nitrogen atom with an optionally substituted alkyl group;
Wherein two consecutive groups of A ₁ b, A ₂ b, A ₃ b and A ₄ b are optionally substituted 4,5-ethylene together with the benzimidazole group to which they are linked. May form a dioxybenzimidazole group or an optionally substituted 4,5-methylenedioxybenzimidazole group;
A ₅ b represents a hydrogen atom;

All the above groups including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenyl Amino, phenylalkylamino, acylamino (NH—COR ⁶ b), —C (═O) OR ⁶ b, acyl-C (═O) R ⁶ b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) _{n -alk, S (O) n -NH} 2, S (O) n -NH (alk), S (O) n -N (alk) 2, CF 3, OCF 3, NO 2, CN, phenyl, itself Optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy _{, -C (= O) -NH 2} , -C (= O) -NH (alk) and C (= O) -N (alk ) is substituted with more than one or one group selected from the ₂ groups And;
n represents an integer of 0 to 2;
And R ⁶ b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl or cycloalkyl,
All the alkyl, alkenyl, alkoxy and alkylthio groups described above are straight or branched and contain no more than 10 carbon atoms;
All the phenyl groups mentioned above are further compounds of formula (I) as defined above corresponding to formula (IAb) optionally further substituted with a dioxole group,
The compounds of formula (IAb) are any possible racemates, enantiomers or diastereoisomers and addition salts of the compounds of formula (IAb) with inorganic or organic acids or with inorganic bases It is.

That is, one requirement of the present invention is that, in particular, Ab is hydrogen, halogen atom and alkyl, alkynyl, —COR ⁶ b, phenyl, phenylalkyl, CF ₃ , NO ₂ , CN, NY ¹ bY ² b, —NH—C ( ^{= O) NY 1 bY 2 b} , NH-CO-R 6 b, S (O) n -alk, S (O) n -NY 1 bY 2 b, -C (= O) -NY 1 bY 2 b, ^{-C (= O) OR 6 b} , -NH-C (= O) R 6 b, -NH-S (O) n R 6 b, -NH-C (= O) OR 6 b, -N (R ⁶ b) C (═O) NY ¹ bY ² b and thienyl groups, all of which are optionally substituted, pyrazolyl optionally substituted with one or more groups selected from Group,
All others ^{OH, -OR 6 b, -O-} COR 6 b, -OS (O) n R 6 b, -O (CH 2) n -CO-R 6 b and -OC (= O) NY Selected from ¹ bY ² b groups, all of which are optionally substituted;
Where NY ¹ bY ² b is as follows: Y ¹ b and Y ² b are the same or different and are hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, Selected from phenylalkyl, phenylalkylthio and naphthylalkyl, or Y ¹ b and Y ² b together with the nitrogen atom to which they are attached a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group; Forming;
A ₁ b, A ₂ b, A ₃ b and A ₄ b are the same or different and two of them represent a hydrogen atom, and two of them are the same or different and represent a hydrogen atom, a halogen atom, Atom, hydroxyl, alkyl, alkenyl, —OR ⁶ b (including alkoxy), —CO—R ⁶ b, —O—COR ⁶ b, —OS (O) _n R ⁶ b, —O (CH ₂ ) _n — CO—R ⁶ b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thiantenyl, phenyl and phenoxy groups and free, salt form, esterified with alkyl group or carboxylated with group NA ⁶ bA ⁷ b is selected from the group wherein A ⁶ b and A ⁷ b are identical or different, hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, Shikuroa Killalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidinylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl All these groups are optionally substituted, or A ⁶ b and A ⁷ b together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholino or piperazinyl group, The piperazinyl group is optionally substituted on the second nitrogen atom with an optionally substituted alkyl group itself;

A ₅ b represents a hydrogen atom,
All the above groups including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenyl Amino, phenylalkylamino, acylamino (NH—COR ⁶ b), —C (═O) OR ⁶ b, acyl-C (═O) R ⁶ b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) _{n -alk, S (O) n -NH} 2, S (O) n -NH (alk), S (O) n -N (alk) 2, CF 3, OCF 3, NO 2, CN, phenyl, itself Substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= Substituted with one or more groups selected from the group O) —NH ₂ , —C (═O) —NH (alk) and C (═O) —N (alk) ₂ ;
n represents an integer of 0 to 2;
And R ⁶ b is hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl,
Represents thienyl, naphthyl, isoxazole, adamantyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl or cycloalkyl, all of which are optionally morpholino, piperidyl or phenyl groups, themselves optionally halogen atoms and cyano, CF _3, OCF _3, alkyl, phenyl -S (O) _n -alk- phenyl, _{alkoxy, NH 2, NHalk, n (} alk) 2, SO 2 NH 2, SO 2 Nalk or SO ₂ n (alk) Substituted with one or more than one group selected from _two groups;
All the alkyl, alkenyl, alkoxy and alkylthio groups described above are straight or branched and contain no more than 10 carbon atoms;
All the phenyl groups mentioned above are further compounds of formula (I) as defined above corresponding to formula (IAb) optionally further substituted with a dioxole group,
The compounds of formula (IAb) are any possible racemates, enantiomers or diastereoisomers and addition salts of the compounds of formula (IAb) with inorganic or organic acids or with inorganic bases It is.

Thus, one requirement of the present invention particularly denotes a pyrazolyl or indazolyl group optionally substituted with one or more groups wherein Ab is selected from halogen atoms and alkyl, alkoxy and thienyl groups;
A ₁ b, A ₂ b, A ₃ b and A ₄ b are the same or different and are a hydrogen atom; a halogen atom; the following groups: hydroxyl, alkyl, alkenyl, optionally substituted with phenyl Phenyl itself is optionally substituted with one or more halogen atoms, alkoxy, nitro, cyano, furyl, thienyl but optionally substituted with acyl COalk, benzothienyl, naphthyl, thiantenyl, phenyl and phenoxy But optionally substituted; and free, salted, selected from carboxyl groups esterified with alkyl groups or amidated with groups NA ⁶ bA ⁷ b, where A ⁶ b and A ⁷ b are the same Or different and only hydrogen and the following groups: alkyl, alkoxyalkyl Containing not more than 6 carbon atoms, phenoxyalkyl optionally substituted with acylamino NH-C (O) alk, phenyl, optionally substituted phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl Optionally substituted with one or more alkyl groups, naphthylalkyl, thienylalkyl but optionally substituted with alkyl or thienyl, piperidylalkyl but optionally free, salted or esterified with alkyl groups Substituted with a selected carboxyl group, pyridylalkyl, optionally substituted with one or more groups selected from halogen and CF3, benzothienylalkyl, pyrazolylalkyl but optionally alkyl groups Substituted with one or more, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl, optionally substituted with one or more alkyl groups Is selected from:
Or A ⁶ b and A ⁷ b together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholino or piperazinyl group, the piperazinyl group optionally substituted on the second nitrogen atom with an alkyl group And
Wherein two consecutive groups of A ₁ b, A ₂ b, A ₃ b and A ₄ b are optionally substituted 4,5-ethylene together with the benzimidazole group to which they are linked. Forming a dioxybenzimidazole group or an optionally substituted 4,5-methylenedioxybenzimidazole group;
A ₅ b represents a hydrogen atom;
The phenyl, phenoxy and phenylalkyl groups mentioned above are optionally halogen atoms, hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and NH-COalk groups, free, salted or alkylated esterified carboxyl group in the group, and hydroxyalkyl, carboxyalkyl, phenoxy, _{alkylthio, SO 2 -alk, SO 2 NH} 2, SO 2 -NH (alk), SO 2 -N (alk) 2, CF 3 , OCF ₃ , NO ₂ , CN, phenyl, per se substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, —C (═O) —NH ₂ , —C ( = O) -NH (alk), C (= O) -N (alk) ₂ and C (O) substituted with one or more groups selected from CH ₃ groups,
All the above alkyl or alk, alkenyl, alkoxy and alkylthio groups are straight-chain or branched and contain no more than 4 carbon atoms,
All phenyl groups of the above-mentioned groups are compounds of formula (I) as defined above corresponding to formula (IAb) optionally further substituted with a dioxole group,
The compounds of formula (IAb) are any possible racemates, enantiomers or diastereoisomers and addition salts of the compounds of formula (IAb) with inorganic or organic acids or with inorganic bases It is.

That is, the requirements of the present invention are in particular Ab, A ₁ b, A ₂ b, A ₃ b, A ₄ b and A ₅ b have any of the meanings described above, and A ₁ b, A ₂ b, When one of A ₃ b and A ₄ b represents a carboxyl group amidated with the group NA ⁶ bA ⁷ b, either A ⁶ b or A ⁷ b represents a hydrogen atom or an alkyl group, and A ⁶ b and whether the other a ⁷ b is selected from the meanings as defined for a ⁶ b and a ⁷ b, or, a ⁶ b and a ⁷ b is 5 or together with the nitrogen atom to which they are linked A compound of formula (I) as defined above corresponding to formula (IAb) forming a 6-membered cyclic group,
The compounds of formula (IAb) are any possible racemates, enantiomers or diastereoisomers and addition salts of the compounds of formula (IAb) with inorganic or organic acids or with inorganic bases It is.

That is, one requirement of the present invention is in particular that X, W, Y and Z, two or three of these represent CH, and the others are selected from CR ² and CR ³ and, where appropriate, When two of them represent CH and CR ² and CR ³ are adjacent to each other, it is a compound of formula (I) as defined above capable of forming a dioxole group;
R ² , R ³ and other substituents of the compound of formula (I) are compounds of formula (I) having any of the meanings defined above;
The compounds of formula (I) are any possible racemates, enantiomers or diastereoisomers, and addition salts of the compounds of formula (I) with inorganic or organic acids or with inorganic bases It is.

That is, one requirement of the present invention is in particular that A ₁ , A ₂ , A ₃ and A ₄ are two or three of them representing hydrogen atoms and the others are A ₁ , A ₂ , A ₃ and Selected from the meaning of A ₄ and, if appropriate, two of them are hydrogen atoms and the other two are on adjacent carbon atoms, can form a dioxole group;
Other substituents of the compound of formula (IA) are compounds of formula (I) having any of the meanings defined above;
The compounds of formula (IA) are any possible racemates, enantiomers or diastereoisomers, and addition salts of the compounds of formula (IA) with inorganic or organic acids or with inorganic bases It is.

［式中、Ａａはピラゾリル、トリアゾリルまたはインダゾリル基を示し、この複素環Ａａは場合により、ハロゲン原子、アルキル、アルコキシ、アルキルチオ基およびアルキル基で場合により置換されたチエニル基から選択される基ＸＡ¹、ＸＡ²またはＸＡ³の１個または１個より多くで置換されており；
Ａ₁ａ、Ａ₂ａ、Ａ₃ａおよびＡ₄ａは同じかまたは異なっていて、水素原子、ハロゲン原子、ヒドロキシル、アルキル、アルコキシ、ニトロ、シアノ、フェニルおよびフェノキシ基、および、遊離、塩形態化またはアルキル基でエステル化または基ＮＡ⁶ａＡ⁷ａでアミド化されたカルボキシル基から選択され、ここでＡ⁶ａおよびＡ⁷ａは同じかまたは異なっていて、水素原子およびアルキル、フェニル、フェニルアルキル、シクロアルキルアルキル、シクロアルキル、フリルアルキル、チエニルアルキルおよびピリジルアルキル基から選択されるか、または、Ａ⁶ａおよびＡ⁷ａはそれらが連結している窒素原子と一緒になってそれ自体場合により置換されているアルキルまたはフェニル基で第２窒素原子上で場合により置換されているピロリジニル、ピラゾリジニル、ピラゾリニル、ピペリジニル、モルホリノまたはピペラジニル基を形成し、
ここでＡ₁ａ、Ａ₂ａ、Ａ₃ａおよびＡ₄ａのうちの２つの連続する基はそれらが連結しているベンゾイミダゾール基と一緒になって酸素原子１個または２個を含む場合により置換されている５〜６員の炭素系の環を形成してよく、
Ａ₅ａは水素原子またはアルキル基を示し；
上記したフェニルおよびフェノキシ基は場合によりハロゲン原子およびヒドロキシル、シアノ、トリフルオロメチル、トリフルオロメトキシ、アルキル、アルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、フェニルアミノ、フェニルアルキルアミノ、遊離、塩形態化またはエステル化されたカルボキシルおよびジオキソール基から選択される基１個または１個より多くで置換されており；
全て上記したアルキル、アルコキシおよびアルキルチオ基は直鎖または分枝鎖であり、そして６個より多くない炭素原子を含む］
に相当する上記定義した式（Ｉ）の化合物であり、
式（ＩＡａ）の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオマーの異性体、および式（ＩＡａ）の該化合物の無機または有機の酸との、または無機の塩基との付加塩である。 One requirement of the invention is also in particular the following formula (IAa):

Wherein Aa represents a pyrazolyl, triazolyl or indazolyl group, wherein the heterocyclic ring Aa is a group XA ¹ selected from a thienyl group optionally substituted with a halogen atom, alkyl, alkoxy, alkylthio group and alkyl group. Substituted with one or more of XA ² or XA ³ ;
A ₁ a, A ₂ a, A ₃ a and A ₄ a are the same or different and are hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, and free, salt form Selected from carboxyl groups esterified or esterified with an alkyl group or amidated with the group NA ⁶ aA ⁷ a, wherein A ⁶ a and A ⁷ a are the same or different and are hydrogen atoms and alkyl, phenyl, phenyl Selected from alkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl groups, or when A ⁶ a and A ⁷ a are themselves together with the nitrogen atom to which they are attached Optionally substituted on the second nitrogen atom with an alkyl or phenyl group substituted by Pyrrolidinyl, formed pyrazolidinyl, pyrazolinyl, piperidinyl, morpholino or piperazinyl group,
Where two consecutive groups of A ₁ a, A ₂ a, A ₃ a and A ₄ a together with the benzimidazole group to which they are linked contain one or two oxygen atoms May form a 5-6 membered carbon-based ring substituted by
A ₅ a represents a hydrogen atom or an alkyl group;
The phenyl and phenoxy groups mentioned are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salt form or ester Substituted with one or more groups selected from activated carboxyl and dioxole groups;
All the alkyl, alkoxy and alkylthio groups described above are straight or branched and contain no more than 6 carbon atoms]
A compound of formula (I) as defined above corresponding to
The compounds of formula (IAa) are any possible racemates, enantiomers or diastereoisomers, and addition salts of the compounds of formula (IAa) with inorganic or organic acids or with inorganic bases It is.

  One requirement of the invention is in particular compounds of formula (I) in which R represents a pyrazolyl or indazolyl group and the other substituents have the meanings described above or below.

Preferred compounds to note are:
Aa represents a pyrazolyl or indazolyl group optionally substituted as described above or below;
A ₁ a, A ₂ a, A ₃ a and A ₄ a are selected from the following meanings;
-A ₁ a represents hydrogen or carboxyl or forms a ring with the adjacent member A ₂ a;
-A ₄ a represents hydrogen or carboxyl or forms a ring with the adjacent member A ₃ a;
-A ₂ a represents free, salt-formation, carboxyl group esterified with an optionally substituted alkyl group or amidated carboxyl;
-A ₂ a and A ₃ a represent two optionally substituted alkyl groups;
A ₅ a represents a hydrogen atom,
It is a compound of formula (I).

［式中、Ａｂはピラゾリルまたはインダゾリル基、ただし場合によりハロゲン原子およびアルキルから選択される基１個または１個より多くで置換されたもの、および、チエニル基を示し；
Ａ₁ｂ、Ａ₂ｂ、Ａ₃ｂおよびＡ₄ｂは同じかまたは異なっていて、水素原子、ハロゲン原子、ヒドロキシル、アルキルおよびアルコキシ、ニトロ、シアノ、フェニルおよびフェノキシ基および遊離、塩形態化、アルキル基でエステル化または基ＮＡ⁶ｂＡ⁷ｂでアミド化されたカルボキシル基から選択され、ここでＡ⁶ｂおよびＡ⁷ｂは同じかまたは異なっていて、アルキル、フェニル、フェニルアルキル、シクロアルキルアルキル、シクロアルキルおよびフリルアルキル基から選択されるか、または、Ａ⁶ｂおよびＡ⁷ｂはそれらが連結している窒素原子と一緒になってピロリジニル、モルホリノまたはピペラジニル基ただし場合によりアルキル基で第２窒素上で置換されているものを形成し、
ここでＡ₁ｂ、Ａ₂ｂ、Ａ₃ｂおよびＡ₄ｂのうちの２つの連続する基はそれらが連結しているベンゾイミダゾール基と一緒になって場合により置換された４,５−エチレンジオキ
シベンゾイミダゾール基または４,５−メチレンジオキシベンゾイミダゾール基を形成してよく；
Ａ₅ｂは水素原子を示し；
上記したフェニルおよびフェノキシ基は場合によりハロゲン原子およびヒドロキシル、シアノ、アルキル、アルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、フェニルアミノ、フェニルアルキルアミノ、遊離、塩形態化またはエステル化されたカルボキシルから選択される基１個または１個より多くで置換されており、
全て上記したアルキル、アルコキシおよびアルキルチオ基は直鎖または分枝鎖であり、そして４個より多くない炭素原子を含む］
に相当する上記定義した式（Ｉ）の化合物であり、
式（ＩＡｂ）の該化合物は何れかの可能なラセミ体、エナンチオマーまたはジアステレオマーの異性体、および式（ＩＡｂ）の該化合物の無機または有機の酸との、または無機の塩基との付加塩である。 One requirement of the invention is more particularly the following formula (IAb):

[Wherein Ab represents a pyrazolyl or indazolyl group, optionally substituted with one or more groups selected from a halogen atom and alkyl, and a thienyl group;
A ₁ b, A ₂ b, A ₃ b and A ₄ b are the same or different and are hydrogen atom, halogen atom, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy groups and free, salt-formation, Selected from carboxyl groups esterified with alkyl groups or amidated with group NA ⁶ bA ⁷ b, wherein A ⁶ b and A ⁷ b are the same or different and are alkyl, phenyl, phenylalkyl, cycloalkylalkyl , Cycloalkyl and furylalkyl groups, or A ⁶ b and A ⁷ b together with the nitrogen atom to which they are attached are pyrrolidinyl, morpholino or piperazinyl groups, but optionally an alkyl group Form what is substituted on nitrogen,
Wherein two consecutive groups of A ₁ b, A ₂ b, A ₃ b and A ₄ b are optionally substituted 4,5-ethylene together with the benzimidazole group to which they are linked. May form a dioxybenzimidazole group or a 4,5-methylenedioxybenzimidazole group;
A ₅ b represents a hydrogen atom;
The phenyl and phenoxy groups mentioned above are optionally selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salt-formated or esterified carboxyl Substituted with one or more groups,
All the alkyl, alkoxy and alkylthio groups described above are straight or branched and contain no more than 4 carbon atoms]
A compound of formula (I) as defined above corresponding to
The compounds of formula (IAb) are any possible racemates, enantiomers or diastereoisomers and addition salts of the compounds of formula (IAb) with inorganic or organic acids or with inorganic bases It is.

［式中、Ｒ⁷、Ｒ⁸およびＲ⁹は前述の通り定義される］を示す。当然ながら、Ｒ¹がヘテロアリール部分：

を示し、そして、Ｒ⁷が水素である式（Ｉｘ）の化合物は互変異体型：

で存在することができる。 For the above formula (Ix), the following are preferred groups.
R ¹ particularly denotes optionally substituted heteroaryl. Examples of optionally substituted heteroaryl include dihydrofuropyrazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl, oxodihydropyrodazinyl, oxodihydropyridinopyrazolyl, oxodihydropyridinyl, oxotetrahydropyrrolopyrazolyl, pyrazolyl, Thiazolyl, thienopyrazolyl, tetrahydrocyclopentapyrazolyl, tetrahydroindazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, tetrahydropyrrolopyrazolyl or triazolyl are included. Optional substituents include carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR. ⁴ , —N (R ⁶ ) C (═O) R ⁴ , —N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , —N (R _{^{6) SO 2 R 4, -N}} (R 6) SO 2 NY 1 Y 2, -NY 1 Y 2, -OR 4, -OCF 2 H, -OCF 3, -OC (= O) R 4, -OC One or more selected from (═O) NY ¹ Y ² , —S (O) _n R ⁴ and —S (O) ₂ NY ¹ Y ² are included. R ¹ is more preferably a heteroaryl moiety:

[Wherein R ⁷ , R ⁸ and R ⁹ are defined as described above]. Of course, R ¹ is a heteroaryl moiety:

And the compound of formula (Ix) wherein R ⁷ is hydrogen is a tautomeric form:

Can exist in

When X represents CR ² , Y represents CH or CR ³ , and Z represents CH or CR ³ , W particularly represents CH.
If X represents N, Y represents CH or CR ³ , and Z represents CH or CR ³ , W again particularly represents CH.

If X represents CH or CR ² , Y represents CH or CR ³ , and Z represents CH or CR ³ , W will again particularly represent N.
If X represents CH or CR ² , Y represents CH or CR ³ , and Z represents N, then W again particularly represents N.

  The present invention is meant to encompass all suitable combinations of the specific and preferred groups described herein.

［式中、Ｗ、Ｘ、Ｙ、ＺおよびＲ⁷は式（Ｉｘ）の化合物に関して前記定義したとおりであり、そしてＲ⁸およびＲ⁹は独立して水素、カルボキシ、シアノ、ハロ、ハロアルキル、ヒドロキシ、ニトロ、Ｒ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂ＮＹ¹Ｙ²、−ＮＹ¹Ｙ²、−ＯＲ⁴、−ＯＣ(＝Ｏ)Ｒ⁴、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²、−Ｓ(Ｏ)_nＲ⁴および−Ｓ(Ｏ)₂ＮＹ¹Ｙ²から選択される］
の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A particular group of compounds of the invention is represented by the following formula (Ixa):

Wherein W, X, Y, Z and R ⁷ are as defined above for the compound of formula (Ix) and R ⁸ and R ⁹ are independently hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy , ^{nitro, R 4, -C (= O} ) R 4, -C (= O) NY 1 Y 2, -C (= O) OR 4, -N (R 6) C (= O) R 4, - N (R ⁶ ) C (═O) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , —N (R ⁶ ) SO ₂ R ⁴ , —N (R ⁶ ) SO ₂ NY ¹ Y ² , —NY ¹ Y ² , —OR ⁴ , —OC (═O) R ⁴ , —OC (═O) NY ¹ Y ² , —S (O) _n R ⁴ and —S (O) ₂ NY ¹ Selected from Y ² ]
And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixa) And its N-oxides, and their prodrugs and their acid biological equivalents.

Preference is given to compounds of the formula (Ixa) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C—CH ₃ .

(iii) Ｃ−ＣＮ；
(iv) Ｃ−ＮＯ₂；
(ｖ) Ｃ−ハロ［例えば、Ｃ−Ｂｒ、Ｃ−ＣｌまたはＣ−Ｆ］；
(vi) Ｃ−ハロアルキル［例えば、Ｃ−ＣＦ₃］； W represents CH, X represents CH, Z represents CH, and Y represents
(i) C—C _1-4 alkyl [eg, C—CH ₃ , C—CH ₂ CH ₃ , C—CH ₂ CH ₂ CH ₃ or C—CH (CH ₃ ) ₂ ];
(ii) C-aryl [eg,

(iii) C-CN;
(iv) C-NO ₂ ;
(v) C-halo [eg C-Br, C-Cl or C-F];
(vi) C-haloalkyl [eg C-CF ₃ ];

である式（Ｉｘａ）の化合物も好ましい。

Also preferred are compounds of formula (Ixa)

を示し、そして、ＺがＣＨを示す式（Ｉｘａ）の化合物も好ましい。 W represents CH and X represents C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH ₃ , C—Br or C—Cl. , Y is C—CH ₃ , C—CH ₂ CH ₃ , C—OCH ₃ , C—Br, C—Cl, C—F,

Also preferred are compounds of formula (Ixa), wherein Z represents CH.

Also preferred are compounds of formula (Ixa), wherein W represents CH, X represents CH, Y represents C—CH ₃ and Z represents C—CH ₃ .
Formula where W represents CH, X represents CR ² and Y represents CR ³ , where R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ and Z represents CH Also preferred are compounds of (Ixa).

W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. The compounds of the formula (Ixa) shown are also preferred.

（ｖ) −ＯＲ⁵［例えば−ＯＣＨ₂ＣＨ₃］
である式（Ｉｘａ）の化合物も好ましい。 Preference is also given to compounds of the formula (Ixa) in which R ⁷ represents hydrogen.
R ⁸ is
(i) hydrogen;
(ii) C _1-4 alkyl [eg, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ ];

(V) —OR ⁵ [eg, —OCH ₂ CH ₃ ]
Also preferred are compounds of formula (Ixa)

(ｖ) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、特に−ＮＨＣ(＝Ｏ)Ｒ⁴、ただしここで、（ａ)Ｒ⁴は場合によりアリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＮＹ¹Ｙ²または−ＯＲ⁵で置換されたアルキル［例えば、 R ⁹ is
(i) hydrogen;
(ii) C _1-7 alkyl [eg, —CH ₃ , —CH ₂ CH ₂ CH ₃ , —CH (CH ₃ ) ₂ or —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ];
(iii) aryl [eg phenyl];

(v) —N (R ⁶ ) C (═O) R ⁴ , in particular —NHC (═O) R ⁴ , where (a) R ⁴ is optionally aryl, cycloalkyl, heteroaryl, heterocycloalkyl , NY ¹ Y ² or alkyl substituted with —OR ⁵ [eg,

であるもの；

What is

である式（Ｉｘａ）の化合物が好ましい。

A compound of formula (Ixa) is preferred.

(ｖ) −ＯＲ⁵［例えば−ＯＣＨ₂ＣＨ₃］を示し；Ｒ⁹は（ｉ）水素；(ii) Ｃ_1-7アルキル［例えば、−ＣＨ₃、−ＣＨ₂ＣＨ₂ＣＨ₃、−ＣＨ(ＣＨ₃)₂または−ＣＨ₂−ＣＨ₂−ＣＨ(ＣＨ₃)₂］；(iii) アリール［例えばフェニル］；(iv) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(ｖ) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、特に−ＮＨＣ(＝Ｏ)Ｒ⁴、ただしここで、(ａ) Ｒ⁴は場合によりアリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＮＹ¹Ｙ²または−ＯＲ⁵で置換されたアルキル［例えば、 A preferred group of compounds of the invention are: W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH ₃ ; R ⁷ represents hydrogen; R ⁸ represents (i ) Hydrogen, (ii) C _1-4 alkyl [eg CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ ],

(v) —OR ⁵ [eg —OCH ₂ CH ₃ ]; R ⁹ is (i) hydrogen; (ii) C _1-7 alkyl [eg —CH ₃ , —CH ₂ CH ₂ CH ₃ , —CH (CH ₃ ) ₂ or —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ]; (iii) aryl [eg phenyl]; (iv) —C (═O) NY ¹ Y ² [eg

(v) —N (R ⁶ ) C (═O) R ⁴ , in particular —NHC (═O) R ⁴ , where (a) R ⁴ is optionally aryl, cycloalkyl, heteroaryl, heterocycloalkyl , NY ¹ Y ² or alkyl substituted with —OR ⁵ [eg,

であるもの；

What is

である式（Ｉｘａ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of the compounds of formula (Ixa) (E.g., hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

(iii) Ｃ−ＣＮ、（iv) Ｃ−ＮＯ₂、（ｖ) Ｃ−ハロ［例えば、Ｃ−Ｂｒ、Ｃ−ＣｌまたはＣ−Ｆ］、（vi) Ｃ−ハロアルキル［例えばＣ−ＣＦ₃］、（vii) Ｃ−ヘテロアリール［例えば、 A further preferred group of compounds according to the invention are: W represents CH; X represents CH; Z represents CH; Y represents (i) C—C _1-4 alkyl [eg C—CH ₃ , C— _{CH 2 CH 3, C-CH} 2 CH 2 CH 3 or _{C-CH (CH 3) 2} ]; (ii) C- aryl [e.g.,

(iii) C-CN, (iv) C-NO ₂ , (v) C-halo [eg C-Br, C-Cl or CF], (vi) C-haloalkyl [eg C-CF ₃ ] , (Vii) C-heteroaryl [e.g.

または（ｖ) −ＯＲ⁵［例えば−ＯＣＨ₂ＣＨ₃］を示し；Ｒ⁹が（ｉ）水素；（ii）Ｃ_1-7アルキル［例えば、−ＣＨ₃、−ＣＨ₂ＣＨ₂ＣＨ₃、−ＣＨ(ＣＨ₃)₂または−ＣＨ₂−ＣＨ₂−ＣＨ(ＣＨ₃)₂］；(iii) アリール［例えばフェニル］；(iv) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(ｖ) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、特に−ＮＨＣ(＝Ｏ)Ｒ⁴、ただしここで、(ａ) Ｒ⁴は場合によりアリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＮＹ¹Ｙ²または−ＯＲ⁵で置換されたアルキル［例えば、

Or (v) —OR ⁵ [eg —OCH ₂ CH ₃ ]; R ⁹ is (i) hydrogen; (ii) C _1-7 alkyl [eg —CH ₃ , —CH ₂ CH ₂ CH ₃ , — CH (CH ₃ ) ₂ or —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ]; (iii) aryl [eg phenyl]; (iv) —C (═O) NY ¹ Y ² [eg

(v) —N (R ⁶ ) C (═O) R ⁴ , in particular —NHC (═O) R ⁴ , where (a) R ⁴ is optionally aryl, cycloalkyl, heteroaryl, heterocycloalkyl , NY ¹ Y ² or alkyl substituted with —OR ⁵ [eg,

であるもの；(vi) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、特に−ＮＨＣ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(Vi) —N (R ⁶ ) C (═O) NY ¹ Y ² , especially —NHC (═O) NY ¹ Y ² [e.g.

である式（Ｉｘａ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of the compounds of formula (Ixa) (E.g., hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

を示し；ＺがＣＨを示し；Ｒ⁷が水素を示し；Ｒ⁸が（ｉ) 水素、(ii) Ｃ_1-4アルキル［例えば、ＣＨ₃、ＣＨ₂ＣＨ₃、ＣＨ(ＣＨ₃)₂またはＣＨ(ＣＨ₃)ＣＨ₂ＣＨ₃］、(iii) −ＳＲ⁴［例えば、

または（ｖ) −ＯＲ⁵［例えば−ＯＣＨ₂ＣＨ₃］を示し；Ｒ⁹は（ｉ) 水素；(ii) Ｃ_1-7アルキル［例えば、−ＣＨ₃、−ＣＨ₂ＣＨ₂ＣＨ₃、−ＣＨ(ＣＨ₃)₂または−ＣＨ₂−ＣＨ₂−ＣＨ(ＣＨ₃)₂］；(iii) アリール［例えばフェニル］；(iv) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば、 A further preferred group of compounds according to the invention is that W represents CH; X is C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH _3. , C-Br or C-Cl, wherein Y is

Z represents CH; R ⁷ represents hydrogen; R ⁸ represents (i) hydrogen, (ii) C _1-4 alkyl [eg, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or _{CH (CH 3) CH 2 CH} 3], (iii) -SR 4 [ e.g.,

Or (v) —OR ⁵ [eg —OCH ₂ CH ₃ ]; R ⁹ is (i) hydrogen; (ii) C _1-7 alkyl [eg —CH ₃ , —CH ₂ CH ₂ CH ₃ , — CH (CH ₃ ) ₂ or —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ]; (iii) aryl [eg phenyl]; (iv) —C (═O) NY ¹ Y ² [eg

(ｖ) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、特に−ＮＨＣ(＝Ｏ)Ｒ⁴、ただしここで、(ａ) Ｒ⁴は場合によりアリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＮＹ¹Ｙ²または−ＯＲ⁵で置換されたアルキル［例えば、

(v) —N (R ⁶ ) C (═O) R ⁴ , in particular —NHC (═O) R ⁴ , where (a) R ⁴ is optionally aryl, cycloalkyl, heteroaryl, heterocycloalkyl , NY ¹ Y ² or alkyl substituted with —OR ⁵ [eg,

であるもの；(vi) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、特に−ＮＨＣ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(Vi) —N (R ⁶ ) C (═O) NY ¹ Y ² , especially —NHC (═O) NY ¹ Y ² [e.g.

である式（Ｉｘａ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of the compounds of formula (Ixa) (E.g., hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

または（ｖ) −ＯＲ⁵［例えば−ＯＣＨ₂ＣＨ₃］を示し；Ｒ⁹は（ｉ) 水素；(ii) Ｃ_1-7アルキル［例えば、−ＣＨ₃、−ＣＨ₂ＣＨ₂ＣＨ₃、−ＣＨ(ＣＨ₃)₂または−ＣＨ₂−ＣＨ₂−ＣＨ(ＣＨ₃)₂］；(iii) アリール［例えばフェニル］；(iv) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(ｖ) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、特に−ＮＨＣ(＝Ｏ)Ｒ⁴、ただしここで、（ａ) Ｒ⁴は場合によりアリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＮＹ¹Ｙ²または−ＯＲ⁵で置換されたアルキル［例えば、 A further preferred group of compounds according to the invention are: W represents CH; X represents CH; Y represents C-CH ₃ ; Z represents C-CH ₃ ; R ⁷ represents hydrogen; R ⁸ represents (I) hydrogen, (ii) C _1-4 alkyl [eg CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ ], (iii) —SR ⁴ [eg ,

Or (v) —OR ⁵ [eg —OCH ₂ CH ₃ ]; R ⁹ is (i) hydrogen; (ii) C _1-7 alkyl [eg —CH ₃ , —CH ₂ CH ₂ CH ₃ , — CH (CH ₃ ) ₂ or —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ]; (iii) aryl [eg phenyl]; (iv) —C (═O) NY ¹ Y ² [eg

(v) —N (R ⁶ ) C (═O) R ⁴ , in particular —NHC (═O) R ⁴ , where (a) R ⁴ is optionally aryl, cycloalkyl, heteroaryl, heterocycloalkyl , NY ¹ Y ² or alkyl substituted with —OR ⁵ [eg,

であるもの；(vi) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、特に−ＮＨＣ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(Vi) —N (R ⁶ ) C (═O) NY ¹ Y ² , especially —NHC (═O) NY ¹ Y ² [e.g.

である式（Ｉｘａ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of the compounds of formula (Ixa) (E.g., hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

または（ｖ) −ＯＲ⁵［例えば−ＯＣＨ₂ＣＨ₃］を示し；Ｒ⁹は（ｉ) 水素；(ii) Ｃ_1-7アルキル［例えば、−ＣＨ₃、−ＣＨ₂ＣＨ₂ＣＨ₃、−ＣＨ(ＣＨ₃)₂または−ＣＨ₂−ＣＨ₂−ＣＨ(ＣＨ₃)₂］；(iii) アリール［例えばフェニル］；(iv) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば、 A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ represent the group —CH ₂ —O—CH ₂ —. Z represents CH; R ⁷ represents hydrogen; R ⁸ represents (i) hydrogen, (ii) C _1-4 alkyl [eg, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or _{CH (CH 3) CH 2 CH} 3], (iii) -SR 4 [ e.g.,

Or (v) —OR ⁵ [eg —OCH ₂ CH ₃ ]; R ⁹ is (i) hydrogen; (ii) C _1-7 alkyl [eg —CH ₃ , —CH ₂ CH ₂ CH ₃ , — CH (CH ₃ ) ₂ or —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ]; (iii) aryl [eg phenyl]; (iv) —C (═O) NY ¹ Y ² [eg

(ｖ) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、特に−ＮＨＣ(＝Ｏ)Ｒ⁴、ただしここで、（ａ) Ｒ⁴は場合によりアリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＮＹ¹Ｙ²または−ＯＲ⁵で置換されたアルキル［例えば、

(v) —N (R ⁶ ) C (═O) R ⁴ , in particular —NHC (═O) R ⁴ , where (a) R ⁴ is optionally aryl, cycloalkyl, heteroaryl, heterocycloalkyl , NY ¹ Y ² or alkyl substituted with —OR ⁵ [eg,

であるもの；(vi)−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、特に−ＮＨＣ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(Vi) —N (R ⁶ ) C (═O) NY ¹ Y ² , especially —NHC (═O) NY ¹ Y ² [e.g.

である式（Ｉｘａ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of the compounds of formula (Ixa) (E.g., hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

または（ｖ) −ＯＲ⁵［例えば−ＯＣＨ₂ＣＨ₃］を示し；Ｒ⁹は（ｉ) 水素；(ii) Ｃ_1-7アルキル［例えば、−ＣＨ₃、−ＣＨ₂ＣＨ₂ＣＨ₃、−ＣＨ(ＣＨ₃)₂または−ＣＨ₂−ＣＨ₂−ＣＨ(ＣＨ₃)₂］；(iii) アリール［例えばフェニル］；(iv) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば、 A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ are a group —CH ₂ —CH ₂ —CH ₂ — Z represents CH; R ⁷ represents hydrogen; R ⁸ represents (i) hydrogen, (ii) C _1-4 alkyl [eg, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ or _{CH (CH 3) CH 2 CH} 3], (iii) -SR 4 [ e.g.,

Or (v) —OR ⁵ [eg —OCH ₂ CH ₃ ]; R ⁹ is (i) hydrogen; (ii) C _1-7 alkyl [eg —CH ₃ , —CH ₂ CH ₂ CH ₃ , — CH (CH ₃ ) ₂ or —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ]; (iii) aryl [eg phenyl]; (iv) —C (═O) NY ¹ Y ² [eg

(ｖ) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、特に−ＮＨＣ(＝Ｏ)Ｒ⁴、ただしここで、(ａ) Ｒ⁴は場合によりアリール、シクロアルキル、ヘテロアリール、ヘテロシクロアルキル、ＮＹ¹Ｙ²または−ＯＲ⁵で置換されたアルキル［例えば、

(v) —N (R ⁶ ) C (═O) R ⁴ , in particular —NHC (═O) R ⁴ , where (a) R ⁴ is optionally aryl, cycloalkyl, heteroaryl, heterocycloalkyl , NY ¹ Y ² or alkyl substituted with —OR ⁵ [eg,

であるもの；(vi) −Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、特に−ＮＨＣ(＝Ｏ)ＮＹ¹Ｙ²［例えば、

(Vi) —N (R ⁶ ) C (═O) NY ¹ Y ² , especially —NHC (═O) NY ¹ Y ² [e.g.

である式（Ｉｘａ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of the compounds of formula (Ixa) (E.g., hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

R ⁸ is hydrogen or —CH ₃ , and R ⁹ is —CH ₂ —CH ₂ —CH (CH ₃ ) ₂ ,

である式（Ｉｘａ）の化合物が特に好ましい。

Particularly preferred are compounds of formula (Ixa)

を示す式（Ｉｘａ）の化合物も特に好ましい。 R ⁹ represents hydrogen and R ⁸ is

Also particularly preferred are compounds of the formula (Ixa) which represent

W is CH, X is CH, and Y is

であり、そしてＺがＣＨである式（Ｉｘａ）の化合物が特に好ましい。

Especially preferred are compounds of formula (Ixa), wherein Z is CH.

であり；そしてＺがＣＨである式（Ｉｘａ）の化合物も特に好ましい。 W is CH, X is C—CH ₃ or C—CH ₂ CH ₃ , and Y is

Also particularly preferred are compounds of formula (Ixa), wherein Z is CH.

A formula wherein W is CH, X is C—OCH ₃ , Y is CH, C—CH ₃ , C—CH ₂ CH ₃ , C—Cl or C—OCH ₃ , and Z is CH The compounds of Ixa) are also particularly preferred.

Also particularly preferred are compounds of formula (Ixa), wherein W is CH, X is C—OCH ₂ CH ₃ , Y is C—F, and Z is CH.
W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. Particular preference is also given to compounds of the formula (Ixa).

A formula in which W represents CH, X represents CR ² and Y represents CR ³ wherein R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ — and Z represents CH The compound of (Ixa) is also particularly preferred.

である式（Ｉｘａ）の化合物が特に好ましい。 R ⁸ is hydrogen or —CH ₃ and R ⁹ is

Particularly preferred are compounds of formula (Ixa)

であり、そしてＺがＣＨである式（Ｉｘａ）の化合物が特に好ましい。 W is CH, X is CH, Y is C—OCH ₃ , C—OCH ₂ CH ₃ , C—OCHF ₂ , C—CF ₃ ,

Especially preferred are compounds of formula (Ixa), wherein Z is CH.

W is CH, X is C—CH ₃ or C—CH ₂ CH ₃ , Y is C—CH ₃ or C—CH ₂ CH ₃ , C—Cl or C—F, and Z is CH Also particularly preferred are compounds of the formula (Ixa)

W is CH, X is C—OCH ₃ , Y is C—CH ₃ , C—CH ₂ CH ₃ , C—Cl, C—F or C—OCH ₃ , and Z is CH Particular preference is also given to compounds of the formula (Ixa).

Also particularly preferred are compounds of formula (Ixa), wherein W is CH, X is C—OCH ₂ CH ₃ , Y is C—Cl or C—F, and Z is CH.
W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. Particular preference is also given to compounds of the formula (Ixa).

A formula in which W represents CH, X represents CR ² and Y represents CR ³ wherein R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ — and Z represents CH The compound of (Ixa) is also particularly preferred.

であり、ここでＲ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になって場合により置換されているフェニル環を形成する式（Ｉｘ）の化合物、即ち、下記式（Ｉｘｂ)：

［式中、Ｗ、Ｘ、Ｙ、ＺおよびＲ⁷は式（Ｉｘ）の化合物に関して前記定義したとおりであり、Ｒ¹⁰はカルボキシ、シアノ、ハロ、ハロアルキル、ヒドロキシ、ニトロ、Ｒ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)Ｒ⁴、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｎ(Ｒ⁶)Ｃ(＝Ｏ)ＯＲ⁴、−Ｎ(Ｒ⁶)ＳＯ₂Ｒ⁴、−Ｎ(Ｒ⁶)ＳＯ₂ＮＹ¹Ｙ²、−ＮＹ¹Ｙ²、−ＯＲ⁴、−ＯＣＦ₂Ｈ、−ＯＣＦ₃、−ＯＣ(＝Ｏ)Ｒ⁴、−ＯＣ(＝Ｏ)ＮＹ¹Ｙ²、−Ｓ(Ｏ)_nＲ⁴または−Ｓ(Ｏ)₂ＮＹ¹Ｙ²から選択され；そしてｐはゼロまたは整数１である］
の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘａ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 Another specific group of compounds of the invention is that R ¹ is a heteroaryl moiety:

Where R ⁸ and R ⁹ together with the carbon atom to which they are attached form an optionally substituted phenyl ring, ie a compound of formula (Ixb):

Wherein W, X, Y, Z and R ⁷ are as defined above for the compound of formula (Ix) and R ¹⁰ is carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R ⁴ , —C ( = O) R ⁴ , -C (= O) NY ¹ Y ² , -C (= O) OR ⁴ , -N (R ⁶ ) C (= O) R ⁴ , -N (R ⁶ ) C (= O ) NY ¹ Y ² , —N (R ⁶ ) C (═O) OR ⁴ , —N (R ⁶ ) SO ₂ R ⁴ , —N (R ⁶ ) SO ₂ NY ¹ Y ² , —NY ¹ Y ² , —OR ⁴ , —OCF ₂ H, —OCF ₃ , —OC (═O) R ⁴ , —OC (═O) NY ¹ Y ² , —S (O) _n R ⁴ or —S (O) ₂ NY ¹ Selected from Y ² ; and p is zero or the integer 1]
And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixa) And its N-oxides, and their prodrugs and their acid biological equivalents.

Preference is given to compounds of the formula (Ixb) in which W represents CH; X represents CH; Y represents CH; and Z represents CH or C-CH ₃ .
W represents CH; X represents CH; Z represents CH; and Y represents:
(i) C—C _1-4 alkyl [eg, C—CH ₃ , C—CH ₂ CH ₃ , C—CH ₂ CH ₂ CH ₃ or C—CH (CH ₃ ) ₂ ];

(iii) Ｃ−ＣＮ；
(iv) Ｃ−ＮＯ₂；
(ｖ) Ｃ−ハロ［例えば、Ｃ−Ｂｒ、Ｃ−ＣｌまたはＣ−Ｆ］；
(vi) Ｃ−ハロアルキル［例えばＣ−ＣＦ₃］； (ii) C-aryl [eg,

(iii) C-CN;
(iv) C-NO ₂ ;
(v) C-halo [eg C-Br, C-Cl or C-F];
(vi) C-haloalkyl [eg C-CF ₃ ];

(vii) C-heteroaryl [eg,

(xi) Ｃ−Ｃ(＝Ｏ)ＯＲ⁴［例えば、Ｃ−Ｃ(＝Ｏ)ＯＨまたはＣ−Ｃ(＝Ｏ)ＯＣＨ₃］；
(xii) Ｃ−ＮＨＣ(＝Ｏ)Ｒ⁴［例えば、Ｃ−ＮＨＣ(＝Ｏ)ＣＨ₃、Ｃ−ＮＨＣ(＝Ｏ)ＣＨ(ＣＨ₃)₂、

である式（Ｉｘｂ)の化合物も好ましい。 (x) C—C (═O) NY ¹ Y ² [for example,

(xi) C—C (═O) OR ⁴ [eg, C—C (═O) OH or C—C (═O) OCH ₃ ];
(xii) C—NHC (═O) R ⁴ [eg, C—NHC (═O) CH ₃ , C—NHC (═O) CH (CH ₃ ) ₂ ,

Also preferred are compounds of formula (Ixb).

を示し；そしてＺがＣＨを示す式（Ｉｘｂ）の化合物も好ましい。 W represents CH and X represents C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH ₃ , C—Br or C—Cl. , Y is C—CH ₃ , C—CH ₂ CH ₃ , C—OCH ₃ , C—Br, C—Cl, C—F,

Also preferred are compounds of formula (Ixb) wherein Z represents CH.

Preference is also given to compounds of the formula (Ixb) in which W represents CH, X represents CH, Y represents C—CH ₃ and Z represents C—CH ₃ .
A formula in which W represents CH, X represents CR ² and Y represents CR ³ wherein R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ — and Z represents CH Also preferred are compounds of (Ixb).

W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. Also preferred are compounds of formula (Ixb).
Preference is given to compounds of the formula (Ixb) in which R ⁷ represents hydrogen.
Preference is given to compounds of the formula (Ixb) in which p is zero or 1.

R ¹⁰ is
(i) cyano,
(ii) halo [eg chloro, fluoro],
(iii) C _1-4 alkyl [eg methyl],
(iv) —OR ⁴ [eg, —OCH ₃ , —OCH ₂ CH ₃ ]; or
(v) —C (═O) NY ¹ Y ² [eg, —C (═O) —NH ₂ , —C (═O) —NHCH (CH ₃ ) ₂ , —C (═O) —N (CH _{3 2} ]
A compound of formula (Ixb) is preferred.

A preferred group of compounds of the invention are: W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH ₃ ; R ⁷ represents hydrogen; R ¹⁰ represents (i ) Cyano, (ii) halo [eg chloro, fluoro], (iii) C _1-4 alkyl [eg methyl], (iv) —OR ⁴ [eg —OCH ₃ or —OCH ₂ CH ₃ ] or (v) − C (═O) NY ¹ Y ² [eg, —C (═O) —NH ₂ , —C (═O) —NHCH (CH ₃ ) ₂ or —C (═O) —N (CH ₃ ) ₂ ] A compound of formula (Ixb) as shown; and its corresponding N-oxide, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates of compounds of formula (Ixb) ( Hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

A further preferred group of compounds according to the invention are: W represents CH; X represents CH; Z represents CH; and Y represents (i) C—C _1-4 alkyl [eg C—CH ₃ , C _{-CH 2 CH 3, C-CH} 2 CH 2 CH 3 or _{C-CH (CH 3) 2} ], (ii) C- aryl [e.g.,

または（ｘｖ) Ｃ−Ｓ(Ｏ)_nＲ⁴［例えば、Ｃ−ＳＯ₂ＣＨ₃］であり；Ｒ⁷が水素を示し；ｐがゼロまたは１であり；Ｒ¹⁰が（ｉ) シアノ、(ii) ハロ［例えばクロロ、フルオロ］、(iii) Ｃ_1-4アルキル［例えばメチル］、(iv) −ＯＲ⁴［例えば−ＯＣＨ₃または−ＯＣＨ₂ＣＨ₃］または（ｖ) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば−Ｃ(＝Ｏ)−ＮＨ₂、−Ｃ(＝Ｏ)−
ＮＨＣＨ(ＣＨ₃)₂または−Ｃ(＝Ｏ)−Ｎ(ＣＨ₃)₂］を示す式（Ｉｘｂ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｂ)の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

Or (xv) C—S (O) _n R ⁴ [eg, C—SO ₂ CH ₃ ]; R ⁷ represents hydrogen; p is zero or 1; R ¹⁰ is (i) cyano, ( ii) halo [eg chloro, fluoro], (iii) C _1-4 alkyl [eg methyl], (iv) —OR ⁴ [eg —OCH ₃ or —OCH ₂ CH ₃ ] or (v) —C (═O ) NY ¹ Y ² [for example, —C (═O) —NH ₂ , —C (═O) —
NHCH (CH ₃ ) ₂ or —C (═O) —N (CH ₃ ) ₂ ]; compounds of formula (Ixb); and their corresponding N-oxides, and their prodrugs and their acid biological equivalents And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixb) and their N-oxides, and their prodrugs and their acid biological equivalents.

を示し；ＺがＣＨを示し；Ｒ⁷が水素を示し；ｐがゼロまたは１であり；Ｒ¹⁰が（ｉ) シアノ、(ii) ハロ［例えばクロロ、フルオロ］、(iii) Ｃ_1-4アルキル［例えばメチル］、(iv) −ＯＲ⁴［例えば−ＯＣＨ₃または−ＯＣＨ₂ＣＨ₃］または（ｖ) −Ｃ(＝Ｏ)ＮＹ¹Ｙ²［例えば−Ｃ(＝Ｏ)−ＮＨ₂、−Ｃ(＝Ｏ)−ＮＨＣＨ(ＣＨ₃)₂または−Ｃ(＝Ｏ)−Ｎ(ＣＨ₃)₂］を示す式（Ｉｘｂ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｂ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention is that W represents CH; X is C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH _3. , C-Br or C-Cl;

Z represents CH; R ⁷ represents hydrogen; p is zero or 1; R ¹⁰ is (i) cyano, (ii) halo [eg chloro, fluoro], (iii) C _1-4 Alkyl [eg methyl], (iv) —OR ⁴ [eg —OCH ₃ or —OCH ₂ CH ₃ ] or (v) —C (═O) NY ¹ Y ² [eg —C (═O) —NH ₂ , -C (= O) -NHCH (CH 3) 2 or -C (= O) -N (CH 3) compounds of formula (Ixb) showing a _2]; and the corresponding N- oxides thereof, and their prodrugs and Its acid biological equivalents; and pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixb) and their N-oxides, and their prodrugs and their acid biologicals It is an equivalent.

A further preferred group of compounds of the invention are: W represents CH; X represents CH; Y represents C—CH ₃ ; Z represents C—CH ₃ ; R ⁷ represents hydrogen; p is zero Or R ¹⁰ is (i) cyano, (ii) halo [eg chloro, fluoro], (iii) C _1-4 alkyl [eg methyl], (iv) —OR ⁴ [eg —OCH ₃ or — OCH ₂ CH ₃ ] or (v) —C (═O) NY ¹ Y ² [eg —C (═O) —NH ₂ , —C (═O) —NHCH (CH ₃ ) ₂ or —C (═O ) -N (CH ₃ ) ₂ ]; and the corresponding N-oxide and its prodrugs and acid biological equivalents thereof; and a pharmaceutical of the compound of formula (Ixb) Acceptable salts and solvates (eg hydrates) and their N-oxides, and their prodrugs and their acid organisms Is the scientific equivalent.

A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ represent the group —CH ₂ —O—CH ₂ —. Z represents CH; R ⁷ represents hydrogen; p is zero or 1; R ¹⁰ is (i) cyano, (ii) halo [eg chloro, fluoro], (iii) C _1-4 Alkyl [eg methyl], (iv) —OR ⁴ [eg —OCH ₃ or —OCH ₂ CH ₃ ] or (v) —C (═O) NY ¹ Y ² [eg —C (═O) —NH ₂ , -C (= O) -NHCH (CH 3) 2 or -C (= O) -N (CH 3) compounds of formula (Ixb) showing a _2]; and the corresponding N- oxides thereof, and their prodrugs and Its acid biological equivalents; and pharmaceutically acceptable salts and solvates (eg hydrates) and compounds thereof of the formula (Ixb) N- oxides, and their prodrugs and their acid bioisosteres.

A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ are a group —CH ₂ —CH ₂ —CH ₂ —. Z represents CH; R ⁷ represents hydrogen; p is zero or 1; R ¹⁰ is (i) cyano, (ii) halo [eg chloro, fluoro], (iii) C _{1- 4} alkyl [eg methyl], (iv) -OR ⁴ [
For example, —OCH ₃ or —OCH ₂ CH ₃ ] or (v) —C (═O) NY ¹ Y ² [eg, —C (═O) —NH ₂ , —C (═O) —NHCH (CH ₃ ) ₂ or -C (= O) -N (CH 3) compounds of formula (Ixb) showing a _2]; and its corresponding N- oxide, and its prodrugs, and their acid bioisosteres; and formula (Ixb ) Pharmaceutically acceptable salts and solvates (eg hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

Particular preference is given to compounds of the formula (Ixb) in which R ⁷ represents hydrogen and p is zero.
R ⁷ represents hydrogen; p is 1; and R ¹⁰ is cyano, chloro, fluoro, methyl, —OCH ₃ , —OCH ₂ CH ₃ , —C (═O) —NH ₂ , —C (═O Particular preference is also given to compounds of the formula (Ixb) which represent) —NHCH (CH ₃ ) ₂ or —C (═O) —N (CH ₃ ) ₂ .

W is CH; X is CH; Y is

であり；そしてＺがＣＨである式（Ｉｘｂ）の化合物が特に好ましい。

And compounds of formula (Ixb) wherein Z is CH are particularly preferred.

であり、そしてＺがＣＨである式（Ｉｘｂ）の化合物も特に好ましい。 W is CH, X is C—CH ₃ or C—CH ₂ CH ₃ , and Y is

Also particularly preferred are compounds of formula (Ixb), wherein Z is CH.

Formula (Ixb) where W is CH, X is C—OCH ₃ , Y is CH, C—CH ₃ , C—CH ₂ CH ₃ , C—Cl or C—OCH ₃ , and Z is CH ) Is also particularly preferred.

Also particularly preferred are compounds of formula (Ixb), wherein W is CH, X is C—OCH ₂ CH ₃ , Y is C—F and Z is CH.
W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. Particular preference is also given to compounds of the formula (Ixb).

A formula in which W represents CH, X represents CR ² and Y represents CR ³ wherein R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ — and Z represents CH The compound of (Ixb) is also particularly preferred.
Particular preference is given to compounds of the formula (Ixb) in which R ⁷ represents hydrogen and p is zero.

—OCH ₃ , —OCH ₂ CH ₃ or —C (═O) —NHCH (CH ₃ ) _{2 in which} R ⁷ represents hydrogen, p is 1, and R ¹⁰ is linked to the 5-position of the imidazolyl ring. Also particularly preferred are compounds of the formula (Ixb) which represent
A compound of formula (Ixb) wherein W is CH, X is C-CH ₃ or C-CH ₂ CH ₃ , Y is C-CH ₃ or C-CH ₂ CH ₃ and Z is CH Is also particularly preferred.

であり、ここでＲ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になって場合により置換されたＣ_5-8シクロアルキル環を形成するものである式（Ｉｘ）の化合物、即ち、下記式（Ｉｘｃ)：

［式中、Ｗ、Ｘ、Ｙ、Ｚ、Ｘおよびｐは式（Ｉｘ）の化合物に関して前記定義したとおりであり、下記構造物：

はＣ_5-8シクロアルキル環であり、そしてＲ¹²はアシル、アシルアミノ、アルコキシ、アルコキシカルボニル、アルキレンジオキシ、アルキルスルフィニル、アルキルスルホニル、アルキルチオ、アロイル、アロイルアミノ、アリール、アリールアルキルオキシ、アリールアルキルオキシカルボニル、アリールアルキルチオ、アリールオキシ、アリールオキシカルボニル、アリールスルフィニル、アリールスルホニル、アリールチオ、カルボキシ（または酸生物学的等価体)、シアノ、シクロアルキル、ハロ、ヘテロアロイル、ヘテロアリール、ヘテロアリールアルキルオキシ、ヘテロアロイルアミノ、ヘテロアリールオキシ、ヘテロシクロアルキル、ヒドロキシ、ニトロ、トリフルオロメチル、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−ＮＹ¹−Ｃ(＝Ｏ)アルキル、−ＮＹ¹ＳＯ₂アルキル、−ＮＹ¹Ｙ²、−ＳＯ₂ＮＹ¹Ｙ²または各々が場合によりアリール、シクロアルキル、ヘテロアリール、ヒドロキシ、−Ｃ(＝Ｏ)ＯＲ⁶、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−ＮＹ¹Ｙ²または−ＯＲ⁵で置換されているアル
キル、アルケニルまたはアルキニルである］
の化合物およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｃ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 Another particularly preferred group of compounds of the invention is that R ¹ is a pyrazolyl moiety:

Wherein R ⁸ and R ⁹ together with the carbon atom to which they are _attached form an optionally substituted C _5-8 cycloalkyl ring, ie The following formula (Ixc):

Wherein W, X, Y, Z, X and p are as defined above for the compound of formula (Ix) and have the following structure:

Is a C _5-8 cycloalkyl ring and R ¹² is acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl , Arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or acid biological equivalent), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroyl amino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, ^{trifluoromethyl, -C (= O) NY 1} Y 2, -NY 1 -C (= O) Al Le, -NY ¹ SO ₂ alkyl, -NY ¹ Y ^2, aryl optionally -SO ^₂ NY ¹ Y _2, or each, cycloalkyl, heteroaryl, ^{hydroxy, -C (= O) OR 6} , -C (= O) is alkyl, alkenyl or alkynyl substituted with NY ¹ Y ² , —NY ¹ Y ² or —OR ⁵ ]
And the corresponding N-oxides, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixc) and Its N-oxide, and its prodrug and its acid biological equivalent.

(iii) Ｃ−ＣＮ；
(iv) Ｃ−ＮＯ₂；
(ｖ) Ｃ−ハロ［例えば、Ｃ−Ｂｒ、Ｃ−ＣｌまたはＣ−Ｆ］；
(vi) Ｃ−ハロアルキル［例えばＣ−ＣＦ₃］；

Preference is given to compounds of the formula (Ixc) in which W represents CH, X represents CH, Y represents CH and Z represents CH or CH ₃ .
W represents CH, X represents CH, Z represents CH, and Y represents
(i) C—C _1-4 alkyl [eg, C—CH ₃ , C—CH ₂ CH ₃ , C—CH ₂ CH ₂ CH ₃ or C—CH (CH ₃ ) ₂ ];
(ii) C-aryl [eg,

(iii) C-CN;
(iv) C-NO ₂ ;
(v) C-halo [eg C-Br, C-Cl or C-F];
(vi) C-haloalkyl [eg C-CF ₃ ];

である式（Ｉｘｃ）の化合物も好ましい。

Also preferred are compounds of formula (Ixc).

を示し、そしてＺがＣＨを示す式（Ｉｘｃ）の化合物も好ましい。 W represents CH and X represents C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH ₃ , C—Br or C—Cl. , Y is

Also preferred are compounds of formula (Ixc), wherein Z represents CH.

Preference is also given to compounds of the formula (Ixc) in which W represents CH, X represents CH, Y represents C—CH ₃ and Z represents C—CH ₃ .
A formula in which W represents CH, X represents CR ² and Y represents CR ³ wherein R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ — and Z represents CH Also preferred are compounds of (Ixc).

W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. Also preferred are compounds of formula (Ixc).
Preference is given to compounds of the formula (Ixc) in which R ⁷ represents hydrogen.

がシクロペンチル、シクロヘキシルまたはシクロヘプチル環である式（Ｉｘｃ)の化合物が好ましい。
ｑがゼロである式（Ｉｘｃ）の化合物が好ましい。 The following structures:

Preference is given to compounds of the formula (Ixc) in which is a cyclopentyl, cyclohexyl or cycloheptyl ring.
Preference is given to compounds of the formula (Ixc) in which q is zero.

がシクロペンチル、シクロヘキシルまたはシクロヘプチル環を示し、そしてｑがゼロである式（Ｉｘｃ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｃ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A preferred group of compounds according to the invention is that W represents CH, X represents CH, Y represents CH, Z
Represents CH or C—CH ₃ , R ⁷ represents hydrogen, and the following structure:

A compound of formula (Ixc) in which Q represents a cyclopentyl, cyclohexyl or cycloheptyl ring and q is zero; and its corresponding N-oxide, and its prodrug and its acid biological equivalent; and formula (Ixc ) Pharmaceutically acceptable salts and solvates (eg hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

A further preferred group of compounds according to the invention is that W represents CH; X represents CH; Z represents CH; Y represents (i) C—C _1-4 alkyl [eg C—CH ₃ , C— _{CH 2 CH 3, C-CH} 2 CH 2 CH 3 or _{C-CH (CH 3) 2} ], (ii) C- aryl [e.g.,

を示し；Ｒ⁷が水素を示し；下記構造物：

がシクロペンチル、シクロヘキシルまたはシクロヘプチル環を示し；ｑがゼロである式（Ｉｘｃ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｃ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

R ⁷ represents hydrogen; the following structure:

Represents a cyclopentyl, cyclohexyl or cycloheptyl ring; a compound of formula (Ixc) in which q is zero; and its corresponding N-oxide, and its prodrug and its acid biological equivalent; and formula (Ixc) Pharmaceutically acceptable salts and solvates (eg, hydrates) and N-oxides thereof, and prodrugs and acid biological equivalents thereof.

を示し；ＺがＣＨを示し；Ｒ⁷が水素を示し；下記構造物：

がシクロペンチル、シクロヘキシルまたはシクロヘプチル環を示し；そしてｑがゼロである式（Ｉｘｃ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｃ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention is that W represents CH; X is C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH _3. , C-Br or C-Cl;

Z represents CH; R ⁷ represents hydrogen;

Represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and a compound of formula (Ixc) in which q is zero; and its corresponding N-oxide, and its prodrug and its acid biological equivalent; and formula (Ixc ) Pharmaceutically acceptable salts and solvates (eg hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

がシクロペンチル、シクロヘキシルまたはシクロヘプチル環を示し；そしてｑがゼロである式（Ｉｘｃ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｃ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds of the present invention are: W represents CH; X represents CH; Y represents C—CH ₃ ; Z represents C—CH ₃ ; R ⁷ represents hydrogen; :

Represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and a compound of formula (Ixc) in which q is zero; and its corresponding N-oxide, and its prodrug and its acid biological equivalent; and formula (Ixc ) Pharmaceutically acceptable salts and solvates (eg hydrates) and their N-oxides, and their prodrugs and their acid biological equivalents.

がシクロペンチル、シクロヘキシルまたはシクロヘプチル環を示し；ｑがゼロである式（Ｉｘｃ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｃ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ represent the group —CH ₂ —O—CH ₂ —. Z represents CH; R ⁷ represents hydrogen;

Represents a cyclopentyl, cyclohexyl or cycloheptyl ring; a compound of formula (Ixc) in which q is zero; and its corresponding N-oxide, and its prodrug and its acid biological equivalent; and formula (Ixc) Pharmaceutically acceptable salts and solvates (eg, hydrates) and N-oxides thereof, and prodrugs and acid biological equivalents thereof.

がシクロペンチル、シクロヘキシルまたはシクロヘプチル環を示し；ｑがゼロである式（Ｉｘｃ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｃ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物)およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ are a group —CH ₂ —CH ₂ —CH ₂ —. Z represents CH; R ⁷ represents hydrogen;

Represents a cyclopentyl, cyclohexyl or cycloheptyl ring; a compound of formula (Ixc) in which q is zero; and its corresponding N-oxide, and its prodrug and its acid biological equivalent; and formula (Ixc) And pharmaceutically acceptable salts and solvates (eg, hydrates) and N-oxides thereof, and prodrugs and acid biological equivalents thereof.

Particular preference is given to compounds of the formula (Ixc) in which R ⁷ represents hydrogen and p is zero.
Also particularly preferred are compounds of formula (Ixc), wherein W is CH, X is C—CH ₃ , Y is C—CH ₃ and Z is CH.

がシクロペンチルである式（Ｉｘｃ)の化合物が特に好ましい。 The following structures:

Particular preference is given to compounds of the formula (Ixc) in which is cyclopentyl.

であり、ここでＲ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になって場合により置換されたヘテロシクロアルキル環を形成するものである式（Ｉｘ）の化合物、即ち、下記式（Ｉｘｄ)：

［式中、Ｗ、Ｘ、Ｙ、ＺおよびＸは式（Ｉｘ）の化合物に関して前記定義したとおりであり、Ｘ¹はＯ、Ｓ、ＳＯ₂またはＮＹ⁵（ここでＹ⁵は水素、Ｒ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴であるかＹ⁵は−ＳＯ₂Ｒ⁴である)であり；ｒはゼロまたは１または２の整数であり、そしてＲ¹³はアルキルであるか、または,同じ炭素原子に連結しているＲ¹³基２個がオキソ基を形成する］
の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｄ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 Another particularly preferred group of compounds of the invention is that R ¹ is a pyrazolyl moiety:

Where R ⁸ and R ⁹ together with the carbon atom to which they are attached form an optionally substituted heterocycloalkyl ring, ie a compound of the formula (Ixd):

Wherein W, X, Y, Z and X are as defined above for the compound of formula (Ix), wherein X ¹ is O, S, SO ₂ or NY ⁵ (where Y ⁵ is hydrogen, R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR ⁴ or Y ⁵ is —SO ₂ R ⁴ ); An integer of 1 or 2 and R ¹³ is alkyl or two R ¹³ groups linked to the same carbon atom form an oxo group]
And the corresponding N-oxide, and prodrugs and acid biological equivalents thereof; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compound of formula (Ixd) And its N-oxides, and their prodrugs and their acid biological equivalents.

(iii) Ｃ−ＣＮ；
(iv) Ｃ−ＮＯ₂；
(ｖ) Ｃ−ハロ［例えば、Ｃ−Ｂｒ、Ｃ−ＣｌまたはＣ−Ｆ］；
(vi) Ｃ−ハロアルキル［例えばＣ−ＣＦ₃］； Preference is given to compounds of the formula (Ixd) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C—CH ₃ .
W represents CH, X represents CH, Z represents CH, and Y represents
(i) C—C _1-4 alkyl [eg, C—CH ₃ , C—CH ₂ CH ₃ , C—CH ₂ CH ₂ CH ₃ or C—CH (CH ₃ ) ₂ ];
(ii) C-aryl [eg,

(iii) C-CN;
(iv) C-NO ₂ ;
(v) C-halo [eg C-Br, C-Cl or C-F];
(vi) C-haloalkyl [eg C-CF ₃ ];

である式（Ｉｘｄ）の化合物も好ましい。

Also preferred are compounds of formula (Ixd).

を示し、そしてＺがＣＨを示す式（Ｉｘｄ)の化合物も好ましい。 W represents CH and X represents C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH ₃ , C—Br or C—Cl. , Y is

Also preferred are compounds of formula (Ixd), wherein Z represents CH.

Also preferred are compounds of formula (Ixd), wherein W represents CH, X represents CH, Y represents C-CH ₃ and Z represents C-CH ₃ .
Formula where W represents CH, X represents CR ² and Y represents CR ³ , where R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ and Z represents CH Also preferred are compounds of (Ixd).

W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. The compounds of the formula (Ixd) shown are also preferred.
Preference is given to compounds of the formula (Ixd) in which R ⁷ represents hydrogen.

(iv) Ｎ−Ｃ(＝Ｏ)ＯＲ⁴［例えばＮ−Ｃ(＝Ｏ)ＯＣＨ₃またはＮ−Ｃ(＝Ｏ)ＯＣＨ₂ＣＨ₃］；または、
(ｖ) Ｎ−ＳＯ₂Ｒ⁴［例えばＮ−ＳＯ₂ＣＨ₃またはＮ−ＳＯ₂ＣＨ(ＣＨ₃)₂］；
である式（Ｉｘｄ）の化合物が好ましい。
ｒがゼロである式（Ｉｘｄ）の化合物が好ましい。 X ¹ is
(i) O;

(iv) N—C (═O) OR ⁴ [eg, N—C (═O) OCH ₃ or N—C (═O) OCH ₂ CH ₃ ]; or
(v) N—SO ₂ R ⁴ [eg N—SO ₂ CH ₃ or N—SO ₂ CH (CH ₃ ) ₂ ];
A compound of formula (Ixd) is preferred.
Preference is given to compounds of the formula (Ixd) in which r is zero.

(iv) Ｎ−Ｃ(＝Ｏ)ＯＲ⁴［例えばＮ−Ｃ(＝Ｏ)ＯＣＨ₃またはＮ−Ｃ(＝Ｏ)ＯＣＨ₂ＣＨ₃］；または、(ｖ) Ｎ−ＳＯ₂Ｒ⁴［例えばＮ−ＳＯ₂ＣＨ₃またはＮ−ＳＯ₂ＣＨ(ＣＨ₃)₂］であり；ｒがゼロである式（Ｉｘｄ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｄ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A preferred group of compounds of the invention are: W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH ₃ ; R ⁷ represents hydrogen; X ¹ represents (i ) O; (ii) N—C (═O) R ⁴ [eg,

(iv) N—C (═O) OR ⁴ [eg, N—C (═O) OCH ₃ or N—C (═O) OCH ₂ CH ₃ ]; or (v) N—SO ₂ R ⁴ [eg, N-SO ₂ CH ₃ or _{N-SO 2 CH (CH 3} ) is _2]; compound of r is zero formula (IXd); and their corresponding N- oxides, and their prodrugs, and their acid biology And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixd) and their N-oxides, and their prodrugs and their acid biological equivalents. .

A further preferred group of compounds according to the invention are: W represents CH; X represents CH; Z represents CH; and Y represents (i) C—C _1-4 alkyl [eg C—CH ₃ , C _{-CH 2 CH 3, C-CH} 2 CH 2 CH 3 or _{C-CH (CH 3) 2} ], (ii) C- aryl [e.g.,

(iv) Ｎ−Ｃ(＝Ｏ)ＯＲ⁴［例えばＮ−Ｃ(＝Ｏ)ＯＣＨ₃またはＮ−Ｃ(＝Ｏ)ＯＣＨ₂ＣＨ₃］；または、(ｖ) Ｎ−ＳＯ₂Ｒ⁴［例えばＮ−ＳＯ₂ＣＨ₃またはＮ−ＳＯ₂ＣＨ(ＣＨ₃)₂］であり、そしてｒがゼロである式（Ｉｘｄ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｄ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。

(iv) N—C (═O) OR ⁴ [eg, N—C (═O) OCH ₃ or N—C (═O) OCH ₂ CH ₃ ]; or (v) N—SO ₂ R ⁴ [eg, N—SO ₂ CH ₃ or N—SO ₂ CH (CH ₃ ) ₂ ] and r is zero; and the corresponding N-oxide, and its prodrug and its acid organism And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixd) and their N-oxides, and their prodrugs and their acid biological equivalents is there.

(iv) Ｎ−Ｃ(＝Ｏ)ＯＲ⁴［例えばＮ−Ｃ(＝Ｏ)ＯＣＨ₃またはＮ−Ｃ(＝Ｏ)ＯＣＨ₂ＣＨ₃］；または、(ｖ)Ｎ−ＳＯ₂Ｒ⁴［例えばＮ−ＳＯ₂ＣＨ₃またはＮ−ＳＯ₂ＣＨ(ＣＨ₃)₂］であり、そしてｒがゼロである式（Ｉｘｄ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｄ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention is that W represents CH; X is C—CH ₃ , C—CH ₂ CH ₃ , C—CH (CH ₃ ) ₂ , C—OCH ₃ , C—OCH ₂ CH _3. , C-Br or C-Cl;

(iv) N—C (═O) OR ⁴ [eg N—C (═O) OCH ₃ or N—C (═O) OCH ₂ CH ₃ ]; or (v) N—SO ₂ R ⁴ [eg N—SO ₂ CH ₃ or N—SO ₂ CH (CH ₃ ) ₂ ] and r is zero; and the corresponding N-oxide, and its prodrug and its acid organism And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixd) and their N-oxides, and their prodrugs and their acid biological equivalents is there.

(iv) Ｎ−Ｃ(＝Ｏ)ＯＲ⁴［例えばＮ−Ｃ(＝Ｏ)ＯＣＨ₃またはＮ−Ｃ(＝Ｏ)ＯＣＨ₂ＣＨ₃］；または、(ｖ) Ｎ−ＳＯ₂Ｒ⁴［例えばＮ−ＳＯ₂ＣＨ₃またはＮ−ＳＯ₂ＣＨ(ＣＨ₃)₂］であり、そしてｒがゼロである式（Ｉｘｄ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｄ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention are: W represents CH; X represents CH; Y represents C-CH ₃ ; Z represents C-CH ₃ ; R ⁷ represents hydrogen; X ¹ represents (I) O; (ii) N—C (═O) R ⁴ [eg

(iv) N—C (═O) OR ⁴ [eg, N—C (═O) OCH ₃ or N—C (═O) OCH ₂ CH ₃ ]; or (v) N—SO ₂ R ⁴ [eg, N—SO ₂ CH ₃ or N—SO ₂ CH (CH ₃ ) ₂ ] and r is zero; and the corresponding N-oxide, and its prodrug and its acid organism And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixd) and their N-oxides, and their prodrugs and their acid biological equivalents is there.

(iv) Ｎ−Ｃ(＝Ｏ)ＯＲ⁴［例えばＮ−Ｃ(＝Ｏ)ＯＣＨ₃またはＮ−Ｃ(＝Ｏ)ＯＣＨ₂ＣＨ₃］；または、(ｖ) Ｎ−ＳＯ₂Ｒ⁴［例えばＮ−ＳＯ₂ＣＨ₃またはＮ−ＳＯ₂ＣＨ(ＣＨ₃)₂］であり、そしてｒがゼロである式（Ｉｘｄ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｄ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ represent the group —CH ₂ —O—CH ₂ —. Z represents CH; R ⁷ represents hydrogen; X ¹ is (i) O; (ii) N—C (═O) R ⁴ [eg

(iv) N—C (═O) OR ⁴ [eg, N—C (═O) OCH ₃ or N—C (═O) OCH ₂ CH ₃ ]; or (v) N—SO ₂ R ⁴ [eg, N—SO ₂ CH ₃ or N—SO ₂ CH (CH ₃ ) ₂ ] and r is zero; and the corresponding N-oxide, and its prodrug and its acid organism And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixd) and their N-oxides, and their prodrugs and their acid biological equivalents is there.

(iv) Ｎ−Ｃ(＝Ｏ)ＯＲ⁴［例えばＮ−Ｃ(＝Ｏ)ＯＣＨ₃またはＮ−Ｃ(＝Ｏ)ＯＣＨ₂ＣＨ₃］；または、(ｖ) Ｎ−ＳＯ₂Ｒ⁴［例えばＮ−ＳＯ₂ＣＨ₃またはＮ−ＳＯ₂ＣＨ(ＣＨ₃)₂］であり、そしてｒがゼロである式（Ｉｘｄ）の化合物；およびその相当するＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体；および、式（Ｉｘｄ）の化合物の薬学的に許容される塩および溶媒和物（例えば水和物）およびそのＮ−オキシド、およびそのプロドラッグおよびその酸生物学的等価体である。 A further preferred group of compounds according to the invention is that W represents CH; X represents CR ² and Y represents CR ³ wherein R ² and R ³ are a group —CH ₂ —CH ₂ —CH ₂ —. Z represents CH; R ⁷ represents hydrogen; X ¹ represents (i) O; (ii) N—C (═O) R ⁴ [e.g.

(iv) N—C (═O) OR ⁴ [eg, N—C (═O) OCH ₃ or N—C (═O) OCH ₂ CH ₃ ]; or (v) N—SO ₂ R ⁴ [eg, N—SO ₂ CH ₃ or N—SO ₂ CH (CH ₃ ) ₂ ] and r is zero; and the corresponding N-oxide, and its prodrug and its acid organism And pharmaceutically acceptable salts and solvates (eg hydrates) of the compounds of formula (Ixd) and their N-oxides, and their prodrugs and their acid biological equivalents is there.

であり、そしてｒがゼロである式（Ｉｘｄ）の化合物が特に好ましい。 X ¹ is

Especially preferred are compounds of formula (Ixd) in which r is zero.

であり、そしてＺがＣＨである式（Ｉｘｄ）の化合物が特に好ましい。 W is CH, X is CH, and Y is

Especially preferred are compounds of formula (Ixd), wherein Z is CH.

であり、そしてＺがＣＨである式（Ｉｘｄ）の化合物も特に好ましい。 W is CH, X is C—CH ₃ or C—CH ₂ CH ₃ , and Y is

Also particularly preferred are compounds of formula (Ixd), wherein Z is CH.

A formula wherein W is CH, X is C—OCH ₃ , Y is CH, C—CH ₃ , C—CH ₂ CH ₃ , C—Cl or C—OCH ₃ , and Z is CH The compounds of Ixa) are particularly preferred.

Also particularly preferred are compounds of formula (Ixd), wherein W is CH, X is C—OCH ₂ CH ₃ , Y is C—F and Z is CH.
W represents CH, X represents CR ² and Y represents CR ³ where R ² and R ^{3 form} the group —CH ₂ —CH ₂ —CH ₂ — and Z represents CH. Particular preference is also given to compounds of the formula (Ixd).

A formula in which W represents CH, X represents CR ² and Y represents CR ³ wherein R ² and R ^{3 form} the group —CH ₂ —O—CH ₂ — and Z represents CH Also particularly preferred are compounds of (Ixd).

であり、そしてｒがゼロである式（Ｉｘｄ）の化合物が特に好ましい。 X ¹ is

Especially preferred are compounds of formula (Ixd) in which r is zero.

Particular preference is given to compounds of the formula (Ixd) in which W represents CH, X represents C—CH ₃ , Y represents C—CH ₃ or C—Cl and Z represents CH.

Certain compounds of the invention of formula (Ix) are represented in Table 1 by the benzimidazole, imidazo [4,5-b] pyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine fragment ( A1 to A110) selected from compounds formed by bonding one carbon atom (C ^* ) to one carbon atom ( ^* C) in one heteroaryl moiety of the fragments (B1 to B168) shown in Table 2 The

Certain compounds of the invention of formula (Ixa) are represented by the benzimidazole, imidazo [4,5-b] pyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine fragments shown in Table 1 One carbon atom (C ^* ) of A1-A110) in one pyrazole ring of a fragment (B1-B48, B74-B107, B124-B127, 130-142 or 144-150) shown in Table 2 ( ^* Selected from compounds formed by binding to C).

Certain compounds of the invention of formula (Ixb) are also shown in Table 1 as benzimidazole, imidazo [4,5-b] pyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine fragments. One carbon atom (C ^* ) of (A1 to A110) is bonded to the carbon atom ( ^* C) in one 5-membered ring of the fragment (B63 to B73, B108 to B114, B128 or B151) shown in Table 2 Selected from these compounds.

Certain compounds of the invention of formula (Ixc) are represented in Table 1 by the benzimidazole, imidazo [4,5-b] pyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine fragment ( From compounds formed by bonding one carbon atom (C ^* ) of A1-A110) to one carbon atom ( ^* C) in one five-membered ring of a fragment (B56, B59 or B129) shown in Table 2 Selected.

Certain compounds of the invention of formula (Ixd) are represented in Table 1 by the benzimidazole, imidazo [4,5-b] pyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine fragment ( From compounds formed by bonding one carbon atom (C ^* ) of A1-A110) to one carbon atom ( ^* C) in one five-membered ring of a fragment (B115 to B123 or B157) shown in Table 2 Selected.

  Specific compounds of formula (IX) of the present invention, shown as products combining groups A1 to A110 in Table 1 and B1 to B169 in Table 2, are exemplified below.

であって、下記する実施例２３０（ａ）に記載したものである。
ＳＹＫ阻害のための本発明の式（Ｉｘ）の化合物の特定のものは次のとおりである：
2-(1H-インダゾール-3-イル)-1H-ベンゾイミダゾール-5-カルボン酸ベンジルアミド;
2-(1H-インダゾール-3-イル)-1H-ベンゾイミダゾール-5-カルボン酸N-メチルアミド;
2-(1H-インダゾール-3-イル)-1H-ベンゾイミダゾール-5-カルボン酸N-エチルアミド;
2-(1H-インダゾール-3-イル)-1H-ベンゾイミダゾール-5-カルボン酸N-イソプロピルアミド;
2-(1H-インダゾール-3-イル)-1H-ベンゾイミダゾール-5-カルボン酸N-フェニルアミド;
2-(1H-インダゾール-3-イル)-1H-ベンゾイミダゾール-5-カルボン酸N-フェネチルアミド;
5,6-ジメチル-2-(5-メチルスルファニル-1H-ピラゾール-3-イル)-1H-ベンゾイミダゾール;
6-クロロ-5-メチル-2-(5-メチルスルファニル-1H-ピラゾール-3-イル)-1H-ベンゾイミダゾール;
6-クロロ-2-(5-エチルスルファニル-1H-ピラゾール-3-イル)-5-メチル-1H-ベンゾイミダゾール;
2-(5-メチルスルファニル-1H-ピラゾール-3-イル)-5-トリフルオロメチル-1H-ベンゾイミダゾール;
2-(5-シクロプロピルメチルスルファニル-1H-ピラゾール-3-イル)-5,6-ジメチル-1H-ベンゾイミダゾール;
2-(5-エチルスルファニル-1H-ピラゾール-3-イル)-5,6-ジメチル-1H-ベンゾイミダゾール;
5,6-ジメチル-2-[5-(ピリジン-3-イルメチルスルファニル)-1H-ピラゾール-3-イル]-1H-ベンゾイミダゾール;
5-フルオロ-2-[5-メチルスルファニル)-1H-ピラゾール-3-イル]-1H-ベンゾイミダゾール;
5,6-ジメチル-2-(5-フェネチルスルファニル-1H-ピラゾール-3-イル)-1H-ベンゾイミダゾール;
4-メチル-2-(5-メチルスルファニル-1H-ピラゾール-3-イル)-1H-ベンゾイミダゾール;
5,6-ジメチル-2-(5-ベンジルスルファニル-1H-ピラゾール-3-イル)-1H-ベンゾイミダゾール;
6-クロロ-5-メチル-2-(5-モルホリン-4-イル-1H-ピラゾール-3-イル)-1H-ベンゾイミダゾール;
5,6-ジメチル-2-[5-(チオフェン-2-イルメチルスルファニル)-1H-ピラゾール-3-イル]-1H-ベンゾイミダゾール;
2-(5-エチルスルファニル-1H-ピラゾール-3-イル)-5-メトキシ-1H-ベンゾイミダゾール塩酸塩;
5-メチル-2-(5-メチルスルファニル-4-プロピル-1H-ピラゾール-3-イル)-1H-ベンゾイ
ミダゾール;
2-(5-(4-メトキシ-ベンジルスルファニル)-4-プロピル-1H-ピラゾール-3-イル)- 5-メチル-1H-ベンゾイミダゾール;
2-(5-ベンジルスルファニル-4-イソプロピル-1H-ピラゾール-3-イル)-5-メチル-1H-ベンゾイミダゾール;
2-(5-メチルスルファニル-4-メチル-1H-ピラゾール-3-イル)-5-メトキシ-1H-ベンゾイミダゾール;
2-(5-メチルスルファニル-4-メチル-1H-ピラゾール-3-イル)-5-メチル-1H-ベンゾイミダゾール;
3-(5-クロロ-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5,6-ジクロロ-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5,6-ジメチル-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5-エチル-6-メチル-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(6-クロロ-5-メトキシ-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5-メトキシ-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5-エトキシ-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5-フルオロ-6-メチル-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5-トリフルオロメトキシ-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
3-(5-トリフルオロメチル-1H-ベンゾイミダゾール-2-イル)-1H-ピラゾール-4-イルアミン;
2-(4-アミノ-1H-ピラゾール-3-イル)-1H-ベンゾイミダゾール-5-カルボン酸メチルエステル;
3-(1H-ベンゾイミダゾール-2-イル)-1H-インダゾール;
3-(5-メトキシ-1H-ベンゾイミダゾール-2-イル)-1H-インダゾール;
[2-(インダゾール-3-イル)-1H-ベンゾイミダゾール-5-イル]-フェニル-メタノン;
2-(1H-インダゾール-3-イル)-3H-ベンゾイミダゾール-4-オール;
2-フェニル-1H-イミダゾ[4,5-b]ピラジン;
3-(5,6-ジメチル-1H-ベンゾイミダゾール-2-イル)-1H-インダゾール; Thus, for example, the compounds shown as A9-B9 in the above list are products that combine group A9 of Table 1 and B9 of Table 2, ie,

And it is described in Example 230 (a) described below.
Specific of the compounds of formula (Ix) of the present invention for SYK inhibition are as follows:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide;
5,6-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
6-chloro-5-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
6-chloro-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;
2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole;
2- (5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
5,6-dimethyl-2- [5- (pyridin-3-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole;
5-fluoro-2- [5-methylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole;
5,6-dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
4-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
5,6-dimethyl-2- (5-benzylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
6-chloro-5-methyl-2- (5-morpholin-4-yl-1H-pyrazol-3-yl) -1H-benzimidazole;
5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole;
2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole hydrochloride;
5-methyl-2- (5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl) -1H-benzimidazole;
2- (5- (4-methoxy-benzylsulfanyl) -4-propyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;
2- (5-benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;
2- (5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole;
2- (5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;
3- (5-chloro-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5,6-dichloro-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5-Ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
2- (4-amino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester;
3- (1H-benzoimidazol-2-yl) -1H-indazole;
3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-indazole;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanone;
2- (1H-indazol-3-yl) -3H-benzimidazol-4-ol;
2-Phenyl-1H-imidazo [4,5-b] pyrazine;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole;

2- (1H-indazol-3-yl) -3H-imidazo [4,5-c] pyridine;
2- (1H-indazol-3-yl) -3H-imidazo [4,5-b] pyridine;
2- (1H-pyrazol-3yl) -1H-benzimidazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methoxy-1H-indazole;
3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -5-methoxy-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-fluoro-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -6-fluoro-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methyl-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -6-methoxy-1H-indazole;
5,6-dimethyl-2- (4-phenyl-1H-pyrazol-3-yl) -1H-benzimidazole;
3- (5-ethyl-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-Isopropyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-Bromo-6-methyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-Bromo-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5- (3-cyano) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (pyrid-3-yl) -1H-benzimidazol-2-yl) -1H-indazole;
3- (6-Methyl-5-phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (2-fluoro) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (5,6-methylenedioxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (2-methoxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (4-chloro) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (4-methyl) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-benzyloxy-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5,6-methylenedioxy-1H-benzimidazol-2-yl) -1H-indazole;
3- (5,6-dimethoxy-1H-benzimidazol-2-yl) -1H-indazole;
3- (5,6-diethyl-1H-benzoimidazol-2-yl) -1H-indazole;
3- (4,5-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carbonitrile;
3- (5-methoxycarbonyl-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-ethoxy-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -pyrazole-4-carboxylic acid ethyl ester;
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid ethyl ester;
3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide;
3- (5-methoxy-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid propylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide;

3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile;
3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide;
3- (6-Ethyl-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile;
2- (5-methyl-1H-pyrazol-3-yl) -1H-benzimidazole;
2- (5-Ethoxy-1H-pyrazol-3-yl) -1H-benzimidazole;
2- (5-methylsulfanyl-isoxazol-3-yl) -1H-benzimidazole;
5-chloro-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
5,6-dichloro-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
(Benzimidazol-2-yl) -5-methylthio-3-pyrazole;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-indazole;
2- (5-isopropyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
5,6-dimethyl-2- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1H-benzimidazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -4-fluoro-1H-indazole;
4-chloro-3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-chloro-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-indazol-5-ol;
3- (5-n-propyl-1H-benzoimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-sulfonic acid benzylamide;
3- (5-methanesulfonyl-1H-benzoimidazol-2-yl) -1H-indazole;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanol;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, methylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, dimethylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, isopropylamide;
1H-Benzimidazol-5-yl] -carboxylic acid, benzylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzamide;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide;
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide;
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid phenylmethyl-amide;

2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-methoxy-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-cyano-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide;
2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid;
3- (5,6-dimethyl-1H-benzimidazol-5-yl) -pyrazole-4-carboxylic acid;
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide;
N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-butyramide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-phenyl-acetamide;
Cyclopropanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Methoxyacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopentanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Trimethylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;

tert-butylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Butanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Isoxazole-5-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
S (+)-2-methylbutanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- [3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl]-
1,1-dimethylurea;
Cyclopropanecarboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-trifluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
N- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide;
Cyclopropanecarboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3,5-dimethyl-isoxazole-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide;
Furan-3-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -4-methyl-benzamide;
5,6-dimethyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
5-ethyl-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
6-chloro-5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
5-fluoro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
2- (4-nitro-1H-pyrazol-3-yl) -5-trifluoromethoxy-1H-benzimidazole;
2- (4-nitro-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole;
5-chloro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide;
Cyclopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone;
Isopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone;

1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2,2 -Dimethyl-propan-1-one;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine;
3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine;
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine;
3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester;
5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
5-ethoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester;
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carvone Acid tert-butyl ester;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole;
3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester;
N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -2-morpholin-4-yl-acetamide;
2-dimethylamino-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2- (1H-1,2,3,4-tetraazol-1-yl ) -Acetamide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isonicotinamide;
2-cyclopropyl-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isopropyl-urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-phenyl-urea;
1-benzyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide;
Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-ylamine;
4-methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide;

1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-s-indasen-2-yl) -1H-pyrazol-4-yl] urea;
Cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
Morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)
-1H-pyrazol-4-yl] amide;
3- [6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea;
5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole;
Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide;
3- [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea;
Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide;
Morpholine-4-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea;
Piperidine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea;
Morpholine-4-carboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1-yl -Methanone;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] piperidin-1-yl- Methanone;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4-yl -Methanone;
3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carvone Acid diethylamide;

3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [2- (2H-tetrazol-5-yl) -ethyl] -amide;
1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
1- [3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-
Methyl-urea;
4-methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1- [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea;
Morpholine-4-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
4-methyl-piperazine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1-methyl-3- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
1- [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea;
4-methyl-piperazine-1-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1-tert-butyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-ethyl-urea;
4-methyl-piperazine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1-cyclopropyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isobutyl-urea;
1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid amide dihydrochloride;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid;
2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid;
3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea;
3- (5-nitro-1H-benzimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide;
N- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -isobutyramide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-piperidin-1-ylacetamide;
2- (1H-indazol-3-yl) -3H-benzimidazol-5-amine;
Piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide and the corresponding N-oxide, prodrugs thereof Acceptable salts, solvates (eg hydrates) and their N-oxides and prodrugs.

Preferred compounds of formula (Ixa) for inhibition of SYK are as follows:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide;
5,6-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
6-chloro-5-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
6-chloro-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;
2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole;
2- (5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
5,6-dimethyl-2- [5- (pyridin-3-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole;
5-fluoro-2- [5-methylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole;
5,6-dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
4-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
5,6-dimethyl-2- (5-benzylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole;
5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole;
2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole hydrochloride;
5-methyl-2- (5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl) -1H-benzimidazole;
2- (5- (4-methoxy-benzylsulfanyl) -4-propyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;

2- (5-benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;
2- (5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole;
2- (5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole;
3- (5-chloro-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
3- (5,6-dichloro-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine;
5,6-dimethyl-2- (4-phenyl-1H-pyrazol-3-yl) -1H-benzimidazole;
3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide;
3- (5-methoxy-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid propylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide;
3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide;
3- (6-Ethyl-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
2- (5-Ethoxy-1H-pyrazol-3-yl) -1H-benzimidazole;
(Benzimidazol-2-yl) -5-methylthio-3-pyrazole;
2- (5-isopropyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide;
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide;
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid phenylmethyl-amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide;
2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide;

N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-butyramide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-phenyl-acetamide;
Cyclopropanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Methoxyacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopentanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Trimethylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
tert-butylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Butanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Isoxazole-5-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
S (+)-2-methylbutanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- [3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethylurea;
Cyclopropanecarboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-trifluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
N- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide;
Cyclopropanecarboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3,5-dimethyl-isoxazole-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide;
Furan-3-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -4-methyl-benzamide;
N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -2-morpholin-4-yl-acetamide;
2-dimethylamino-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide;

N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2- (1H-
1,2,3,4-tetrazol-1-yl) -acetamide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isonicotinamide;
2-cyclopropyl-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isopropyl-urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-phenyl-urea;
1-benzyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
4-methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide;
1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-indasen-2-yl) -1H-pyrazol-4-yl] urea;
Cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
Morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1Hbenzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide;
3- [6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea;
Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide;
3- [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea;
Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Cyclopropanecarboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide;
Morpholine-4-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea;
Piperidine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
3- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea;

Morpholine-4-carboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
1- [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea;
4-methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
Piperidine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1- [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea;
Morpholine-4-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
4-methyl-piperazine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1-methyl-3- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
1- [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea;
4-methyl-piperazine-1-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1-tert-butyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-ethyl-urea;
4-methylpiperazine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide;
1-cyclopropyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isobutyl-urea;
1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea;
3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-2-ylmethyl) -amide;
N- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] isobutyramide;
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-piperidin-1-yl-acetamide;

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methylpiperazino) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (isobutyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (cyclohexylmethyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide;
Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate;
5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid;
2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid;
5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole;
5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole;
2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole;
2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole;
2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H benzimidazole;
2- (5-Ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole and corresponding N-oxides, prodrugs thereof Pharmaceutically acceptable salts, solvates of such compounds (eg Hydrate) and its N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixa) for the inhibition of SYK are as follows:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide, Example 1;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide, Example 2;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide, Example 3;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide, Example 4;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide,
Example 5;
2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide, Example 6
5,6-Dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole (compound shown as A9-B9), Example 230 (a);
6-chloro-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole (compound shown as A12-B9), Example 230 (b);
6-chloro-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole (compound shown as A12-B10), Example 230 (c);
2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole (compound shown as A4-B9), Example 230 (d);
2- (5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole (compound shown as A9-B11), Example 230 (e);
2- (5-Ethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole (compound shown as A9-B10), Example 230 (f);
3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ah);
3- (5-methoxy-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (ai);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide, Example 235 (ak);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid propylamide, Example 235 (al);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (tetrahydropyran-4-yl) -amide, Example 235 (am);
3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (ao);
3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ap);
3- (6-Ethyl-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic isopropylamide, Example 235 (aq);
2- (5-Isopropyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole (compound shown as A9-B83), Example 241 (b);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, (compound shown as A9-B106), Example 246 (g);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide, shown as A9-B25 Compound), Example 246 (h);
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide, (compound shown as A40-B106), Example 246 i);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide, (compound shown as A9-B105), Example 246 (j );
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid phenylmethylamide, (compound shown as A17-B106), Example 246 (k);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246 (v);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 246 (w);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide, Example 246 (x);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide, Example 246 (y);
2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide, Example 246 (aa);
N- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide, (compound designated as A9-B85), Example 248 (a) ;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-butyramide, (compound designated as A9-B86), Example 248 (b);
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-phenyl-acetamide, (a compound designated as A9-B36), Example 248 (c);
Cyclopropanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B89), Example 248 (d );

Methoxy acetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B94), Example 248 (e);
Cyclopentanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B87), Example 248 (f );
Trimethylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B88), Example 248 (g);
tert-Butylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound designated as A9-B90), Example 248 (h );
Butanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B91), Example 248 (i);
Isoxazole-5-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B96), Examples 248 (j);
S (+)-2-methylbutanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B93), Example 248 (k);
Cyclopropanecarboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound designated as A55-B89), Example 248 (l);
Piperidine-1-carboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (m);
3- [3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethylurea, Example 248 (n);
Cyclopropanecarboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (o);
Cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (p);
Cyclopropanecarboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (q);
Cyclopropanecarboxylic acid [3- (5-trifluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (r);
Cyclopropanecarboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (s);
N- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide, Example 248 (t);
Cyclopropanecarboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (u);
3,5-Dimethyl-isoxazole-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (v) ;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide, Example 248 (w);
Furan-3-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (x);
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -4-methyl-benzamide, Example 248 (y);
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-morpholin-4-yl-acetamide, (compound shown as A9-B99) , Example 253;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2- (1H-1,2,3,4-tetrazol-1-yl) -Acetamide, (compound shown as A9-B97), Example 254 (a);
N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isonicotinamide; carried 254 (b);
2-cyclopropyl-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide; Example 254 (c);

1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea (compound shown as A9-B38), Example 255 (a);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isopropyl-urea (compound shown as A9-B103), Example 255 (b);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-phenyl-urea (compound shown as A9-B40), Example 255 (c);
1-Benzyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea (compound shown as A9-B39), Example 255 (d);
Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 256 (a);
4-Methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide, Examples 256 (c);
1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-s-indasen-2-yl) -1H-pyrazol-4-yl] urea, Example 256 (d);
Cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (a);
Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (b);
Morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (c);
Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (d);
3- [6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea, Example 257 (e);
Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide, Example 257 (g);
3- [3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea, Example 257 (h);
Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 257 (i);
Cyclopropanecarboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (a);
Cyclopropanecarboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide, Example 258 (b);
Morpholine-4-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 c);
Piperidine-1-carboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (d);
3- [3- (5-Methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (e);
Piperidine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (f);
3- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (g);
Morpholine-4-carboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (h);
Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (n);
Piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (o);
1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (a);

1- [3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea, Example 260 (b);
4-Methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (c);
Piperidine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (d);
1- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea, Example 260 (e);
Morpholine-4-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (f);
4-methylpiperazine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (g);
1-methyl-3- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (h);
1- [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea, Example 260 (i);
4-Methyl-piperazine-1-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (j);
1-tert-butyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (k);
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-ethyl-urea, Example 260 (l);
4-Methyl-piperazine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (m);
1-cyclopropyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (n);
3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea, Example 260 (o);
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isobutyl-urea, Example 260 (p);
1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (q);
3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (r);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide, Example 246 (ab);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-2-ylmethyl) -amide, Example 246 (ac);
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-piperidin-1-yl-acetamide, Example 253 (c)
As well as the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts of such compounds,
Solvates (eg hydrates) and their N-oxides and prodrugs.

Particularly preferred compounds of the formula (Ixa) according to the invention for the inhibition of SYK shown as the product of the combination of group A1 in table 1 and group B1 in table 2 are
3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ah);
3- (5-methoxy-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (ai);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide, Example 235 (ak);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid propylamide, Example 235 (al);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide, Example 235 (am);
3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (ao);
3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ap);
3- (6-Ethyl-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (aq);
3- (5,6-Dimethyl-1H-benzoimidar-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, (compound shown as A9-B106), Example 246 (g);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide, shown as A9-B25 Compound), Example 246 (h);
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide, (compound shown as A40-B106), Example 246 i);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide, (compound shown as A9-B105), Example 246 (j );
2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid phenylmethyl-amide, (compound shown as A17-B106), Example 246 (k);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246 (v);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 246 (w);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide, Example 246 (x);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide, Example 246 (y);
2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide, Example 246 (aa);
N- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide, (compound designated as A9-B85), Example 248 (a) ;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-butyramide, (compound designated as A9-B86), Example 248 (b);
Cyclopropanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B89), Example 248 (d );
Methoxy acetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B94), Example 248 (e);
Cyclopentanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B87), Example 248 (f );
Trimethylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B88), Example 248 (g);
tert-Butylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound designated as A9-B90), Example 248 (h );
Butanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B91), Example 248 (i);
Isoxazole-5-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B96), Examples 248 (j);

S (+)-2-methylbutanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound shown as A9-B93), Example 248 (k);
Cyclopropanecarboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound designated as A55-B89), Example 248 (l);
Piperidine-1-carboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (m);
3- [3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethylurea, Example 248 (n);
Cyclopropanecarboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (o);
Cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (p);
Cyclopropanecarboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (q);
Cyclopropanecarboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (s);
N- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide, Example 248 (t);
Cyclopropanecarboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (u);
3,5-Dimethyl-isoxazole-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (v) ;
Furan-3-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 248 (x);
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-morpholin-4-yl-acetamide, (compound shown as A9-B99) , Example 253;
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2- (1H-1,2,3,4-tetrazol-1-yl) -Acetamide, (compound shown as A9-B97), Example 254 (a);
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isonicotinamide; Example 254 (b);
2-cyclopropyl-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide; Example 254 (c);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea (compound shown as A9-B38), Example 255 (a);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isopropyl-urea (compound shown as A9-B103), Example 255 (b);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-phenyl-urea (compound shown as A9-B40), Example 255 (c);
1-Benzyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea (compound shown as A9-B39), Example 255 (d);
Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 256 (a);
4-Methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide, Examples 256 (c);
1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-indasen-2-yl) -1H-pyrazol-4-yl] urea, Example 256 (d);
Cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (a);

Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (b);
Morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (c);
Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (d);
3- [6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea, Example 257 (e);
3- [3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea, Example 257 (h);
Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 257 (i);
Cyclopropanecarboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (a);
Cyclopropanecarboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide, Example 258 (b);
Morpholine-4-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 c);
Piperidine-1-carboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (d);
3- [3- (5-Methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (e);
Piperidine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (f);
3- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (g);
Morpholine-4-carboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (h);
Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (n);
Piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (o);
1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (a);
1- [3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea, Example 260 (b);
4-Methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (c);
Piperidine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1
H-pyrazol-4-yl] -amide, Example 260 (d);
1- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea, Example 260 (e);
Morpholine-4-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (f);
1-methyl-3- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (h);
1- [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea, Example 260 (i);
4-Methyl-piperazine-1-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (j);
1-tert-butyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (k);
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-ethyl-urea, Example 260 (l);
4-Methyl-piperazine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (m);
1-cyclopropyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (n);
3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea, Example 260 (o);
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isobutyl-urea, Example 260 (p);
1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (q);
3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea (compound shown as A9-B142), carried out Example 258 (r)
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

The most particularly preferred compounds of formula (Ixa) of the present invention for inhibition of SYK are as follows:
3- (5-methoxy-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (ai);
3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ah);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide, Example 235 (am);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246 (v);
Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 256 (a);
1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-indasen-2-yl) -1H-pyrazol-4-yl] urea, Example 256 (d);
Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide, Example 257 (d);
3- [6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea, Example 257 (e);
3- [3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea, Example 257 (h);
Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 257 (i);
Cyclopropanecarboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide, Example 258 (b);
Piperidine-1-carboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (d);
Piperidine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (f);
Piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 258 (o);
1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (a);
Piperidine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide, Example 260 (d);
1-tert-butyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (k);
1-cyclopropyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (n);
3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea, Example 260 (o);
1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (q);
3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (r)
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixb) for inhibition of SYK are as follows:
3- (1H-benzoimidazol-2-yl) -1H-indazole;
3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-indazole;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanone;
2- (1H-indazol-3-yl) -3H-benzimidazol-4-ol;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -3H-imidazo [4,5-c] pyridine;
2- (1H-indazol-3-yl) -3H-imidazo [4,5-b] pyridine;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methoxy-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-fluoro-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -6-fluoro-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methyl-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -6-methoxy-1H-indazole;
3- (5-ethyl-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-Isopropyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-Bromo-6-methyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-Bromo-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5- (3-cyano) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-pyrid-3-yl) -1H-benzimidazol-2-yl) -1H-indazole;
3- (6-Methyl-5-phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (2-fluoro) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (5,6-methylenedioxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (2-methoxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (4-chloro) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (4-methyl) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5-benzyloxy-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5,6-methylenedioxy-1H-benzimidazol-2-yl) -1H-indazole;
3- (5,6-dimethoxy-1H-benzimidazol-2-yl) -1H-indazole;
3- (5,6-diethyl-1H-benzoimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carbonitrile;
3- (5-methoxycarbonyl-1H-benzoimidazol-2-yl) -1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-ethoxy-1H-indazole;
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1H-indazole;
3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile;

3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -4-fluoro-1H-indazole;
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-chloro-1H-indazole;
3- (5-n-propyl-1H-benzoimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-sulfonic acid benzylamide;
3- (5-methanesulfonyl-1H-benzoimidazol-2-yl) -1H-indazole;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanol;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, methylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, dimethylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, isopropylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-methoxy-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-cyano-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid;
3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid amide dihydrochloride and the corresponding N-oxide, prodrug thereof Possible salts, solvates (eg hydrates) and their N-oxides and prodrugs.

Particularly preferred compounds of the formula (Ixb) according to the invention for the inhibition of SYK shown as the product of the combination of group A1 in table 1 and group B1 in table 2 are
3- (1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A1-B63), Example 234 (a);
3- (5-Methoxy-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A6-B63), Example 234 (b);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A9-B63), Example 234 (f);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methoxy-1H-indazole, (compound shown as A9-B68), Example 235 (b);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-fluoro-1H-indazole, (a compound shown as A9-B70), Example 235 (d);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -6-fluoro-1H-indazole, (compound shown as A9-B71), Example 235 (e);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-indazole, (compound shown as A9-B64), Example 235 (f);
3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -6-methoxy-1H-indazole, (compound shown as A9-B69), Example 235 (g);
3- (5-Ethyl-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A27-B63), Example 235 (i);
3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A55-B63), Example 235 (j);
3- (5-Isopropyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A54-B63), Example 235 (k);
3- (5-Bromo-6-methyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A58-B63), Example 235 (l);
3- (5-Bromo-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A32-B63), Example 235 (m);
3- (5- (3-cyano) phenyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A68-B63), Example 235 (n);
3- (5- (pyrid-3-yl) -1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A69-B63), Example 235 (o);
3- (6-Methyl-5-phenyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A57-B63), Example 235 (p);
3- (5-phenyl-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A60-B63), Example 235 (q);
3- (5- (2-fluoro) phenyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A65-B63), Example 235 (r);
3- (5- (3,4-methylenedioxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole, (a compound shown as A66-B63), Example 235 (s);
3- (5-Benzyloxy-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A74-B63), Example 235 (w);
3- (5,6-methylenedioxy-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A22-B63), Example 235 (x);
3- (5,6-dimethoxy-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A23-B63), Example 235 (y);
3- (5,6-diethyl-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A56-B63), Example 235 (z);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carbonitrile, (compound shown as A33-B63), Example 235 (ab);
3- (5-Methoxycarbonyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A35-B63), Example 235 (ac);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-ethoxy-1H-indazole, (compound shown as A9-B63), (compound shown as A9-B112), Example 235 (ad);
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1H-indazole, Example 235 (aj);
3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile, Example 235 (an);

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile, Example 235 (ar);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4-fluoro-1H-indazole, (compound shown as A9-B110), Example 242 (a);
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-chloro-1H-indazole, (compound shown as A9-B109), Example 242 (c);
3- (5-n-propyl-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A28-B63), Example 244 (a);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-sulfonic acid benzylamide, Example 244 (b);
3- (5-Methanesulfonyl-1H-benzoimidazol-2-yl) -1H-indazole; Example 244 (c)
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanol, (compound shown as A34-B63), Example 245;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, ethylamide, (compound shown as A36-B63), Example 246 (a);
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, methylamide, (compound shown as A15-B63), Example 246 (b);
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, isopropylamide, (compound shown as A16-B63), Example 246 (d);
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzylamide, (compound shown as A17-B63), Example 246 (e);
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzamide, (compound shown as A52-B63), Example 246 (f);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide, Example 246 (m);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide, Example 246 (n);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methyl-benzylamide, Example 246 (o);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide, Example 246 (p);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide, Example 246 (q);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-methoxy-ethyl) -amide, Example 246 (r);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-cyano-ethyl) -amide, Example 246 (s);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide, Example 246 (t);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide, Example 246 (u),
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide, Example 246 (x);
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, (compound shown as A14-B63), Example 247 (a);
3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid amide dihydrochloride, Example 262
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixb) for the inhibition of SYK are as follows:
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methoxy-1H-indazole, (compound shown as A9-B68), Example 235 (b);
3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole, (compound shown as A55-B63), Example 235 (j);
3- (5,6-diethyl-1H-benzoimidazol-2-yl) -1H-indazole, (compound shown as A56-B63), Example 235 (z);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide, Example 246 (x)
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixc) for the inhibition of SYK are as follows:
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-indazole;
5,6-dimethyl-2- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1H-benzimidazole;
3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,5,6,7,8-hexahydro-cycloheptapyrazole and the corresponding N-oxides, prodrugs thereof Acceptable salts, solvates (eg hydrates) and their N-oxides and prodrugs.

Particularly preferred compounds of the formula (Ixc) according to the invention for the inhibition of SYK shown as the product of the combination of group A1 of table 1 and group B1 of table 2 are
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-indazole, (compound shown as A9-B59), Example 241 (a);
5,6-Dimethyl-2- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1H-benzimidazole (compound shown as A9-B56), Example 241 (d)
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixd) for inhibition of SYK are as follows:
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide;
Cyclopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone;
Isopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone;
1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -ethanone;
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2-methyl -Propan-1-one;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide;
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -3-methylbutane -1-one;
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2,2 -Dimethyl-propan-1-one;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1-yl -Methanone;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidin-1-yl -Methanone;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4-yl -Methanone;
3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carvone Acid diethylamide;
3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2,2 -Dimethyl-propan-1-one;
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5- (propane-2-sulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine ;
3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyran [4,3-c] pyrazole as well as the corresponding N-oxides, prodrugs thereof Pharmaceutically acceptable salts, solvates (eg hydrates) and the N-oxides and prodrugs thereof.

Particularly preferred compounds of the formula (Ixd) according to the invention for the inhibition of SYK shown as the product of the combination of group A1 in table 1 and group B1 in table 2 are
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide, (A9-B121 Compound shown as), Example 250 (a);
Cyclopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone, (Compound shown as A9-B122);
Isopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone;
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2,2 -Dimethyl-propan-1-one;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester;
3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide; 26 (e)
Preparation 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1-yl -Methanone;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] piperidin-1-yl- Methanone;
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4-yl -Methanone;
3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carvone Acid diethylamide;
3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide;
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide, (A9-B119 Compounds shown as);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2-methyl -Propan-1-one, (compound shown as A9-B117);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester, (A9-B120 Compounds shown as);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -3-methyl -Butan-1-one, (compound shown as A9-B118);
1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2,2 -Dimethyl-propan-1-one, (compound shown as A9-B123);
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of the formula (Ixd) according to the invention for the inhibition of SYK shown as the product of the combination of group A1 in table 1 and group B1 in table 2 are
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide, (A9-B121 Compound shown as), Example 250 (a);
Cyclopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone, (Compound shown as A9-B122); Example 250 (b);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide, Example 255 e);
Preparation 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide, Example 258 i);
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1-yl -Methanone, Example 258 (j);
[3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidin-1-yl -Methanone, Example 258 (k);
3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide, Example 258 (m);
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide, (A9-B119 Compound shown as
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

In particular, the compounds of the formula (Ix) according to the invention for the inhibition of SYK are as follows:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide;
2- (1H-indazol-3-yl) -1H benzimidazole-5-carboxylic acid N-isopropylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methylpiperazino) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (isobutyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (cyclohexylmethyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide;
Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate;
5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole;
5-methoxy-2- (1H-indazol-3-yl) -1H-benzimidazole;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid;
5-Bromo 2- (1H-indazol-3-yl) -3H-benzimidazole;
2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid;
5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole;
5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole;
2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole;
2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole;
2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole;
2- (5-Ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole
2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-ethoxy-propyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (naphthalen-1-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-dimethylamino-benzylamide;
4-({[2- (1H-indazol-3-yl) -1H-benzimidazol-5-carbonyl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-bromo-benzylamide;

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-phenoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-isopropoxy-propyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1-methyl-1H-pyrazol-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-isopropyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (benzo [b] thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid [3- (3-acetylamino-phenoxy) -propyl] -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid ([2,2 '] bithiophenyl-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-cyano-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (5-chloro-benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -amide;

2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1-methyl-1H-benzimidazol-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chloro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-sulfamoyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (3-ethoxy-propyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-bromo-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (naphthalen-1-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-dimethylamino-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-nitro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-bromo-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-methoxy-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-phenoxy-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (furan-3-ylmethyl) -amide;

2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2-nitro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-chloro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid phenylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid phenethyl-amide;
3- (6-phenyl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (2,4-dichloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-Naphthalen-1-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (4-Fluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Chloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-methoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-Chloro-4-fluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3,5-dichloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-thianthren-1-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-biphenyl-4-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-p-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-m-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-o-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-thiophen-3-yl-1H-benzoimidazol-2-yl) -2H-indazole;
3- [6- (3-trifluoromethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-trifluoromethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-Chloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-methoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3,5-dimethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3,4-dimethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-Benzo [1,3] dioxol-5-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (4-tert-butyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-hex-1-enyl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (3,4-dimethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenol;
4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenol;
3- [6- (3,4-dichloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-trifluoromethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
1- {4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl} -ethanone;
3- (6-Benzo [b] thiophen-2-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (3,4,5-trimethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
1- {5- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -thiophen-2-yl} -ethanone;

1- {3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl} -ethanone;
3- [6- (4-Benzyloxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (2-Fluoro-biphenyl-4-yl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-Benzo [b] thiophen-3-yl-1H-benzimidazol-2-yl) -2H-indazole;
{3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl} -methanol;
3- [6- (4-Ethylsulfanyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (2,4-difluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-trifluoromethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Fluoro-2-methyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- {6- [2- (4-fluoro-phenyl) -vinyl] -1H-benzimidazol-2-yl} -2H-indazole;
3- {6- [2- (4-chloro-phenyl) -vinyl] -1H-benzimidazol-2-yl} -2H-indazole;
3- {4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl} -propionic acid;
{4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl} -methanol;
3- (6-furan-2-yl-1H-benzoimidazol-2-yl) -2H-indazole;
3- [6- (3-Benzyloxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Isopropyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Methanesulfonyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-acetylamino-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid isopropylamide;
[2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -morpholin-4-yl-methanone;
[2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl]-(4-methyl-piperazin-1-yl) -methanone;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzyl-methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,6-difluoro-benzylamide;

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,4-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (4′-chloro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3 ′, 5′-dichloro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (4'-fluoro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide;
4- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-fluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide;
2- [5- (benzodioxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3-Phenyl-allyloxy) 2H-pyrazol-3-yl] -1H-benzimidazole;

2- [5- (2-Methyl-allyloxy) 2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3,7-dimethyl-octa-2,6-dienyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3-Bromo-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
3- [5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yloxymethyl] -benzonitrile;
2- [5- (4-trifluoromethyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3,4-dichloro-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5-pentafluorophenylmethoxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (4-tert-butyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (2-benzenesulfonylmethyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
4- [5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yloxymethyl] -benzonitrile;
2- [5- (biphenyl-4-ylmethoxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2,3-dichloro-benzenesulfonic acid 5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yl ester;
2- [5- (2-morpholin-4-yl-ethoxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (2-Piperidin-1-yl-ethoxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3-methoxy-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (1H-Benzimidazol-2-yl) -1H-pyrazol-3-yloxy] -1-p-tolyl-ethanone;
1- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -3,3,4,4,4-pentafluoro-butan-2-one;
2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -1-biphenyl-4-yl-ethanone;
1- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -butan-2-one;
2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -1- (4-dimethylamino-phenyl) -ethanone;
2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -1- (3-phenyl-isoxazol-5-yl) -ethanone;
2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -N-phenyl-acetamide;
1- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -3,3-dimethyl-butan-2-one;
1-adamantan-1-yl-2- [5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yloxy] -ethanone;
2- [5- (1H-Benzimidazol-2-yl) -1H-pyrazol-3-yloxy] -1-naphthalen-2-yl-ethanone;
4- {2- [5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yloxy] -acetyl} -benzonitrile;
6- {2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -acetyl} -3,4-dihydro-1H-quinolin-2-one;
2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -1- (4-trifluoromethoxy-phenyl) -ethanone;

5- {2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -acetyl} -2-chloro-benzenesulfonamide;
2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -1- (4-methoxy-phenyl) -ethanone;
2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -1-cyclopropyl-ethanone;
Isonicotinic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
2,2-dimethyl-propionic acid 5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yl ester;
Benzyloxy-acetic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
Benzoic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
4-methoxy-benzoic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
Phenyl-acetic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
2,3,4,5,6-pentafluoro-benzoic acid 5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yl ester;
Cyclopropanecarboxylic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
2,2,3,3,4,4,4-heptafluoro-butyric acid 5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yl ester;
Cyclopentanecarboxylic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
3-phenyl-propionic acid 5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yl ester;
Biphenyl-4-carboxylic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
3,5-bis-trifluoromethyl-benzoic acid 5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yl ester;
4-trifluoromethyl-benzoic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
Thiophene-2-carboxylic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester and the corresponding N-oxide, prodrugs thereof Pharmaceutically acceptable salts, solvates of such compounds (Eg hydrates) and their N-oxides and prodrugs.

Particularly preferred compounds of the formula (Ixa) according to the invention for the inhibition of KDR shown as the product of the combination of group A1 in table 1 and group B1 in table 2 are
2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole (compound shown as A9-B3);
2- (5-Methyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole (compound shown as A9-B2)
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of the formula (Ixb) according to the invention for the inhibition of KDR as products of the combination of group A1 in table 1 and group B1 in table 2 are
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide, (compound shown as A17-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide, (compound shown as A15-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide, (compound shown as A36-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide, (compound shown as A37-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide,
(Compound shown as A52-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide, (compound shown as A51-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide, (compound shown as A92-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methylpiperazino) amide, (compound shown as A93-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide, (compound shown as A91-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide, (compound shown as A82-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide, (compound shown as A83-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide, (compound shown as A84-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzoyl-N-methylamide, (compound shown as A90-B63);
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-ethoxy-propyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (naphthalen-1-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-dimethylamino-benzylamide;
4-({[2- (1H-indazol-3-yl) -1H-benzimidazol-5-carbonyl] -amino} -methyl) -piperidine-1-carboxylic acid tert-butyl ester;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-bromo-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;

2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-phenoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-isopropoxy-propyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1-methyl-1H-pyrazol-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-isopropyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (benzo [b] thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid [3- (3-acetylamino-phenoxy) -propyl] -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid ([2,2 '] bithiophenyl-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-cyano-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide;

2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1-methyl-1H-benzimidazol-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chloro-benzylamide;
2- (1H-Indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-sulfamoyl-
Benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-methoxy-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2-nitro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid phenylamide;
3- [6- (4-Fluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-methoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-Chloro-4-fluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-m-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-o-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-thiophen-3-yl-1H-benzoimidazol-2-yl) -2H-indazole;
3- [6- (3-Chloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-methoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3,5-dimethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-Benzo [1,3] dioxol-5-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-hex-1-enyl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (3,4-dimethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenol;
4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenol;
3- [6- (3,4,5-trimethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
1- {5- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -thiophen-2-yl} -ethanone;
{3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl} -methanol;
3- [6- (2,4-difluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Fluoro-2-methyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
{4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl} -methanol;
3- (6-furan-2-yl-1H-benzoimidazol-2-yl) -2H-indazole;
3- [6- (4-Isopropyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;

2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-acetylamino-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid isopropylamide;
[2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -morpholin-4-yl-methanone;
[2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl]-(4-methyl-piperazin-1-yl) -methanone;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzyl-methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,6-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,4-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide;
4- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester;

2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) amide;
2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,4-dichloro-6-
Fluoro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-fluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide;
2- [5- (benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3-Phenyl-allyloxy) 2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3,7-dimethyl-octa-2,6-dienyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3-Bromo-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3,4-dichloro-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (2-benzenesulfonylmethyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5-biphenyl-4-ylmethoxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
2- [5- (3-methoxy-benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole;
Isonicotinic acid 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
Benzoic acid 5- (1-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester;
3-phenyl-propionic acid 5- (1H-benzimidazol-2-yl) -1H-pyrazol-3-yl ester;
Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate;
5-methoxy-2- (1H-indazol-3-yl) -1H-benzimidazole;
5-Bromo 2- (1H-indazol-3-yl) -3H-benzimidazole (compound shown as A32-B63)
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of the formula (Ixb) for the inhibition of KDR are as follows:
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (cyclohexylmethyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chloro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-fluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl) amide;
2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide and the corresponding N-oxide, prodrugs thereof Acceptable salts, solvates (eg hydrates) and their N-oxides and prodrugs.

In particular, the compounds of formula (Ix) according to the invention for the inhibition of ITK are as follows:
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide, Example 246 (ab);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-2-ylmethyl) -amide, Example 246 (ac);
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide, Example 246 (ad);
N- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -isobutyramide, Example 246 (ae);
N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-piperidin-1-yl-acetamide, Example 253 (c)
And the corresponding N-oxides, prodrugs thereof, pharmaceutically acceptable salts, solvates (eg hydrates) of such compounds and their N-oxides and prodrugs.

  The compounds of formula (Ix) of the present invention have useful pharmacological activity and are therefore formulated in pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. Thus, in another aspect, the present invention provides a compound comprising a compound of formula (Ix) of the present invention and a compound of formula (Ix) of the present invention for use in therapy.

The compounds of formula (Ix) encompassed by the present invention block kinase catalytic activity according to literature tests and in vitro procedures described below, and the results of these tests are indicative of pharmacological activity in humans and other mammals. It is considered to correlate with That is, in another embodiment, the invention provides a formula of the invention for use in the treatment of a patient suffering from or susceptible to a condition that can be ameliorated by administration of a protein kinase inhibitor (eg, Syk, KDR, tie2 or ITK). A composition comprising a compound of Ix) and a compound of formula (Ix) of the present invention is provided. For example, the compounds of the formula (Ix) according to the invention are inflammatory diseases such as asthma, atopic dermatitis, inflammatory dermatoses (eg psoriasis, herpes dermatitis, eczema, necrotic and cutaneous vasculitis, bullous diseases, Acute and chronic urticaria); allergic rhinitis and allergic conjunctivitis; joint inflammation such as arthritis, rheumatoid arthritis and other arthritic symptoms such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella Useful in the treatment of arthritis, psoriatic arthritis and osteoarthritis. Compounds of formula (Ix) are also used in chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atheroma Atherosclerosis, peripheral vascular disease, cardiovascular disorder, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxin shock, gram-negative bacterial sepsis, diabetes, multiple sclerosis, restenosis, myocardium Inflammation, B-cell lymphoma, systemic lupus erythematosus, viral infection, bacterial infection, parasitic infection, graft-versus-host disease and other transplant-related rejection, reperfusion injury, Crohn's disease and ulcerative colitis, cancer and Tumors (eg colorectal, prostate, breast, thyroid, colon and lung cancer), atherosclerosis, degenerative muscle disease, obesity, congestive heart disease, parka Son's disease, depression, schizophrenia, stroke, head injury, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis, visceral fibrotic disease, or inflammatory It is also useful in the treatment of bowel disease.

  The product of the present invention as a SYK inhibitor has the following diseases: asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, chronic joint Rheumatism, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and acute and chronic urticaria, skin and systemic anaphylaxis, endotoxemia, sepsis, septic shock, Endotoxin shock, Gram-negative septicemia, diabetes, multiple sclerosis, systemic lupus erythematosus, viral infection, bacterial infection, parasitic infection, graft-versus-host disease, organ transplant rejection, reperfusion injury, Crohn's disease And may be used for the treatment of diseases selected from ulcerative colitis.

  The products of the present invention as KDR inhibitors include the following groups: cancer, in particular breast cancer, colon cancer, lung cancer and prostate cancer, atherosclerosis, degenerative muscle disease, obesity, congestive heart disease, Parkinson's disease For the treatment or prevention of depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis and visceral fibrosis May be used in particular.

A particular embodiment of the treatment method of the present invention is the treatment of asthma.
Another particular embodiment of the treatment method of the present invention is the treatment of psoriasis.
Another particular embodiment of the treatment method of the invention is the treatment of joint inflammation.
Another specific embodiment of the treatment method of the present invention is the treatment of inflammatory bowel disease.
Another particular embodiment of the treatment method of the invention is the treatment of cancer and tumors.

  According to another aspect of the present invention, there is provided a method for treating a condition that can be ameliorated by administration of a protein kinase inhibitor (eg, Syk, KDR, tie2 or ITK), such as a human or animal patient suffering from or susceptible to the aforementioned condition. A method is provided comprising administering to a patient an effective amount of a compound of the invention or a composition containing a compound of the invention. “Effective amount” means an amount of a compound of the invention effective to inhibit the catalytic activity of a protein kinase such as Syk, KDR, tie2 or ITK and thereby provide the desired therapeutic effect.

When treatment is discussed herein, it is intended to include prophylactic treatment as well as treatment of established symptoms.
The present invention includes within its scope at least one of the compounds of formula (Ix) of the present invention as defined above or a pharmaceutically acceptable salt or prodrug thereof, as appropriate, together with a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is also included.

  The pharmaceutical compositions of the present invention for the treatment of KDR or tie2-related disease states may also optionally include other anti-mitotic drugs, such as, in particular, taxol, cisplatin, DNA intercalation drugs, etc. An active ingredient can be contained.

  The compounds of formula (Ix) of the present invention may be administered by any suitable means. Indeed, the compounds of formula (Ix) according to the invention are generally administered parenterally, topically, topically, rectally, orally, by inhalation, or intravenously or intramuscularly by topical application to the skin and mucous membranes, especially orally. It may be administered by route.

  The compositions of the present invention may be manufactured according to conventional methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include in particular diluents, sterile aqueous media, and various non-toxic organic solvents. The composition is provided in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups and is selected from the group consisting of sweeteners, flavoring agents, coloring agents or stabilizers A pharmaceutically acceptable preparation can be obtained by containing one or more. The choice of solvent and the content of active substance in the solvent are generally determined according to the solubility and chemical properties of the active compound, the particular method of administration, and the conditions to be consulted in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and tablet disintegrants such as starch, Al silver and certain silicates, magnesium stearate, sodium lauryl sulfate and It may be used for the manufacture of tablets in combination with a lubricant such as talc. For the production of capsules, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used, they can contain emulsifiers or substances that facilitate suspending. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

  For parenteral administration, the production of the invention in vegetable oils such as sesame oil, peanut oil or olive oil, or in aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate Product emulsions, suspensions or solutions, and sterile aqueous solutions of pharmaceutically acceptable salts. The salt solution of the product of the present invention is particularly useful for administration by intramuscular or subcutaneous injection. An aqueous solution containing a solution of a salt in pure distilled water is appropriately adjusted in pH, buffered appropriately, isotonic with a sufficient amount of glucose or sodium chloride, and heated, irradiated or microfiltered. As long as it is sterilized, it may be used for intravenous administration.

  For topical administration, gels (aqueous or alcoholic), creams or ointments containing a compound of formula (Ix) of the present invention may be used. The compound of formula (Ix) of the present invention may also be formulated in a gel or matrix base for administration in the form of a patch that allows controlled release of the compound across the transdermal barrier.

For administration by inhalation, the compound of formula (Ix) of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or suspension or solution aerosol, or dry powder inhalation. It may be adsorbed or sorbed onto a suitable solid for use in the agent.
Solid compositions for rectal administration include suppositories formulated in a known manner containing at least one compound of the invention.

  The ratio of the active ingredient in the composition of the present invention may vary, and it is necessary to configure the ratio so that an appropriate dosage is obtained. Of course, several unit doses may be administered generally at the same time. The dose to be used is determined by the physician and depends on the desired therapeutic effect, the route of administration and the duration of treatment, and the condition of the patient. In adults, the dosage is generally about 0.001 to about 50, preferably about 0.001 to about 5 mg / kg body weight per day for inhalation, and about 0.01 to about 100 per day for oral administration. Preferably 0.1 to 70, more preferably 0.5 to 10 mg / kg body weight, and in the case of intravenous administration, about 0.001 to about 10, preferably about 0.01 to 1 mg / kg body weight per day. is there. In each particular case, the dose will be determined according to factors specific to the subject to be treated, such as age, weight, general health and other characteristics that may affect the drug's efficacy.

  The compounds of formula (Ix) of the present invention may be administered as frequently as necessary to obtain the desired therapeutic effect. Some patients respond quickly to higher or lower doses, and a weaker maintenance dose may be sufficient. In other patients, long-term treatment may be required with a frequency of 1 to 4 doses per day depending on the physiological needs of each particular patient. Generally, the active product is administered 1 to 4 times per day. Of course, some patients require medication no more than once or twice per day.

  The compounds of the formula (Ix) according to the invention can be applied to or adapted from known methods, i.e. the methods used so far or the methods described in the literature, such as the method described in RC Larock's Comprehensive Organic Transformations, VCH publishers, 1989. May be manufactured.

  In the reactions described below, the reactive functional groups desired in the final product, such as hydroxy, amino, imino, thio or carboxy groups, need to be protected to avoid undesired participation in those reactions. Conventional protecting groups may be used in accordance with standard practice, see for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley and Sons, 1991.

［式中Ｗ、Ｘ、ＹおよびＺは式（Ｉｘ）の化合物に関して前に定義したものである］の化合物の下記式（IIIｘ）：
Ｒ¹−ＣＯ₂Ｈ （IIIｘ）
［式中Ｒ¹は式（Ｉｘ）の化合物に関して前に定義したものである］の酸との約１６０℃の温度での反応により製造してよい。或いは、反応は(ｉ）概ね還流温度で塩酸の存在下に、または、概ね１６０℃でポリリン酸の存在下に行うか、または(ii）電子レンジ中で行ってよい。 Compounds of formula (Ix) in which W, X, Y, Z and R ¹ are as defined above for compounds of formula (Ix) and A ₅ is H are represented by the following formula (IIx):

[Wherein W, X, Y and Z are as defined above for the compound of formula (Ix)]
R ¹ —CO ₂ H (IIIx)
May be prepared by reaction at a temperature of about 160 ° C. with an acid of the formula wherein R ¹ is as defined above for the compound of formula (Ix). Alternatively, the reaction may be carried out (i) in the presence of hydrochloric acid at about reflux temperature, or in the presence of polyphosphoric acid at about 160 ° C., or (ii) in a microwave oven.

Compounds of formula (Ix) in which W, X, Y, Z and R ¹ are as defined above for compounds of formula (Ix), and A ₅ is H are dimethylform at temperatures up to about 145 ° C. The following formula (IVx) of the compound of formula (IIx), wherein W, X, Y and Z in the presence of an inert solvent such as imide or nitrobenzene are as defined above for the compound of formula (Ix):
R ¹ —CHO (IVx)
Wherein R ¹ is as defined above with respect to the compound of formula (Ix). Alternatively, the reaction may be carried out (i) in the presence of sodium bisulfite at about reflux temperature or (ii) in a microwave oven at a temperature of about 200 ° C.

［式中Ｗ、Ｘ、Ｙ、ＺおよびＲ¹は式（Ｉｘ）の化合物に関して前に定義したものである］の化合物の環化により製造してよい。環化は約１２０℃までの温度で酢酸のような酸触媒の存在下に加熱することにより行ってよい。 Compounds of formula (Ix) in which W, X, Y, Z and R ¹ are as defined above for compounds of formula (Ix) and A ₅ is H are represented by the following formula (Vx):

It may be prepared by cyclization of a compound of the formula wherein W, X, Y, Z and R ¹ are as defined above for the compound of formula (Ix). The cyclization may be performed by heating in the presence of an acid catalyst such as acetic acid at a temperature up to about 120 ° C.

［式中Ｒ⁹は式（Ｉｘ）の化合物に関して前に定義したものであり、Ｒ⁷は水素であり、そしてＲ⁸はＳＲ⁴である］である式（Ｉｘａ）の化合物、即ち式（IXａａ）の化合物は、スキーム１に示すとおり製造してよい。 W, X, Y and Z are as defined above for the compound of formula (Ix) and R ¹ is

Wherein R ⁹ is as defined above for the compound of formula (Ix), R ⁷ is hydrogen, and R ⁸ is SR ⁴ , ie a compound of formula (IXaa) ) May be prepared as shown in Scheme 1.

For example, a diamine of formula (IIx) where W, X, Y and Z are as previously defined for a compound of formula (Ix) may be treated with formic acid in the presence of hydrochloric acid at a temperature of about 50 ° C. in step 1. . The resulting imino group of the compound of formula (VIx) where W, X, Y and Z are as defined above for the compound of formula (Ix) may then be protected in step 2 with a suitable protecting group. At this time, for example, if this is a 2- (trimethylsilanyl) ethoxymethyl group, the protection is conveniently (i) reaction with sodium hydride in dimethylformamide, followed by (ii) 2- (trimethyl It is carried out by reaction with silanyl) ethoxymethyl chloride. Formula (VIIx) where W, X, Y and Z obtained are as defined above for the compound of formula (Ix) and R ¹¹ is a suitable protecting group, for example a 2- (trimethylsilanyl) ethoxymethyl group Then, in step 3, (i) lithium diisopropylamide in an inert solvent such as tetrahydrofuran at a temperature of about −78 ° C., then (ii) the formula R ⁹ —C (═O) —N (CH ₃ ) ₂ may be treated with an acetamide of the formula wherein R ⁹ is as defined above for the compound of (Ix). The resulting compound of formula (Xx) wherein W, X, Y, Z, R ⁹ and R ¹¹ are as defined above for the compound of formula (Ix) [or (i) a process at a temperature of about 70 ° C. Reaction of a diamine of formula (IIx) with a β-hydroxy acid of formula R ⁹ CH ₂ CH (OH) CO ₂ H, wherein R ⁹ is as defined above for the compound of (Ix), ii) oxidation of the compound of formula (VIIIx) obtained in step 2a with manganese dioxide in an inert solvent such as chloroform at a temperature of about 60 ° C., and (iii) step 3a as described in step 2 above. Is then prepared in step 4 by (i) sodium tert-butoxide in an inert solvent such as benzene or tetrahydrofuran at -5 ° C., then (ii) carbon disulfide, and then ( iii) Formula R ⁴ —X ¹ may be treated with a compound of the formula wherein R ⁴ is as defined above for the compound of formula (Ix) and X ¹ is halo. The resulting compound of formula (XIx) in which W, X, Y, Z, R ⁴ , R ⁹ and R ¹¹ are as previously defined for the compound of formula (Ix) is It may be treated with hydrazine in an additional solvent such as ethanol at a temperature generally up to reflux. The resulting compound of formula (XIIx) in which W, X, Y, Z, R ⁴ , R ⁹ and R ¹¹ are as defined above for the compound of formula (Ix) is then deprotected {eg R ^{When 11} is a 2- (trimethylsilanyl) ethoxymethyl group, by treatment with hydrochloric acid in an inert solvent such as ethanol at about room temperature to about reflux temperature}, W, X, Y, The pyrazole of formula (Ixaa) may be liberated where Z, R ⁴ and R ⁹ are as defined above for the compound of formula (Ix). Compounds of formula (XIx) where R ¹¹ is a tetrahydropyran-2-yl protecting group may be deprotected by treatment with an acid such as p-toluenesulfonic acid in water at reflux temperature, and then from about room temperature to W, X, Y, Z, R ⁴ and R ⁹ are as previously defined for compounds of formula (Ix) by treatment with hydrazine in an inert solvent such as ethanol at a temperature generally at reflux. A pyrazole of the formula (Ixaa) may be obtained.

［式中Ｒ⁹は式（Ｉｘ）の化合物に関して前に定義したものであり、Ｒ⁷は水素であり、そしてＲ⁸はＯＲ⁴である］である式（Ｉｘ）の化合物、即ち式（IXａｂ）の化合物は、スキーム２に示すとおり製造してよい。 W, X, Y and Z are as defined above for the compound of formula (Ix) and A ⁵ is H and R ¹ is

Wherein R ⁹ is as defined above for the compound of formula (Ix), R ⁷ is hydrogen, and R ⁸ is OR ⁴ , ie a compound of formula (IXab ) May be prepared as shown in Scheme 2.

For example, the compound of formula (XIx) in which W, X, Y, Z, R ⁹ , R ¹¹ are as defined above for the compound of formula (Ix) and R ⁴ is lower alkyl is Treatment with a sodium salt of an alcohol of the formula R ⁴ —OH (wherein R ⁴ is lower alkyl) such as ethoxide, followed by treatment with hydrazine as described in Scheme 1 above. The resulting compound of formula (XIIIx) in which W, X, Y, Z, R ⁴ , R ⁹ and R ¹¹ are as defined above for the compound of formula (Ix) is then deprotected in step 2 [eg When R ¹¹ is a 2- (trimethylsilanyl) ethoxymethyl group, the pyrazole of formula (Ixab) may be liberated by treatment with trifluoroacetic acid at about 50 ° C.

［式中Ｒ⁹は式（Ｉｘ）の化合物に関して前に定義したものであり、Ｒ⁷は水素であり、そしてＲ⁸は−ＮＹ¹Ｙ²である］である式（Ｉｘ）の化合物、即ち式（IXａｃ）の化合物は、スキーム３に示すとおり製造してよい。 W, X, Y and Z are as defined above for the compound of formula (Ix) and A ⁵ is H and R ¹ is

A compound of formula (Ix) wherein R ⁹ is as defined above for the compound of formula (Ix), R ⁷ is hydrogen and R ⁸ is -NY ¹ Y ² , ie Compounds of formula (IXac) may be prepared as shown in Scheme 3.

For example, in step 1, the compound of formula (XIx), wherein W, X, Y, Z, R ⁹ and R ¹¹ are as defined above for the compound of formula (Ix) and R ⁴ is lower alkyl, is represented by the formula HNY ¹ Y ² may be treated with an amine such as morpholine, where Y ¹ and Y ² are as defined above for the compound of (Ix). The resulting compound of formula (XIVx) wherein W, X, Y, Z, R ⁹ , R ¹¹ , Y ¹ and Y ² are as defined above for the compound of formula (Ix) and R ⁴ is lower alkyl May then be treated with hydrazine as described above for Scheme 1 in Step 2. The resulting compound of formula (XVx) wherein W, X, Y, Z, R ⁹ , R ¹¹ , Y ¹ and Y ² are as defined above for the compound of formula (Ix) is then described above in Step 3. The pyrazole of formula (Ixac) may be liberated by deprotection as described.

である式（Ｉｘ）の化合物、即ち式（IXａｄ）の化合物は、スキーム４に示すとおり製造してよい。 W, X, Y and Z are as defined above for the compound of formula (Ix) and A ⁵ is H and R ¹ is

A compound of formula (Ix), ie a compound of formula (IXad), may be prepared as shown in Scheme 4.

For example, the compound of formula (XIx) in which W, X, Y, Z, R ⁹ , R ¹¹ are as defined above for the compound of formula (Ix) and R ⁴ is lower alkyl is Treatment with hydroxylamine in the presence of sodium methoxide at temperature. The resulting compound of formula (XVIx) where W, X, Y, Z, R ⁹ , R ¹¹ are as defined above for the compound of formula (Ix) is then deprotected as described above in Step 2. To release the isoxazole of formula (Ixad).

Compounds of the invention of formula (Ix) may be prepared by conversion of other compounds of the invention.
Thus, for example, a compound of formula (Ix) containing a carboxy group may be prepared by hydrolysis of the corresponding ester. Hydrolysis is carried out using an organic solvent such as dioxane, tetrahydrofuran or methanol in the presence of an aqueous / organic solvent mixture at a temperature generally between ambient temperature and approximately reflux temperature, such as an alkali metal hydroxide such as lithium hydroxide or alkali metal. It may conveniently be carried out by alkaline hydrolysis with a carbonate, for example a base such as potassium carbonate. The hydrolysis of the ester is also acid hydrolysis with an inorganic acid such as hydrochloric acid in the presence of an aqueous / inert organic solvent mixture using an organic solvent such as dioxane or tetrahydrofuran at a temperature of about 50 ° C. to about 80 ° C. May be performed.

  Another example of a compound of formula (Ix) containing a carboxy group is the t-butyl group of the corresponding t-butyl ester using standard reaction conditions using, for example, reaction with trifluoroacetic acid at about room temperature. It may be produced by acid catalyst removal.

As another example, compounds of formula (Ix) containing a carboxy group may be prepared by hydrogenation of the corresponding benzyl ester. The reaction may be carried out at about reflux temperature, preferably in a solvent such as methanol or ethanol, in the presence of a suitable metal catalyst, such as palladium, supported on an inert support such as ammonium formate and carbon. Alternatively, the reaction may be carried out in a solvent such as methanol or ethanol, preferably in the presence of a suitable metal catalyst such as platinum or palladium, optionally supported on an inert support such as carbon.
As another example, a compound of formula (Ix) containing a carboxy group may be prepared by treating a compound of formula I (x) containing a cyano group with hydrochloric acid in acetic acid at a temperature of about 100 ° C.

As another example of an interconversion method, a compound of formula (Ix) containing a —C (═O) —NY ¹ Y ² group can be obtained in an inert solvent such as dimethylformamide at a temperature of about 80 ° C., for example 1 A compound of formula (Ix) containing a carboxy group is prepared using standard peptide coupling methods such as coupling in the presence of-(3-dimethylaminopropyl) -3-ethylcarbodiimide, hydroxybenzotriazole and diisopropylethylamine. It may be prepared by reacting with an amine of the formula HNY ¹ Y ² to form an amide bond. Alternatively, the reaction is performed at room temperature in tetrahydrofuran (or dimethylformamide) with O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine). ) In the presence of

As another example of an interconversion method, a compound of formula (Ix) containing a —NH—C (═O) —R ⁴ group is represented by (i) a compound of formula R ⁴ —CO using standard coupling conditions as described above. Coupling of a compound of formula (Ix) containing an amino group with a ₂ H acid, or (ii) in the presence of a tertiary base such as diisopropylethylamine in an inert solvent such as dichloromethane at about room temperature. R ⁴ —C (═) O—Cl may be prepared by reaction of a compound of formula (Ix) containing an amino group with an acid chloride. In some cases, bisacylated derivatives are obtained by reaction of a compound of formula (Ix) containing an amino group and A ₅ being H with an acid chloride of formula R ⁴ —C (═) O—Cl. These bisacylated derivatives can be treated by treatment with potassium hydroxide in aqueous methanol at a temperature of about 60 ° C. (Ix) containing an —NH—C (═O) —R ⁴ group and A ₅ being H. May be converted to

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は−Ｃ(＝Ｏ)Ｒ⁴である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物は、概ね室温の温度でジクロロメタンのような不活性溶媒中ジイソプロピルエチルアミンのような第三級塩基の存在下、式Ｒ⁴−Ｃ(＝)Ｏ−Ｃｌの酸クロリドとのＲ¹がピラゾリル部分：

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は水素である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物の反応により製造してよい。 As another example of interconversion, R ¹ is a pyrazolyl moiety:

And R ⁸ and R ⁹ together with the carbon atom to which they are attached contain a NY ⁵ group (where Y ⁵ is —C (═O) R ⁴ ) The ring-forming compound of formula (Ix) is of the formula R ⁴ —C (═) O—Cl in the presence of a tertiary base such as diisopropylethylamine in an inert solvent such as dichloromethane at about room temperature. R ¹ with acid chloride is a pyrazolyl moiety:

Wherein R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 5- or 6-membered heterocycle containing a NY ⁵ group (where Y ⁵ is hydrogen) (Ix ).

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は−Ｃ(＝Ｏ)ＮＹ¹Ｙ²である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物は、概ね室温の温度でジクロロメタンのような不活性溶媒中ジイソプロピルエチルアミンのような第三級塩基の存在下、式Ｙ¹Ｙ²Ｎ−Ｃ(＝Ｏ)−ＣｌのカルバモイルクロリドとのＲ¹がピラゾリル部分：

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は水素である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物の反応により製造してよい。 As another example of interconversion, R ¹ is a pyrazolyl moiety:

And R ⁸ and R ⁹ together with the carbon atom to which they are attached contain a NY ⁵ group, where Y ⁵ is —C (═O) NY ¹ Y ² compounds of formula (Ix) to form a heterocyclic ring is generally the presence of a tertiary base such as an inert solvent diisopropylethylamine such as dichloromethane at room temperature temperature, formula ^{Y 1 Y 2 N-C (} = O) R ¹ is pyrazolyl portion between -Cl carbamoyl chloride:

Wherein R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 5- or 6-membered heterocycle containing a NY ⁵ group (where Y ⁵ is hydrogen) (Ix ).

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は−Ｃ(＝Ｏ)ＯＲ⁴である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物は、概ね室温の温度でジクロロメタンのような不活性溶媒中ジイソプロピルエチルアミンのような第三級塩基の存在下、式Ｒ⁴Ｏ−Ｃ(＝Ｏ)−ＣｌのクロロホルメートとのＲ¹がピラゾリル部分：

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は水素である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物の反応により製造してよい。 As another example of interconversion, R ¹ is a pyrazolyl moiety:

And R ⁸ and R ⁹ together with the carbon atom to which they are attached contain a NY ⁵ group (where Y ⁵ is —C (═O) OR ⁴ ) The compound of formula (Ix) forming the ring is of the formula R ⁴ O—C (═O) —Cl in the presence of a tertiary base such as diisopropylethylamine in an inert solvent such as dichloromethane at about room temperature. R ¹ with chloroformate is a pyrazolyl moiety:

Wherein R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 5- or 6-membered heterocycle containing a NY ⁵ group (where Y ⁵ is hydrogen) (Ix ).

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は−ＳＯ₂Ｒ⁴である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物は、概ね室温の温度でジクロロメタンのような不活性溶媒中ジイソプロピルエチルアミンのような第三級塩基の存在下、式Ｒ⁴ＳＯ₂−ＣｌのスルホニルクロリドとのＲ¹がピラゾリル部分：

であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になってＮＹ⁵基（ここでＹ⁵は水素である）を含む５または６員の複素環を形成する式（Ｉｘ）の化合物の反応により製造してよい。 As another example of interconversion, R ¹ is a pyrazolyl moiety:

And R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 5- or 6-membered heterocycle containing a NY ⁵ group (where Y ⁵ is —SO ₂ R ⁴ ). In the presence of a tertiary base such as diisopropylethylamine in an inert solvent such as dichloromethane at about room temperature and R ¹ with the sulfonyl chloride of formula R ⁴ SO ₂ —Cl Pyrazolyl moiety:

Wherein R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 5- or 6-membered heterocycle containing a NY ⁵ group (where Y ⁵ is hydrogen) (Ix ).

As another example of the interconversion process, compounds of formula (Ix) containing -NH-C (= O) -R 4 groups wherein R ⁴ is alkyl substituted by NY ¹ Y ² are, (i) approximately Coupling of a compound of formula (Ix) containing an amino group with an appropriate chloroalkyl acid chloride in the presence of a tertiary base such as diisopropylethylamine in an inert solvent such as dichloromethane at room temperature, then (ii ) It may be prepared by reaction with an amine of formula HNY ¹ Y ² .

Another example of an interconversion method is the group —N (R ⁶ ) C (═O) NY ¹ Y ² , wherein R ⁶ is hydrogen, Y ¹ is hydrogen, and Y ² is alkenyl, aryl , Cycloalkyl, heteroaryl, or optionally substituted alkyl] is a compound of formula Y ² N═C═O in an inert solvent such as tetrahydrofuran at about room temperature. Y ² is alkenyl, aryl, cycloalkyl, heteroaryl, or optionally substituted alkyl] may be prepared by reaction of a compound of formula (Ix) containing an amino group with an isocyanate.

As another example of an interconversion method, a compound of formula (Ix) containing a —N (R ⁶ ) C (═O) NY ¹ Y ² group, wherein R ⁶ is hydrogen, is about 60 ° C. It may be prepared by reaction of a compound of formula (Ix) containing an amino group with 1,1-carbonyldiimidazole in an inert solvent such as tetrahydrofuran at temperature followed by reaction with an amine of formula HNY ¹ Y ² .

  As another example of an interconversion method, a compound of formula (Ix) containing an amino group may be prepared by reduction of a corresponding compound of formula (Ix) containing a nitro group. For example, the reduction is conveniently by hydrogenation in the presence of a suitable metal catalyst, such as platinum or palladium, optionally supported on an inert support such as carbon, preferably in a solvent such as methanol or ethanol. You can go. The reduction may also conveniently be carried out by reduction with tin chloride in an inert solvent such as methanol or ethanol at about reflux temperature. Alternatively, the reaction with tin chloride may be carried out in a microwave oven at a temperature of about 140 ° C.

As another example of interconversion, compounds of formula (Ix) containing a —CH ₂ OH group may be prepared by reduction of the corresponding compound of formula (Ix) containing a —CHO or —CO ₂ lower alkyl group. For example, the reduction may conveniently be performed by reaction with lithium aluminum hydride in an inert solvent such as tetrahydrofuran at a temperature between about room temperature and about the reflux temperature.

As another example of an interconversion method, a compound of formula (Ix) containing a —CH (OH) R ⁴ group can be represented by —C ( ═O) may be prepared by treating a compound of formula (Ix) containing a R ⁴ group.

As an example of another interconversion method, a compound of formula (Ix) wherein R ¹ is aryl or heteroaryl substituted with hydroxy is obtained by reacting 3 odors in an inert solvent such as dichloromethane at a temperature of about 0 ° C. to about room temperature. It may be prepared by reacting a Lewis acid such as boron halide with a corresponding compound of formula (Ix) wherein R ¹ is aryl or heteroaryl substituted with methoxy.

  As another example of interconversion, compounds of formula (Ix) having a sulfoxide bond may be prepared by oxidation of the corresponding compound containing a —S— bond. For example, the oxidation is conveniently carried out by reaction with a peracid such as 3-chloroperbenzoic acid, preferably in the vicinity of room temperature, preferably in an inert solvent such as dichloromethane, or at a temperature of about 0 ° C. to room temperature. By using potassium hydrogen monosulfate in a medium such as aqueous methanol buffered at about pH 5. This latter method is suitable for compounds containing acid labile groups.

  As another example of an interconversion method, a compound of formula (Ix) having a sulfone bond may be prepared by oxidation of the corresponding compound containing a —S— bond. For example, the oxidation may conveniently be performed by reaction with a peracid, such as 3-chloroperbenzoic acid, preferably in an inert solvent such as dichloromethane, preferably near room temperature.

As an example of another interconversion method, a compound of formula (Ix) having a cyano group is a corresponding compound of formula (Ix) comprising a —C (═O) —NH ₂ group with phosphorus pentachloride in the presence of triethylamine. It may be produced by the reaction of This reaction may conveniently be carried out in an inert solvent such as tetrahydrofuran at about the reflux temperature.
As another example of interconversion, a compound of formula (Ix) containing a —C (═O) —NH ₂ group is represented by the corresponding formula (Ix containing a cyano group with hydrogen peroxide in the presence of sodium hydroxide. ). The reaction may conveniently be carried out in methanol at about room temperature. Alternatively, a compound of formula (Ix) containing a —C (═O) —NH ₂ group is reacted with hydrochloric acid in acetic acid and the corresponding compound of formula (Ix) having a cyano group at a temperature of about 80 to about 100 ° C. May be manufactured.

  As another example of interconversion, a compound of formula (Ix) containing a tetrazolyl group may be prepared by reacting an azidotributyltin with a corresponding compound of formula (Ix) having a cyano group. The reaction may conveniently be carried out in an inert solvent such as toluene at about reflux temperature.

  According to another feature of the invention, acid addition salts of the compounds of the invention may be prepared by reacting the free base with the appropriate acid by application or adaptation of known methods. For example, acid addition salts of the compounds of the present invention can be isolated by dissolving the free base in water or aqueous alcohol solution or other suitable solvent containing the appropriate acid and evaporating the solution, or May be prepared by reacting the free base and acid in an organic solvent and separating the salt directly or by concentrating the solution.

  The compounds of the invention can be regenerated from their acid addition salts by the application or adaptation of known methods. For example, the parent compound of the present invention can be regenerated from its acid addition salt by treating with an alkali such as aqueous sodium bicarbonate or aqueous ammonia.

  According to yet another aspect of the invention, the base addition salts of the invention may be prepared by reacting the free acid with the appropriate base by application or adaptation of known methods. For example, a base addition salt of a compound of the invention can be isolated by dissolving the free acid in water or aqueous alcohol solution or other suitable solvent containing the appropriate base and evaporating the solution, or May be prepared by reacting the free acid and base in an organic solvent and separating the salt directly or by concentrating the solution.

  The compounds of the invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, the parent compound of the invention can be regenerated from its base addition salt by treatment with an acid, such as hydrochloric acid.

The compounds of the present invention may be conveniently prepared or formed during the processes of the present invention as solvates (eg hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxane, tetrahydrofuran or methanol.
Starting materials and intermediates may be prepared by application or adaptation of known methods, for example by the methods described in the reference examples or by obvious chemical equivalents thereof.

［式中Ｗ、Ｘ、ＹおよびＺは式（Ｉｘ）の化合物に関して前に定義したものである］の相当するニトロ化合物の還元により製造してよい。例えば、還元は好都合には概ね室温でメタノールまたはエタノールのような不活性溶媒中、塩化スズとの反応により行ってよい。或いは、反応は約１４０℃の温度で電子レンジ中で行ってよい。 Intermediates of formula (IIx), where W, X, Y and Z are as defined above for compounds of formula (Ix), are represented by the following formula (1)

It may be prepared by reduction of the corresponding nitro compound of where W, X, Y and Z are as defined above for the compound of formula (Ix). For example, the reduction may conveniently be carried out by reaction with tin chloride in an inert solvent such as methanol or ethanol at about room temperature. Alternatively, the reaction may be performed in a microwave oven at a temperature of about 140 ° C.

［式中Ｗ、Ｘ、ＹおよびＺは式（Ｉｘ）の化合物に関して前に定義したものである］の相当するジニトロ化合物の還元により製造してよい。 Intermediates of formula (IIx), where W, X, Y and Z are as defined above for compounds of formula (Ix), are represented by formula (2)

It may be prepared by reduction of the corresponding dinitro compound of where W, X, Y and Z are as defined above for the compound of formula (Ix).

［式中ＸはＣ−Ｒ²であり、そしてＹはＣ−Ｒ³であり、ここでＲ³は式（Ｉｘ）の化合物に関して前に定義したものである］の相当するアニリンから、(ｉ）約０℃〜概ね室温でジクロロメタンのような不活性溶媒中トリエチルアミンの存在下に無水酢酸と反応させることにより、(ii）約−５℃の温度で酢酸および無水酢酸の存在下に硝酸と反応させることにより、そして（iii）室温においてメタノール中ナトリウムメトキシドのようなアルカリ金属アルコキシドと反応させることにより製造してよい。 W is CH, X is C—R ² , Y is C—R ³ , and Z is CH wherein R ³ is as defined above for the compound of formula (Ix) The nitro compound of formula (1) is represented by the following formula (3):

From the corresponding aniline of the formula (i) wherein X is C—R ² and Y is C—R ³ , wherein R ³ is as defined above for the compound of formula (Ix) By reacting with acetic anhydride in the presence of triethylamine in an inert solvent such as dichloromethane at about 0 ° C. to about room temperature, and (ii) reacting with nitric acid in the presence of acetic acid and acetic anhydride at a temperature of about −5 ° C. And (iii) reacting with an alkali metal alkoxide such as sodium methoxide in methanol at room temperature.

［式中ＸはＣ−Ｒ²（式中Ｒ²はアルキル）であり、そしてＸ²はヨードである］の化合物を反応させることにより製造してよい。 W is CH, X is C—R ² (wherein R ² is alkyl), Y is C—R ³ (wherein R ³ is an aryl or a group), and Z is CH Certain nitro compounds of formula (1) can be converted to aryl (or heteroaryl) boronic acids in the presence of a suitable catalyst such as tetrakis (triphenylphosphine) palladium in an inert solvent such as tetrahydrofuran at a temperature of about 85 ° C. Formula (4):

It may be prepared by reacting a compound of the formula wherein X is C—R ² (wherein R ² is alkyl) and X ² is iodo.

［式中Ｒ⁷は水素であり、Ｒ⁸はアルキルであり、そして、Ｒ⁹は水素またはアルキルである］の式（IIIｘ）の中間体は下記式（５）：

［式中Ｒ⁸はアルキルであり、そして、Ｒ⁹は水素である］の化合物を還流温度で酢酸の存在下ヒドラジンと反応させ、その後、加水分解することにより製造してよい。 R ¹ is part:

The intermediate of formula (IIIx) in which R ⁷ is hydrogen, R ⁸ is alkyl, and R ⁹ is hydrogen or alkyl is represented by the following formula (5):

It may be prepared by reacting a compound of [wherein R ⁸ is alkyl and R ⁹ is hydrogen] with hydrazine in the presence of acetic acid at reflux temperature followed by hydrolysis.

［式中Ｒ⁷は水素であり、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になって５、６または７員の炭素環を形成する］の式（IIIｘ）の中間体は、同様に、Ｒ⁸およびＲ⁹はそれらが連結している炭素原子と一緒になって５、６または７員の炭素環を形成する式（５）の化合物をヒドラジンと反応させ、その後加水分解することにより製造してよい。 R ¹ is part:

An intermediate of formula (IIIx) in which R ⁷ is hydrogen and R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 5, 6 or 7 membered carbocycle Similarly, R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 5-, 6- or 7-membered carbocyclic ring and react with a hydrazine, followed by hydrolysis. You may manufacture by decomposing | disassembling.

［式中Ｒ⁷は水素であり、Ｒ¹³はアルキルであり、そして、Ｘ¹はＯ、Ｓ、ＳＯ₂またはＮＹ⁵（ここでＹ⁵はＲ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴または−ＳＯ₂Ｒ⁴である）である］の式（IIIｘ）の中間体は、同様に、下記式（６）：

［式中Ｒ¹³はアルキルであり、そして、Ｘ¹はＯ、Ｓ、ＳＯ₂またはＮＹ⁵（ここでＹ⁵はＲ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴または−ＳＯ₂Ｒ⁴である）である］の化合物をヒドラジンと反応させ、その後加水分解することにより製造してよい。 R ¹ is part:

Wherein R ⁷ is hydrogen, R ¹³ is alkyl, and X ¹ is O, S, SO ₂ or NY ⁵ (where Y ⁵ is R ⁴ , —C (═O) R ⁴ , — C (═O) NY ¹ Y ² , —C (═O) OR ⁴ or —SO ₂ R ⁴ )], and the intermediate of formula (IIIx) is similarly represented by the following formula (6):

Wherein R ¹³ is alkyl and X ¹ is O, S, SO ₂ or NY ⁵ (where Y ⁵ is R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR ⁴ or —SO ₂ R ⁴ )] may be reacted with hydrazine followed by hydrolysis.

［式中Ｒ⁸はアルキルである］の化合物を、約６０℃の温度でエタノールのような不活性溶媒中ナトリウムエトキシドのようなアルカリ金属アルコキシドの存在下にシュウ酸ジエチルと反応させることにより製造してよい。 A compound of formula (5) wherein R ⁸ is alkyl and R ⁹ is hydrogen is represented by the following formula (7):

Prepared by reacting a compound of the formula wherein R ⁸ is alkyl with diethyl oxalate in the presence of an alkali metal alkoxide such as sodium ethoxide in an inert solvent such as ethanol at a temperature of about 60 ° C. You can do it.

Compounds of formula (5) in which R ⁸ and R ⁹ together with the carbon atom to which they are linked form a 5-, 6- or 7-membered carbocyclic ring are similarly substituted by cyclopentanone or cyclohexanone with oxalic acid It may be produced by reacting with diethyl.

［式中Ｒ¹³はアルキルであり、そして、Ｘ¹はＯ、Ｓ、ＳＯ₂またはＮＹ⁵（ここでＹ⁵はＲ⁴、−Ｃ(＝Ｏ)Ｒ⁴、−Ｃ(＝Ｏ)ＮＹ¹Ｙ²、−Ｃ(＝Ｏ)ＯＲ⁴または−ＳＯ₂Ｒ⁴である）である］の化合物をシュウ酸ジエチルと反応させることにより製造してよい。 R ¹³ is alkyl, and X ¹ is O, S, SO ₂ or NY ⁵ (where Y ⁵ is R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , -C (= O) oR ⁴ or -SO ₂ R ⁴⁾ formula (compound 6) likewise formula (8):

Wherein R ¹³ is alkyl and X ¹ is O, S, SO ₂ or NY ⁵ (where Y ⁵ is R ⁴ , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR ⁴ or —SO ₂ R ⁴ )] may be reacted with diethyl oxalate.

（式中Ｒ¹⁰およびｐは前述の通り定義される）である式（IVｘ）の中間体に適している。 Intermediates of formula (IVx), where R ¹ is as defined above for the compound of formula (Ix), are the following formula (9):
R ¹ —CH ₂ OH (9)
It may be prepared by oxidation of a compound of the formula wherein R ¹ is as defined above for the compound of formula (Ix). The oxidation may conveniently be performed with manganese dioxide or pyridinium chlorochromate in an inert solvent such as chloroform or dichloromethane at a temperature of about 60 ° C. This procedure is especially for R ¹ :

Suitable for intermediates of formula (IVx) where R ¹⁰ and p are defined as above.

The compound of formula (9), wherein R ¹ is as previously defined for the compound of formula (Ix), is a compound of formula (10):
R ¹ —CO ₂ H (10)
May be prepared by reduction of an acid of the formula wherein R ¹ is as defined above for the compound of formula (Ix). The reduction may conveniently be performed using lithium aluminum hydride in an inert solvent such as tetrahydrofuran at about room temperature.

The compound of formula (9), wherein R ¹ is as defined above for the compound of formula (Ix), is a compound of formula (10a):
R ¹ —CO ₂ alkyl (10a)
It may be carried out by reduction of an alkyl ester of the formula wherein R ¹ is as defined above for the compound of formula (Ix). The reduction may conveniently be performed using lithium aluminum hydride in an inert solvent such as tetrahydrofuran at about room temperature.

［式中Ｒ¹⁰およびｐは前述の通り定義される］である式（10）の酸は下記式（11）：

［式中Ｒ¹⁰およびｐは前述の通り定義される］のインドールジオンを（ｉ）水酸化ナトリウムと５０℃で、(ii）亜硝酸ナトリウム次いで硫酸と５℃で、および、(iii）塩化スズ（II）と反応させることにより製造してよい。 R ¹ is part:

Wherein R ¹⁰ and p are defined as above, the acid of formula (10) is represented by the following formula (11):

Indole dione of the formula (wherein R ¹⁰ and p are defined above) at (i) sodium hydroxide at 50 ° C., (ii) sodium nitrite then sulfuric acid at 5 ° C. and (iii) tin chloride It may be produced by reacting with (II).

［式中Ｒ¹⁰は前述の通り定義される］の化合物をポリリン酸と約８０℃の温度で反応させることにより製造してよい。 The compound of the formula (11) in which R ¹⁰ is defined as described above and p is 1 is represented by the following formula (12):

It may be produced by reacting a compound of [wherein R ¹⁰ is defined above] with polyphosphoric acid at a temperature of about 80 ° C.

［式中Ｒ¹⁰は前述の通り定義される］のアニリンを包水クロラールおよびヒドロキシルアミンと塩酸の存在下約８０℃の温度で反応させることにより製造してよい。 The compound of the formula (12) in which R ¹⁰ is defined as described above has the following formula (13):

It may be prepared by reacting an aniline of the formula wherein R ¹⁰ is as defined above with chlorinated water and hydroxylamine in the presence of hydrochloric acid at a temperature of about 80 ° C.

The intermediate of formula (Vx), where W, X, Y, Z and R ¹ are as previously defined for the compound of formula (Ix), is optionally pyridine in an inert solvent such as dichloromethane at about room temperature. May be prepared by reacting an acid chloride of formula R ¹ —C (═O) —Cl with a compound of formula (1) in the presence of a third base such as

Reference is made to the following documents, which may be used in the context of the present invention for the preparation of benzimidazoles, pyrazoles or indazoles.
-GR Newkome, WW Paudler, Comtemporary Heterocyclic Chemistry, Syntheses, Reactions and Applications, J. Wiley, 1982. − Preston, Heterocyclic Compounds, Benzimidazoles and congeneric tricyclic compounds, J. Wiley, 1981. -Behr, Fusco, Jarboe, Heterocyclic Compounds, Pyrazoles, Pyrazolines, Pyrazolidines, indazoles and condensed rings, J. Wiley, 1967.

  The following schemes, Schemes 5-13, illustrate the synthesis of certain examples described in the specification using the methods described above using appropriate protecting groups as appropriate.

The present invention is further illustrated by the following illustrative and reference examples, but is not limited thereto.
400 MHz ¹ H nuclear magnetic resonance (NMR) was recorded on a Varian Unity INOVA machine. In nuclear magnetic resonance (NMR), chemical shift (δ) is expressed in ppm relative to tetramethylsilane. Abbreviations have the following meanings: s = 1 double line; d = double line; t = triple line; m = multiple line; q = quad line; dd = double line double line; Let it be a double line of a double line.
_Rf values for thin layer chromatography (TLC) were measured using Merck silica plates.

The conditions of high performance liquid chromatography-mass spectrum (LC-MS) for measuring retention time (R _T ) and associated mass ions are as follows.
Method A:
Mass spectrum analyzer (MS)-LCT time of flight (Micromass UK Ltd) serial number KA014 [ionization mode: electron spray (positive ion); scan: MS T (full scan m / z 100-1200, sum of 0.4s) @ 50us / scan) Centroid mode]. Liquid chromatography (LC): Hewlett Packard HP1100 series binary pump (serial number US80301343) & deaerator (serial number JP73008973). Hypersil BDS C-18, 3 micron (4.6 mm x 50 mm), reverse phase column (A) water containing 0.05% trifluoroacetic acid, and (B) 0.05% trifluoroacetic acid. Operate under gradient elution conditions using acetonitrile as the mobile phase (gradient: 0.00 min, 100% A; linear gradient to 100% B in 2 min; then hold for 1.5 min); 1 ml / min for the detector, 0.75 ml / min for the ELS detector by flow splitting after the UV detector, and 0.25 ml / min for the mass spectrum analyzer; the injection volume is 10 μl; the auxiliary detector is (i) Hewlett Packard HP1100 series UV detector (serial number JP73704703), wavelength = 220 nm; (ii) SEDEX75 evaporative light scattering (EL) from Sedere (France) ) And the detector (serial number 9970002A); temperature = 46 ° C., the nitrogen gas pressure = 4 bar; Autosampler / Injector: Gilson 215 type liquid handler, and with 819 type injection valve (serial number 259E8280).

Method B:
Waters Symmetry C8 3.5 μm HPLC column is a mobile phase (gradient: 0.00 min, 95%) with a mixture of (A) water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. A: 5%; 0.75 min, 95% A: 5% B; 3.00 min 100% V; 4.00 min 100B; 4.25 min 95% A: 5% B) Operate down; flow rate is 1.5 ml / min, split to about 200 μl / min sent to mass spectrometer; injection volume is 20 μl; inline diode array (210-300 nm), inline evaporative light scattering ( ELS) Detector ELS—temperature 40 ° C., gain 7 to 1.5 ml / min; source temperature 150 ° C.

Method C:
The Waters Symmetry C8 3.5 μm HPLC column is a mobile phase (gradient: 0.00 min, 95% A: 5%) with a mixture of (A) water containing 10 mM ammonium acetate and (B) methanol containing 10 mM ammonium acetate. 0.75 min, 95% A: 5% B; 3.00 min 100% V; 4.00 min 100B; 4.25 min 95% A: 5% B). Flow rate is 1.5 ml / min, sent to the mass spectrometer by splitting about 200 μl / min; injection volume is 20 μl; in-line diode array (210-300 nm), in-line evaporative light scattering (ELS) detector ELS temperature 40 ° C., gain 7 to 1.5 ml / min; source temperature 150 ° C.

Method D:
A C18 Phenomenex Luna 5 μM (250 × 4.6 mm) column was charged with a mixture of (A) methanol containing 10 mM ammonium acetate and (B) water containing 10 mM ammonium acetate in a mobile phase (gradient: 0-2 min 10% A 90% B; up to 100% A over 2-23 minutes; 23-30 minutes 100% A; 30-37 minutes 10% A: 90% B), with a flow rate of 1 ml / min To do.

Method E:
Mass spectrum analyzer (MS)-LCT time of flight (Micromass UK Ltd) serial number KA014 [ionization mode: electron spray (positive ion); scan: MS T (full scan m / z 100-1200, sum of 0.4s) @ 50us / scan) Centroid mode]. Liquid chromatography (LC): Hewlett Packard HP1100 series binary pump (serial number US80301343) & deaerator (serial number JP73008973). Synergi 2U hydro reversed phase 20 x 4 mm column. Solvent A is 0.1% trifluoroacetic acid in water; Solvent B is 0.1% trifluoroacetic acid in acetonitrile. The gradient is 5% B to 2 minutes at 0% and 90% B to 100% B for 5 minutes; the flow rate is 1 ml / min for the column and UV detector, and after the UV detector is 0.5% for the ELS detector by flow splitting. 75 ml / min, and 0.25 ml / min for mass spectrometer; injection volume 10 μl; auxiliary detector (i) Hewlett Packard HP1100 series UV detector (serial number JP73704703), wavelength = 220 nm; (ii) Sedere (France) SEDEX 75 type evaporative light scattering (ELS) detector (serial number 9970002A); temperature = 46 ° C., nitrogen gas pressure = 4 bar; autosampler / injector: Gilson 215 type liquid handler, type 819 With an injection valve (serial number 259E8280).

Method F:
An Agilent 1100 series HPLC was equipped with a YMC CombiScreen Pro C18 5.5 μm 4.6 mm × 33 mm reverse phase column and gradient elution was (A) acetonitrile / 0.1% trifluoroacetic acid and (B) water / 0.1% trimethyl. Fluoroacetic acid (5% A: 95% B to 95% A: 5% B over 5.1 minutes) with a flow rate of 1.2 ml / min; 2 μL injection using an Agilent 1100 series well plate autosampler Quantities; with Agilent 1100 series diode array detectors at wavelengths of 215, 254 and 300 nm; using Hewlett Packard 1100 series mass spectral analyzers with electrospray and cationization.

Method G:
Rainin HPXL dual pump HPLC system with Rainin Dynamax UV-DII detector for 254 nM wavelength, C18 Metachem Monochrom 10 μM (100 × 4.6 mm) column (A) water containing 0.1% trifluoroacetic acid, and , (B) a gradient elution using a mixture of acetonitrile as the mobile phase (90% A: 10% B to 0% A in 12 minutes) with a flow rate of 1.0 ml / min and C18 Phenomenex Luna 5 μM (150 X 4.6 mm) column with (A) methanol and (B) a mixture of water containing 10 mM ammonium acetate in mobile phase (0-2 min 10% A: 90% B; 100% over 2-25 min Up to A; 25-32 minutes 100% A; 32-33 minutes 10% A: 90% B), with a flow rate of 1.0 ml / min.

Method H:
Waters Symmetry C8 3.5 μm column is a mixture of (A) water / 0.1% formic acid and (B) acetonitrile / 0.1% formic acid (5% B: 95% A to 100% B for 3.5 minutes) 100% B for 1 minute, 100% B to 5% B: 95% A for 0.1 minute, equilibrated 5% B: 95% A for 0.49 minutes, total elution time 5 minutes) With gradient elution, flow rate 1.5 ml / min; detection at 210-300 nM with 2 nM intervals; column temperature 30 ° C .; mass spec quadropole, electrospray, cone voltage 25 V, +/− ion switching Centroid data, 140 to 850 Da, 0.6 second scan, and 0.4 second interscan delay.

Method J:
The Waters Symmetry C8 3.5 μm column is a mixture of (A) 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile (5% B: 95% A for 0.75 minutes, 100 minutes in 4 minutes). Used for gradient elution with 100% B for 5 minutes, 100% B for 1 minute to 5% B: 95% A, total elution time 5 minutes), flow rate 1.5 ml / min; Column temperature is 30 ° C .; mass spec quadropole, electrospray, cone voltage 25 V, +/− ion switching, centroid data, 140 to 850 Da, 0.6 second scan, 0.6. The interscan delay is 4 seconds.

Method K:
The Waters Symmetry C8 3.5 μm column is (A) 10 mM ammonium acetate in water and (B) a mixture of 10 mM ammonium acetate in acetonitrile (5% B: 95% A for 0.75 minutes, 4 minutes to 100% B, Used for gradient elution with 100% B for 5 minutes, 100% B to 5% B for 1 minute: 95% A, total elution time 5 minutes), with a flow rate of 1.5 ml / min; detection is 210-300 nM Column temperature 30 ° C; mass spec quadropole, electrospray, cone voltage 25V, +/- ion switching, centroid data, 140-850 Da, 0.6 second scan, 0.4 second interscan Let it be a delay.

Method L:
A Phenomenex Luna C18 (2) 3 μM column (150 × 4.6 mm) was mixed with (A) 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile (20% B: 80% A to 100 10 minutes to% B, 2 minutes for 100% B, 0.5 minutes from 100% B to 20% B: 80% A, 3.5 minutes for 20% B: 80% A, total elution time 16 minutes ) With a flow rate of 1.0 ml / min; 210-300 nM, 220 and 254 nM extraction and ELSD; column temperature 30%; mass spec quadropole, electrospray, cone voltage 25 V, +/− Ion switching, centroid data, 100-900 Da, 0.6 second scan, 0.4 second interscan delay.

Method M:
A Phenomenex Luna C18 (2) 3 μM column (150 × 4.6 mm) was mixed with (A) 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile (5% B: 95% A to 60%). % B: 40% A in 10 minutes, 60% B: 40% A for 2 minutes, 60% B: 40% A to 5% B: 95% A in 0.5 minutes, 5% B: 95% A is used for gradient elution with 3.5 minutes, total elution time of 16 minutes) with a flow rate of 1.0 ml / min; 210-300 nM, 220 and 254 nM extraction and ELSD; column temperature 30%; mass spec quadro Pole, electronic spray, cone voltage 25V, +/- ion switching, centroid data, 100-900 Da, 0.6 second scan, 0.4 second interscan delay.

Method N:
The Waters Symmetry C8 3.5 μm column is (A) 10 mM ammonium acetate in water and (B) a mixture of 10 mM ammonium acetate in acetonitrile (5% B: 95% A to 100% B in 3.5 minutes for 1 minute 100 % B, 100% B to 5% B: 95% A for 0.1 minute, equilibrated 5% BV: 95% A for 0.49 minutes, total elution time 5 minutes) Flow rate is 1.5 ml / min; detection is 210-300 nM at 2 nM intervals; column temperature is 30 ° C .; mass spec quadropole, electrospray, cone voltage 25 V, +/− ion switching, centroid data, 140— 850 Da, 0.6 second scan, and 0.4 second interscan delay.

Method P:
Phenomenex Luna C18 (2) 3 μM column (150 × 4.6 mm) (A) 10 in water
mM ammonium acetate and (B) 10 mM ammonium acetate in methanol (5% B: 95% A to 60% B: 40% A in 10 minutes, 60% B: 40% A for 2 minutes, 60% B: Gradient elution with 40% A to 5% B: 95% A for 0.5 minutes and 5% B: 95% A for 3.5 minutes with a total elution time of 16 minutes) with a flow rate of 1. 110 ml / min; 210-300 nM, 220 and 254 nM extraction and ELSD; column temperature 30%; mass spec quadropole, electrospray, cone voltage 25 V, +/- ion switching, centroid data, 100-900 Da, 0.6 Second scan, 0.4 second interscan delay.

Method Q:
A Phenomenex Luna C18 (2) 3 μM column (150 × 4.6 mm) was (A) 10 mM ammonium acetate in water and (B) 10 mM ammonium acetate in methanol (20% B: 80% A to 100% B in 10 minutes). Gradient elution using 100% B for 2 minutes, 100% B-20% B: 80% A for 0.5 minutes, 20% B: 80% A for 3.5 minutes, total elution time 16 minutes) With a flow rate of 1.0 ml / min; 210-300 nM, 220 and 254 nM extraction and ELSD; column temperature 30%; mass spec quadropole, electrospray, cone voltage 25 V, +/- ion switching, centroid data , 100 to 900 Da, 0.6 second scan, and 0.4 second interscan delay.

Method R:
A Phenomenex Luna C18 (2) 3 μM column (150 × 4.6 mm) was (A) 10 mM ammonium acetate in water and (B) 10 mM ammonium acetate in methanol (40% B: 60% A to 100% B in 10 minutes). Gradient elution using 100% B for 2 minutes, 100% B to 40% B: 60% A for 0.5 minutes, 40% B: 60% A for 3.5 minutes, total elution time 16 minutes) With a flow rate of 1.0 ml / min; 210-300 nM, 220 and 254 nM extraction and ELSD; column temperature 30%; mass spec quadropole, electrospray, cone voltage 25 V, +/- ion switching, centroid data , 100 to 900 Da, 0.6 second scan, and 0.4 second interscan delay.

The high performance liquid chromatography conditions for measuring the retention time (R _T ) were as follows.
Method A1:
A YMC ODS-AQ (2 × 50 mm) column was used as the mobile phase with gradient elution [95/5 / 0.1% to 5/95 / 0.1%] with a mixture of acetonitrile, water and formic acid, with a flow rate of 0. 0.4 ml / min.

Method B1:
A C18 Phenomenex Luna 5 μM (150 × 4.6 mm) column was passed through a mobile phase (gradient: 0-2) with (A) acetonitrile containing 0.1% formic acid and (B) water containing 0.1% formic acid. Min. 10% A: 90% B; up to 100% A over 2-25 minutes; 25-32 minutes 100% A; 32-33 minutes 10% A: 90% B). 1.0 ml / min.

Method C1:
C18 Phenomenex Luna 5 μM (150 × 4.6 mm) column was passed through a mixture of water containing (A) methanol and (B) 10 mM ammonium acetate in mobile phase (gradient: 0-2 min 10% A: 90% B; 2 Used for gradient elution to 100% A over 25 minutes; 25-32 minutes 100% A; 32-33 minutes 10% A: 90% B), with a flow rate of 1.0 ml / min.

Method D1:
A flow rate of 1 using a C18 Phenomenex Luna 3 μM (150 × 4.6 mm) column with gradient elution using a mixture of (A) acetonitrile containing 0.1% formic acid and (B) water containing 0.1% formic acid. Use at 0.0 ml / min.

Method E1:
C18 Phenomenex Luna 3 μM (150 × 4.6 mm) column was mixed with (A) methanol and (B) a mixture of water containing 10 mM ammonium acetate in the mobile phase (20% A: 80% B-100% A in 10 minutes). Used for gradient elution with 100% A for 2 minutes; 100% A to 20% A: 80% B for 0.5 minutes, 20% A: 80% B for 3.5 minutes. 0.0 ml / min.

Method F1:
A C18 Phenomenex Luna 3 μM (150 × 4.6 mm) column is used with a flow rate of 1.0 ml / min by gradient elution with a mixture of acetonitrile and water.

Method G1:
A C18 Phenomenex Luna 3 μM (150 × 4.6 mm) column was passed through a mobile phase (5% A: 95% B to 60% A: 40% B) with a mixture of water containing (A) methanol and (B) 10 mM ammonium acetate. 60% A: 40% B for 2 minutes; 60% A: 40% B to 5% A: 95% B for 0.5 minutes; 5% A: 95% B for 3.5 minutes ) And gradient elution with a flow rate of 1.5 ml / min.

Gas chromatography-mass spectral analysis (GC-MS) conditions for retention time (R _T ) and related mass ion measurements were as follows.
A Varian 3800 gas chromatograph, a Chromopack 0.25 mm diameter fused silica 30 m column, was used, eluting for 20 minutes with a temperature gradient of 25 ° C./min from 50 to 300 ° C. over 1 to 11 minutes; Minutes; an injection volume of 3-8 μL with an injection split ratio of 50:50; a Varian 2000R mass spectrometer is used in electron impact detection for 40-650 m / z ions.

General method for LC-MS purification of Examples 1-229: A Waters Fraction Lynx system was used, the separation was on a Waters Symmetry column (C18, 19 x 50 mm, catalog number 186021010) and the elution was 0.07% Tri A linear gradient of acetonitrile containing 0.07% trifluoroacetic acid (v / v) in water containing fluoroacetic acid (v / v) was performed, and the gradient was 5% to 95% (v / v over 8 minutes). v) acetonitrile / trifluoroacetic acid and then 95% acetonitrile / trifluoroacetic acid for 2 minutes, flow rate 10 ml / min. The product is injected as a solution in dimethyl sulfoxide and collected according to its molecular weight detection.
The names of the compounds were made using autonom plugs in ISIS 2.3 or ISIS 2.4.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸ベンジルアミドを以下の方法で製造してよい。
ジメチルホルムアミド０.２ｍｌ中のＨＢＴＵ２７.３ｍｇの溶液を２０℃程度で無水ジメチルホルムアミド０.４２ｍｌ中の２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇの溶液に添加する。２０℃程度で１時間攪拌後、ベンジルアミン１５.７ｍｌを添加し、ついでジメチルホルムアミド０.３２ｍｌに溶解したＮ,Ｎ−ジイソプロピルエチルアミン１２.４ｍｌを添加する。２０℃程度で２０時間後、反応中間体を４０℃程度で減圧下に濃縮する。得られた粗製の残存物をＤＭＳＯに溶解し、分取ＬＣ−ＭＳにより精製する。所望の生成物を含む画分を合わせ、４０℃程度で減圧下に濃縮する。このようにしてクリーム色粉末の形状で得られる２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸ベンジルアミド２０ｍｇの特性は以下の通り。
ＬＣ−ＭＳ保持時間＝２.８６分 [Example 1]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide may be prepared by the following method.
A solution of 27.3 mg of HBTU in 0.2 ml of dimethylformamide was added to a solution of 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid in 0.42 ml of anhydrous dimethylformamide at about 20 ° C. Added. After stirring at about 20 ° C. for 1 hour, 15.7 ml of benzylamine is added, and then 12.4 ml of N, N-diisopropylethylamine dissolved in 0.32 ml of dimethylformamide is added. After 20 hours at about 20 ° C., the reaction intermediate is concentrated under reduced pressure at about 40 ° C. The crude residue obtained is dissolved in DMSO and purified by preparative LC-MS. Fractions containing the desired product are combined and concentrated at about 40 ° C. under reduced pressure. The properties of 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide thus obtained in the form of cream powder are as follows.
LC-MS retention time = 2.86 minutes

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid may be prepared by the following method.
1.3 g of sodium metabisulfite and 1.04 g of 3,4-diaminobenzoic acid are added at about 20 ° C. to a solution of 1 g of 1H-indazole-3-carboxaldehyde in 10 ml of dimethylformamide. The reaction mixture is refluxed for 1 hour, then cooled to around 20 ° C., diluted with dichloromethane and the mixture is filtered. The collected filtrate is concentrated under reduced pressure. The resulting brown lacquer (340 mg) is purified by preparative LC-MS. There are thus obtained 138.8 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid in the form of a beige powder.

1H-indazole-3-carboxaldehyde may be produced by the following method.
A solution of 2.27 g of (1H-indazol-3-yl) methanol in 220 ml of 1,2-dimethoxyethane is added to 13.32 g of manganese dioxide. After 1 hour at around 20 ° C., the reaction mixture is refluxed for 15 minutes. After cooling to about 20 ° C., the reaction intermediate is filtered through a sintered funnel packed with celite. The collected filtrate is concentrated at about 40 ° C. under reduced pressure. The properties of 2.02 g of 1H-indazole-3-carboxaldehyde thus obtained in the form of a yellow powder are as follows.
¹ H NMR (DMSO d6, 400 MHz): 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.75 ppm (doublet, 1H); 8.18 ppm (doublet, 1H); 10.23 ppm (singlet, 1H) ; 14.2 ppm (multiplet, 1H)

(1H-indazol-3-yl) methanol may be produced by the following method.
3.2 g of lithium aluminum hydride is added little by little to a solution of 7.08 g of methyl 3-indazolecarboxylate in 80 ml of tetrahydrofuran and cooled to about 0 ° C. with an ice bath. After 4 hours at about 0 ° C., 1.6 g of lithium aluminum hydride is added. After 2 hours at a temperature of around 0 ° C., the reaction intermediate is in turn treated with 6 ml of water, then with 6 ml of 1N aqueous sodium hydroxide solution and finally with 18 ml of water. The reaction mixture is filtered through filter paper and then the aqueous filtrate is extracted with dichloromethane. The collected organic fractions are combined, dried over magnesium sulfate, and concentrated under reduced pressure at about 40 ° C. The properties of 3.15 g of (1H-indazol-3-yl) methanol obtained in the form of an off-white powder are as follows.
¹ H NMR (DMSO d6, 400 MHz): 4.80 ppm (doublet, 2H); 5.25 ppm (triplet, 1H); 7.15 ppm (triplet, 1H); 7.35 ppm (triplet, 1H); 7.51 ppm (doublet, 1H) ; 7.87 ppm (doublet, 1H); 12.81 ppm (multiplet, 1H)

Methyl 3-indazolecarboxylate may be prepared by the following method.
Concentrated sulfuric acid (95%) 0.5 ml is added dropwise at around 20 ° C. to a solution of 9.13 g 3-indazolecarboxylic acid in 100 ml methanol. After refluxing for 20 hours, the reaction intermediate is concentrated under reduced pressure at about 40 ° C. The resulting aqueous residue is extracted with dichloromethane. The organic layers are combined, washed with water until neutral, dried over magnesium sulfate, and then concentrated at about 40 ° C. under reduced pressure. The resulting yellow powder is washed with ethyl ether. A white powder is obtained. The filtrate is concentrated under reduced pressure until a yellow powder is obtained. The yellow powder is washed again with ethyl ether until a white powder is obtained. The yellow filtrate is concentrated three times under reduced pressure and the collected yellow powder itself is also washed with ethyl ether. Combine all fractions of white powder. In this way 7.08 g of methyl 3-indazolecarboxylate is obtained in the form of a white powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−メチルアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびメチルアミン溶液（テトラヒドロフラン中２Ｍ）７１.８μｌを出発物質とし、期待された生成物１４.８ｍｇを得る。 [Example 2]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N-methylamide may be prepared.
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 71.8 μl of a methylamine solution (2M in tetrahydrofuran), 14.8 mg of the expected product are obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−エチルアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびエチルアミン溶液（水中３３％）１９.４ｍｌを出発物質として、２−（
１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−エチルアミド１４.８ｍｇを得る。 [Example 3]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N-ethylamide may be prepared.
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 19.4 ml of ethylamine solution (33% in water), 2- (
14.8 mg of 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide are obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−イソプロピルアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびイソプロピルアミン１２.３ｍｌを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−イソプロピルアミド１６.５ｍｇを得る。 [Example 4]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N-isopropylamide may be prepared.
Using 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 12.3 ml of isopropylamine as starting materials, 2- (1H-indazol-3-yl) -1H-benzimidazole- 16.5 mg of 5-carboxylic acid N-isopropylamide are obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−フェニルアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびアニリン１３.１ｍｌを出発物質として、白色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−フェニルアミド１４.１ｍｇを得る。 [Example 5]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N-phenylamide may be prepared.
Starting from 20 mg 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 13.1 ml aniline, 2- (1H-indazol-3-yl) -1H in the form of a white powder -14.1 mg of benzimidazole-5-carboxylic acid N-phenylamide are obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−フェネチルアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびフェネチルアミン１８ｍｌを出発物質として、白色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−フェネチルアミド１７.７ｍｇを得る。 [Example 6]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N-phenethylamide may be prepared.
Starting from 20 mg 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 18 ml phenethylamine in the form of a white powder 2- (1H-indazol-3-yl) -1H-benzo 17.7 mg of imidazole-5-carboxylic acid N-phenethylamide are obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−モルホリノアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびモルホリン１２.５ｍｌを出発物質として、淡黄色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−モルホリノアミドを得る。 [Example 7]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (Example 1), 2- (1H-indazol-3-yl) -1H-benzimidazole- 5-Carboxylic acid N-morpholinoamide may be prepared.
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 12.5 ml of morpholine, 2- (1H-indazol-3-yl)- 1H-benzimidazole-5-carboxylic acid N-morpholinoamide is obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（Ｎ′−メチル−ピペラジノ）アミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸
２０ｍｇおよびＮ−メチルピペラジン１５.９ｍｌを出発物質として、黄色油状物の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（Ｎ′−メチル−ピペラジノ）アミド１６.１ｍｇを得る。 [Example 8]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methyl-piperazino) amide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N- (N'-methyl-piperazino) amide may be prepared.
Starting from 20 mg 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 15.9 ml N-methylpiperazine in the form of a yellow oil, 2- (1H-indazole-3- Yl) -1H-benzimidazole-5-carboxylic acid N- (N'-methyl-piperazino) amide 16.1 mg.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ピロリジノアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびピロリジン１２ｍｌを出発物質として、淡黄色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ピロリジノアミド１７.７ｍｇを得る。 [Example 9]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N-pyrrolidinoamide may be prepared.
Starting from 20 mg 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 12 ml pyrrolidine, 2- (1H-indazol-3-yl) -1H- in the form of a pale yellow powder 17.7 mg of benzimidazole-5-carboxylic acid N-pyrrolidinoamide are obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（イソブチル）アミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびイソブチルアミン１４.６ｍｌを出発物質として、淡黄色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（イソブチル）アミド７.６ｍｇを得る。 [Example 10]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N- (isobutyl) amide may be prepared.
Starting from 20 mg 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 14.6 ml isobutylamine, 2- (1H-indazol-3-yl) in the form of a pale yellow powder 7.6 mg of -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide is obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（シクロヘキシルメチル）アミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびシクロヘキシルメチルアミン１８.７ｍｌを出発物質として、白色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（シクロヘキシルメチル）アミド１６.１ｍｇを得る。 [Example 11]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide may be prepared.
Starting from 20 mg 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 18.7 ml cyclohexylmethylamine, 2- (1H-indazol-3-yl) in the form of a white powder 16.1 mg of -1H-benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide are obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（２−フルフリル）アミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよび２−フルフリルアミン１３.３ｍｌを出発物質として、白色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（２−フルフリル）アミド１４.８ｍｇを得る。 [Example 12]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N- (2-furfuryl) amide may be prepared.
Starting from 20 mg 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 13.3 ml 2-furfurylamine in the form of a white powder, 2- (1H-indazol-3-yl ) -14.8 mg of 1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide is obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジル−Ｎ−メチルアミドを製造してよい。
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇおよびＮ−メチルベンジルアミン１８.６ｍｌを出発物質として、淡黄色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジル−Ｎ−メチルアミド７.３ｍｇを得る。 [Example 13]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide

According to the procedure for the preparation of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1), 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid N-benzyl-N-methylamide may be prepared.
Starting with 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 18.6 ml of N-methylbenzylamine, 2- (1H-indazole-3 Yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide 7.3 mg is obtained.

メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレートを以下の方法で製造してよい。
ニトロベンゼン１０ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド０.１ｇとメチル３,４−ジアミノベンゾエート１１３.７ｍｇの混合物を１４５℃程度で３時間４５分維持する。２０℃程度に冷却後、反応混合物をＳＰＥ（ＳＣＸ相５ｇ、メタノールで処理および洗浄し、２Ｎアンモニア性メタノール溶液で抽出）上に精製した。その後分離の間に収集したアンモニア性溶液を４０℃程度で減圧下に濃縮した。得られた橙色ラッカー１９８.３ｍｇを分取ＬＣ−ＭＳにより精製した。このようにしてベージュ色粉末の形状で得られるメチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート４２.７ｍｇの特性は以下の通り。
¹H NMR (DMSO d6, 400 MHz): 3.95 ppm (singlet, 3H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.75 ppm (doublet, 1H); 7.77 ppm (doublet, 1H); 7.95 ppm (doublet, 1H); 8.57 ppm (doublet, 1H); 13.85 ppm (multiplet, 1H) [Example 14]
Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate

Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate may be prepared by the following method.
A mixture of 0.1 g of 1H-indazole-3-carboxaldehyde and 113.7 mg of methyl 3,4-diaminobenzoate in 10 ml of nitrobenzene is maintained at about 145 ° C. for 3 hours and 45 minutes. After cooling to around 20 ° C., the reaction mixture was purified on SPE (SCX phase 5 g, treated and washed with methanol, extracted with 2N ammoniacal methanol solution). Thereafter, the ammoniacal solution collected during the separation was concentrated at about 40 ° C. under reduced pressure. The obtained orange lacquer 198.3 mg was purified by preparative LC-MS. The characteristics of 42.7 mg of methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate thus obtained in the form of a beige powder are as follows:
¹ H NMR (DMSO d6, 400 MHz): 3.95 ppm (singlet, 3H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.75 ppm (doublet, 1H); 7.77 ppm (doublet, 1H) ; 7.95 ppm (doublet, 1H); 8.57 ppm (doublet, 1H); 13.85 ppm (multiplet, 1H)

メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート（実施例１４）の製造の操作法に従って、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造してよい。
ニトロベンゼン１０ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド２００ｍｇおよび４,５−ジメチル−１,２−フェニレンジアミン１７７ｍｇを出発物質として、暗赤色粉末の形状で得られる５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール１５.９ｍｇの特性は以下の通り。
¹H NMR (DMSO d6, 400 MHz): 2.60 ppm (singlet, 6H); 7.42 ppm (triplet, 1H); 7.53 ppm (singlet, 2H); 7.58 ppm (triplet, 1H); 7.78 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 14.05 ppm (multiplet, 1H) [Example 15]
5,6-Dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole

According to the procedure for the preparation of methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate (Example 14), 5,6-dimethyl-2- (1H-indazol-3-yl) ) -1H-benzimidazole may be produced.
Starting from 200 mg of 1H-indazole-3-carboxaldehyde and 177 mg of 4,5-dimethyl-1,2-phenylenediamine in 10 ml of nitrobenzene, 5,6-dimethyl-2- (1H obtained in the form of a dark red powder -Indazol-3-yl) -1H-benzimidazole 15.9 mg has the following characteristics.
¹ H NMR (DMSO d6, 400 MHz): 2.60 ppm (singlet, 6H); 7.42 ppm (triplet, 1H); 7.53 ppm (singlet, 2H); 7.58 ppm (triplet, 1H); 7.78 ppm (doublet, 1H) ; 8.52 ppm (doublet, 1H); 14.05 ppm (multiplet, 1H)

5,6-Dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole may also be prepared according to the following procedure.
389 mg of sodium metabisulfite is added at about 20 ° C. to a solution of 300 mg of 1H-indazole-3-carboxaldehyde and 279 mg of 4,5-dimethyl-1,2-phenylenediamine in 3 ml of dimethylformamide. The reaction mixture is refluxed for 4 hours, then cooled to about 20 ° C. and filtered through filter paper. The collected filtrate is concentrated under reduced pressure. The resulting brown lacquer (340 mg) is purified by preparative LC-MS. There are thus obtained 138.8 mg of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole in the form of a beige powder.

メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート（実施例１４）の製造の操作法に従って、５−メトキシ−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造してよい。
ニトロベンゼン１０ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド２００ｍｇおよび４−メトキシ−１,２−フェニレンジアミン二塩酸塩２７４.４ｍｇを出発物質として、明茶色粉末の形状で得られる５−メトキシ−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール４５.６ｍｇの特性は以下の通り。
¹H NMR (DMSO d6, 400 MHz): 3.90 ppm (singlet, 3H); 7.00 ppm (doublet, 1H); 7.18 ppm (doublet, 1H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.64 ppm (doublet, 1H); 7.73 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.91 ppm (multiplet, 1H) [Example 16]
5-Methoxy-2- (1H-indazol-3-yl) -1H-benzimidazole

According to the procedure for the preparation of methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate (Example 14), 5-methoxy-2- (1H-indazol-3-yl)- 1H-benzimidazole may be prepared.
Starting from 200 mg of 1H-indazole-3-carboxaldehyde and 274.4 mg of 4-methoxy-1,2-phenylenediamine dihydrochloride in 10 ml of nitrobenzene, 5-methoxy-2- () obtained in the form of a light brown powder The characteristics of 1H-indazol-3-yl) -1H-benzimidazole 45.6 mg are as follows.
¹ H NMR (DMSO d6, 400 MHz): 3.90 ppm (singlet, 3H); 7.00 ppm (doublet, 1H); 7.18 ppm (doublet, 1H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H) ; 7.64 ppm (doublet, 1H); 7.73 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.91 ppm (multiplet, 1H)

メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート（実施例１４）の製造の操作法に従って、２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−４−カルボン酸を製造してよい。
ニトロベンゼン１０ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド２３７ｍｇおよび２,３−ジアミノ安息香酸塩酸塩３０５.５ｍｇを出発物質として、ベージュ色粉末の形状で得られる２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−４−カルボン酸２０.５ｍｇの特性は以下の通り。
¹H NMR, DMSO d6, 400 MHz: 7.40 ppm (triplet, 1H); 7.42 ppm (triplet, 1H); 7.55
ppm (triplet, 1H); 7.72 ppm (doublet, 1H);7.90 ppm (doublet, 1H); 8.02 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.68 ppm (multiplet, 1H) [Example 17]
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid

According to the procedure for the preparation of methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate (Example 14), 2- (1H-indazol-3-yl) -3H-benzimidazole -4-carboxylic acid may be produced.
2- (1H-indazol-3-yl) obtained in the form of a beige powder starting from 237 mg of 1H-indazole-3-carboxaldehyde and 305.5 mg of 2,3-diaminobenzoic acid hydrochloride in 10 ml of nitrobenzene Characteristics of 20.5 mg of -3H-benzimidazole-4-carboxylic acid are as follows.
¹ H NMR, DMSO d6, 400 MHz: 7.40 ppm (triplet, 1H); 7.42 ppm (triplet, 1H); 7.55
ppm (triplet, 1H); 7.72 ppm (doublet, 1H); 7.90 ppm (doublet, 1H); 8.02 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.68 ppm (multiplet, 1H)

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造の操作法に従って、５−ブロモ−２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾールを製造してよい。
ジメチルホルムアミド１５ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド６４３ｍｇ、４−ブロモ−１,２−フェニレンジアミン８１６ｍｇおよびメタ重亜硫酸ナトリウム８３６.５ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）ついでシリカ上の加圧クロマトグラフィーによる精製後、赤レンガ色粉末の形状で２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−４−カルボン酸９３９ｍｇを得る。 [Example 18]
5-Bromo-2- (1H-indazol-3-yl) -3H-benzimidazole

According to the procedure for the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 5-bromo-2- (1H-indazol-3-yl)- 3H-benzimidazole may be prepared.
Starting with 643 mg of 1H-indazole-3-carboxaldehyde, 816 mg of 4-bromo-1,2-phenylenediamine and 836.5 mg of sodium metabisulfite in 15 ml of dimethylformamide, SPE (SCX phase, washed with methanol, 2N ammonia After extraction by pressure chromatography on silica), 939 mg of 2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid is obtained in the form of a red brick powder.

水素およびパラジウムのような触媒存在下にベンジル群の脱保護化により、２−（２−ベンジル−５−エトキシ−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−４−カルボン酸から２−（５−エトキシ−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−４−カルボン酸が得られる。 [Example 19]
2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid

Deprotection of the benzyl group in the presence of a catalyst such as hydrogen and palladium yields 2- (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid to 2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid is obtained.

According to the procedure for the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 2- (2-benzyl-5-ethoxy-2H-pyrazole-3 -Yl) -1H-benzimidazole-4-carboxylic acid may be prepared.
Starting with 21.6 mg 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde and 17.7 mg 3,4-diaminobenzoic acid hydrochloride in 1 m nitrobenzene, SPE (SCX phase, washed with methanol, 2N After purification by extraction with ammoniacal methanol, 2- (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid is obtained in the form of a yellow lacquer.

2-Benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde may be prepared by the following method.
4Å molecular sieves are added to a solution of 45.7 mg (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol in 0.5 ml dichloromethane, followed by 43.1 mg pyridinium chlorochromate. After 20 hours at around 20 ° C., the reaction mixture is filtered through celite. The insoluble material formed is washed with ethyl acetate and then with dichloromethane. Wash the filtrate with water. After separating the layers by settling, the aqueous layer is re-extracted with dichloromethane. The organic layers are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The properties of 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde thus obtained in the form of a brown lacquer are as follows:
¹ H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 4.25 ppm (quartet, 2H); 5.30 ppm (singlet, 2H); 6.30 ppm (singlet, 1H); 7.25-7.40 ppm (multiplet, 5H); 9.72
ppm (singlet, 1H)

(2-Benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol may be prepared by the following method.
11.1 mg of lithium aluminum hydride is added to a solution of 76 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate in 0.75 ml of tetrahydrofuran and cooled to about 0 ° C. with an ice bath. After 3 hours at about 0 ° C., 22.2 mg of lithium aluminum hydride is added and the reaction intermediate is returned to about 20 ° C. After 30 minutes at about 20 ° C., 10 ml of ice-cold water is added and the reaction mixture is then filtered through celite. After separating the layers by settling, the aqueous layer is extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate and concentrated under reduced pressure. The properties of 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol thus obtained in the form of a brown lacquer are as follows:
¹ H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 4.15 ppm (quartet, 2H); 4.30 ppm (doublet, 2H); 5.00 ppm (triplet, 1H); 5.08 ppm (singlet, 2H) ; 5.70 ppm (singlet, 1H); 7.20-7.40 ppm (multiplet, 5H)

Methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate may be prepared by the following method.
5 mg sodium iodide, 36 μl bromoethane and 70 mg potassium carbonate are added at around 20 ° C. to a solution of 100 mg methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate in 1 ml acetone. The reaction mixture is refluxed for 9 hours, cooled to about 20 ° C. and filtered. The filtrate is concentrated under reduced pressure. The properties of methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate thus obtained in solid form are as follows:
¹ H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 3.50 ppm (singlet, 3H); 4.22 ppm (quartet, 2H); 5.22 ppm (singlet, 2H); 6.28 ppm (singlet, 1H) ; 7.20-7.40 ppm (multiplet, 5H)

Methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate may be prepared by the following method.
1.72 ml of dimethyl acetylenedicarboxylate is added at about 20 ° C. to a solution of 2.73 g of benzylhydrazine dihydrochloride in 45 ml of glacial acetic acid. The reaction mixture is refluxed for 3 hours, cooled to about 20 ° C., and then concentrated under reduced pressure. The properties of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate collected in the form of a white solid after filtering off the insoluble material formed are as follows.
¹ H NMR (DMSO d6, 400 MHz): 3.76 ppm (singlet, 3H); 5.19 ppm (singlet, 2H); 5.85 ppm (singlet, 1H); 7.25-7.45 ppm (multiplet, 5H); 11.69 ppm (multiplet, 1H)

  The filtrate is purified by flash chromatography on 400 g of 20-45 μm silica (applying a 25/75 ethyl acetate / cyclohexane mixture; eluent: 25/75 then 40/60 ethyl acetate / cyclohexane) and added in the form of a white powder. Of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate.

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、５,６−ジメチル−２−（５−メチル−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール０.５ｍｌおよびジメチルホルムアミド１.５ｍｌ中の５−メチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド５３.３ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン６５.９ｍｇ、およびメタ重亜硫酸ナトリウム９２ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついでシリカ上の加圧クロマトグラフィーに付した後、白色粉末の形状で５,６−ジメチル−２−（５−メチル−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール２０.８ｍｇを得る。
メチル３−インダゾールカルボキシレートを出発物質とし、１Ｈ−インダゾール−３−カルボキシアルデヒドの製造法に記載された操作法に従って、市販のエチル５−メチル−２Ｈ−ピラゾール−３−カルボキシレートから５−メチル−２Ｈ−ピラゾール−３−カルボキシアルデヒドを製造してよい。 [Example 20]
5,6-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 5,6-dimethyl-2- (5-methyl) -2H-pyrazol-3-yl) -1H-benzimidazole may be prepared.
5-methyl-2H-pyrazole-3-carboxaldehyde 53.3 mg, 4,5-dimethyl-1,2-phenylenediamine 65.9 mg, and sodium metabisulfite 92 mg in 0.5 ml ethanol and 1.5 ml dimethylformamide Was purified by SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol) and then subjected to pressure chromatography on silica, followed by 5,6-dimethyl-2- 20.8 mg of (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole are obtained.
Starting from methyl 3-indazolecarboxylate as the starting material and following the procedure described in the preparation of 1H-indazole-3-carboxaldehyde, commercially available ethyl 5-methyl-2H-pyrazole-3-carboxylate to 5-methyl- 2H-pyrazole-3-carboxaldehyde may be prepared.

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、５,６−ジメチル−２−（５−チオフェン−２−イル−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール０.２ｍｌおよびジメチルホルムアミド０.６ｍｌ中の５−チオフェン−２−イル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１６.２ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン１２.４ｍｇ、およびメタ重亜硫酸ナトリウム１７.３ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついでシリカ上の加圧クロマトグラフィーおよびＬＣ−ＭＳによる精製後、白色粉末の形状で５,６−ジメチル−２−（５−メチル−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを得る。
メチル３−インダゾールカルボキシレートを出発物質とし、１Ｈ−インダゾール−３−カルボキシアルデヒドの製造法に記載された操作法に従って、市販のエチル５−チオフェン−２−イル−２Ｈ−ピラゾール−３−カルボキシレートから５−チオフェン−２−イル−２Ｈ−ピラゾール−３−カルボキシアルデヒドを製造してよい。 [Example 21]
5,6-Dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 5,6-dimethyl-2- (5-thiophene) -2-yl-2H-pyrazol-3-yl) -1H-benzimidazole may be prepared.
16.2 mg of 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde in 0.2 ml of ethanol and 0.6 ml of dimethylformamide, 12.4 mg of 4,5-dimethyl-1,2-phenylenediamine, and meta Starting from 17.3 mg sodium bisulfite, purified by SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol), then purified by pressure chromatography on silica and LC-MS, then in the form of a white powder To give 5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole.
From commercially available ethyl 5-thiophen-2-yl-2H-pyrazole-3-carboxylate according to the procedure described in the preparation of 1H-indazole-3-carboxaldehyde starting from methyl 3-indazolecarboxylate 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde may be prepared.

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、２−（４−ブロモ−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール１ｍｌおよびジメチルホルムアミド２ｍｌ中の市販の４−ブロモ−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン７７.８ｍｇ、およびメタ重亜硫酸ナトリウム１０８.６ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついでシリカ上の加圧クロマトグラフィー後、黄色泡状物の形状で２−（４−ブロモ−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾール１４３.２ｍｇを得る。 [Example 22]
2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 2- (4-bromo-2H-pyrazole-3 -Yl) -5,6-dimethyl-1H-benzimidazole may be prepared.
Starting with 100 mg of commercially available 4-bromo-2H-pyrazole-3-carboxaldehyde in 7 ml of ethanol and 2 ml of dimethylformamide, 77.8 mg of 4,5-dimethyl-1,2-phenylenediamine, and 108.6 mg of sodium metabisulfite After purification by SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol), followed by pressure chromatography on silica, 2- (4-bromo-2H-pyrazole- 143.2 mg of 3-yl) -5,6-dimethyl-1H-benzimidazole are obtained.

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン１１０ｍｇ、およびメタ重亜硫酸ナトリウム１５３ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついで逆相ＨＰＬＣ（５ｍｍ Ｃ１８相、容積１００×２５ｍｍ、流量２０ｍｌ／分、アセトニトリル／０.０７％ＴＦＡ〜水／０.０７％ＴＦＡ５〜９５から９５〜５（ｖ／ｖ）勾配溶離）およびＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による脱塩化後、ベージュ色粉末の形状で得られる２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾール８２ｍｇの特性は以下の通り。
¹H NMR (DMSO d6, 300 MHz): 1.26 (t, J = 7 Hz: 3H); 2.31 (s: 6H); 2.70 (broad q, J = 7 Hz: 2H); 6.60 (broad s: 1H); 7.22 (mult: 1H); 7.36 (mult: 1H); 12.37 (mult: 1H); 12.92 (mult: 1H) [Example 23]
2- (5-Ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 2- (5-ethyl-2H-pyrazole-3 -Yl) -5,6-dimethyl-1H-benzimidazole may be prepared.
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde in 110 ml of ethanol and 3 ml of dimethylformamide, 110 mg of 4,5-dimethyl-1,2-phenylenediamine and 153 mg of sodium metabisulfite as starting materials, SPE (SCX Phase, washed with methanol, extracted with 2N ammoniacal methanol), followed by reverse phase HPLC (5 mm C18 phase, volume 100 × 25 mm, flow rate 20 ml / min, acetonitrile / 0.07% TFA to water / 0.07% TFA5 2- (5-ethyl) obtained in the form of a beige powder after dechlorination by ~ 95 to 95-5 (v / v) gradient elution) and SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol). -2H-pyrazol-3-yl) -5,6-dimethyl-1H Characteristics are as follows benzimidazole 82 mg.
¹ H NMR (DMSO d6, 300 MHz): 1.26 (t, J = 7 Hz: 3H); 2.31 (s: 6H); 2.70 (broad q, J = 7 Hz: 2H); 6.60 (broad s: 1H) 7.22 (mult: 1H); 7.36 (mult: 1H); 12.37 (mult: 1H); 12.92 (mult: 1H)

Starting from methyl 3-indazolecarboxylate and following the procedure described in the preparation of 1H-indazole-3-carboxaldehyde, ethyl 5-ethyl-2H-pyrazole-3-carboxylate to 5-ethyl-2H- Pyrazole-3-carboxaldehyde may be prepared.
Ethyl 5-ethyl-2H-pyrazole-3-carboxylate may be prepared according to the general procedure referenced below: Kunio Seki et al., Chem. Pharm. Bull., 32 (4), 1568-1577 ( 1984).

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４,５−エチレンジオキシ−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、３,４−エチレンジオキシ−１,２−フェニレンジアミン１３４ｍｇ、およびメタ重亜硫酸ナトリウム１５３ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついで逆相ＨＰＬＣ（５ｍｍ、Ｃ１８相、容積１００×２５ｍｍ、流量２０ｍｌ／分、アセトニトリル／０.０７％ＴＦＡ〜水／０.０７％ＴＦＡ５〜９５から９５〜５（ｖ／ｖ）勾配溶離）およびＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による脱塩化後、茶色ラッカーの形状で得られる２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４,５−エチレンジオキシ−１Ｈ−ベンゾイミダゾール６０ｍｇの特性は以下の通り。
¹H NMR (DMSO d6, 300 MHz): 1.27 (t, J = 7 Hz: 3H); 2.70 (broad q, J = 7 Hz: 2H); 4.20〜4.45 (mt: 4H); 6.61 (broad s: 1H); 6.72 (d, J = 8 Hz: 1H); 6.88 (broad d, J=8 Hz: 1H); 12.50 (mult: 1H); 12.94 (mult: 1H) [Example 24]
2- (5-Ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 2- (5-ethyl-2H-pyrazole-3 -Yl) -4,5-ethylenedioxy-1H-benzimidazole may be prepared.
Starting from 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde in 134 ml of ethanol and 3 ml of dimethylformamide, 134 mg of 3,4-ethylenedioxy-1,2-phenylenediamine and 153 mg of sodium metabisulfite were used as starting materials. Purification by (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by reverse phase HPLC (5 mm, C18 phase, volume 100 × 25 mm, flow rate 20 ml / min, acetonitrile / 0.07% TFA to water / 0.00 2- (5 obtained in the form of a brown lacquer after dechlorination with 07% TFA 5 to 95 to 95 to 5 (v / v) gradient elution) and SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol) -Ethyl-2H-pyrazol-3-yl) -4,5-ethylene The characteristics of 60 mg of dioxy-1H-benzimidazole are as follows.
¹ H NMR (DMSO d6, 300 MHz): 1.27 (t, J = 7 Hz: 3H); 2.70 (broad q, J = 7 Hz: 2H); 4.20-4.45 (mt: 4H); 6.61 (broad s: 6.72 (d, J = 8 Hz: 1H); 6.88 (broad d, J = 8 Hz: 1H); 12.50 (mult: 1H); 12.94 (mult: 1H)

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−メトキシ−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、４−メトキシ−１,２−フェニレンジアミン１３８ｍｇ、およびメタ重亜硫酸ナトリウム１５３ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついで逆相ＨＰＬＣ（５ｍｍ Ｃ１８相、容積１００×２５ｍｍ、流量２０ｍｌ／分、勾配溶離：アセ
トニトリル／０.０７％ＴＦＡ〜水／０.０７％ＴＦＡ５〜９５から９５〜５（ｖ／ｖ））およびＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による脱塩化後、茶色ラッカーの形状で得られる２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−メトキシ−１Ｈ−ベンゾイミダゾール６１ｍｇの特性は以下の通り。
¹H NMR (DMSO d6 数滴のCD₃COODを添加, 300 MHz): 1.26 (t, J = 7 Hz: 3H); 2.70 (q, J = 7 Hz: 2H); 3.79 (s: 3H); 6.61 (s: 1H); 6.81 (dd, J= 8.5 および 2.5 Hz: 1H); 7.03 (broad s: 1H); 7.42 (d, J = 8.5 Hz: 1H) [Example 25]
2- (5-Ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 2- (5-ethyl-2H-pyrazole-3 -Yl) -5-methoxy-1H-benzimidazole may be prepared.
Starting with 100 mg 5-ethyl-2H-pyrazole-3-carboxaldehyde, 138 mg 4-methoxy-1,2-phenylenediamine and 153 mg sodium metabisulfite in 1 ml ethanol and 3 ml dimethylformamide, SPE (SCX phase, Purification by washing with methanol, extraction with 2N ammoniacal methanol) followed by reverse phase HPLC (5 mm C18 phase, volume 100 × 25 mm, flow rate 20 ml / min, gradient elution: acetonitrile / 0.07% TFA to water / 0.07% 2- (5-ethyl-2H) obtained in the form of a brown lacquer after dechlorination with TFA 5 to 95 to 95-5 (v / v)) and SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol) -Pyrazol-3-yl) -5-methoxy-1H-ben Characteristics of imidazole 61mg are as follows.
¹ H NMR (DMSO d6 with a few drops of CD ₃ COOD, 300 MHz): 1.26 (t, J = 7 Hz: 3H); 2.70 (q, J = 7 Hz: 2H); 3.79 (s: 3H); 6.61 (s: 1H); 6.81 (dd, J = 8.5 and 2.5 Hz: 1H); 7.03 (broad s: 1H); 7.42 (d, J = 8.5 Hz: 1H)

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４−ヒドロキシ−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、２,３−ジアミノフェノール１００ｍｇ、およびメタ重亜硫酸ナトリウム１５３ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついで逆相ＨＰＬＣ（５ｍｍ、Ｃ１８相、容積１００×２５ｍｍ、流量２０ｍｌ／分、勾配溶離：アセトニトリル／０.０７％ＴＦＡ〜水／０.０７％ＴＦＡ５〜９５から９５〜５（ｖ／ｖ））およびＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による脱塩化後、茶色ラッカーの形状で得られる２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４−ヒドロキシ−１Ｈ−ベンゾイミダゾール１６ｍｇの特性は以下の通り。
¹H NMR (DMSO d6 数滴のCD₃COODを添加, 300 MHz): 1.26 (t, J= 7 Hz: 3H); 2.70 (q,
J = 7 Hz: 2H); 6.55 (t, J = 4.5 Hz: 1H); 6.66 (s: 1H); 6.96 (broad d, J = 4.5 Hz: 2H) [Example 26]
2- (5-Ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 2- (5-ethyl-2H-pyrazole-3 -Yl) -4-hydroxy-1H-benzimidazole may be prepared.
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde in 100 ml of ethanol and 3 ml of dimethylformamide, 100 mg of 2,3-diaminophenol and 153 mg of sodium metabisulfite, SPE (SCX phase, washed with methanol, Purification by 2N ammoniacal methanol) followed by reverse phase HPLC (5 mm, C18 phase, volume 100 × 25 mm, flow rate 20 ml / min, gradient elution: acetonitrile / 0.07% TFA to water / 0.07% TFA 5 to 95 2- (5-ethyl-2H-pyrazole-) obtained in the form of a brown lacquer after dechlorination by SPE (SCX phase, washed with methanol, washed with methanol, extracted with 2N ammoniacal methanol) 3-yl) -4-hydroxy-1H-benzimidazo Characteristics are as follows Le 16 mg.
¹ H NMR (DMSO d6 with a few drops of CD ₃ COOD, 300 MHz): 1.26 (t, J = 7 Hz: 3H); 2.70 (q,
J = 7 Hz: 2H); 6.55 (t, J = 4.5 Hz: 1H); 6.66 (s: 1H); 6.96 (broad d, J = 4.5 Hz: 2H)

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造法に記載された操作法に従って、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−ブロモ−１Ｈ−ベンゾイミダゾールを製造してよい。
エタノール１ｍｌおよびジメチルホルムアミド２ｍｌ中の５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド２０ｍｇ、４−ブロモ−１,２−フェニレンジアミン３０ｍｇ、およびメタ重亜硫酸ナトリウム３０ｍｇを出発物質とし、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による精製、ついで逆相ＨＰＬＣ（
５ｍｍ Ｃ１８相、容積１００×２５ｍｍ、流量２０ｍｌ／分、勾配溶離：アセトニトリル／０.０７％ＴＦＡ〜水／０.０７％ＴＦＡ５〜９５から９５〜５（ｖ／ｖ））およびＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノールで抽出）による脱塩化後、黄色粉末の形状で得られる２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−ブロモ−１Ｈ−ベンゾイミダゾール２１ｍｇの特性は以下の通り。
¹H NMR (DMSO d6, 300 MHz): 1.28 (t, J = 7 Hz: 3H); 2.71 (q, J = 7 Hz: 2H); 6.67 (s: 1H); 7.30 (dd, J = 8.5 および 2.5 Hz: 1H); 7.49 (mt: 1H); 7.712 (broad s: 1H); 12.5〜13.5 (broad mult: 2H) [Example 27]
2- (5-Ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole

According to the procedure described in the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15), 2- (5-ethyl-2H-pyrazole-3 -Yl) -5-bromo-1H-benzimidazole may be prepared.
Starting from 20 mg 5-ethyl-2H-pyrazole-3-carboxaldehyde, 30 mg 4-bromo-1,2-phenylenediamine and 30 mg sodium metabisulfite in 1 ml ethanol and 2 ml dimethylformamide, SPE (SCX phase, Purification by washing with methanol and extraction with 2N ammoniacal methanol) followed by reverse phase HPLC (
5 mm C18 phase, volume 100 × 25 mm, flow rate 20 ml / min, gradient elution: acetonitrile / 0.07% TFA to water / 0.07% TFA 5 to 95-5 (v / v)) and SPE (SCX phase, Characteristics of 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole 21 mg obtained in the form of a yellow powder after dechlorination by washing with methanol and extraction with 2N ammoniacal methanol) Is as follows.
¹ H NMR (DMSO d6, 300 MHz): 1.28 (t, J = 7 Hz: 3H); 2.71 (q, J = 7 Hz: 2H); 6.67 (s: 1H); 7.30 (dd, J = 8.5 and 2.5 Hz: 1H); 7.49 (mt: 1H); 7.712 (broad s: 1H); 12.5 to 13.5 (broad mult: 2H)

以下の表３に表す本出願の実施例９７から１４５の生成物は、以下に示す操作法に従い、上記スキームに従って製造してよい。 The product of formula (I) of the present application may also be prepared according to the following procedure.

The products of Examples 97 to 145 of this application shown in Table 3 below may be prepared according to the above scheme according to the procedure shown below.

[Example 97]
3- (6-Phenyl-1H-benzimidazol-2-yl) -2H-indazole Step 1: Synthesis of 3- (6-Bromo-1H-benzimidazol-2-yl) -2H-indazole (Example 18) Another manufacturing method)
4.25 g of 1-hydroxybenzotriazole and 4.3 g of calcium sulfate are added at ambient temperature to a solution of 4.6 g of indazole-3-carboxylic acid in 50 ml of dimethylformamide. The reaction mixture is cooled to about 0 ° C. and then 4.9 ml of N, N-diisopropylcarbodiimide is slowly added. After stirring for 2 hours at ambient temperature, 5.9 g of 4-bromo-o-phenylenediamine are added. After stirring for 60 minutes at ambient temperature, the reaction mixture is concentrated to dryness under reduced pressure. The resulting brown oil is dissolved in 50 ml of water and extracted three times with 50 ml of ethyl acetate. The organic layers are combined, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. 18 g of the brown oil thus obtained are dissolved in 100 ml of 20% hydrochloric acid solution in ethanol. The mixture is refluxed for 4 hours and then concentrated to dryness. The resulting brown oil is dissolved in 20 ml of water and an aqueous ammonia solution is injected until a pH of the mixture of about 8-9 is obtained. The aqueous layer is then extracted three times with 30 ml of ethyl acetate, the organic layers are combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by pressure chromatography on silica (eluting with water / acetonitrile), 5 g of 3- (6-bromo-1H-benzimidazol-2-yl) -2H-indazole are thus obtained.
IR spectrum (KBr): characteristic band 1621, 1570, 1441, 1344, 1324, 1273, 1239, 1135
, 1042, 914, 804, 774 and 746 cm ^-1

Step 2: Synthesis of 1- [2- (1-acetyl-1H-indazol-3-yl) -5-bromobenzoimidazol-1-yl] ethanone 3- (6-Bromo-1H-benzimidazol-2-yl) ) -2H-indazole 5 g is added to a solution of 40 ml acetic anhydride and 40 ml pyridine. The mixture is refluxed for 4 hours and then allowed to return to ambient temperature before being concentrated to dryness. The resulting brown solid is dissolved in 50 ml of ethyl acetate and washed with 50 ml of saturated sodium bicarbonate solution until pH 7-8 is obtained. The organic layer is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The resulting light brown solid is triturated in 20 ml of ethyl acetate and then filtered off on a sintered glass funnel. In this way, 1.5 g of the compound 1- [2- (1-acetyl-1H-indazol-3-yl) -5-bromobenzoimidazol-1-yl] ethanone is obtained. The filtrate obtained above is subjected to pressure chromatography on silica (cyclohexane / ethyl acetate) to give a second yield, ie 1.3 g of the same compound.
Compound properties:
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ in ppm).
A mixture of two regioisomers in a 50/50 ratio is observed.
2.61 and 2.62 (2 s, 3H in all); 2.80 (s, 3H); 7.62 (broad t, J = 7.5 Hz, 1H); 7.68 and 7.71 (2 dd, J = 9 and 2 Hz, 1H in all) 7.80 (ddd, J = 8.5, 7.5 and 0.5 Hz, 1H); 7.91 and 8.01 (2 d, J = 9 Hz, 1H); 8.18 and 8.20 (2 d, J = 2 Hz, 1H in all); 8.27 And 8.30 (2 d, J = 7.5 Hz, 1H in all); 8.46 (d, J = 8.5Hz, 1H)
IR spectrum (KBr): Characteristic bands 1727, 1610, 1450, 1405, 1374, 1326, 1290, 1198, 1176, 964 and 760 cm ^-1

Step 3: Synthesis of 3- (6-phenyl-1H-benzimidazol-2-yl) -2H-indazole Sodium carbonate 40 mg, dihydrogen dichlorobis (di-t-butylphosphonite-κP) paradate (2-) (POPd [0]) 7 mg and phenylboronic acid 46 mg under argon atmosphere in 1- [2- (1-acetyl-1H-indazol-3-yl) -5-bromobenzimidazol-1-yl] ethanone in 800 μl of anhydrous tetrahydrofuran Add to 50 mg of solution. The reaction mixture is refluxed for 3 hours and then cooled to ambient temperature. The mixture is then diluted with 3 ml of ethyl acetate and then washed twice with 2 ml of water. The organic layer is dried over magnesium sulfate and then concentrated to dryness under reduced pressure. 48 mg of the obtained brown solid is dissolved in 500 μl of tetrahydrofuran, and 500 μl of diethylamine is added thereto. The reaction mixture is heated at 60 ° C. for 4 hours and then returned to ambient temperature. The mixture was then concentrated to dryness and the resulting brown solid was then purified by LC-MS to yield 12.5 mg of 3- (6-phenyl-1H-benzoimidazol-2-yl) -2H-indazole (6). To do. Analytical retention time 3.10, MS 311 [M + H] ⁺ .

実施例９８から１４５の合成は、フェニルボロン酸を化学式ＲＢ（ＯＨ）₂のボロン酸で置き換える以外は、３−（６−フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−２Ｈ−インダゾール（実施例９７）と同様の方法で実施される。 The invention, in particular the products of formula (I) of Examples 98 to 145 may be prepared according to the following procedure.

The synthesis of Examples 98 to 145 was performed using 3- (6-phenyl-1H-benzoimidazol-2-yl) -2H-indazole (Examples) except that phenylboronic acid was replaced with boronic acid of formula RB (OH) _2. 97).

  The products of Formula (I) of this application that constitute Examples 28 to 96 and 146 to 180 of this application are listed in Table 3. These products may in particular be prepared according to the above scheme described above in Example 1.

上記のスキームにおいて、Ｚ３およびＺ４は上記で定義したＲ２およびＲ３から選ばれ、Ｚ１および−ＯＺ２はＲ１がピラゾール基を表わすものであるＸ１、Ｘ２またはＸ３から選ばれる。 The product of formula (I) of the present invention can also be prepared by the following method:

In the above scheme, Z3 and Z4 are selected from R2 and R3 as defined above, and Z1 and -OZ2 are selected from X1, X2 or X3 wherein R1 represents a pyrazole group.

When Z1, Z3 and Z4 represent hydrogen atoms, the products of the formula (I) according to the invention can in particular be prepared by the following synthetic scheme.

  The products of formula (I) of the present invention that constitute Examples 181 to 228 of the present invention are shown in Table 4 below, and these products can be prepared according to the scheme described above, but in particular the Examples The product of 181 can be manufactured by the following steps. The products of Examples 182 to 228 can be prepared similarly to the product of Example 181.

[Example 181]
2- [5- (Benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole Step 1: Cyclization to Chem Pharm. Bull., 31 (4), 1228-1234 (1983); J. Org Chem, 47 (2), 214-221 (1982).

Step 2: To 1.015 g of crude ester in 50 ml of MeOH was added 5.5 ml of 6N NaOH and the mixture was heated to reflux for 2 hours. After evaporation of most of the methanol, the medium was cooled and concentrated HCl was carefully added until pH = 2. After further evaporation to dryness, the solid was triturated three times with 30 ml of a 1/1 mixture of MeOH / AcOEt and the filtrate was evaporated to give 0.875 g of a light brown solid after drying.
LCMS [gradient acetonitrile / water 0.1% HCOOH; Xterra RP 182.1 × 50 mm] retention time 0.53 min, MH ⁺ = 129.95% purity

Step 3: 0.701 g of 1,2-phenylenediamine and 0.87 g of acid from Step 2 were added to 3.5 g of PPA (polyphosphoric acid). The mixture was heated to 150 ° C. for 1.5 hours. After cooling, concentrated NH ₄ OH was added until pH = 3. The green precipitate was filtered, washed with water and then with acetone. Drying overnight at 50 ° C. under vacuum left 2.1 g of a solid containing approximately 50% mineral salt.
MS: EIM ⁺ = 200

Step 4: Example 181: To 80 mg of the solid in Step 3 in 4 ml of NMP, 137 mg of cesium carbonate and 72 mg of benzyl bromide were added. After 2 hours the mixture was hydrolyzed with saturated KH ₂ PO ₄ and extracted with AcOEt. After evaporation, the crude mixture was subjected to preparative LC-MS to give 8 mg of pure compound.
LC-MS [gradient acetonitrile / water 0.1% HCOOH; Xterra RP 182.1 × 50 mm] retention time 3.17 min, MH ⁺ = 291.97% purity

  Similarly, step 4 was performed in DMF or NMP using benzoyl bromide or allyl bromide, 15α-bromocarbonyl compound, and 15 acid chloride to give the expected compounds in Table 4. Examples 181 to 228 of the present invention are shown in Table 4.

[Example 229]
Pharmaceutical composition Tablets of the following formulation were prepared.
Product of Example 1: 0.2 g
Final tablet-containing excipient: 1 g
(Excipient details: lactose, talc, starch, magnesium stearate).
Example 1 is an example of a pharmaceutical preparation, which can be made as desired using other products of the examples of the present invention.

５,６−ジメチル−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［９０ｍｇ、参考実施例１（ａ）］、塩酸（２ｍＬ、４Ｎ）およびエタノール（４ｍＬ）の混合物を還流温度で１６時間加熱し、その後室温に冷却した。飽和重炭酸ナトリウム溶液を添加して反応混合物のｐＨを７に調整した。得られた固体を濾過し、その後水で洗浄し、その後真空オーブン中に乾燥し、５,６−ジメチル−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（３８ｍｇ）を得た。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝２.２２分；２５９（Ｍ＋Ｈ)⁺。 [Example 230]
(A) 5,6-Dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole

5,6-Dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [90 mg, Reference Example 1 (a) ], A mixture of hydrochloric acid (2 mL, 4N) and ethanol (4 mL) was heated at reflux for 16 hours and then cooled to room temperature. Saturated sodium bicarbonate solution was added to adjust the pH of the reaction mixture to 7. The resulting solid was filtered, then washed with water, then dried in a vacuum oven, and 5,6-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole ( 38 mg) was obtained. LC-MS (Method A): R _T = 2.22 min; 259 (M + H) ⁺ .

６−クロロ−５−メチル−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｂ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、６−クロロ−５−メチル−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。 (B) 6-chloro-5-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole

6-chloro-5-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (b) In the same manner as in Example 230 (a) above, 6-chloro-5-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole was obtained. Manufactured.

６−クロロ−２−（５−エチルスルファニル−１Ｈ−ピラゾール−３−イル）−５−メチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｃ）］を使用する以外は、上記実施例２３０（ａ）と同様の操作法に従って、６−クロロ−２−（５−エチルスルファニル−１Ｈ−ピラゾール−３−イル）−５−メチル−１Ｈ−ベンゾイミダゾールを製造した。 (C) 6-chloro-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole

6-chloro-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (c) In the same manner as in Example 230 (a) above, 6-chloro-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole was used. Manufactured.

２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−５−トリフルオロメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｄ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−５−トリフルオロメチル−１Ｈ−ベンゾイミダゾールを製造した。 (D) 2- (5-Methylsulfanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole

2- (5-Methylsulfanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (d)] 2- (5-Methylsulfanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole was produced according to the same method as in Example 230 (a) except that it was used.

２−（５−シクロプロピルメチルスルファニル−１Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｅ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、２−（５−シクロプロピルメチルスルファニル−１Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾールを製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝２.４７分；２９９（Ｍ＋Ｈ)⁺。 (E) 2- (5-Cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

2- (5-Cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (e) In the same manner as in Example 230 (a) above, 2- (5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole was obtained. Manufactured. LC-MS (Method A): R _T = 2.47 min; 299 (M + H) ⁺ .

５,６−ジメチル−２−（５−エチルスルファニル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｆ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、２−（５−エチルスルファニル−１Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾールを製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝２.３２分；２７３（Ｍ＋Ｈ)⁺。 (F) 2- (5-Ethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

5,6-Dimethyl-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (f)] 2- (5-Ethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole was produced according to the same method as in Example 230 (a) except that it was used. LC-MS (Method A): R _T = 2.32 min; 273 (M + H) ⁺ .

５,６−ジメチル−２−［５−（ピリジン−３−イル）メチルスルファニル−１Ｈ−ピラゾール−３−イル］−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｇ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、無色の固体として５,６−ジメチル−２−［５−（ピリジン−３−イルメチルスルファニル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾールを製造した。 (G) 5,6-Dimethyl-2- [5- (pyridin-3-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole

5,6-Dimethyl-2- [5- (pyridin-3-yl) methylsulfanyl-1H-pyrazol-3-yl] -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [reference implementation Except for using Example 1 (g)], 5,6-dimethyl-2- [5- (pyridin-3-ylmethylsulfanyl)-as a colorless solid according to the same procedure as in Example 230 (a) above. 1H-pyrazol-3-yl] -1H-benzimidazole was prepared.

５−フルオロ−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｈ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、５−フルオロ−２−［５−メチルスルファニル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾールを製造した。ＭＳ：２４９（Ｍ＋Ｈ)⁺。 (H) 5-fluoro-2- [5-methylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole

5-Fluoro-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (h)] is used. Except for the above, 5-fluoro-2- [5-methylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole was produced in the same manner as in Example 230 (a) above. MS: 249 (M + H) ^<+> .

５,６−ジメチル−２−（５−フェネチルスルファニル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｉ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、５,６−ジメチル−２−（５−フェネチルスルファニル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。 (I) 5,6-Dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole

5,6-Dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (i)] Except for use, 5,6-dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole was produced according to the same method as in Example 230 (a) above.

４−メチル−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｊ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、４−メチル−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。ＭＳ：２４５（Ｍ＋Ｈ)⁺。 (J) 4-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole

4-Methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (j)] is used. Except that, 4-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole was produced in the same manner as in Example 230 (a) above. MS: 245 (M + H) ^<+> .

２−（５−ベンジルスルファニル−１Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｋ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、５,６−ジメチル−２−（５−ベンジルスルファニル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。 (K) 5,6-Dimethyl-2- (5-benzylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole

2- (5-Benzylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (k)] Except for use, 5,6-dimethyl-2- (5-benzylsulfanyl-1H-pyrazol-3-yl) -1H-benzimidazole was produced in the same manner as in Example 230 (a) above.

６−クロロ−５−メチル−２−（５−モルホリン−４−イル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｌ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、６−クロロ−５−メチル−２−（５−モルホリン−４−イル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。 (L) 6-chloro-5-methyl-2- (5-morpholin-4-yl-1H-pyrazol-3-yl) -1H-benzimidazole

6-chloro-5-methyl-2- (5-morpholin-4-yl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 6-chloro-5-methyl-2- (5-morpholin-4-yl-1H-pyrazol-3-yl) according to a method similar to that of Example 230 (a) except that (l)] is used. -1H-benzimidazole was prepared.

５,６−ジメチル−２−［５−（チオフェン−２−イルメチルスルファニル）−１Ｈ−ピラゾール−３−イル］−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［参考実施例１（ｍ）］を使用する以外は、上記実施例２３０（ａ）と同様の方法に従って、５,６−ジメチル−２−［５−（チオフェン−２−イルメチルスルファニル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾールを製造した。 (M) 5,6-Dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1H-benzimidazole

5,6-Dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1H-pyrazol-3-yl]-(2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 1 (M)] According to the same method as in Example 230 (a) above, 5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1H-pyrazole-3- IL] -1H-benzimidazole was prepared.

エタノール（６ｍＬ）中の３,３−ビス−エチルスルファニル−１−［５−メトキシ−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−プロペノン［〜０.７８ミリモル、参考実施例２（ｊ）］およびヒドラジン水和物（５００μＬ）の混合物を還流温度で１８時間加熱し、その後蒸発させた。残存物をFlashmaster上に精製し、得られた（２−（５−エチルスルファニル−１Ｈ−ピラゾール−３−イル）−５−メトキシ−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾールをエタノール（６ｍＬ）および塩酸（３ｍＬ）で処理した。この混合物を還流温度で１８時間加熱し、その後蒸発させて（２−（５−エチルスルファニル−１Ｈ−ピラゾール−３−イル）−５−メトキシ−１Ｈ−ベンゾイミダゾール塩酸塩を得た。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝２.１７分；２７５（Ｍ＋Ｈ)⁺。 [Example 231]
(2- (5-Ethylsulfanyl-1H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole hydrochloride

3,3-bis-ethylsulfanyl-1- [5-methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone [˜0. 0 in ethanol (6 mL). A mixture of 78 mmol, Reference Example 2 (j)] and hydrazine hydrate (500 μL) was heated at reflux for 18 hours and then evaporated. The residue was purified on Flashmaster and the resulting (2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5-methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzo The imidazole was treated with ethanol (6 mL) and hydrochloric acid (3 mL) The mixture was heated at reflux for 18 hours and then evaporated to give (2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -5- Methoxy-1H-benzimidazole hydrochloride was obtained, LC-MS (Method A): R _T = 2.17 min; 275 (M + H) ⁺ .

エタノール（６ｍＬ）中の２−（ビス−メチルスルファニル−メチレン）−１−（５−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−ペンタン−１−オン［〜０.４９ミリモル、参考実施例２（ｌ）］およびヒドラジン水和物（２００μＬ）の混合物を還流温度で２日間加熱し、その後蒸発させた。その後、混合物を塩酸（４ｍＬ、４Ｎ）で処理し、還流温度でさらに２４時間加熱を続行した。反応混合物を冷却し、その後水酸化ナトリウム溶液（４Ｎ）を添加して中和し、その後ジクロロメタンで抽出した。抽出物を蒸発させて５−メチル−２−（５−メチルスルファニル−４−プロピル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを得た。ＭＳ：２８７（Ｍ＋Ｈ)⁺。 [Example 232]
(A) 5-methyl-2- (5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl) -1H-benzimidazole

2- (Bis-methylsulfanyl-methylene) -1- (5-methyl-1H-benzimidazol-2-yl) -pentan-1-one [˜0.49 mmol, Reference Example 2 in ethanol (6 mL) (L)] and hydrazine hydrate (200 μL) were heated at reflux temperature for 2 days and then evaporated. The mixture was then treated with hydrochloric acid (4 mL, 4N) and heating was continued for an additional 24 hours at reflux temperature. The reaction mixture was cooled and then neutralized by adding sodium hydroxide solution (4N) and then extracted with dichloromethane. The extract was evaporated to give 5-methyl-2- (5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl) -1H-benzimidazole. MS: 287 (M + H) ^<+> .

２−［ビス−（４−メトキシ−ベンジルスルファニル）−メチレン］−１−（５−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−ペンタン−１−オン［参考実施例２（ｍ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、２−（５−（４−メトキシ−ベンジルスルファニル）−４−プロピル−１Ｈ−ピラゾール−３−イル）−５−メチル−１Ｈ−ベンゾイミダゾールを製造した。ＭＳ：３９３（Ｍ＋Ｈ)⁺。 (B) 2- (5- (4-Methoxy-benzylsulfanyl) -4-propyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole

Using 2- [bis- (4-methoxy-benzylsulfanyl) -methylene] -1- (5-methyl-1H-benzoimidazol-2-yl) -pentan-1-one [Reference Example 2 (m)] Except that, 2- (5- (4-methoxy-benzylsulfanyl) -4-propyl-1H-pyrazol-3-yl) -5-methyl-1H— was prepared in the same manner as in Example 233 (a) above. Benzimidazole was prepared. MS: 393 (M + H) ^<+> .

２−（ビス−ベンジルスルファニル−メチレン）−３−メチル−１−［５−メチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−ブタン−１−オン［参考実施例（２ｎ）］を使用する以外は、上記実施例２３２（ａ）と同様の方法に従って、２−（５−ベンジルスルファニル−４−イソプロピル−１Ｈ−ピラゾール−３−イル）−５−メチル−１Ｈ−ベンゾイミダゾールを製造した。ＭＳ：３６３（Ｍ＋Ｈ)⁺。 (C) 2- (5-Benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole

2- (Bis-benzylsulfanyl-methylene) -3-methyl-1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -butan-1-one 2- (5-Benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl) -5- according to the same method as in Example 232 (a) except that [Reference Example (2n)] was used. Methyl-1H-benzimidazole was prepared. MS: 363 (M + H) ^<+> .

１−［５−メトキシ−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−メチル−３−（ビス−メタンスルファニル）−１−プロペノン［参考実施例２（ｒ）］を使用する以外は、上記実施例２３２（ａ）と同様の方法に従って、２−（５−メチルスルファニル−４−メチル−１Ｈ−ピラゾール−３−イル）−５−メトキシ−１Ｈ−ベンゾイミダゾールを製造した。 (D) 2- (5-Methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole

1- [5-Methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -2-methyl-3- (bis-methanesulfanyl) -1-propenone [Reference Example 2- (5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methoxy-1H according to a method similar to that of Example 232 (a) above except that 2 (r)] is used. -Benzimidazole was prepared.

１−［５−メチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−２−メチル−３−（ビス−メタンスルファニル）−１−プロペノン［参考実施例２（ｔ）］を使用する以外は、上記実施例２３２（ａ）と同様の方法に従って、２−（５−メチルスルファニル−４−メチル−１Ｈ−ピラゾール−３−イル）−５−メチル−１Ｈ−ベンゾイミダゾールを製造した。 (E) 2- (5-Methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methyl-1H-benzimidazole

1- [5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -2-methyl-3- (bis-methanesulfanyl) -1-propenone [Reference Example 2- (5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methyl-1H according to the same method as in Example 232 (a) except that 2 (t)] is used. -Benzimidazole was prepared.

エタノール（４０ｍＬ）中の５−クロロ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［９１ｍｇ、実施例２３９（ａ）］の溶液を窒素下にＰｄ／Ｃ（スパーテルチップ、５％）で処理した。混合物を水素下に３時間攪拌し、その後セライトを通して濾過した。濾過パッドをジクロロメタンでよく洗浄した。合わせた濾液と洗浄液を蒸発させて、３−（５−クロロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン（１１６ｍｇ）を得た。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝２分；２３４（Ｍ＋Ｈ)⁺。 [Example 233]
(A) 3- (5-Chloro-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

A solution of 5-chloro-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [91 mg, Example 239 (a)] in ethanol (40 mL) was dissolved in Pd / C ( Treated with spatula chips, 5%). The mixture was stirred under hydrogen for 3 hours and then filtered through celite. The filter pad was washed thoroughly with dichloromethane. The combined filtrate and washings were evaporated to give 3- (5-chloro-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine (116 mg). LC-MS (Method A): R _T = 2 min; 234 (M + H) ⁺ .

５,６−ジクロロ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［実施例２３９（ｂ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、３−（５,６−ジクロロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝２.３７分；２６８（Ｍ＋Ｈ)⁺。 (B) 3- (5,6-Dichloro-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Similar to Example 233 (a) above, except that 5,6-dichloro-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [Example 239 (b)] is used. According to the method, 3- (5,6-dichloro-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine was prepared. LC-MS (Method A): R _T = 2.37 min; 268 (M + H) ⁺ .

５,６−ジメチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［実施例２４９（ａ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２９分；２２８.２５（Ｍ＋Ｈ)⁺。 (C) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Similar to Example 233 (a) above, except that 5,6-dimethyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [Example 249 (a)] is used. According to the method, 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine was prepared. LC-MS (Method B): R _T = 2.29 min; 228.25 (M + H) ⁺ .

５−エチル−６−メチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［実施例２４９（ｂ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、茶色固体として３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.１４分、２４２.２０（Ｍ＋Ｈ)⁺。 (D) 3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Example 233 (a) above except that 5-ethyl-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [Example 249 (b)] was used. According to a similar method, 3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine was prepared as a brown solid. LC-MS (Method B): R _T = 2.14 min, 242.20 (M + H) ⁺ .

６−クロロ−５−メトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［０.７ｇ、実施例２４９（ｃ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、茶色泡状物として３−（６−クロロ−５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン（０.５４ｇ）を製造した。ＭＳ２６４（Ｍ＋Ｈ)⁺。 (E) 3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Example 233 above, except using 6-chloro-5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [0.7 g, Example 249 (c)]. 3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine (0.54 g) was prepared as a brown foam according to the same method as in (a). . MS 264 (M + H) ^<+> .

５−メトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［３７３ｍｇ、実施例２５７（ｆ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、暗茶色固体として３−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン（２５７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝１.２３分、２３０.２５（Ｍ＋Ｈ)⁺、２２８.２５（Ｍ−Ｈ)^-。 (F) 3- (5-Methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Similar to Example 233 (a) above except using 5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [373 mg, Example 257 (f)]. According to the method, 3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine (257 mg) was prepared as a dark brown solid. LC-MS (Method H): R _T = 1.23 min, 230.25 (M + H) ⁺ , 228.25 (M−H) ⁻ .

５−エトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［４０７ｍｇ、実施例２５２（ｃ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、暗茶色油状物として３−（５−エトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン（３７５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝１.４３分、２４４.２６（Ｍ＋Ｈ)⁺、２４２.２８（Ｍ−Ｈ)^-。 (G) 3- (5-Ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Same as Example 233 (a) above, except using 5-ethoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [407 mg, Example 252 (c)]. According to the method, 3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine (375 mg) was prepared as a dark brown oil. LC-MS (Method H): R _T = 1.43 min, 244.26 (M + H) ⁺ , 242.28 (M−H) ⁻ .

５−フルオロ−６−メチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［実施例２４９（ｄ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、茶色固体として３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン（０.５９０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.２５分、ＭＳ：２３２.２９（Ｍ＋Ｈ)⁺。 (H) 3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Example 233 (a) above except that 5-fluoro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [Example 249 (d)] was used. According to a similar method, 3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine (0.590 g) was prepared as a brown solid. LC-MS (Method J): R _T = 2.25 min, MS: 232.29 (M + H) ⁺ .

５−トリフルオロメトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［実施例２４９（ｅ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、茶色固体として３−（５−トリフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン（０.９２０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.７６分、２８４.２３（Ｍ＋Ｈ)⁺。 (I) 3- (5-trifluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Similar to Example 233 (a) above, except using 5-trifluoromethoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [Example 249 (e)]. According to the method, 3- (5-trifluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine (0.920 g) was prepared as a brown solid. LC-MS (Method J): R _T = 2.76 min, 284.23 (M + H) ⁺ .

５−トリフルオロメチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［実施例２４９（ｆ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、茶色固体として３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン（０.１５０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.００分、２６８.１６（Ｍ＋Ｈ)⁺。 (J) 3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

Similar to Example 233 (a) above, except using 5-trifluoromethyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [Example 249 (f)]. According to the method, 3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine (0.150 g) was prepared as a brown solid. LC-MS (Method B): R _T = 3.00 min, 268.16 (M + H) ⁺ .

２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸メチルエステル［実施例２４９（ｈ）］を使用する以外は、上記実施例２３３（ａ）と同様の方法に従って、オフホワイトの固体として２−（４−アミノ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸メチルエステル（１.１０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４０分、２５８.１７（Ｍ＋Ｈ)⁺。 (K) 2- (4-Amino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester

Similar to Example 233 (a) except using 2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester [Example 249 (h)]. According to the method, 2- (4-amino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester (1.10 g) was produced as an off-white solid. LC-MS (Method B): R _T = 2.40 min, 258.17 (M + H) ⁺ .

１,２−ジアミノベンゼン（１０８ｍｇ）、インダゾール−３−カルボン酸（１１８ｍｇ）およびポリリン酸（１ｍＬ）の混合物を１５０〜１６０℃で２４時間加熱した。混合物を冷却し、その後氷水（１０ｍＬ）に希釈し、その後酢酸エチル（１０ｍＬ）で処理した。固体炭酸カリウムを添加して水層を塩基化した。層を分離し、水層を酢酸エチル（１０ｍＬ）で抽出した。合わせた有機層を乾燥し、その後蒸発させた。残存物をヘプタンと酢酸エチルの混合物を溶離剤とするシリカ上のクロマトグラフィーに付し、３−（１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール（７８ｍｇ）を得た。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝１.２８分；２３５（Ｍ＋Ｈ)⁺。 [Example 234]
(A) 3- (1H-Benzimidazol-2-yl) -1H-indazole

A mixture of 1,2-diaminobenzene (108 mg), indazole-3-carboxylic acid (118 mg) and polyphosphoric acid (1 mL) was heated at 150-160 ° C. for 24 hours. The mixture was cooled and then diluted in ice water (10 mL) and then treated with ethyl acetate (10 mL). Solid potassium carbonate was added to basify the aqueous layer. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were dried and then evaporated. The residue was chromatographed on silica eluting with a mixture of heptane and ethyl acetate to give 3- (1H-benzoimidazol-2-yl) -1H-indazole (78 mg). LC-MS (Method A): R _T = 1.28 min; 235 (M + H) ⁺ .

塩酸４−メトキシ−１,２−ジアミノベンゼンを使用する以外は、上記実施例２３４（ａ）と同様の方法に従って、固体として３−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝１.２８分；２６５（Ｍ＋Ｈ)⁺。 (B) 3- (5-Methoxy-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Methoxy-1H-benzoimidazol-2-yl) -1H as a solid according to the same method as in Example 234 (a) except that 4-methoxy-1,2-diaminobenzene hydrochloride was used. -Indazole was produced. LC-MS (Method A): R _T = 1.28 min; 265 (M + H) ⁺ .

３,４−ジアミノベンゾフェノンを使用する以外は、上記実施例２３４（ａ）と同様の方法に従って、固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−フェニル−メタノンを製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝１.７３分；３３９（Ｍ＋Ｈ)⁺。 (C) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanone

[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl- as a solid according to the same method as in Example 234 (a) except that 3,4-diaminobenzophenone was used. Methanone was produced. LC-MS (Method A): R _T = 1.73 min; 339 (M + H) ⁺ .

２,３−ジアミノフェノールを使用する以外は、上記実施例２３４（ａ）と同様の方法に従って、固体として２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−４−オールを製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝１.６３分；２５１（Ｍ＋Ｈ)⁺。 (D) 2- (1H-indazol-3-yl) -3H-benzimidazol-4-ol

2- (1H-indazol-3-yl) -3H-benzimidazol-4-ol was produced as a solid according to the same method as in Example 234 (a) except that 2,3-diaminophenol was used. . LC-MS (Method A): R _T = 1.63 min; 251 (M + H) ⁺ .

２,３−ジアミノピラジン［参考実施例９］および安息香酸を使用する以外は、上記実施例２３４（ａ）と同様の方法に従って、淡茶色固体として２−フェニル−１Ｈ−イミダゾール［４,５−ｂ］ピラジンを製造した。融点２３９〜２４０℃。ＨＰＬＣ（方法Ａ１）：Ｒ_T＝１０.１８分。 (E) 2-Phenyl-1H-imidazole [4,5-b] pyrazine

According to the same method as in Example 234 (a) except that 2,3-diaminopyrazine [Reference Example 9] and benzoic acid were used, 2-phenyl-1H-imidazole [4,5- b] Pyrazine was prepared. 239-240 ° C. HPLC (Method A1): R _T = 10.18 min.

１,２−ジアミノ−４,５−ジメチルベンゼンを使用する以外は、上記実施例２３４（ａ）と同様の方法に従って、３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール（２８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝１.３４分；２６３（Ｍ＋Ｈ)⁺。 (F) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole

3- (5,6-Dimethyl-1H-benzoimidazol-2-yl)-was prepared in the same manner as in Example 234 (a) except that 1,2-diamino-4,5-dimethylbenzene was used. 1H-indazole (28 mg) was prepared. LC-MS (Method A): R _T = 1.34 min; 263 (M + H) ⁺ .

３,４−ジアミノピリジンを使用する以外は、上記実施例２３４（ａ）と同様の方法に従って、固体として２−（１Ｈ−インダゾール−３−イル）−３Ｈ−イミダゾール［４,５−ｃ］ピリジンを製造した。ＭＳ：２３６（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ａ）：Ｒ_T＝２.４８分。 (G) 2- (1H-Indazol-3-yl) -3H-imidazole [4,5-c] pyridine

2- (1H-indazol-3-yl) -3H-imidazole [4,5-c] pyridine as a solid according to a method similar to Example 234 (a) except that 3,4-diaminopyridine is used. Manufactured. MS: 236 (M + H) ^<+> . HPLC (Method A): R _T = 2.48 min.

２,３−ジアミノピリジンを使用する以外は、上記実施例２３４（ａ）と同様の方法に従って、固体として２−（１Ｈ−インダゾール−３−イル）−３Ｈ−イミダゾ［４,５−ｂ］ピリジンを製造した。ＭＳ：２３６（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ａ）：Ｒ_T＝２.４９分。 (H) 2- (1H-indazol-3-yl) -3H-imidazo [4,5-b] pyridine

2- (1H-indazol-3-yl) -3H-imidazo [4,5-b] pyridine as a solid according to a method similar to Example 234 (a) except that 2,3-diaminopyridine is used. Manufactured. MS: 236 (M + H) ^<+> . HPLC (Method A): R _T = 2.49 min.

１Ｈ−ピラゾール−３−カルバルデヒド（０.９６１ｇ、参考実施例１０）、ｏ−フェニレンジアミン（０.９７３ｇ）、重亜硫酸ナトリウム（１.８９８ｇ）および乾燥ジメチルホルムアミド（１０ｍＬ）の混合物を還流下に２時間攪拌し、その後室温に冷却し、その後粉砕氷（３５ｇ）上に注ぎ込んだ。混合物を濾過し、固体を重炭酸ナトリウム水、その後水で洗浄した。固体を７０℃で真空乾燥し、その後エタノールから再結晶化して、淡黄色味を帯びた固体として２−（１Ｈ−ピラゾール−３イル）−１Ｈ−ベンゾイミダゾール（０.６４５ｇ）を得た。融点３３５〜３３８℃。［元素分析値：Ｃ ６２.５６％、Ｈ ４.０４％、Ｎ ２９.１４％ 計算値（Ｃ₁₀Ｈ₈Ｎ₄）：Ｃ ６５.１９％、Ｈ ４.３９％、Ｎ ３０.４２％］ [Example 235]
(A) 2- (1H-pyrazol-3yl) -1H-benzimidazole

A mixture of 1H-pyrazole-3-carbaldehyde (0.961 g, Reference Example 10), o-phenylenediamine (0.973 g), sodium bisulfite (1.898 g) and dry dimethylformamide (10 mL) was refluxed. Stir for 2 hours, then cool to room temperature and then pour onto crushed ice (35 g). The mixture was filtered and the solid was washed with aqueous sodium bicarbonate followed by water. The solid was vacuum dried at 70 ° C. and then recrystallized from ethanol to give 2- (1H-pyrazol-3yl) -1H-benzimidazole (0.645 g) as a pale yellowish solid. Mp 335-338 ° C. [Elemental analysis values: C 62.56%, H 4.04%, N 29.14% Calculated value (C ₁₀ H ₈ N ₄ ): C 65.19%, H 4.39%, N 30.42% ]

３−ホルミル−５−メトキシ−インダゾール−１−カルボン酸ｔ−ブチルエステル［参考実施例２０（ａ）］および４,５−ジメチルベンゼン−１,２−ジアミンを使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メトキシ−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３５分；２８９（Ｍ＋Ｈ)⁺。 (B) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methoxy-1H-indazole

Example 235 above, except that 3-formyl-5-methoxy-indazole-1-carboxylic acid t-butyl ester [Reference Example 20 (a)] and 4,5-dimethylbenzene-1,2-diamine are used. According to the same method as (a), 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methoxy-1H-indazole was produced as a white solid. LC-MS (Method B): R _T = 2.35 min; 289 (M + H) ⁺ .

３−ホルミル−５−メトキシ−インダゾール−１−カルボン酸ｔ−ブチルエステル［参考実施例２０（ａ）］および４−エチル−５−メチルフェニレンジアミン［参考実施例３０］を使用し、反応生成物を酢酸エチルと４０〜６０ペトロールの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付すこと以外は、上記実施例２３５（ａ）と同様の方法に従って、淡黄色固体として３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メトキシ−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４８分；３０７（Ｍ＋Ｈ)⁺。 (C) 3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -5-methoxy-1H-indazole

Using 3-formyl-5-methoxy-indazole-1-carboxylic acid t-butyl ester [Reference Example 20 (a)] and 4-ethyl-5-methylphenylenediamine [Reference Example 30], the reaction product Is subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40-60 petrol (1: 1, v / v) according to the same method as in Example 235 (a) above. 3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -5-methoxy-1H-indazole was prepared as a pale yellow solid. LC-MS (Method B): R _T = 2.48 min; 307 (M + H) ⁺ .

５−フルオロ−１Ｈ−インダゾール−３−カルバルデヒド［参考実施例６（ｃ）］および４,５−ジメチルベンゼン−１,２−ジアミンを使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−フルオロ−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４１分；２８１（Ｍ＋Ｈ)⁺。 (D) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-fluoro-1H-indazole

Similar to Example 235 (a) above, except using 5-fluoro-1H-indazole-3-carbaldehyde [Reference Example 6 (c)] and 4,5-dimethylbenzene-1,2-diamine. According to the method, 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-fluoro-1H-indazole was prepared as a brown solid. LC-MS (Method B): R _T = 2.41 min; 281 (M + H) ⁺ .

６−フルオロ−１Ｈ−インダゾール−３−カルバルデヒド［参考実施例６（ｄ）］および４,５−ジメチルベンゼン−１,２−ジアミンを使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−６−フルオロ−１Ｈ−インダゾール（０.１０４ｇ）を得た。ＭＳ：２８１（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２３.６分。 (E) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -6-fluoro-1H-indazole

Similar to Example 235 (a) above except that 6-fluoro-1H-indazole-3-carbaldehyde [Reference Example 6 (d)] and 4,5-dimethylbenzene-1,2-diamine are used. According to the method, 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -6-fluoro-1H-indazole (0.104 g) was obtained as a brown solid. MS: 281 (M + H) ^<+> . HPLC (Method B1): R _T = 23.6 min.

５−メチル−１Ｈ−インダゾール−３−カルバルデヒド［参考実施例６（ｅ）］を使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メチル−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３５分；２７７（Ｍ＋Ｈ)⁺。 (F) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-indazole

According to the same method as in the above Example 235 (a) except that 5-methyl-1H-indazole-3-carbaldehyde [Reference Example 6 (e)] was used, 3- (5,6- Dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-indazole was prepared. LC-MS (Method B): R _T = 2.35 min; 277 (M + H) ⁺ .

６−メトキシ−１Ｈ−インダゾール−３−カルバルデヒド［参考実施例６（ｆ）］を使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、淡橙色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−６−メトキシ−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５２分；２９３（Ｍ＋Ｈ)⁺。 (G) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -6-methoxy-1H-indazole

Except for using 6-methoxy-1H-indazole-3-carbaldehyde [Reference Example 6 (f)], 3- (5,6) as a pale orange solid was prepared in the same manner as in Example 235 (a) above. -Dimethyl-1H-benzimidazol-2-yl) -6-methoxy-1H-indazole was prepared. LC-MS (Method B): R _T = 2.52 min; 293 (M + H) ⁺ .

４−フェニル−１Ｈ−ピラゾール−３−カルバルデヒド［参考実施例６（ｇ）］を使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、白色固体として５,６−ジメチル−２−（４−フェニル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３５分；２８９（Ｍ＋Ｈ)⁺。 (H) 5,6-Dimethyl-2- (4-phenyl-1H-pyrazol-3-yl) -1H-benzimidazole

Except for using 4-phenyl-1H-pyrazole-3-carbaldehyde [Reference Example 6 (g)], in the same manner as in Example 235 (a) above, 5,6-dimethyl-2 as a white solid -(4-Phenyl-1H-pyrazol-3-yl) -1H-benzimidazole was prepared. LC-MS (Method B): R _T = 2.35 min; 289 (M + H) ⁺ .

４−エチル−フェニレンジアミン［参考実施例２９（ａ）］を使用し、反応温度１６０℃で、反応生成物を酢酸エチルとヘキサンの混合物（２：１）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付す以外は、上記実施例２３５（ａ）と同様の方法に従って、オフホワイトの固体として３−（５−エチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝２３.１３分、２６３.３（Ｍ＋Ｈ)⁺。 (I) 3- (5-Ethyl-1H-benzimidazol-2-yl) -1H-indazole

A flash column on silica using 4-ethyl-phenylenediamine [Reference Example 29 (a)] at a reaction temperature of 160 ° C. and eluting with a mixture of ethyl acetate and hexane (2: 1) as the reaction product. 3- (5-Ethyl-1H-benzimidazol-2-yl) -1H-indazole was produced as an off-white solid according to the same method as in Example 235 (a), except that it was subjected to chromatography. LC-MS (Method D): R _T = 23.13 min, 263.3 (M + H) ⁺ .

４−エチル−５−メチル−フェニレンジアミン［参考実施例３０（ａ）］を使用する以外は上記実施例２３５（ｉ）と同様の方法に従って、オフホワイトの固体として３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝２３.７９分、２７７.３（Ｍ＋Ｈ)⁺。 (J) 3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Ethyl-6) as an off-white solid according to a method similar to Example 235 (i) above except that 4-ethyl-5-methyl-phenylenediamine [Reference Example 30 (a)] is used. -Methyl-1H-benzimidazol-2-yl) -1H-indazole was prepared. LC-MS (Method D): R _T = 23.79 min, 277.3 (M + H) ⁺ .

４−イソプロピル−５−メチル−フェニレンジアミン［参考実施例３０（ｂ）］を使用する以外は上記実施例２３５（ｉ）と同様の方法に従って、オフホワイトの固体として３−（５−イソプロピル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：２９１.０３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２３.３９分。 (K) 3- (5-Isopropyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Isopropyl-6) as an off-white solid according to the same procedure as in Example 235 (i) except that 4-isopropyl-5-methyl-phenylenediamine [Reference Example 30 (b)] was used. -Methyl-1H-benzimidazol-2-yl) -1H-indazole was prepared. MS: 291.03 (M + H) ^<+> . HPLC (Method B1): R _T = 23.39 min.

４−ブロモ−５−メチル−フェニレンジアミン［参考実施例３０（ｃ）］を使用する以外は上記実施例２３５（ｉ）と同様の方法に従って、オフホワイトの固体として３−（５−ブロモ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３２９.０９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２２.７４分。 (L) 3- (5-Bromo-6-methyl-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Bromo-6) as an off-white solid according to the same procedure as in Example 235 (i) above, except that 4-bromo-5-methyl-phenylenediamine [Reference Example 30 (c)] was used. -Methyl-1H-benzimidazol-2-yl) -1H-indazole was prepared. MS: 329.09 (M + H) ^<+> . HPLC (Method B1): R _T = 22.74 min.

４−ブロモ−フェニレンジアミン［参考実施例３０（ｅ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、茶色固体として３−（５−ブロモ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝２３.４６分、３１５.１５（Ｍ＋Ｈ)⁺。 (M) 3- (5-Bromo-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Bromo-1H-benzimidazole-2) as a brown solid according to the same method as in Example 235 (i) except that 4-bromo-phenylenediamine [Reference Example 30 (e)] was used. -Yl) -1H-indazole was prepared. LC-MS (Method D): R _T = 23.46 min, 315.15 (M + H) ⁺ .

３′,４′−ジアミノビフェニル−３−カルボニトリル［参考実施例３０（ｆ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−（３−シアノ）フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３３５.３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２１.４７分。 (N) 3- (5- (3-Cyano) phenyl-1H-benzimidazol-2-yl) -1H-indazole

Except for using 3 ', 4'-diaminobiphenyl-3-carbonitrile [Reference Example 30 (f)], 3- (5- ( 3-Cyano) phenyl-1H-benzoimidazol-2-yl) -1H-indazole was prepared. MS: 335.3 (M + H) ^<+> . HPLC (Method B1): R _T = 21.47 min.

４−（ピリジン−３−イル）ベンゼン−１,２−ジアミン［参考実施例３０（ｇ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−（ピリジン−３−イル）−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３１２.２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝８.５８分。 (O) 3- (5- (Pyridin-3-yl) -1H-benzimidazol-2-yl) -1H-indazole

3- (Pyridin-3-yl) benzene-1,2-diamine [Reference Example 30 (g)] was used in the same manner as in Example 235 (i) above except that 3- ( 5- (Pyridin-3-yl) -1H-benzimidazol-2-yl) -1H-indazole was prepared. MS: 312.2 (M + H) ^<+> . HPLC (Method B1): R _T = 8.58 min.

６−メチルビフェニル−３,４−ジアミン［参考実施例３０（ｈ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（６−メチル−５−フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３２５.３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１４.４８分。 (P) 3- (6-Methyl-5-phenyl-1H-benzimidazol-2-yl) -1H-indazole

Except for using 6-methylbiphenyl-3,4-diamine [Reference Example 30 (h)], 3- (6-Methyl-5- Phenyl-1H-benzoimidazol-2-yl) -1H-indazole was prepared. MS: 325.3 (M + H) ^<+> . HPLC (Method B1): R _T = 14.48 min.

４−ビフェニル−３,４−ジアミン［参考実施例３０（ｉ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３１１.２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｄ）：Ｒ_T＝２４.５４分。 (Q) 3- (5-Phenyl-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Phenyl-1H-benzoate as a white solid according to the same method as in Example 235 (i) above, except that 4-biphenyl-3,4-diamine [Reference Example 30 (i)] was used. Imidazole-2-yl) -1H-indazole was prepared. MS: 311.2 (M + H) ^<+> . HPLC (Method D): R _T = 24.54 min.

２′−フルオロビフェニル−３,４−ジアミン［参考実施例３０（ｊ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−（２−フルオロ）フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３２９.２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ）：Ｒ_T＝２２.５４分。 (R) 3- (5- (2-Fluoro) phenyl-1H-benzimidazol-2-yl) -1H-indazole

Except for using 2'-fluorobiphenyl-3,4-diamine [Reference Example 30 (j)], 3- (5- (2- Fluoro) phenyl-1H-benzimidazol-2-yl) -1H-indazole was prepared. MS: 329.2 (M + H) ^<+> . HPLC (Method B): R _T = 22.54 min.

４−ベンゾ［１,３］ジオキソール−５−イルベンゼン−１,２−ジアミン［参考実施例３０（ｋ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−（５,６−メチレンジオキシ）フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３５５.２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２２.０４分。 (S) 3- (5- (3,4-Methylenedioxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole

A white solid was prepared in the same manner as in Example 235 (i) above, except that 4-benzo [1,3] dioxol-5-ylbenzene-1,2-diamine [Reference Example 30 (k)] was used. 3- (5- (5,6-methylenedioxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole was prepared as MS: 355.2 (M + H) ^<+> . HPLC (Method B1): R _T = 22.04 min.

２′−メトキシビフェニル−３,４−ジアミン［参考実施例３０（ｌ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−（２−メトキシ）フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３４１.２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２２.０９分。 (T) 3- (5- (2-methoxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole

Except for using 2'-methoxybiphenyl-3,4-diamine [Reference Example 30 (l)], 3- (5- (2- Methoxy) phenyl-1H-benzoimidazol-2-yl) -1H-indazole was prepared. MS: 341.2 (M + H) ^<+> . HPLC (Method B1): R _T = 22.09 min.

４′−クロロビフェニル−３,４−ジアミン［参考実施例３０（ｍ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−（４−クロロ）フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３４５.２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２３.７１分。 (U) 3- (5- (4-Chloro) phenyl-1H-benzimidazol-2-yl) -1H-indazole

Except for using 4'-chlorobiphenyl-3,4-diamine [Reference Example 30 (m)], 3- (5- (4- Chloro) phenyl-1H-benzoimidazol-2-yl) -1H-indazole was prepared. MS: 345.2 (M + H) ^<+> . HPLC (Method B1): R _T = 23.71 min.

４′−メチルビフェニル−３,４−ジアミンジアミン［参考実施例３０（ｎ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−（４−メチル）フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３２５.１（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｃ１）：Ｒ_T＝１５.２２分。 (V) 3- (5- (4-Methyl) phenyl-1H-benzimidazol-2-yl) -1H-indazole

According to a method similar to that of Example 235 (i) above except that 4'-methylbiphenyl-3,4-diaminediamine [Reference Example 30 (n)] was used, 3- (5- (4 -Methyl) phenyl-1H-benzimidazol-2-yl) -1H-indazole was prepared. MS: 325.1 (M + H) ^<+> . HPLC (Method C1): R _T = 15.22 min.

４−ベンジルオキシベンゼン−１,２−ジアミン［参考実施例３０（ｏ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−ベンジルオキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：３３９.３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝２２.３２分。 (W) 3- (5-Benzyloxy-1H-benzimidazol-2-yl) -1H-indazole

Except for using 4-benzyloxybenzene-1,2-diamine [Reference Example 30 (o)], in the same manner as in Example 235 (i) above, 3- (5-benzyloxy- 1H-Benzimidazol-2-yl) -1H-indazole was prepared. MS: 339.3 (M + H) ^<+> . HPLC (Method B1): R _T = 22.32 min.

ベンゾ［１,３］ジオキソール−５,６−ジアミン［参考実施例３０（ｐ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５,６−メチレンジオキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２５分；２７９.２２（Ｍ＋Ｈ)⁺。 (X) 3- (5,6-Methylenedioxy-1H-benzimidazol-2-yl) -1H-indazole

3- (5,6) as a white solid according to the same procedure as in Example 235 (i) above, except that benzo [1,3] dioxol-5,6-diamine [Reference Example 30 (p)] was used. -Methylenedioxy-1H-benzoimidazol-2-yl) -1H-indazole was prepared. LC-MS (Method B): R _T = 2.25 min; 279.22 (M + H) ⁺ .

４,５−ジメトキシベンゼン−１,２−ジアミン［参考実施例３０（ｑ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５,６−ジメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.１６分；２９５.２６（Ｍ＋Ｈ)⁺。 (Y) 3- (5,6-dimethoxy-1H-benzimidazol-2-yl) -1H-indazole

Except for the use of 4,5-dimethoxybenzene-1,2-diamine [Reference Example 30 (q)], 3- (5,6- Dimethoxy-1H-benzoimidazol-2-yl) -1H-indazole was prepared. LC-MS (Method B): R _T = 2.16 min; 295.26 (M + H) ⁺ .

４,５−ジエチルベンゼン−１,２−ジアミン［参考実施例３０（ｒ）］を使用する以外
は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５,６−ジエチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４９分；２９１.３２（Ｍ＋Ｈ)⁺。 (Z) 3- (5,6-Diethyl-1H-benzimidazol-2-yl) -1H-indazole

3- (5,6-Diethyl as a white solid according to the same procedure as in Example 235 (i) above, except that 4,5-diethylbenzene-1,2-diamine [Reference Example 30 (r)] was used. -1H-benzoimidazol-2-yl) -1H-indazole was prepared. LC-MS (Method B): R _T = 2.49 min; 291.32 (M + H) ⁺ .

３,４−ジメチルベンゼン−１,２−ジアミンを使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（４,５−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３１分；２６３.２４（Ｍ＋Ｈ)⁺。 (Aa) 3- (4,5-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole

Except for using 3,4-dimethylbenzene-1,2-diamine, 3- (4,5-dimethyl-1H-benzimidazol-2-yl ester as a white solid was prepared in the same manner as in Example 235 (i) above. Yl) -1H-indazole. LC-MS (Method B): R _T = 2.31 min; 263.24 (M + H) ⁺ .

３,４−ジアミノベンゾニトリルアミンを使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボニトリルを製造した。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝２１.８１分、ＭＳ：２６０.１０（Ｍ＋Ｈ)⁺。 (Ab) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carbonitrile

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carbohydrate as a white solid according to the same method as in Example 235 (i) except that 3,4-diaminobenzonitrileamine is used. Nitrile was produced. LC-MS (Method D): R _T = 21.81 min, MS: 260.10 (M + H) ⁺ .

３,４−ジアミノ安息香酸、メチルエステルを使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−メトキシカルボニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝２２.１３分、２９３.１６（Ｍ＋Ｈ)⁺。 (Ac) 3- (5-Methoxycarbonyl-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Methoxycarbonyl-1H-benzoimidazol-2-yl)-as a white solid according to the same method as in Example 235 (i) except that 3,4-diaminobenzoic acid and methyl ester were used. 1H-indazole was produced. LC-MS (Method D): R _T = 22.13 min, 293.16 (M + H) ⁺ .

５−エトキシ−３−ホルミル−インダゾール−１−カルボン酸ｔ−ブチルエステル［参考実施例２０（ｄ）］を使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、淡橙色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−エトキシ−１Ｈ−インダゾールを製造した。ＭＳ：３０７（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１３.５８分。 (Ad) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-ethoxy-1H-indazole

According to the same method as in Example 235 (a) except that 5-ethoxy-3-formyl-indazole-1-carboxylic acid t-butyl ester [Reference Example 20 (d)] was used, as a pale orange solid 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-ethoxy-1H-indazole was prepared. MS: 307 (M + H) ^<+> . HPLC (Method B1): R _T = 13.58 min.

３−ホルミル−ピラゾール−４−カルボン酸エチルエステル［参考実施例６（ｉ）］を使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、淡茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−ピラゾール−４−カルボン酸エチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：２.５６分；２８５（Ｍ＋Ｈ)⁺。 (Ae) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -pyrazole-4-carboxylic acid ethyl ester

3- (5,6) as a light brown solid according to the same method as in Example 235 (a) except that 3-formyl-pyrazole-4-carboxylic acid ethyl ester [Reference Example 6 (i)] was used. -Dimethyl-1H-benzimidazol-2-yl) -pyrazole-4-carboxylic acid ethyl ester was prepared. LC-MS (Method B): 2.56 min; 285 (M + H) ^<+> .

３−ホルミル−ピラゾール−４−カルボン酸イソプロピルアミド［参考実施例６（ｊ）］およびメチル−３,４−ジアミノベンゾエートを使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、黄色固体として２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸メチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：２.９９分；３２８（Ｍ＋Ｈ)⁺。 (Af) 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester

According to a method similar to Example 235 (a) above except that 3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example 6 (j)] and methyl-3,4-diaminobenzoate are used. 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester was prepared as a solid. LC-MS (Method B): 2.99 min; 328 (M + H) ^<+> .

３−ホルミル−５−メチル−ピラゾール−４−カルボン酸エチルエステル［参考実施例６（ｋ）］を使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メチル−ピラゾール−４−カルボン酸エチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５９分；２９９（Ｍ＋Ｈ)⁺。 (Ag) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid ethyl ester

3- (Formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester [Reference Example 6 (k)] was used in the same manner as in Example 235 (a) above except that 3- ( 5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid ethyl ester was prepared. LC-MS (Method B): R _T = 2.59 min; 299 (M + H) ⁺ .

インダン−５,６−ジアミン（１３０ｍｇ）および３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド［１５０ｍｇ、参考実施例６（ｑ）］を使用し、反応生成物をシリカ上のクロマトグラフィー［酢酸エチル／７５〜０％勾配ヘプタンを溶離剤とする］に付し、ついでアセトンで磨砕する以外は、上記実施例２３５（ａ）と同様の方法に従って、白色固体として３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド（３１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ａ）：Ｒ_T＝２.８５分、３０８（Ｍ＋Ｈ)⁺。 (Ah) 3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide

Chromatography of the reaction product on silica using indane-5,6-diamine (130 mg) and 3-formyl-1H-pyrazole-4-carboxylic acid cyclopropylamide [150 mg, Reference Example 6 (q)] Except for subjecting to [ethyl acetate / 75 to 0% gradient heptane as eluent] and then triturating with acetone, 3- (1, 5,6,7-Tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide (31 mg) was prepared. LC-MS (Method A): R _T = 2.85 min, 308 (M + H) ⁺ .

３−ホルミル−ピラゾール−４−カルボン酸イソプロピルアミド［１９８ｍｇ、参考実施例６（ｊ）］および４−メトキシ−５−メチル−ベンゼン−１,２−ジアミン［１６６ｍｇ、参考実施例２９（ｂ）］を使用し、反応生成物をジクロロメタン／メタノール（９５：５）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、ついで酢酸エチルとｎ−ペンタンの混合物から再結晶化する以外は、上記実施例２３５（ａ）と同様の方法に従って、白色固体として３−（５−メトキシ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミド（１４５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝２.０９分、３１４.２７（Ｍ＋Ｈ)⁺、３１２.２９（Ｍ−Ｈ)^-。 (Ai) 3- (5-Methoxy-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide

3-Formyl-pyrazole-4-carboxylic acid isopropylamide [198 mg, Reference Example 6 (j)] and 4-methoxy-5-methyl-benzene-1,2-diamine [166 mg, Reference Example 29 (b)] And the reaction product is subjected to flash column chromatography on silica eluting with dichloromethane / methanol (95: 5) followed by recrystallization from a mixture of ethyl acetate and n-pentane. According to a method similar to that of Example 235 (a), 3- (5-methoxy-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide (145 mg) was obtained as a white solid. Manufactured. LC-MS (Method H): R _T = 2.09 min, 314.27 (M + H) ⁺ , 312.29 (M−H) ⁻ .

４−（２−モルホリン−４−イル−エトキシ）−ベンゼン−１,２−ジアミン［参考実施例２９（ｃ）］を使用し、反応生成物を分取ＬＣ−ＭＳに付する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−［５−（２−モルホリン−４−イル−エトキシ）−１Ｈ−ベンゾイミダゾール−２−イル］−１Ｈ−インダゾール（２５ｍｇ）を得た。ＭＳ：３６４（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１９.３８分。 (Aj) 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1H-indazole

The above except that 4- (2-morpholin-4-yl-ethoxy) -benzene-1,2-diamine [Reference Example 29 (c)] was used and the reaction product was subjected to preparative LC-MS. According to a method similar to that in Example 235 (i), 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1H-indazole (25 mg) was obtained as a white solid. It was. MS: 364 (M + H) ^<+> . HPLC (Method B1): R _T = 19.38 min.

４,５−ジメチルベンゼン−１,２−ジアミンおよび３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸（２−メトキシ−エチル）−アミド［参考実施例６（ｎ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、クリーム色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸（２−メトキシ−エチル）−アミド（８７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝４.２３分、３１４.２（Ｍ＋Ｈ)⁺。 (Ak) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide

The above except that 4,5-dimethylbenzene-1,2-diamine and 3-formyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide [Reference Example 6 (n)] were used. 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) as a cream colored solid according to a method similar to Example 235 (i) -The amide (87 mg) was prepared. LC-MS (Method L): R _T = 4.23 min, 314.2 (M + H) ⁺ .

４,５−ジメチルベンゼン−１,２−ジアミンおよび３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸プロピルアミド［参考実施例６（ｏ）］を使用する以外は、上記実施例６（ｉ）と同様の方法に従って、淡黄色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸プロピルアミド（７３ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝４.９４分、２９８.２９（Ｍ＋Ｈ)⁺。 (Al) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid propylamide

Except for the use of 4,5-dimethylbenzene-1,2-diamine and 3-formyl-1H-pyrazole-4-carboxylic acid propylamide [Reference Example 6 (o)] with Example 6 (i) above According to a similar method, 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid propylamide (73 mg) was produced as a pale yellow solid. LC-MS (Method L): R _T = 4.94 min, 298.29 (M + H) ⁺ .

４,５−ジメチル−１,２−フェニレンジアミンおよび３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸（テトラヒドロ−ピラン−４−イル）−アミド［参考実施例６（ｐ）］を使用し、反応生成物をメタノールから再結晶化する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸（テトラヒドロ−ピラン−４−イル）−アミド（２２８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｒ）：Ｒ_T＝９.４０分、３６０（Ｍ＋Ｈ)⁺。 (Am) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide

Reaction using 4,5-dimethyl-1,2-phenylenediamine and 3-formyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide [Reference Example 6 (p)] 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole as a white solid according to the same method as in Example 235 (i) above except that the product was recrystallized from methanol. -4-carboxylic acid (tetrahydro-pyran-4-yl) -amide (228 mg) was prepared. LC-MS (Method R): R _T = 9.40 min, 360 (M + H) ⁺ .

４−エチル−５−メチル−フェニレンジアミン［参考実施例３０（ａ）］および３−ホルミル−１Ｈ−インダゾール−５−カルボニトリル［参考実施例６８］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、淡黄色固体として３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボニトリル（１３３ｍｇ）を製造した。ＭＳ：３０２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１６.４５分。 (An) 3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile

Example 235 (i) above except that 4-ethyl-5-methyl-phenylenediamine [Reference Example 30 (a)] and 3-formyl-1H-indazole-5-carbonitrile [Reference Example 68] were used. ) To produce 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carbonitrile (133 mg) as a pale yellow solid. MS: 302 (M + H) ^<+> . HPLC (Method B1): R _T = 16.45 min.

４−ジフルオロメトキシ−ベンゼン−１,２−ジアミン［参考実施例３０（ｙ）］および３−ホルミル−ピラゾール−４−カルボン酸イソプロピルアミド［参考実施例６（ｊ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、白色固体として３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミド（１１８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝１０.４６分、３３６.１９（Ｍ＋Ｈ)⁺。 (Ao) 3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide

The above except that 4-difluoromethoxy-benzene-1,2-diamine [Reference Example 30 (y)] and 3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example 6 (j)] were used. According to a method similar to that in Example 235 (i), 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide (118 mg) was produced as a white solid. LC-MS (Method L): R _T = 10.46 min, 336.19 (M + H) ⁺ .

３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド［参考実施例６（ｑ）］を使用する以外は、上記実施例２３５（ａｏ）と同様の方法に従って、白色固体として３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド（６３ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝１０.１８分、３３４.１７（Ｍ＋Ｈ)⁺。 (Ap) 3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide

Except for using 3-formyl-1H-pyrazole-4-carboxylic acid cyclopropylamide [Reference Example 6 (q)] according to the same method as in Example 235 (ao) above, 3- (5 -Difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide (63 mg) was prepared. LC-MS (Method L): R _T = 10.18 min, 334.17 (M + H) ⁺ .

４−エチル−５−メトキシ−ベンゼン−１,２−ジアミン［２００ｍｇ、参考実施例３０（ｚ）］および３−ホルミル−ピラゾール−４−カルボン酸イソプロピルアミド［参考実施例６（ｊ）］を使用する以外は、上記実施例２３５（ｉ）と同様の方法に従って、オフホワイトの固体として３−（６−エチル−５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミド（１１５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝１１.３４分、３２８.２４（Ｍ＋Ｈ)⁺。 (Aq) 3- (6-Ethyl-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide

Using 4-ethyl-5-methoxy-benzene-1,2-diamine [200 mg, Reference Example 30 (z)] and 3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example 6 (j)] Except that, 3- (6-Ethyl-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid as an off-white solid was prepared in the same manner as in Example 235 (i) above. Acid isopropylamide (115 mg) was prepared. LC-MS (Method L): R _T = 11.34 min, 328.24 (M + H) ⁺ .

（ｉ）４,５−ジメチル−フェニレンジアミンおよび３−ホルミル−１Ｈ−インダゾール−５−カルボニトリル［参考実施例６８］を使用し、（ii）メタノール中の反応生成物の懸濁液を１,４−ジオキサン中の塩酸（４Ｍ）溶液で処理し、ついで混合物を蒸発させ、（iii）残存物をメタノールで磨砕し、（iv）ジエチルエーテルから再結晶化する以外は、上記実施例２３５（ｉ）と同様の方法に従って、オフホワイトの固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボニトリル二塩酸塩（１３３ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３２分。ＭＳ：２８８（Ｍ＋Ｈ)⁺。 (Ar) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile dihydrochloride

(I) 4,5-dimethyl-phenylenediamine and 3-formyl-1H-indazole-5-carbonitrile [Reference Example 68] were used, and (ii) the reaction product suspension in methanol was 1, Example 235 above, except that it was treated with a solution of hydrochloric acid (4M) in 4-dioxane, then the mixture was evaporated, (iii) the residue was triturated with methanol, and (iv) recrystallized from diethyl ether. According to the same method as i), 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile dihydrochloride (133 mg) was prepared as an off-white solid. LC-MS (Method B): R _T = 2.32 min. MS: 288 (M + H) ^<+> .

４−ニトロフェニレンジアミンを使用する以外は、上記実施例２３５（ａ）と同様の方法に従って、赤色固体として３−（５−ニトロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾールを製造した。ＭＳ：２８０.１７（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝３.００分。 (As) 3- (5-Nitro-1H-benzimidazol-2-yl) -1H-indazole

3- (5-Nitro-1H-benzimidazol-2-yl) -1H-indazole was produced as a red solid according to the same method as in Example 235 (a) except that 4-nitrophenylenediamine was used. . MS: 280.17 (M + H) ^<+> . HPLC (Method B1): R _T = 3.00 min.

ｏ−フェニレンジアミン（１.０８ｇ）および５−メチルピラゾール−３−カルボン酸（１.２６６ｇ）の混合物を微細に粉砕し、微細粉砕物質を１６０℃で３時間加熱し、その後周囲温度に冷却した。反応混合物をエチルアルコール（５０ｍＬ）から再結晶化し、明青色固体（０.２７ｇ）を得た。濾液を放置して別の収量分（０.１ｇ）を得た。合わせた固体をエチルアルコールから再結晶化し、ライラック色の固体として２−（５−メチル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（２２３ｍｇ）を得た。融点３２２〜３２４℃。［元素分析値：Ｃ ６６.５４％；Ｈ ４.８０％；Ｎ ２８.１４％、計算値（Ｃ₁₁Ｈ₁₀Ｎ₄）：Ｃ ６６.６４％；Ｈ ５.０９％；Ｎ ２８.２７％］。 [Example 236]
2- (5-Methyl-1H-pyrazol-3-yl) -1H-benzimidazole

A mixture of o-phenylenediamine (1.08 g) and 5-methylpyrazole-3-carboxylic acid (1.266 g) was finely ground and the finely ground material was heated at 160 ° C. for 3 hours and then cooled to ambient temperature. . The reaction mixture was recrystallized from ethyl alcohol (50 mL) to give a light blue solid (0.27 g). The filtrate was left to obtain another yield (0.1 g). The combined solids were recrystallized from ethyl alcohol to give 2- (5-methyl-1H-pyrazol-3-yl) -1H-benzimidazole (223 mg) as a lilac solid. 322-324 ° C. [Elemental analysis values: C 66.54%; H 4.80%; N 28.14%, calculated value (C ₁₁ H ₁₀ N ₄ ): C 66.64%; H 5.09%; N 28.27 %].

トリフルオロ酢酸（６ｍＬ）および２−（５−エトキシ−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール（３００ｍｇ、参考実施例１１）の混合物を５０℃で１.５時間攪拌した。反応混合物を蒸発させ、残存物を酢酸エチルと水（ｐＨ１０）の間に分配した。有機層を乾燥し、その後蒸発させた。残存物をジクロロメタンとメタノールの混合物（９：１、ｖ／ｖ）を溶離剤とするシリカ上のクロマトグラフィーに付し、その後トルエンから再結晶化して、無色の固体として２−（５−エトキシ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（０.１ｇ）を得た。融点２１７〜２１９.５℃。［元素分析値：Ｃ ６２.２６％；Ｈ ５.２３％；Ｎ ２３.４４％、計算値（Ｃ₁₂Ｈ₁₂Ｎ₄Ｏ）：Ｃ ６３.１５％；Ｈ ５.３０％；Ｎ ２４.５５％］。 [Example 237]
2- (5-Ethoxy-1H-pyrazol-3-yl) -1H-benzimidazole

Mixture of trifluoroacetic acid (6 mL) and 2- (5-ethoxy-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole (300 mg, Reference Example 11) Was stirred at 50 ° C. for 1.5 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water (pH 10). The organic layer was dried and then evaporated. The residue was chromatographed on silica eluting with a mixture of dichloromethane and methanol (9: 1, v / v) and then recrystallized from toluene to give 2- (5-ethoxy-) as a colorless solid. 1H-pyrazol-3-yl) -1H-benzimidazole (0.1 g) was obtained. Melting point 217-219.5 [deg.] C. [Elemental analysis: C 62.26%; H 5.23%; N 23.44%, calculated (C ₁₂ H ₁₂ N ₄ O): C 63.15%; H 5.30%; N 24. 55%].

２−（５−メチルスルファニル−イソキサゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール（１６０ｍｇ、参考実施例１２）、メタノール（１２ｍＬ）および濃塩酸水（２.４５ｍＬ）の混合物を還流下に４時間加熱し、その後冷却し、その後蒸発させた。残存物を重炭酸ナトリウム水で処理し、混合物を酢酸エチルで抽出した。抽出物を乾燥し、その後蒸発させて、オフホワイトの固体として２−（５−メチルスルファニル−イソキサゾール−３−イル）−１Ｈ−ベンゾイミダゾール（９６ｍｇ）を得た。融点１７９〜１８１℃。¹Ｈ−ＮＭＲ［（ＣＤ₃)₂ＳＯ］：δ４.６５（ｓ, ３Ｈ）,９.００（ｓ, １Ｈ）,９.１５〜９.６（ｍ, ４Ｈ）。 [Example 238]
2- (5-Methylsulfanyl-isoxazol-3-yl) -1H-benzimidazole

2- (5-methylsulfanyl-isoxazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole (160 mg, Reference Example 12), methanol (12 mL) and concentrated aqueous hydrochloric acid ( (2.45 mL) of the mixture was heated under reflux for 4 hours, then cooled and then evaporated. The residue was treated with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried and then evaporated to give 2- (5-methylsulfanyl-isoxazol-3-yl) -1H-benzimidazole (96 mg) as an off-white solid. Mp 179-181 ° C. ¹ H-NMR [(CD ₃ ) ₂ SO]: δ 4.65 (s, 3H), 9.00 (s, 1H), 9.15 to 9.6 (m, 4H).

塩酸（４Ｎ）中の４−クロロ−ベンゼン−１,２−ジアミン（５００ｍｇ）の溶液を４−ニトロ−ピラゾール−３−カルボン酸（８２６ｍｇ）で処理し、その後窒素下に還流温度で加熱した。反応混合物を室温に冷却し、その際水酸化アンモニウムを添加してｐＨを８に調整し、混合物を酢酸エチルで抽出した。抽出物を蒸発させて、５−クロロ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを得た。 [Example 239]
(A) 5-chloro-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

A solution of 4-chloro-benzene-1,2-diamine (500 mg) in hydrochloric acid (4N) was treated with 4-nitro-pyrazole-3-carboxylic acid (826 mg) and then heated at reflux temperature under nitrogen. The reaction mixture was cooled to room temperature, ammonium hydroxide was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate. The extract was evaporated to give 5-chloro-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole.

４,５−ジクロロ−１,２−ジアミノベンゼンを使用する以外は、上記実施例２３９（ａ）と同様の方法に従って、５,６−ジクロロ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。 (B) 5,6-Dichloro-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

Except for the use of 4,5-dichloro-1,2-diaminobenzene, 5,6-dichloro-2- (4-nitro-1H-pyrazole-3-) was prepared in the same manner as in Example 239 (a) above. Yl) -1H-benzimidazole was prepared.

１−［（３,３−ビス（メチルチオ））ベンゾイミダゾール−２−イル］プロペン−２−オン［５.５ｇ、参考実施例１５］、ヒドラジン水和物（１.０２ｇ）およびアセトニトリル（５０ｍＬ）の混合物を還流下に１８時間攪拌した。反応混合物を冷却し、沈殿物を濾過により単離した。エタノール水から再結晶化し、ベージュ色の結晶固体として（ベンゾイミダゾール−２−イル）−５−メチルチオ−３−ピラゾール（３.３６ｇ）を得た。融点２４２℃。［元素分析値：Ｃ ５７.８％；Ｈ ４.５％；Ｎ ２４.０％、計算値（Ｃ₁₁Ｈ₁₀Ｎ₄Ｓ）：Ｃ ５７.３７％；Ｈ ４.３８％；Ｎ ２４.３３％］。 [Example 240]
(Benzimidazol-2-yl) -5-methylthio-3-pyrazole

1-[(3,3-bis (methylthio)) benzimidazol-2-yl] propen-2-one [5.5 g, Reference Example 15], hydrazine hydrate (1.02 g) and acetonitrile (50 mL) The mixture was stirred at reflux for 18 hours. The reaction mixture was cooled and the precipitate was isolated by filtration. Recrystallization from ethanol water gave (benzimidazol-2-yl) -5-methylthio-3-pyrazole (3.36 g) as a beige crystalline solid. Mp 242 ° C. [Elemental analysis values: C 57.8%; H 4.5%; N 24.0%, calculated value (C ₁₁ H ₁₀ N ₄ S): C 57.37%; H 4.38%; N 24. 33%].

４,５−ジメチルベンゼン−１,２−ジアミン（９０ｍｇ）および４,５,６,７−テトラヒドロ−１Ｈ−インダゾール−３−カルボン酸［１１０ｍｇ、参考実施例１７（ａ）］をガラスビン中に混合し、その後マイクロ波放射（９００Ｗ、家庭用オーブン）に２分間２回付した。得られた固体を酢酸エチルとヘキサンの混合物（８５：１５、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、淡茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−インダゾールを得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２８分；２６７（Ｍ＋Ｈ)⁺。 [Example 241]
(A) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-indazole

4,5-Dimethylbenzene-1,2-diamine (90 mg) and 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [110 mg, Reference Example 17 (a)] were mixed in a glass bottle. And then subjected to microwave radiation (900 W, home oven) twice for 2 minutes. The resulting solid was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (85:15, v / v) to give 3- (5,6-dimethyl-1H as a light brown solid. -Benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-indazole was obtained. LC-MS (Method B): R _T = 2.28 min; 267 (M + H) ⁺ .

５−イソプロピル−１Ｈ−ピラゾール−３−カルボン酸［参考実施例１７（ｂ）］を使用する以外は、上記実施例２４１（ａ）と同様の方法に従って、茶色固体として２−（５−イソプロピル−１Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾール（８０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２７分；２５５（Ｍ＋Ｈ)⁺。 (B) 2- (5-Isopropyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

Except that 5-isopropyl-1H-pyrazole-3-carboxylic acid [Reference Example 17 (b)] was used, 2- (5-isopropyl- 1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole (80 mg) was prepared. LC-MS (Method B): R _T = 2.27 min; 255 (M + H) ⁺ .

５−エチル−１Ｈ−ピラゾール−３−カルボン酸［参考実施例１７（ｃ）］を使用し、茶色固体の反応生成物を酢酸エチルとヘキサンの混合物（１：１、ｖ／ｖ）で磨砕する以外は、上記実施例２４１（ａ）と同様の方法に従って、明茶色固体として２−（５−エチル−１Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２２分；２４１（Ｍ＋Ｈ)⁺。 (C) 2- (5-Ethyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

Using 5-ethyl-1H-pyrazole-3-carboxylic acid [Reference Example 17 (c)], the brown solid reaction product was triturated with a mixture of ethyl acetate and hexane (1: 1, v / v). Except that, 2- (5-ethyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole was produced as a light brown solid according to the same method as in Example 241 (a) above. . LC-MS (Method B): R _T = 2.22 min; 241 (M + H) ⁺ .

１,４,５,６−テトラヒドロ−シクロペンタピラゾール−３−カルボン酸［参考実施例１７（ｆ）］を使用し、反応生成物を酢酸エチル、エーテルおよびメタノールで磨砕する以外は、上記実施例２１４（ａ）と同様の方法に従って、オフホワイトの固体として５,６−ジメチル−２−（１,４,５,６−テトラヒドロ−シクロペンタピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（５０ｍｇ）を製造した。ＭＳ：２５３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１１.１７分。 (D) 5,6-dimethyl-2- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1H-benzimidazole

The above procedure was followed except that 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid [Reference Example 17 (f)] was used and the reaction product was triturated with ethyl acetate, ether and methanol. According to a method similar to Example 214 (a), 5,6-dimethyl-2- (1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1H-benzimidazole (50 mg as an off-white solid) ) Was manufactured. MS: 253 (M + H) ^<+> . HPLC (Method B1): R _T = 11.17 min.

ジメチルホルムアミド（８ｍｌ）中の４,５−ジメチルベンゼン−１,２−ジアミン（７０ｍｇ）および４−フルオロ−１Ｈ−インダゾール−３−カルバルデヒド［８０ｍｇ、参考実施例２０（ｂ）］の混合物を１２０℃に３０分間、その後１００℃で１６時間加熱した。反応混合物を冷却し、その後酢酸エチルに希釈し、その後塩水で５回洗浄した。有機層を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を４０／６０ペトロールと酢酸エチルの混合物（１：５、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、明茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４−フルオロ−１Ｈ−インダゾール（１０４ｍｇ）を得た。ＭＳ：２８１（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１０.０８分。 [Example 242]
(A) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -4-fluoro-1H-indazole

A mixture of 4,5-dimethylbenzene-1,2-diamine (70 mg) and 4-fluoro-1H-indazole-3-carbaldehyde [80 mg, Reference Example 20 (b)] in dimethylformamide (8 ml) was 120. C. for 30 minutes and then at 100.degree. C. for 16 hours. The reaction mixture was cooled and then diluted in ethyl acetate and then washed 5 times with brine. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (1: 5, v / v) as 3- (5,6-dimethyl- 1H-Benzimidazol-2-yl) -4-fluoro-1H-indazole (104 mg) was obtained. MS: 281 (M + H) ^<+> . HPLC (Method B1): R _T = 10.08 min.

４−クロロ−３−ホルミル−インダゾール−１−カルボン酸ｔ−ブチルエステル［参考実施例２０（ｃ）］を使用する以外は、上記実施例２４２（ａ）と同様の方法に従って、オフホワイトの固体として４−クロロ−３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール（２５ｍｇ）を製造した。ＭＳ：２９９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１０.５９分。 (B) 4-chloro-3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole

An off-white solid was prepared in the same manner as in Example 242 (a) above, except that 4-chloro-3-formyl-indazole-1-carboxylic acid t-butyl ester [Reference Example 20 (c)] was used. 4-chloro-3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-indazole (25 mg) was prepared as MS: 299 (M + H) ^<+> . HPLC (Method B1): R _T = 10.59 min.

５−クロロ−１Ｈ−インダゾール−３−カルバルデヒド［参考実施例６（ｈ）］を使用する以外は、上記実施例２４２（ａ）と同様の方法に従って、淡茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−クロロ−１Ｈ−インダゾール（２５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝２４.２４分、２９９（Ｍ＋Ｈ)⁺。 (C) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-chloro-1H-indazole

Except that 5-chloro-1H-indazole-3-carbaldehyde [Reference Example 6 (h)] was used, 3- (5, 6 -Dimethyl-1H-benzimidazol-2-yl) -5-chloro-1H-indazole (25 mg) was prepared. LC-MS (Method D): R _T = 24.24 min, 299 (M + H) ⁺ .

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メトキシ−１Ｈ−インダゾール［３４ｍｇ、実施例２３５（ｂ）］の溶液を０℃でジクロロメタン中の三臭化ホウ素の溶液（０.３０ｍＬ、１Ｍ）で処理した。その後、混合物を還流温度で４時間加熱し、その後冷却し、その後水を滴下処理した。飽和重炭酸ナトリウム水溶液を添加してｐＨを７〜８の間に調整し、その後この混合物を酢酸エチルで２回抽出した。合わせた抽出物を塩水で洗浄し、硫酸マグネシウム上に乾燥し、その後蒸発させた。淡黄色固体の残存物を酢酸エチルとトリエチルアミンの混合物（９９：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、白色固体として３−（５,６
−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−オール（２３ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.１９分；２７９（Ｍ＋Ｈ)⁺。 [Example 243]
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazol-5-ol

A solution of 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methoxy-1H-indazole [34 mg, Example 235 (b)] was dissolved in boron tribromide in dichloromethane at 0 ° C. Treated with solution (0.30 mL, 1M). The mixture was then heated at reflux temperature for 4 hours, then cooled, and then water treated dropwise. Saturated aqueous sodium bicarbonate was added to adjust the pH to between 7-8, after which the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and then evaporated. The pale yellow solid residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and triethylamine (99: 1, v / v) to give 3- (5,6 as a white solid.
-Dimethyl-1H-benzimidazol-2-yl) -1H-indazol-5-ol (23 mg) was obtained. LC-MS (Method B): R _T = 2.19 min; 279 (M + H) ⁺ .

ジメチルホルムアミド（２ｍｌ）中の４−プロピル−ベンゼン−１,２−ジアミン［５７ｍｇ、参考実施例３０（ｄ）］および重亜硫酸ナトリウム（４０ｍｇ）の攪拌溶液をインダゾール−３−カルボキシアルデヒド［参考実施例６（ｌ）］で処理した。反応混合物をSmith Creatorマイクロ波中に２００℃で１３分間加熱し、その後酢酸エチルと水との間に分配した。有機層を塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルとヘキサンの混合物（３：１）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、淡茶色固体として３−（５−ｎ−プロピル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール（７４ｍｇ）を得た。ＭＳ：２７７.３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１２.８１分。 [Example 244]
(A) 3- (5-n-propyl-1H-benzimidazol-2-yl) -1H-indazole

A stirred solution of 4-propyl-benzene-1,2-diamine [57 mg, Reference Example 30 (d)] and sodium bisulfite (40 mg) in dimethylformamide (2 ml) was indazole-3-carboxaldehyde [Reference Example]. 6 (l)]. The reaction mixture was heated in a Smith Creator microwave at 200 ° C. for 13 minutes and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (3: 1) to give 3- (5-n-propyl-1H-benzimidazol-2-yl as a light brown solid. Yl) -1H-indazole (74 mg) was obtained. MS: 277.3 (M + H) ^<+> . HPLC (Method B1): R _T = 12.81 min.

３,４−ジアミノ−Ｎ−ベンジル−ベンゼンスルホンアミド［参考実施例３０（ｘ）］を使用し、２３０℃で加熱する以外は、上記実施例２４４（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−スルホン酸ベンジルアミド（２３５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝６.３５分、４０４.２０（Ｍ＋Ｈ)⁺。 (B) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-sulfonic acid benzylamide

Using 3,4-diamino-N-benzyl-benzenesulfonamide [Reference Example 30 (x)] and heating at 230 ° C. according to the same method as in Example 244 (a) above as a white solid 2- (1H-indazol-3-yl) -1H-benzimidazole-5-sulfonic acid benzylamide (235 mg) was prepared. LC-MS (Method L): R _T = 6.35 min, 404.20 (M + H) ⁺ .

４−メタンスルホニル−ベンゼン−１,２−ジアミン［参考実施例４９（ｆ）］を使用し、２１０℃で加熱する以外は、上記実施例２４４（ａ）と同様の方法に従って、白色固体として３−（５−メタンスルホニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−
インダゾール（１０５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝５.７１分、３１３.２３（Ｍ＋Ｈ)⁺。 (C) 3- (5-Methanesulfonyl-1H-benzimidazol-2-yl) -1H-indazole

Using 4-methanesulfonyl-benzene-1,2-diamine [Reference Example 49 (f)] and heating at 210 ° C. according to the same method as Example 244 (a) above, 3 -(5-Methanesulfonyl-1H-benzoimidazol-2-yl) -1H-
Indazole (105 mg) was prepared. LC-MS (Method L): R _T = 5.71 min, 313.23 (M + H) ⁺ .

テトラヒドロフラン（１０ｍＬ）中の［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−フェニル−メタノン［２００ｍｇ、実施例２３４（ｃ）］の攪拌溶液を、−７８℃で窒素雰囲気下に、テトラヒドロフラン中の水素化ジイソブチルアルミニウムの溶液（１.１８ｍＬ、１Ｎ）で滴下処理した。反応混合物を周囲温度に加温し、その後１６時間攪拌し、その後エーテルと水酸化ナトリウム溶液（２Ｎ）との間に分配した。有機層を水、その後塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルとヘキサンの混合物（３：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、白色固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−フェニル−メタノール（１６１ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝２１.８９分、３４１.３（Ｍ＋Ｈ)⁺。 [Example 245]
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanol

A stirred solution of [2- (indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanone [200 mg, Example 234 (c)] in tetrahydrofuran (10 mL) was added at −78 ° C. with nitrogen. Under atmosphere, treated dropwise with a solution of diisobutylaluminum hydride in tetrahydrofuran (1.18 mL, 1N). The reaction mixture was warmed to ambient temperature and then stirred for 16 hours, then partitioned between ether and sodium hydroxide solution (2N). The organic layer was washed with water followed by brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (3: 1, v / v) as a white solid [2- (indazol-3-yl) -1H- Benzimidazol-5-yl] -phenyl-methanol (161 mg) was obtained. LC-MS (Method D): R _T = 21.89 min, 341.3 (M + H) ⁺ .

ジメチルホルムアミド（３ｍＬ）中の［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−カルボン酸［１３０ｍｇ、実施例２４７（ａ）］、ヒドロキシベンザトリアゾール（１８９ｍｇ）およびジイソプロピルエチルアミン（７３２μＬ）の攪拌溶液をエチルアミンおよび塩酸１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（２６７ｍｇ）で処理した。反応混合物を８０℃で１夜加熱し、その後酢酸エチルと５％クエン酸の間に分配した。水層を酢酸エチルで再抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液、その後塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存した油状物を分取ＨＰＬＣに付し、白色固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］カルボン酸、エチルアミドを得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３７分；３０６.２７（Ｍ＋Ｈ)⁺。 [Example 246]
(A) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] carboxylic acid, ethylamide

[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid [130 mg, Example 247 (a)], hydroxybenztriazole (189 mg) and diisopropylethylamine in dimethylformamide (3 mL) A stirred solution of (732 μL) was treated with ethylamine and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (267 mg). The reaction mixture was heated at 80 ° C. overnight and then partitioned between ethyl acetate and 5% citric acid. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate then brine, then dried over magnesium sulfate and then evaporated. The remaining oil was subjected to preparative HPLC to give [2- (indazol-3-yl) -1H-benzimidazol-5-yl] carboxylic acid, ethylamide as a white solid. LC-MS (Method B): R _T = 2.37 min; 306.27 (M + H) ⁺ .

メチルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−カルボン酸、メチルアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２８分；２９２.３０（Ｍ＋Ｈ)⁺。 (B) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, methylamide

Except for using methylamine, [2- (indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, methylamide was obtained as a white solid according to the same method as in Example 246 (a) above. Manufactured. LC-MS (Method B): R _T = 2.28 min; 292.30 (M + H) ⁺ .

ジメチルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−カルボン酸、ジメチルアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３８分；３０６.２７（Ｍ＋Ｈ)⁺。 (C) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, dimethylamide

[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, dimethylamide as a white solid according to the same method as in Example 246 (a) except that dimethylamine was used Manufactured. LC-MS (Method B): R _T = 2.38 min; 306.27 (M + H) ⁺ .

イソプロピルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−カルボン酸、イソプロピルアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４８分；３２０.３０（Ｍ＋Ｈ)⁺。 (D) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, isopropylamide

[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, isopropylamide as a white solid according to the same method as in Example 246 (a) except that isopropylamine was used Manufactured. LC-MS (Method B): R _T = 2.48 min; 320.30 (M + H) ⁺ .

ベンジルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白
色固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−カルボン酸、ベンジルアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６８分；３６８.２７（Ｍ＋Ｈ)⁺。 (E) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzylamide

[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzylamide as a white solid according to the same method as in Example 246 (a) except that benzylamine is used. Manufactured. LC-MS (Method B): R _T = 2.68 min; 368.27 (M + H) ⁺ .

アニリンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−カルボン酸、ベンズアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７３分；３５４.２６（Ｍ＋Ｈ)⁺。 (F) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzamide

[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid and benzamide are produced as a white solid according to the same method as in Example 246 (a) except that aniline is used. did. LC-MS (Method B): R _T = 2.73 min; 354.26 (M + H) ⁺ .

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−ピラゾール−４−カルボン酸［実施例２４７（ｂ）］およびイソプロピルアミンを使用し、反応生成物をジクロロメタンとメタノールの混合物（１９：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュクロマトグラフィーに付する以外は、上記実施例２４６（ａ）と同様の方法に従って、オフホワイトの固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６７分；２９８（Ｍ＋Ｈ)⁺。 (G) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide

Using 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -pyrazole-4-carboxylic acid [Example 247 (b)] and isopropylamine, the reaction product was mixed with dichloromethane and methanol ( 19: 1, v / v), except for flash chromatography on silica using eluent, according to a method similar to Example 246 (a) above as 3- (5,6- Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide was prepared. LC-MS (Method B): R _T = 2.67 min; 298 (M + H) ⁺ .

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−ピラゾール−４−カルボン酸［参考実施例２４７（ｂ）］および２−アミノ−２−メチル−１−プロパノー
ルを使用し、反応生成物をジクロロメタンとメタノールの混合物（１９：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュクロマトグラフィーに付する以外は、上記実施例２４６（ａ）と同様の方法に従って、淡黄色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸（２−ヒドロキシ−１,１−ジメチル−エチル）−アミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６３分；３２８（Ｍ＋Ｈ)⁺。 (H) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide

Using 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -pyrazole-4-carboxylic acid [Reference Example 247 (b)] and 2-amino-2-methyl-1-propanol, The reaction product is pale yellow according to the same procedure as in Example 246 (a) above except that the reaction product is subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19: 1, v / v). 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide was prepared as a solid. LC-MS (Method B): R _T = 2.63 min; 328 (M + H) ⁺ .

２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸［実施例２４７（ｃ）］および３−（アミノメチル）ピリジンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（ピリジン−３−イルメチル）−アミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４９分；４０４（Ｍ＋Ｈ)⁺。 (I) 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide

The above procedure was followed except that 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid [Example 247 (c)] and 3- (aminomethyl) pyridine were used. According to a method similar to Example 246 (a), 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide as a white solid Manufactured. LC-MS (Method B): R _T = 2.49 min; 404 (M + H) ⁺ .

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メチル−ピラゾール−４−カルボン酸［実施例２４７（ｄ）］およびシクロプロピルアミンを使用し、反応生成物ジクロロメタンとメタノールの混合物（１９：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュクロマトグラフィーに付する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メチル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６７分；３１０（Ｍ＋Ｈ)⁺。 (J) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide

Using 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid [Example 247 (d)] and cyclopropylamine, the reaction product with dichloromethane Except for subjecting to a flash chromatography on silica eluting with a mixture of methanol (19: 1, v / v), 3- (5, 6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide was prepared. LC-MS (Method B): R _T = 2.67 min; 310 (M + H) ⁺ .

２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸［実施例２４７（ｃ）］およびベンジルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、淡黄色固体として２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸フェニルメチル−アミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１７分；４０３（Ｍ＋Ｈ)⁺。 (K) 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid phenylmethyl-amide

Example 246 (a) above except that 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid [Example 247 (c)] and benzylamine are used. According to the same method as described above, 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid phenylmethyl-amide was produced as a pale yellow solid. LC-MS (Method B): R _T = 3.17 min; 403 (M + H) ⁺ .

２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸［実施例２４７（ｃ）］および２−（アミノメチル）ピリジンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、オフホワイトの固体として２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（ピリジン−２−イルメチル）−アミドを製造した。ＬＣ−ＭＳ（方法Ｄ）：Ｒ_T＝９.３３分、３６７.２８（Ｍ＋Ｈ)⁺。 (L) 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide

The above procedure was followed except that 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid [Example 247 (c)] and 2- (aminomethyl) pyridine were used. 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid (pyridin-2-ylmethyl)-as an off-white solid according to a method similar to Example 246 (a) An amide was prepared. LC-MS (Method D): R _T = 9.33 min, 367.28 (M + H) ⁺ .

３−（アミノメチル）ピリジンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、オフホワイトの固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（ピリジン−３−イルメチル）−アミド（４２.２ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝４.９６分、３６７.１９（Ｍ−Ｈ)^-。 (M) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide

Except for using 3- (aminomethyl) pyridine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5 as an off-white solid according to the same method as in Example 246 (a) above. Carboxylic acid (pyridin-3-ylmethyl) -amide (42.2 mg) was prepared. LC-MS (Method L): R _T = 4.96 min, 367.19 (M−H) ⁻ .

３−メチルベンジルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸３−メチル−ベンジルアミド（３３.４ｍｇ）を製造した。ＭＳ：３８２.５２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１６.２２分。 (N) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide

Except for using 3-methylbenzylamine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-carboxylate as a white solid according to the same method as in Example 246 (a) above. Methyl-benzylamide (33.4 mg) was prepared. MS: 382.52 (M + H) ^<+> . HPLC (Method B1): R _T = 16.22 min.

４−メチルベンジルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸４−メチル−ベンジルアミド（６３.５ｍｇ）を製造した。ＭＳ：３８２.５４（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１６.１４分。 (O) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methyl-benzylamide

Except for using 4-methylbenzylamine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-carboxylate as a white solid according to the same method as in Example 246 (a) above. Methyl-benzylamide (63.5 mg) was prepared. MS: 382.54 (M + H) ^<+> . HPLC (Method B1): R _T = 16.14 min.

１−（３−アミノプロピル）−２−ピロリジノンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸［３−（２−オキソ−ピロリジン−１−イル）−プロピル］−アミド（６８.１ｍｇ）を製造した。ＭＳ：４０１.１３（Ｍ−Ｈ)^-。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１１.２９分。 (P) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide

2- (1H-indazol-3-yl) -1H-benzimidazole as a white solid according to the same method as in Example 246 (a) except that 1- (3-aminopropyl) -2-pyrrolidinone was used. -5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide (68.1 mg) was prepared. MS: 401.13 (M-H) -. HPLC (Method B1): R _T = 11.29 min.

４−（２−アミノエチル）モルホリンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（２−モルホリン−４−イル−エチル）−アミド（７０.８ｍｇ）を製造した。ＭＳ：３８９.１２（Ｍ−Ｈ)^-。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝８.５１分。 (Q) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide

Except for using 4- (2-aminoethyl) morpholine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5 as a white solid was prepared in the same manner as in Example 246 (a) above. Carboxylic acid (2-morpholin-4-yl-ethyl) -amide (70.8 mg) was prepared. MS: 389.12 (M-H) ^- . HPLC (Method B1): R _T = 8.51 min.

２−メトキシエチルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（２−メトキシ−エチル）−アミド（５５.２ｍｇ）を製造した。ＭＳ：３３６.５２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１１.３０分。 (R) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl) -amide

Except for the use of 2-methoxyethylamine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2- Methoxy-ethyl) -amide (55.2 mg) was prepared. MS: 336.52 (M + H) ^<+> . HPLC (Method B1): R _T = 11.30 min.

反応混合物を５０℃で加熱し、３−アミノプロピオニトリルを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（２−シアノ−エチル）−アミド（１５.４ｍｇ）を製造した。ＭＳ：３３１.１５（Ｍ＋Ｈ)⁺、３２９.１７（Ｍ−Ｈ)^-。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１２.７２分。 (S) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-cyano-ethyl) -amide

The reaction mixture was heated at 50 ° C. and 2- (1H-indazol-3-yl) -1H as a white solid according to the same procedure as in Example 246 (a) except that 3-aminopropionitrile was used. -Benzimidazole-5-carboxylic acid (2-cyano-ethyl) -amide (15.4 mg) was prepared. MS: 331.15 (M + H) +, 329.17 (M-H) -. HPLC (Method B1): R _T = 12.72 min.

反応混合物を５０℃で加熱し、２−アミノ−２−メチル−１−プロパノールを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、茶色油状物として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（２−ヒドロキシ−１,１−ジメチル−エチル）−アミド（２９.６ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝１０.５７分、３５０.１６（Ｍ＋Ｈ)⁺、３４８.１８（Ｍ−Ｈ)^-。 (T) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide

The reaction mixture was heated at 50 ° C. and 2- (1H-indazole-as a brown oil was obtained in the same manner as in Example 246 (a) except that 2-amino-2-methyl-1-propanol was used. 3-yl) -1H-benzimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide (29.6 mg) was prepared. LC-MS (Method L): R _T = 10.57 min, 350.16 (M + H) ⁺ , 348.18 (M−H) ⁻ .

１−（３−アミノプロピル）イミダゾールを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（３−イミダゾール−１−イル−プロピル）−アミド（３１.９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝８.４５分、３８６.２２（Ｍ＋Ｈ)⁺、３８４.２６（Ｍ−Ｈ)^-。 (U) 2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide

Except for using 1- (3-aminopropyl) imidazole, 2- (1H-indazol-3-yl) -1H-benzimidazole-5 as a white solid according to the same method as in Example 246 (a) above. Carboxylic acid (3-imidazol-1-yl-propyl) -amide (31.9 mg) was prepared. LC-MS (Method B): R _T = 8.45 min, 386.22 (M + H) ⁺ , 384.26 (M−H) ⁻ .

イソブチルアミンを使用する以外は、上記実施例２４６（ｇ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸イソブチル−アミド（１０１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝９.３８分、３１２（Ｍ＋Ｈ)⁺。 (V) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid as a white solid according to the same method as in Example 246 (g) except that isobutylamine was used. Acid isobutyl-amide (101 mg) was prepared. LC-MS (Method M): R _T = 9.38 min, 312 (M + H) ⁺ .

イソプロピルアミンを使用する以外は、上記実施例２４６（ｇ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミド（１００ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝７.２１分、２９８（Ｍ＋Ｈ)⁺。 (W) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid as a white solid according to the same method as in Example 246 (g) except that isopropylamine was used. Acid isopropylamide (100 mg) was prepared. LC-MS (Method L): R _T = 7.21 min, 298 (M + H) ⁺ .

（アミノメチル）シクロプロパンを使用する以外は、上記実施例２４６（ｇ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルメチル−アミド（１０５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝８.７７分、３１０（Ｍ＋Ｈ)⁺。 (X) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole as a white solid according to the same method as in Example 246 (g) except using (aminomethyl) cyclopropane -4-Carboxylic acid cyclopropylmethyl-amide (105 mg) was prepared. LC-MS (Method M): R _T = 8.77 min, 310 (M + H) ⁺ .

ｔ−ブチルアミンを使用する以外は、上記実施例２４６（ｊ）と同様の方法に従って、オフホワイトの固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メチル−１Ｈ−ピラゾール−４−カルボン酸ｔ−ブチルアミド（５７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１３.８６分、３２６（Ｍ＋Ｈ)⁺。 (Y) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid t-butylamide

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl- as an off-white solid according to the same procedure as in Example 246 (j) except that t-butylamine is used. 1H-pyrazole-4-carboxylic acid t-butylamide (57 mg) was prepared. LC-MS (Method M): R _T = 13.86 min, 326 (M + H) ⁺ .

（ｉ）３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボン酸［９７ｍｇ、実施例２６３］および塩酸ジメチルアミン（２３ｍｇ）を使用し、（ii）反応を周囲温度で１夜実行し、そして（iii）反応生成物をフラッシュカラムクロマトグラフィー［酢酸エチルから酢酸エチル／メタノール（９７：３、ｖ／ｖ）を溶離剤とする］に付し、ついで１,４−ジオキサン中の４Ｍ塩化水素で処理し、ジクロロメタンとジエチルエーテルで磨砕する以外は、上記実施例２４６（ｊ）と同様の方法に従って、白色固体として二塩酸３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボン酸ジメチルアミド（８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝９.３７分、３２０（Ｍ＋Ｈ)⁺。 (Z) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide dihydrochloride

(I) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid [97 mg, Example 263] and dimethylamine hydrochloride (23 mg) were used (ii ) The reaction is run overnight at ambient temperature, and (iii) The reaction product is subjected to flash column chromatography [ethyl acetate to ethyl acetate / methanol (97: 3, v / v) as eluent] Subsequent treatment with 4M hydrogen chloride in 1,4-dioxane and trituration with dichloromethane and diethyl ether followed the same procedure as in Example 246 (j) above as a white solid 3- (5,6 dihydrochloride as a white solid. -Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide (8 mg) was prepared. LC-MS (Method M): R _T = 9.37 min, 320 (M + H) ⁺ .

２−（４−イソブチリルアミノ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸［参考実施例３５］およびベンジルアミンを使用する以外は、上記実施例２４６（ａ）と同様の方法に従って、白色固体として２−（４−イソブチリルアミノ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸ベンジルアミド（１７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝１１.００分、４０３（Ｍ＋Ｈ)⁺。 (Aa) 2- (4-Isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide

Example 246 (a) above except that 2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid [Reference Example 35] and benzylamine are used. According to the same procedure as described above, 2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide (17 mg) was produced as a white solid. LC-MS (Method L): R _T = 11.00 min, 403 (M + H) ⁺ .

１−（２−アミノエチル）ピペリジンを使用し、反応混合物を５０℃で６時間加熱する以外は、上記実施例２４６（ａ）と同様の方法に従って、油状物として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（２−ピペリジン−１−イル−エチル）−アミドを製造した。ＭＳ：３８７.２２（Ｍ−Ｈ)^-。ＨＰＬＣ（方法Ｌ）：Ｒ_T＝５.０３分。 (Ab) 2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide

2- (1H-indazole-3) as an oil according to the same method as in Example 246 (a) except that 1- (2-aminoethyl) piperidine was used and the reaction mixture was heated at 50 ° C. for 6 hours. -Yl) -1H-benzimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide was prepared. MS: 387.22 (M-H) ^- . HPLC (Method L): R _T = 5.03 min.

（２−アミノメチル）ピリジンを使用する以外は、上記実施例２４６（ａｂ）と同様の方法に従って、オフホワイトの固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（ピリジン−２−イルメチル）−アミドを製造した。ＭＳ：３６７.２８（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝９.３３分。 (Ac) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide

Except for using (2-aminomethyl) pyridine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5 as an off-white solid according to the same method as in Example 246 (ab) above. Carboxylic acid (pyridin-2-ylmethyl) -amide was prepared. MS: 367.28 (M + H) ^<+> . HPLC (Method B1): R _T = 9.33 min.

４−（３−（アミノプロピル））−１−メチルピペラジンを使用する以外は、上記実施例２４６（ａｂ）と同様の方法に従って、油状物として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸［３−（４−メチル−ピペラジン−１−イル）−プロピル］−アミドを製造した。ＭＳ：４１６.２１（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｌ）：Ｒ_T＝４.４６分。 (Ad) 2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide

2- (1H-indazol-3-yl) -1H as an oil according to the same method as in Example 246 (ab) except that 4- (3- (aminopropyl))-1-methylpiperazine was used. -Benzimidazole-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide was prepared. MS: 416.21 (M + H) ^<+> . HPLC (Method L): R _T = 4.46 min.

イソ酪酸および２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−アミン［実施例２６５］を使用する以外は、上記実施例２４６（ａｂ）と同様の方法に従って、オフホワイトの固体としてＮ−［２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−イソブチルアミドを製造した。ＭＳ：３２０.２３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１９.２８分。 (Ae) N- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -isobutyramide

According to a method similar to Example 246 (ab) above except that isobutyric acid and 2- (1H-indazol-3-yl) -3H-benzimidazol-5-amine [Example 265] were used, N- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -isobutyramide was prepared as a solid. MS: 320.23 (M + H) ^<+> . HPLC (Method B1): R _T = 19.28 min.

テトラヒドロフラン（４ｍＬ）および水（２ｍＬ）中の３−（５−メトキシカルボニル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール［８４.５ｍｇ、実施例２３５（ａｃ）］および水酸化ナトリウム（７４ｍｇ）の攪拌溶液を７５℃で１夜加熱した。反応混合物を蒸発させ、油状の残存物を酢酸エチルと水の間に分配した。水層をｐＨ６に酸性化し、酢酸エチルで抽出した。有機層を硫酸マグネシウム上に乾燥し、その後蒸発させて、油状物として［２−（インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−イル］−カルボン酸（８０ｍｇ）を得た。ＭＳ：２７９.１４（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｈ）：Ｒ_T＝２.８１分。 [Example 247]
(A) [2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid

3- (5-Methoxycarbonyl-1H-benzoimidazol-2-yl) -1H-indazole [84.5 mg, Example 235 (ac)] and sodium hydroxide (74 mg) in tetrahydrofuran (4 mL) and water (2 mL). ) Was heated at 75 ° C. overnight. The reaction mixture was evaporated and the oily residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 6 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then evaporated to give [2- (indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid (80 mg) as an oil. MS: 279.14 (M + H) ^<+> . HPLC (Method H): R _T = 2.81 min.

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−ピラゾール−４−カルボン酸エチルエステル［実施例２３５（ａｅ）］を使用し、反応を６０℃で実行する以外は、上記実施例２４７（ａ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−５−イル）−ピラゾール−４−カルボン酸を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.１７分；２５７（Ｍ＋Ｈ)⁺。 (B) 3- (5,6-Dimethyl-1H-benzimidazol-5-yl) -pyrazole-4-carboxylic acid

The above except that 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -pyrazole-4-carboxylic acid ethyl ester [Example 235 (ae)] was used and the reaction was carried out at 60 ° C. According to a method similar to that in Example 247 (a), 3- (5,6-dimethyl-1H-benzimidazol-5-yl) -pyrazole-4-carboxylic acid was produced as a white solid. LC-MS (Method B): R _T = 2.17 min; 257 (M + H) ⁺ .

２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸メチルエステル［実施例２３５（ａｆ）］を使用し、テト
ラヒドロフランをメタノールで置き換え、反応を６５℃で実行する以外は、上記実施例２４７（ａ）と同様の方法に従って、淡茶色固体として製造した２−（４−イソプロピルカルバモイル−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６７分；３１４（Ｍ＋Ｈ)⁺。 (C) 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid

2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester [Example 235 (af)] was used, tetrahydrofuran was replaced with methanol, and the reaction was conducted at 65 ° C. 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid prepared as a light brown solid according to the same method as in Example 247 (a) except that The acid was used without further purification. LC-MS (Method B): R _T = 2.67 min; 314 (M + H) ⁺ .

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メチル−ピラゾール−４−カルボン酸エチルエステル［実施例２３５（ａｇ）］を使用し、テトラヒドロフランをメタノールで置き換え、反応を６５℃で実行する以外は、上記実施例２４７（ａ）と同様の方法に従って、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−５−メチル−ピラゾール−４−カルボン酸を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７５分；２７１（Ｍ＋Ｈ)⁺。 (D) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid

Using 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid ethyl ester [Example 235 (ag)], tetrahydrofuran was replaced with methanol and the reaction According to the same method as in Example 247 (a) above except that 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methyl-pyrazole- 4-carboxylic acid was prepared. LC-MS (Method B): R _T = 2.75 min; 271 (M + H) ⁺ .

ジクロロメタン（４ｍＬ）中の５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［８３ｍｇ、実施例２３３（ｃ）］およびジイソプロピルエチルアミン（２５６μＬ）の攪拌溶液を塩化イソブチリル（１１５μＬ）で処理した。反応混合物を室温で３０分間攪拌し、その後ピペリジン（５００μＬ）で処理し、さらに１時間攪拌を続行した。反応混合物を５％クエン酸との間に分配した。有機層を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物をヘキサンと酢酸エチルの混合物を溶離剤とするシリカ上のフラッシュクロマトグラフィーに付し、白色固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−イソブチルアミド（４９ｍｇ）を得た。ＭＳ：２９８.２８（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１４.６６分。 [Example 248]
(A) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide

A stirred solution of 5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [83 mg, Example 233 (c)] and diisopropylethylamine (256 μL) in dichloromethane (4 mL) was chlorinated. Treated with isobutyryl (115 μL). The reaction mixture was stirred at room temperature for 30 minutes, then treated with piperidine (500 μL) and stirring was continued for an additional hour. The reaction mixture was partitioned between 5% citric acid. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of hexane and ethyl acetate to give N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H as a white solid. -Pyrazol-4-yl] -isobutyramide (49 mg) was obtained. MS: 298.28 (M + H) ^<+> . HPLC (Method B1): R _T = 14.66 min.

塩化イソバレリルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−メチル−ブチルアミドを製造した。ＭＳ：３１２.２８（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１５.２８分。 (B) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-butyramide

N- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole- was obtained as a white solid according to the same method as in Example 248 (a) except that isovaleryl chloride was used. 4-yl] -3-methyl-butyramide was prepared. MS: 312.28 (M + H) ^<+> . HPLC (Method B1): R _T = 15.28 min.

塩化フェニルアセチルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−２−フェニル−アセトアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８３分、３４６.１８（Ｍ＋Ｈ)⁺。 (C) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-phenyl-acetamide

N- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole as a white solid is prepared according to the same method as in Example 248 (a) except that phenylacetyl chloride is used. -4-yl] -2-phenyl-acetamide was prepared. LC-MS (Method B): R _T = 2.83 min, 346.18 (M + H) ⁺ .

塩化シクロプロパンカルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてシクロプロパンカルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：２９６.２８（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１３.５０分。 (D) Cyclopropanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for the use of cyclopropanecarbonyl chloride, cyclopropanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl)- 1H-pyrazol-4-yl] -amide was prepared. MS: 296.28 (M + H) ^<+> . HPLC (Method B1): R _T = 13.50 min.

塩化メトキシアセチルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてメトキシ酢酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：３００.３３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｃ１）：Ｒ_T＝１４.２５分。 (E) Methoxyacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Methoxyacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole was obtained as a white solid according to the same method as in Example 248 (a) except that methoxyacetyl chloride was used. -4-yl] -amide was prepared. MS: 300.33 (M + H) ^<+> . HPLC (Method C1): R _T = 14.25 min.

塩化シクロペンチルカルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてシクロペンタンカルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：３２４.３９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１７.６４分。 (F) Cyclopentanecarboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for using cyclopentylcarbonyl chloride, cyclopentanecarboxylic acid [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H as a white solid according to the same method as in Example 248 (a) above -Pyrazol-4-yl] -amide was prepared. MS: 324.39 (M + H) ^<+> . HPLC (Method B1): R _T = 17.64 min.

塩化トリメチルアセチルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてトリメチル酢酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：３１２.３９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１９.５２分。 (G) Trimethylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Trimethylacetic acid [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole was obtained as a white solid according to the same method as in Example 248 (a) except that trimethylacetyl chloride was used. -4-yl] -amide was prepared. MS: 312.39 (M + H) ^<+> . HPLC (Method B1): R _T = 19.52 min.

塩化ｔ−ブチルアセチルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてｔ−ブチル酢酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：３２６.２９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１９.５２分。 (H) t-Butylacetic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

T-Butylacetate [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) as a white solid according to the same method as in Example 248 (a) except that t-butylacetyl chloride was used. -1H-pyrazol-4-yl] -amide was prepared. MS: 326.29 (M + H) ^<+> . HPLC (Method B1): R _T = 19.52 min.

塩化ブチリルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてブタン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：２９８.３４（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１５.０７分。 (I) Butanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for using butyryl chloride, butanoic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole- was prepared as a white solid according to the same method as in Example 248 (a) above. 4-yl] -amide was prepared. MS: 298.34 (M + H) ^<+> . HPLC (Method B1): R _T = 15.07 min.

塩化イソオキサゾール−５−カルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてイソオキサゾール−５−カルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：３２３.１６（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１０.０１分。 (J) Isoxazole-5-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Isoxazole-5-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazole] was prepared as a white solid in the same manner as in Example 248 (a) except that isoxazole-5-carbonyl chloride was used. -2-yl) -1H-pyrazol-4-yl] -amide was prepared. MS: 323.16 (M + H) ^<+> . HPLC (Method B1): R _T = 10.01 min.

塩化Ｓ（＋）−２−メチルブチリルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてＳ（＋）−２−メチルブタン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：３１２.１８（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１１.１５分。 (K) S (+)-2-methylbutanoic acid [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for using S (+)-2-methylbutyryl chloride, S (+)-2-methylbutanoic acid [3- (5,6-dimethyl-) as a white solid was prepared in the same manner as in Example 248 (a) above. 1H-Benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide was prepared. MS: 312.18 (M + H) ^<+> . HPLC (Method B1): R _T = 11.15 min.

３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｄ）］および塩化シクロプロパンカルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてシクロプロパンカルボン酸［３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＭＳ：３１０.３２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝８.８８分。 (L) Cyclopropanecarboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

The above examples except using 3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (d)] and cyclopropanecarbonyl chloride. Cyclopropanecarboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide as a white solid according to the same method as 248 (a). Manufactured. MS: 310.32 (M + H) ^<+> . HPLC (Method B1): R _T = 8.88 min.

（ｉ）テトラヒドロフラン（２５ｍＬ）中の３−（６−クロロ−５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［０.２ｇ、実施例２３３（ｅ）］およびジイソプロピルエチルアミン（３９２ｍｇ、４当量）の溶液を塩化ピペリジンカルボニル（４５０ｍｇ、４当量）で処理し、周囲温度で１夜攪拌し、反応混合物を蒸発させ、（ii）反応生成物を水（３０ｍＬ）および酢酸エチル（５０ｍＬ）で磨砕し、水層を酢酸エチルで抽出し、（iii）有機層を合わせ、硫酸マグネシウム上に乾燥し、その後蒸発させ、（iv）残存物をシリカゲル上のクロマトグラフィー（酢酸エチル
）に付し、（ｖ）部分的に精製した物質を酢酸エチル（１５ｍＬ）で１.５時間磨砕し、濾過し、（vi）濾液を蒸発させ、残存物をシリカゲル上のクロマトグラフィー（酢酸エチル／ヘプタン２０〜０％勾配）に付する以外は、上記実施例２４８（ａ）と同様の方法に従って、黄色固体としてピペリジン−１−カルボン酸［３−（６−クロロ−５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（５０ｍｇ）を製造した。融点＞３１０℃。ＬＣ−ＭＳ（方法Ｅ）Ｒ_T＝３.２５分、３７４（Ｍ＋Ｈ)⁺。 (M) Piperidine-1-carboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

(I) 3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [0.2 g, Example 233 (e)] in tetrahydrofuran (25 mL) and A solution of diisopropylethylamine (392 mg, 4 eq) is treated with piperidinecarbonyl chloride (450 mg, 4 eq) and stirred overnight at ambient temperature, the reaction mixture is evaporated, (ii) the reaction product is washed with water (30 mL) and Triturate with ethyl acetate (50 mL), extract the aqueous layer with ethyl acetate, (iii) combine the organic layers, dry over magnesium sulfate and then evaporate; (iv) chromatograph the residue on silica gel ( Ethyl acetate), (v) the partially purified material was triturated with ethyl acetate (15 mL) for 1.5 hours, filtered, and (vi) the filtrate was evaporated to leave Is subjected to chromatography on silica gel (ethyl acetate / heptane 20-0% gradient) in the same manner as in Example 248 (a) above, followed by piperidine-1-carboxylic acid [3- (6 -Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide (50 mg) was prepared. Melting point> 310 ° C. LC-MS (Method E) R _T = 3.25 min, 374 (M + H) ⁺ .

塩化Ｎ,Ｎ−ジメチルカルバミルを使用する以外は、上記実施例２４８（ｍ）と同様の方法に従って、黄色固体として３−［３−（６−クロロ−５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジメチル尿素を製造した。融点＞３００℃。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.４分、３３５（Ｍ＋Ｈ)⁺。 (N) 3- [3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethylurea

3- [3- (6-Chloro-5-methoxy-1H-benzimidazole-2) as a yellow solid according to the same method as in Example 248 (m) except that N, N-dimethylcarbamyl chloride was used. -Yl) -1H-pyrazol-4-yl] -1,1-dimethylurea was prepared. Melting point> 300 ° C. LC-MS (Method E): R _T = 2.4 min, 335 (M + H) ⁺ .

３−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［２８２ｍｇ、実施例２３３（ｆ）］および塩化シクロプロパンカルボニル（０.５５８ｍｌ）を使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、オフホワイトの固体としてシクロプロパンカルボン酸［３−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（７６ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝５.２５分、２９８.２６（Ｍ＋Ｈ)⁺。 (O) Cyclopropanecarboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except using 3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [282 mg, Example 233 (f)] and cyclopropanecarbonyl chloride (0.558 ml) Following the same procedure as in Example 248 (a) above, cyclopropanecarboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide as an off-white solid (76 mg) was produced. LC-MS (Method L): R _T = 5.25 min, 298.26 (M + H) ⁺ .

３−（５−エトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［１８７ｍｇ、実施例２３３（ｇ）］を使用する以外は、上記実施例２４８（ｏ）と同様の方法に従って、淡黄色固体としてシクロプロパンカルボン酸［３−（５−エトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（１１２ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝２.２６分、３１２.２３（Ｍ＋Ｈ)⁺、３１０.３０（Ｍ−Ｈ)^-。 (P) Cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Similar to Example 248 (o) above, except using 3- (5-ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [187 mg, Example 233 (g)]. According to the method, cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide (112 mg) was prepared as a pale yellow solid. LC-MS (Method H): R _T = 2.26 min, 312.23 (M + H) ⁺ , 310.30 (M−H) ⁻ .

３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｈ）］および塩化シクロプロパンカルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてシクロプロパンカルボン酸［３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（１３５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１１.３１分、３００.３１（Ｍ＋Ｈ)⁺。 (Q) Cyclopropanecarboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

The above examples except using 3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (h)] and cyclopropanecarbonyl chloride. Cyclopropanecarboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide (1) as a white solid according to a method similar to 248 (a). 135 mg) was produced. LC-MS (Method M): R _T = 11.31 min, 300.31 (M + H) ⁺ .

３−（５−トリフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｉ）］および塩化シクロプロパンカルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてシクロプロパンカルボン酸［３−（５−トリフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（２７５ｍｇ）を製造した。ＬＣ−
ＭＳ（方法Ｍ）：Ｒ_T＝１３.５７分、３５２.２２（Ｍ＋Ｈ)⁺。 (R) Cyclopropanecarboxylic acid [3- (5-trifluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Example 248 above with the exception that 3- (5-trifluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (i)] and cyclopropanecarbonyl chloride were used. According to the same method as in a), cyclopropanecarboxylic acid [3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide (275 mg) is produced as a white solid. did. LC-
MS (Method M): R _T = 13.57 min, 352.22 (M + H) ⁺ .

３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｊ）］および塩化シクロプロパンカルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてシクロプロパンカルボン酸［３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（８８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１３.６２分、３３８.１２（Ｍ＋Ｈ)⁺。 (S) Cyclopropanecarboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Example 248 above, except that 3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (j)] and cyclopropanecarbonyl chloride were used. According to the same method as in a), cyclopropanecarboxylic acid [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide (88 mg) is produced as a white solid. did. LC-MS (Method M): R _T = 13.62 min, 338.12 (M + H) ⁺ .

塩化イソブチリルを使用する以外は、上記実施例２４８（ｓ）と同様の方法に従って、白色固体としてＮ−［３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−イソブチルアミド（７１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１０.１１分、３３６.１２（Ｍ＋Ｈ)⁺。 (T) N- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isobutyramide

N- [3- (5-Trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazole- was obtained as a white solid according to the same method as in Example 248 (s) except that isobutyryl chloride was used. 4-yl] -isobutyramide (71 mg) was prepared. LC-MS (Method M): R _T = 10.11 min, 336.12 (M + H) ⁺ .

３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２６１］および塩化シクロプロパンカルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてシクロプロパ
ンカルボン酸［３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（４６ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝７.０６分、ＭＳ：３１６.２６（Ｍ＋Ｈ)⁺。 (U) Cyclopropanecarboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Example 248 (a) above, except that 3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 261] and cyclopropanecarbonyl chloride were used. ) And cyclopropanecarboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide (46 mg) as a white solid. Manufactured. LC-MS (Method L): R _T = 7.06 min, MS: 316.26 (M + H) ⁺ .

塩化３,５−ジメチルイソオキサゾール−４−カルボニルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体として３,５−ジメチル−イソオキサゾール−４−カルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（６２ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝８.４５分、３５１.３２（Ｍ＋Ｈ)⁺。 (V) 3,5-dimethyl-isoxazole-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for the use of 3,5-dimethylisoxazole-4-carbonyl chloride, 3,5-dimethyl-isoxazole-4-carboxylic acid [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide (62 mg) was prepared. LC-MS (Method L): R _T = 8.45 min, 351.32 (M + H) ⁺ .

塩化アセチルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アセトアミド（２５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝６.３４分、２７０.１４（Ｍ＋Ｈ)⁺。 (W) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide

N- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole- was obtained as a white solid according to the same method as in Example 248 (a) except that acetyl chloride was used. 4-yl] -acetamide (25 mg) was prepared. LC-MS (Method L): R _T = 6.34 min, 270.14 (M + H) ⁺ .

塩化３−フロイルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてフラン−３−カルボン酸［３−（５,６−ジメチルメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（８０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝７.１０分、３２２.３１（Ｍ＋Ｈ)⁺。 (X) Furan-3-carboxylic acid [3- (5,6-dimethylmethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for the use of 3-furoyl chloride, a furan-3-carboxylic acid [3- (5,6-dimethylmethyl-1H-benzimidazol-2-yl] as a white solid was prepared in the same manner as in Example 248 (a) above. Yl) -1H-pyrazol-4-yl] -amide (80 mg). LC-MS (Method L): R _T = 7.10 min, 322.31 (M + H) ⁺ .

塩化ｐ−トルオイルを使用する以外は、上記実施例２４８（ａ）と同様の方法に従って、白色固体としてＮ−［３−（５,６−ジメチルメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−４−メチル−ベンズアミド（４２ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝１２.２４分、３４６（Ｍ＋Ｈ)⁺。 (Y) N- [3- (5,6-Dimethylmethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -4-methyl-benzamide

N- [3- (5,6-dimethylmethyl-1H-benzoimidazol-2-yl) -1H as a white solid according to the same method as in Example 248 (a) except that p-toluoyl chloride was used. -Pyrazol-4-yl] -4-methyl-benzamide (42 mg) was prepared. LC-MS (Method L): R _T = 12.24 min, 346 (M + H) ⁺ .

酢酸（１００ｍＬ）中の４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４,５−ジメチルフェニル）アミド［５.７ｇ、参考実施例３６（ａ）］の攪拌溶液を１２０℃で１時間加熱し、その後周囲温度に冷却し、その後蒸発させた。油状の残存物を酢酸エチルと水の間に分配した。有機層を硫酸マグネシウム上に乾燥し、蒸発させて、橙色固体として５,６−ジメチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（５.７０ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３０分、２５８.１１（Ｍ＋Ｈ)⁺。 [Example 249]
(A) 5,6-Dimethyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

A stirred solution of 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl) amide [5.7 g, Reference Example 36 (a)] in acetic acid (100 mL) was 120 ° C. For 1 hour, then cooled to ambient temperature and then evaporated. The oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and evaporated to give 5,6-dimethyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole (5.70 g) as an orange solid. It was. LC-MS (Method B): R _T = 2.30 min, 258.11 (M + H) ⁺ .

４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−エチル−５−メチルフェニル）アミド［参考実施例３６（ｂ）］を使用する以外は、上記実施例２４９（ａ）と同様の方法に従って、黄色固体として５−エチル−６−メチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６１分、２７２.２３（Ｍ＋Ｈ)⁺。 (B) 5-ethyl-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethyl-5-methylphenyl) amide [Reference Example 36 (b)] and the above Example 249 (a) According to a similar method, 5-ethyl-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole was prepared as a yellow solid. LC-MS (Method B): R _T = 2.61 min, 272.23 (M + H) ⁺ .

４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−５−クロロ−４−メトキシフェニル）アミド［１.５ｇ、参考実施例３６（ｃ）］を使用する以外は、上記実施例２４９（ａ）と同様の方法に従って、暗色固体として６−クロロ−５−メトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（０.７ｇ）を製造した。ＭＳ：２９４（Ｍ＋Ｈ)⁺。 (C) 6-chloro-5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

Example 249 above, except using 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-5-chloro-4-methoxyphenyl) amide [1.5 g, Reference Example 36 (c)]. According to the same method as (a), 6-chloro-5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole (0.7 g) was produced as a dark solid. MS: 294 (M + H) ^<+> .

４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−フルオロ−５−メチル−フェニル）−アミド［参考実施例３６（ｆ）］を使用する以外は、上記実施例２４９（ａ）と同様の方法に従って、赤色固体として５−フルオロ−６−メチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（０.７３０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.７６分、２６２.２１（Ｍ＋Ｈ)⁺。 (D) 5-fluoro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

Example 249 (a) above except that 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-fluoro-5-methyl-phenyl) -amide [Reference Example 36 (f)] was used. ) To give 5-fluoro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole (0.730 g) as a red solid. LC-MS (Method J): R _T = 2.76 min, 262.21 (M + H) ⁺ .

４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−トリフルオロメトキシ−フェニル）−アミド［参考実施例３６（ｇ）］を使用する以外は、上記実施例２４９（ａ）と同様の方法に従って、赤色固体として２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−５−トリフルオロメトキシ−１Ｈ−ベンゾイミダゾール（１.０２ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.３２分、３１４.１９（Ｍ＋Ｈ)⁺。 (E) 2- (4-Nitro-1H-pyrazol-3-yl) -5-trifluoromethoxy-1H-benzimidazole

4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-trifluoromethoxy-phenyl) -amide [Reference Example 36 (g)] and the above Example 249 (a) According to a similar method, 2- (4-nitro-1H-pyrazol-3-yl) -5-trifluoromethoxy-1H-benzimidazole (1.02 g) was produced as a red solid. LC-MS (Method J): R _T = 3.32 min, 314.19 (M + H) ⁺ .

４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−トリフルオロメチル−フェニル）−アミド［参考実施例３６（ｈ）］を使用する以外は、上記実施例２４９（ａ）と同様の方法に従って、橙色固体として２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール（０.１９５ｇ）を製造した。ＭＳ：２９８.０７（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ）：Ｒ_T＝３.５０分。 (F) 2- (4-Nitro-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole

4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-trifluoromethyl-phenyl) -amide [Reference Example 36 (h)] except that Example 249 (a) above was used. According to a similar method, 2- (4-nitro-1H-pyrazol-3-yl) -5-trifluoromethyl-1H-benzimidazole (0.195 g) was prepared as an orange solid. MS: 298.07 (M + H) ^<+> . HPLC (Method B): R _T = 3.50 min.

４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−クロロ−５−メチル−フェニル）−アミド［参考実施例３６（ｉ）］を使用する以外は、上記実施例２４９（ａ）と同様の方法に従って、橙色固体として５−クロロ−６−メチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（０.３２０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｃ）：Ｒ_T＝３.３６分、３１４.１９（Ｍ＋Ｈ)⁺。 (G) 5-chloro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

Example 249 (a) above except that 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-chloro-5-methyl-phenyl) -amide [Reference Example 36 (i)] was used. ) To give 5-chloro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole (0.320 g) as an orange solid. LC-MS (Method C): R _T = 3.36 min, 314.19 (M + H) ⁺ .

３−アミノ−４−［（４−ニトロ−１Ｈ−ピラゾール−３−カルボニル）−アミノ］安息香酸メチルエステル［参考実施例３６（ｊ）］を使用する以外は、上記実施例２４９（ａ）と同様の方法に従って、黄色固体として２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸メチルエステル（２.５０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７６分、２８８.１２（Ｍ＋Ｈ)⁺。 (H) 2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester

3-amino-4-[(4-nitro-1H-pyrazole-3-carbonyl) -amino] benzoic acid methyl ester [Reference Example 36 (j)] and the above Example 249 (a) According to a similar method, 2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester (2.50 g) was produced as a yellow solid. LC-MS (Method B): R _T = 2.76 min, 288.12 (M + H) ⁺ .

ジメチルホルムアミド（４ｍｌ）中の３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン［０.１５０ｇ、実施例２５１（ａ）］の溶液をジイソプロピルエチルアミン（０.５４ｍｌ）、その後塩化ジメチルカルバミル（０.１２２ｍｌ）で処理した。１時間攪拌後、メタノール（０.１ｍｌ）を添加して反応混合物をクエンチングし、その後酢酸エチルで希釈した。この混合物を塩水で５回洗浄し、その後蒸発させた。残存物をテトラヒドロフラン（９ｍｌ）およびメタノール（３ｍｌ）で処理し、その後得られた溶液を水酸化カリウム（５０ｍｇ）で処理した。この混合物を１時間攪拌し、その後塩酸（１Ｍ）を添加して酸性化し、その後酢酸エチルで３回抽出した。炭酸ナトリウムを添加して水層を塩基性化し、得られた懸濁液を濾過し、その後水で洗浄し、その後風乾し、その後トルエンで共沸し、淡茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸イソプロピルアミドを得た。ＭＳ：３３９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｆ１）：Ｒ_T＝８.６７分。 [Example 250]
(A) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [0 .5] in dimethylformamide (4 ml). A solution of 150 g, Example 251 (a)] was treated with diisopropylethylamine (0.54 ml) followed by dimethylcarbamyl chloride (0.122 ml). After stirring for 1 hour, methanol (0.1 ml) was added to quench the reaction mixture and then diluted with ethyl acetate. The mixture was washed 5 times with brine and then evaporated. The residue was treated with tetrahydrofuran (9 ml) and methanol (3 ml), and then the resulting solution was treated with potassium hydroxide (50 mg). The mixture was stirred for 1 hour, then acidified by addition of hydrochloric acid (1M) and then extracted three times with ethyl acetate. Sodium carbonate is added to basify the aqueous layer, and the resulting suspension is filtered, then washed with water, then air dried, then azeotroped with toluene, and 3- (5,6 as a light brown solid. -Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide was obtained. MS: 339 (M + H) ^<+> . HPLC (Method F1): R _T = 8.67 min.

塩化シクロプロパンカルボニルを使用し、反応混合物を１６時間攪拌する以外は、上記実施例２５０（ａ）と同様の方法に従って、淡黄色固体としてシクロプロピル−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−イル］−メタノン（６８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１０.５７分、３３６（Ｍ＋Ｈ)⁺。 (B) Cyclopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -Methanone

Cyclopropyl- [3- (5,6-dimethyl-1H-) as a pale yellow solid was prepared in the same manner as in Example 250 (a) except that cyclopropanecarbonyl chloride was used and the reaction mixture was stirred for 16 hours. Benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone (68 mg) was prepared. LC-MS (Method M): R _T = 10.57 min, 336 (M + H) ⁺ .

塩化イソプロピルカルボニル、塩化シクロプロピルカルボニルを使用する以外は、上記実施例２５０（ｂ）と同様の方法に従って、白色固体としてイソプロピル−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−イル］−メタノン（６８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝９.２８分、３３８（Ｍ＋Ｈ)⁺。 (C) Isopropyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl]- Methanon

Except for using isopropylcarbonyl chloride and cyclopropylcarbonyl chloride, isopropyl- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl] as a white solid was prepared in the same manner as in Example 250 (b) above. ) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone (68 mg) was prepared. LC-MS (Method M): R _T = 9.28 min, 338 (M + H) ⁺ .

塩化トリメチルアセチルを使用し、炭酸ナトリウムで塩基性化することにより形成された沈殿物を濾過し、ついでトルエンで共沸する以外は、上記実施例２５０（ｂ）と同様の方法に従って、淡黄色固体として１−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−イル］−２,２−ジメチル−プロパン−１−オン（４９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１１.３９分、３５２（Ｍ＋Ｈ)⁺。 (D) 1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl]- 2,2-Dimethyl-propan-1-one

A pale yellow solid was prepared according to the same procedure as Example 250 (b) above except that the precipitate formed by basification with sodium carbonate using trimethylacetyl chloride was filtered and then azeotroped with toluene. 1- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2, 2-Dimethyl-propan-1-one (49 mg) was prepared. LC-MS (Method M): R _T = 11.39 min, 352 (M + H) ⁺ .

メチルクロロホルメートを使用する以外は、上記実施例２５０（ｂ）と同様の方法に従って、淡茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸メチルエステル（８９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝８.９５分、３２６（Ｍ＋Ｈ)⁺。 (E) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester

Except for using methyl chloroformate, 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4, as a light brown solid according to the same method as in Example 250 (b) above. 6,7-Tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester (89 mg) was prepared. LC-MS (Method M): R _T = 8.95 min, 326 (M + H) ⁺ .

メタノール（２０ｍｌ）中の３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾール［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル［１.０１４ｇ、実施例２５２（ａ）］の溶液をジオキサン中の塩化水素の溶液（５ｍｌ、４Ｍ）で処理した。１６時間攪拌後、反応混合物を蒸発させた。得られたベージュ色の固体をメタノールで磨砕し、淡黄色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン（０.５２３ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝０.６３分；２６８（Ｍ＋Ｈ)⁺。 [Example 251]
(A) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazole [4,3-c] pyridine-5-carboxylic acid t in methanol (20 ml) -A solution of the butyl ester [1.014 g, Example 252 (a)] was treated with a solution of hydrogen chloride in dioxane (5 ml, 4M). After stirring for 16 hours, the reaction mixture was evaporated. The resulting beige solid was triturated with methanol to give 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo as a pale yellow solid. [4,3-c] pyridine (0.523 g) was obtained. LC-MS (Method B): R _T = 0.63 min; 268 (M + H) ⁺ .

３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル［実施例２５２（ｄ）］を使用する以外は、上記実施例２５１（ａ）と同様の方法に従って、白色固体として３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン（２２３ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝３.９１分、２８８／２９０（Ｍ＋Ｈ)⁺。 (B) 3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester [ Example 252 (d)] was used in the same manner as in Example 251 (a) above, except that 3- (5-chloro-6-methyl-1H-benzimidazol-2-yl)- 4,5,6,7-Tetrahydro-1H-pyrazolo [4,3-c] pyridine (223 mg) was prepared. LC-MS (Method K): R _T = 3.91 min, 288/290 (M + H) ⁺ .

３−［５−（２−モルホリン−４−イル−エトキシ）−１Ｈ−ベンゾイミダゾール−２−イル］−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル［実施例２５２（ｅ）］を使用する以外は、上記実施例２５１（ａ）と同様の方法に従って、オフホワイトの固体として３−［５−（２−モルホリン−４−イル−エトキシ）−１Ｈ−ベンゾイミダゾール−２−イル］−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン（２００ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝２.５５分、３６９.１９（Ｍ＋Ｈ)⁺。 (C) 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] Pyridine

3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carvone 3- [5- (2-morpholin-4-yl) as an off-white solid according to the same procedure as in Example 251 (a) except that acid t-butyl ester [Example 252 (e)] is used. -Ethoxy) -1H-benzimidazol-2-yl] -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (200 mg) was prepared. LC-MS (Method N): R _T = 2.55 min, 369.19 (M + H) ⁺ .

３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル［実施例２５２（ｇ）］を使用する以外は、上記実施例２５１（ａ）と同様の方法に従って、オフホワイトの固体として３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン（５００ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.２１分、３０８.１７（Ｍ＋Ｈ)⁺。 (D) 3- (5-Trifluoromethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

3- (5-Trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester [Examples] 252 (g)] in the same manner as in Example 251 (a) above, except that 3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -4, 5,6,7-Tetrahydro-1H-pyrazolo [4,3-c] pyridine (500 mg) was prepared. LC-MS (Method N): R _T = 3.21 min, 308.17 (M + H) ⁺ .

酢酸（５ｍｌ）中の１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−３,５−ジカルボン酸,３−（２−アミノ−４,５−ジメチルフェニル）アミド,５−ｔ−ブチルエステル［１.０９１ｇ、参考実施例３９（ａ）］の懸濁液をSmith Creatorマイクロ波中に１００℃に１２分間加熱した。固体炭酸水素ナトリウムを添加して混合物を慎重に中和し、その後酢酸エチルで２回抽出した。合わせた抽出物を蒸発させて３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステルを得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７９分；３６８（Ｍ＋Ｈ)⁺。 [Example 252]
(A) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester

1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid, 3- (2-amino-4,5-dimethylphenyl) amide, 5 in acetic acid (5 ml) A suspension of t-butyl ester [1.091 g, Reference Example 39 (a)] was heated in a Smith Creator microwave at 100 ° C. for 12 minutes. Solid sodium bicarbonate was added to carefully neutralize the mixture, then extracted twice with ethyl acetate. The combined extracts were evaporated to give 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carbon. The acid t-butyl ester was obtained. LC-MS (Method B): R _T = 2.79 min; 368 (M + H) ⁺ .

（ｉ）４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−メトキシ−フェニル）−アミド［４１０ｍｇ、参考実施例３６（ｄ）］を使用し、１２０℃で５分間加熱し、（ii）反応混合物を水に注ぎ込み、２Ｎ水酸化ナトリウムでｐＨ１４に調整し、濾過し、（iii）２Ｎ塩酸で濾液をｐＨ６に調整し、濾過により沈殿物を収集する以外は、上記実施例２５２（ａ）と同様の方法に従って、黄色粉末として５−メトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（３２７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝１.６１分、２６０.２５（Ｍ＋Ｈ)⁺、２５８.２６（Ｍ−Ｈ)^-。 (B) 5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

(I) 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl) -amide [410 mg, Reference Example 36 (d)] was heated at 120 ° C. for 5 minutes. (Ii) Pour the reaction mixture into water, adjust to pH 14 with 2N sodium hydroxide, filter, and (iii) adjust the filtrate to pH 6 with 2N hydrochloric acid and collect the precipitate by filtration. According to the same method as 252 (a), 5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole (327 mg) was produced as a yellow powder. LC-MS (Method H): R _T = 1.61 min, 260.25 (M + H) ⁺ , 258.26 (M−H) ⁻ .

４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−エトキシ−フェニル）−アミド［８２４ｍｇ、参考実施例３６（ｅ）］を使用する以外は、上記実施例２５２（ｂ）と同様の方法に従って、明茶色粉末として５−エトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（４０７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝１.８２分、２７４.２６（Ｍ＋Ｈ)⁺、２７２.３０（Ｍ−Ｈ)^-。 (C) 5-ethoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

Example 252 (b) above except that 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethoxy-phenyl) -amide [824 mg, Reference Example 36 (e)] was used. According to a similar method, 5-ethoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole (407 mg) was produced as a light brown powder. LC-MS (Method H): R _T = 1.82 min, 274.26 (M + H) ⁺ , 272.30 (M−H) ⁻ .

３−（２−アミノ−４−クロロ−５−メチル−フェニルカルバモイル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル［参考実施例３９（ｃ）］を使用し、１１０℃で１５分間加熱する以外は、上記実施例２５２（ｂ）と同様の方法に従って、茶色固体として３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル（３９１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.５３分、３８８（Ｍ＋Ｈ)⁺。 (D) 3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t- Butyl ester

3- (2-Amino-4-chloro-5-methyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester [reference implementation Example 39 (c)] and using 3- (5-chloro-6-methyl-1H-benzo) as a brown solid following the same procedure as in Example 252 (b) above, except heating at 110 ° C. for 15 minutes. Imidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester (391 mg) was prepared. LC-MS (Method J): R _T = 3.53 min, 388 (M + H) ⁺ .

３−［２−アミノ−４−（２−モルホリン−４−イル−エトキシ）−フェニルカルバモイル］−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル［参考実施例３９（ｄ）］を使用する以外は、上記実施例２５２（ｂ）と同様の方法に従って、茶色固体として３−［５−（２−モルホリン−４−イル−エトキシ）−１Ｈ−ベンゾイミダゾール−２−イル］−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル（３５０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.５３分、４６９.２４（Ｍ＋Ｈ)⁺。 (E) 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine- 5-carboxylic acid t-butyl ester

3- [2-Amino-4- (2-morpholin-4-yl-ethoxy) -phenylcarbamoyl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t 3- [5- (2-morpholin-4-yl-ethoxy) as a brown solid according to the same procedure as in Example 252 (b) except that -butyl ester [Reference Example 39 (d)] was used. -1H-Benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester (350 mg) was prepared. LC-MS (Method N): R _T = 3.53 min, 469.24 (M + H) ⁺ .

１,４,６,７−テトラヒドロ−ピラノ［４,３−ｃ］ピラゾール−３−カルボン酸（２−
アミノ−４,５−ジメチル−フェニル）−アミド［参考実施例３９（ｅ）］を使用する以外は、上記実施例２５２（ａ）と同様の方法に従って、淡茶色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラノ［４,３−ｃ］ピラゾール（４９ｍｇ）を製造した。ＭＳ：２６９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｃ１）：Ｒ_T＝１９.６８分。 (F) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole

1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid (2-
3- (5,6) as a light brown solid according to the same procedure as in Example 252 (a) above except that amino-4,5-dimethyl-phenyl) -amide [Reference Example 39 (e)] is used. -Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole (49 mg) was prepared. MS: 269 (M + H) ^<+> . HPLC (Method C1): R _T = 19.68 min.

３−（２−アミノ−４−トリフルオロメチル−フェニルカルバモイル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル［参考実施例３９（ｆ）］を使用する以外は、上記実施例２５２（ａ）と同様の方法に従って、茶色固体として３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル（９５０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.９０分、４０８（Ｍ＋Ｈ)⁺。 (G) 3- (5-Trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester

3- (2-Amino-4-trifluoromethyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester [Reference Example 39 (F)] was used in the same manner as in Example 252 (a) except that 3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6 was obtained as a brown solid. , 7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester (950 mg) was prepared. LC-MS (Method N): R _T = 3.90 min, 408 (M + H) ⁺ .

ジクロロメタン（１０ｍｌ）中の３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［１００ｍｇ、実施例２３３（ｃ）］およびジイソプロピルエチルアミン（３０７μｌ）の攪拌溶液を塩化クロロアセチル（１０５μｌ）で処理した。反応混合物を室温で３０分間攪拌し、その後モルホリン（５７５μｌ）で処理し、その後１夜室温で保持し、その後蒸発させた。油状の残存物を酢酸エチルと水の間に分配し、有機層を水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルを溶離剤とするシリカ上のフラッシュクロマトグラフィーに付し、オフホワイトの固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−２−モルホリン−４−イル−アセトアミド（４９.９ｍｇ）を得た。ＭＳ：３５５.６８（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１
）：Ｒ_T＝８.２８分。 [Example 253]
(A) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-morpholin-4-yl-acetamide

Stirring of 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [100 mg, Example 233 (c)] and diisopropylethylamine (307 μl) in dichloromethane (10 ml) The solution was treated with chloroacetyl chloride (105 μl). The reaction mixture was stirred at room temperature for 30 minutes, then treated with morpholine (575 μl), then kept at room temperature overnight and then evaporated. The oily residue was partitioned between ethyl acetate and water and the organic layer was washed with water and then dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole as an off-white solid. -4-yl] -2-morpholin-4-yl-acetamide (49.9 mg) was obtained. MS: 355.68 (M + H) ^<+> . HPLC (Method B1
): R _T = 8.28 min.

塩酸ジメチルアミンを使用する以外は、上記実施例２５３（ａ）と同様の方法に従って、白色固体として２−ジメチルアミノ−Ｎ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アセトアミド（５２ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝８.２８分、３５５.６８（Ｍ＋Ｈ)⁺。 (B) 2-Dimethylamino-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide

2-Dimethylamino-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl as a white solid according to the same method as in Example 253 (a) except that dimethylamine hydrochloride was used. ) -1H-pyrazol-4-yl] -acetamide (52 mg). LC-MS (Method M): R _T = 8.28 min, 355.68 (M + H) ⁺ .

ピペリジンを使用する以外は、上記実施例２５３（ａ）と同様の方法に従って、白色固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−２−ピペリジン−１−イル−アセトアミド（４ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝７.６９分、３５３.６８（Ｍ＋Ｈ)⁺。 (C) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2-piperidin-1-yl-acetamide

N- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4 as a white solid is prepared according to the same method as in Example 253 (a) except that piperidine is used. -Il] -2-piperidin-1-yl-acetamide (4 mg) was prepared. LC-MS (Method M): R _T = 7.69 min, 353.68 (M + H) ⁺ .

ジメチルホルムアミド（１０ｍｌ）中の塩酸１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（２９５.７ｍｇ）およびジイソプロピルエチルアミン（２６９μｌ）の攪拌溶液を３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［１００ｍｇ、実施例２３３（ｃ）］および２−（１Ｈ−１,２,３,４−テトラアゾール−１−イル）酢酸（１９７.８ｍｇ）で処理した。反応混合物を７２時間攪拌し、その後さらに塩酸１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（２９５.７ｍｇ）、ジイソプロピルエチルアミン（２６９μｌ）および２−（１Ｈ−１,２,３,４−テトラアゾール−１−イル）酢酸（１９７.８ｍｇ）で処理した。さらに４８時間攪拌を続行し、その後反応混合物を酢酸エチルと水の間に分配した。有機層を蒸発させ、残存物をメタノールとテトラヒドロフランの混合物（１：４、８ｍｌ）中の１Ｎ水酸化カリウムで処理した。１時間後この混合物を酢酸エチルで抽出した。抽出物を塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させ、乾燥した。残存物を分取ＨＰＬＣに付し、オフホワイトの固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−２−（１Ｈ−１,２,３,４−テトラアゾール−１−イル）−アセトアミド（１３.７ｍｇ）を得た。ＭＳ：３３８.１４（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝７.２６分。 [Example 254]
(A) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -2- (1H-1,2,3,4-tetraazole- 1-yl) -acetamide

A stirred solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (295.7 mg) and diisopropylethylamine (269 μl) in dimethylformamide (10 ml) was added to 3- (5,6-dimethyl-1H-benzimidazole. -2-yl) -1H-pyrazol-4-ylamine [100 mg, Example 233 (c)] and 2- (1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg) Was processed. The reaction mixture was stirred for 72 hours and then further 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (295.7 mg), diisopropylethylamine (269 μl) and 2- (1H-1,2,3,4-). Treated with tetraazol-1-yl) acetic acid (197.8 mg). Stirring was continued for a further 48 hours, after which the reaction mixture was partitioned between ethyl acetate and water. The organic layer was evaporated and the residue was treated with 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1: 4, 8 ml). After 1 hour, the mixture was extracted with ethyl acetate. The extract was washed with brine, then dried over magnesium sulfate and then evaporated to dryness. The residue was subjected to preparative HPLC and N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -2- (1H as an off-white solid. -1,2,3,4-Tetraazol-1-yl) -acetamide (13.7 mg) was obtained. MS: 338.14 (M + H) ^<+> . HPLC (Method B1): R _T = 7.26 min.

イソニコチン酸を使用する以外は、上記実施例２５４（ａ）と同様の方法に従って、白色固体としてＮ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−イソニコチンアミド（９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝８.７１分、３３１.２１（Ｍ＋Ｈ)⁺。 (B) N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -isonicotinamide

N- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole as a white solid is prepared in the same manner as in Example 254 (a) except that isonicotinic acid is used. -4-yl] -isonicotinamide (9 mg) was prepared. LC-MS (Method L): R _T = 8.71 min, 331.21 (M + H) ⁺ .

シクロプロピル酢酸を使用する以外は、上記実施例２５４（ａ）と同様の方法に従って、明桃色固体として２−シクロプロピル−Ｎ−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アセトアミド（９８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１１.０４分、ＭＳ：３１０（Ｍ＋Ｈ)⁺。 (C) 2-Cyclopropyl-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide

Except for the use of cyclopropylacetic acid, 2-cyclopropyl-N- [3- (5,6-dimethyl-1H-benzimidazol-2-yl] was obtained as a light pink solid according to the same method as in Example 254 (a) above. Yl) -1H-pyrazol-4-yl] -acetamide (98 mg). LC-MS (Method M): R _T = 11.04 min, MS: 310 (M + H) ⁺ .

テトラヒドロフラン（５ｍｌ）中の３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［０.５００ｇ、実施例２３３（ｃ）］の溶液をメチルイソシアネート（０.５０２ｍｌ）で処理し、混合物を周囲温度で１６時間攪拌した。その後混合物を真空下に濃縮し、残存物をメタノールとテトラヒドロフランの混合物（１：３、５ｍｌ）中の１Ｎ水酸化カリウムに再溶解した。混合物をさらに１時間攪拌し、その後濃縮し、その後酢酸エチルと水との間に分配した。水層を酢酸エチルで３回抽出し、合わせた有機抽出物を塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を最初酢酸エチルとヘキサンの混合物（１：１、ｖ／ｖ）、その後酢酸エチルを溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、白色固体として１−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−メチル−尿素（２３０ｍｇ）を得た。ＭＳ：２６９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｄ１）：Ｒ_T＝５.９７分。 [Example 255]
(A) 1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea

A solution of 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [0.500 g, Example 233 (c)] in tetrahydrofuran (5 ml) was added to methyl isocyanate ( 0.502 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was then concentrated in vacuo and the residue was redissolved in 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1: 3, 5 ml). The mixture was stirred for an additional hour, then concentrated and then partitioned between ethyl acetate and water. The aqueous layer was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The residue was first subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 1, v / v) and then ethyl acetate as eluent to give 1- [3- (5, 6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea (230 mg) was obtained. MS: 269 (M + H) ^<+> . HPLC (Method D1): R _T = 5.97 min.

イソプロピルイソシアネートを使用する以外は、上記実施例２５５（ａ）と同様の方法に従って、白色固体として１−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−イソプロピル−尿素を製造した。ＭＳ：３１３（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｄ１）：Ｒ_T＝１０.９４分。 (B) 1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isopropyl-urea

1- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole- was obtained as a white solid according to the same method as in Example 255 (a) except that isopropyl isocyanate was used. 4-yl] -3-isopropyl-urea was prepared. MS: 313 (M + H) ^<+> . HPLC (Method D1): R _T = 10.94 min.

フェニルイソシアネートを使用する以外は、上記実施例２５５（ａ）と同様の方法に従って、白色固体として１−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−フェニル−尿素を製造した。ＭＳ：３４７（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ１）：Ｒ_T＝１６.１６分。 (C) 1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-phenyl-urea

1- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole- was obtained as a white solid according to the same method as in Example 255 (a) except that phenyl isocyanate was used. 4-yl] -3-phenyl-urea was prepared. MS: 347 (M + H) ^<+> . HPLC (Method B1): R _T = 16.16 min.

ベンジルイソシアネートを使用する以外は、上記実施例２５５（ａ）と同様の方法に従って、白色固体として１−ベンジル−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−尿素を製造した。ＭＳ：３６１（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｄ１）：Ｒ_T＝７.７８分。 (D) 1-benzyl- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea

1-Benzyl- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H— was prepared as a white solid according to the same method as in Example 255 (a) except that benzyl isocyanate was used. Pyrazol-4-yl] -urea was prepared. MS: 361 (M + H) ^<+> . HPLC (Method D1): R _T = 7.78 min.

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン［実施例２５１（ａ）］およびイソプロピルイソシアネートを使用し、反応生成物を酢酸エチル／メタノール（１９：１、ｖ／ｖ）を溶離剤とするフラッシュカラムクロマトグラフィーに付する以外は、上記実施例２５５（ａ）と同様の方法に従って、オフホワイトの固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸イソプロピルアミド（９３.３ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１０.１５分、３５３（Ｍ＋Ｈ)⁺。 (E) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [Example 251 (a)] and isopropyl According to a method similar to that of Example 255 (a) above except that isocyanate is used and the reaction product is subjected to flash column chromatography using ethyl acetate / methanol (19: 1, v / v) as an eluent. 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide as an off-white solid (93.3 mg) was produced. LC-MS (Method M): R _T = 10.15 min, 353 (M + H) ⁺ .

エタノール（２５ｍＬ）中のシクロプロパンカルボン酸［３−（５−エトキシ−６−エチル−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド［０.３ｇ、参考実施例４８（ａ）］およびｐ−トルエンスルホン酸水和物（１.２ｇ）の溶液をオイルバス中に８０℃で１時間加熱し、その後冷却し、その後重炭酸ナトリウム水溶液に注ぎ込んだ。水性の混合物を酢酸エチル（７５ｍＬ）で２回抽出した。合わせた抽出物を蒸発させ、残存物を塩化メチレン（１００ｍＬ）とメタノール（１０ｍＬ）の混合物に再溶解した。この溶液を重炭酸ナトリウム水で洗浄して残存するｐ−トルエンスルホン酸を除去し、その後蒸発させて白色固体としてシクロプロパンカルボン酸［３−（５−エトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（１２０ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.３６分、３４０（Ｍ＋Ｈ)⁺。 [Example 256]
(A) Cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide

Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl in ethanol (25 mL) A solution of amide [0.3 g, Reference Example 48 (a)] and p-toluenesulfonic acid hydrate (1.2 g) was heated in an oil bath at 80 ° C. for 1 hour, then cooled, then heavy Pour into aqueous sodium carbonate. The aqueous mixture was extracted twice with ethyl acetate (75 mL). The combined extracts were evaporated and the residue was redissolved in a mixture of methylene chloride (100 mL) and methanol (10 mL). This solution was washed with aqueous sodium bicarbonate to remove residual p-toluenesulfonic acid and then evaporated to give cyclopropanecarboxylic acid [3- (5-ethoxy-1H-benzoimidazol-2-yl) as a white solid. -1H-pyrazol-4-yl] amide (120 mg) was obtained. LC-MS (Method E): R _T = 2.36 min, 340 (M + H) ⁺ .

エタノール（１００ｍＬ）中の３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イルアミン［０.９ｇ、参考実施例４９（ｄ）］およびｐ−トルエンスルホン酸（１.０ｇ）を使用し、反応を５５℃で２時間実行する以外は、上記実施例２５６（ａ）と同様の方法に従って、茶色固体として３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１Ｈ−ピラゾール−４−イルアミン（８００ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝２.６８分、２４０（Ｍ＋Ｈ)⁺。 (B) 3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-ylamine

3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazole-4 in ethanol (100 mL) Using Example 256 (a) above, except that -ylamine [0.9 g, Reference Example 49 (d)] and p-toluenesulfonic acid (1.0 g) were used and the reaction was carried out at 55 ° C. for 2 hours. According to a similar method, 3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-ylamine (800 mg) was prepared as a brown solid. LC-MS (Method G): R _T = 2.68 min, 240 (M + H) ⁺ .

（ｉ）４−メチルピペラジン−１−カルボン酸［３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド［１７１ｍｇ、参考実施例４８（ｂ）］を使用し、（ii）反応を５５℃で１.５時間、その後７０℃で１時間実行し、（iii）反応生成物をシリカゲル上のクロマトグラフィー（酢酸エチル／０から２０％勾配メタノール）に付する以外は、上記実施例２５６（ａ）と同様の方法に従って、白色固体として４−メチルピペラジン−１−カルボン酸［３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（５５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝１.５３分、３６６（Ｍ＋Ｈ)⁺。 (C) 4-Methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide

(I) 4-methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1- (tetrahydropyran-2-yl ) -1H-pyrazol-4-yl] amide [171 mg, Reference Example 48 (b)], (ii) the reaction is carried out at 55 ° C. for 1.5 hours and then at 70 ° C. for 1 hour; ) 4-Methylpiperazine-1--as a white solid according to a method similar to Example 256 (a) above except that the reaction product is chromatographed on silica gel (ethyl acetate / 0 to 20% gradient methanol). Carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide (55 mg) was prepared. LC-MS (Method E): R _T = 1.53 min, 366 (M + H) ⁺ .

１,１−ジメチル−３−［３−（１,５,６,７−テトラヒドロ−ｓ−インダセン−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］尿素（２３０ｍｇ）およびｐ−トルエンスルホン酸水和物［４０ｍｇ、参考実施例４８（ｃ）］を使用する以外は、上記実施例２５６（ｃ）と同様の方法に従って、褐色固体として１,１−ジメチル−３−［３−（１,５,６,７−テトラヒドロ−ｓ−インダセン−２−イル）−１Ｈ−ピラゾール−４−イル］尿素（１０６ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝１.９７分、３１１（Ｍ＋Ｈ)⁺。 (D) 1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-s-indasen-2-yl) -1H-pyrazol-4-yl] urea

1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-s-indasen-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] Except for using urea (230 mg) and p-toluenesulfonic acid hydrate [40 mg, Reference Example 48 (c)], 1,1- Dimethyl-3- [3- (1,5,6,7-tetrahydro-s-indasen-2-yl) -1H-pyrazol-4-yl] urea (106 mg) was prepared. LC-MS (Method E): R _T = 1.97 min, 311 (M + H) ⁺ .

トリフルオロ酢酸とジクロロメタンの１／１混合物（３０ｍＬ）中のシクロプロパンカルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド［９０ｍｇ、参考実施例４８（ｄ）］の溶液を５時間攪拌し、その後蒸発させた。残存物を酢酸エチル（３０ｍＬ）および重炭酸ナトリウム水（３０ｍＬ）と混合した。有機層を蒸発させて、シクロプロパンカルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（４４ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.３４分、３３０（Ｍ＋Ｈ)⁺。 [Example 257]
(A) Cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide

Cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) in a 1/1 mixture (30 mL) of trifluoroacetic acid and dichloromethane ) -1H-pyrazol-4-yl] amide [90 mg, Reference Example 48 (d)] was stirred for 5 hours and then evaporated. The residue was mixed with ethyl acetate (30 mL) and aqueous sodium bicarbonate (30 mL). The organic layer was evaporated to give cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] amide (44 mg). LC-MS (Method E): R _T = 2.34 min, 330 (M + H) ⁺ .

テトラヒドロピラン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド［１２０ｍｇ、参考実施例４８（ｅ）］を使用する以外は、上記実施例２５７（ａ）と同様の方法に従って、テトラヒドロピラン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（６５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.１７分、３７４（Ｍ＋Ｈ)⁺。 (B) Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide

Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide [ Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-] was prepared in the same manner as in Example 257 (a) except that 120 mg, Reference Example 48 (e)] was used. Benzimidazol-2-yl) -1H-pyrazol-4-yl] amide (65 mg) was prepared. LC-MS (Method E): R _T = 2.17 min, 374 (M + H) ⁺ .

モルホリン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド［１４０ｍｇ、参考実施例４８（ｆ）］を使用する以外は、上記実施例２５７（ａ）と同様の方法に従って、モルホリン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（６５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.６２分、３７５（Ｍ＋Ｈ)⁺。 (C) Morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] amide

Morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide [140 mg In the same manner as in Example 257 (a) except that Reference Example 48 (f)] was used, morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazole] was used. -2-yl) -1H-pyrazol-4-yl] amide (65 mg) was prepared. LC-MS (Method E): R _T = 2.62 min, 375 (M + H) ⁺ .

ピペリジン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド［１２７ｍｇ、参考実施例４８（ｇ）］を使用する以外は、上記実施例２５７（ａ）と同様の方法に従って、ピペリジン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（６５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝３.１５分。ＭＳ３７３（Ｍ＋Ｈ)⁺。 (D) Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide

Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide [127 mg Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazole] was prepared in the same manner as in Example 257 (a) except that Reference Example 48 (g)] was used. -2-yl) -1H-pyrazol-4-yl] amide (65 mg) was prepared. LC-MS (Method E): R _T = 3.15 min. MS 373 (M + H) ^<+> .

３−［６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジエチル尿素［１１０ｍｇ、参考実施例４８（ｈ）］を使用する以外は、上記実施例２５７（ａ）と同様の方法に従って、３−［６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジエチル尿素（６５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝３.１３分、３６１（Ｍ＋Ｈ)⁺。 (E) 3- [6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea

3- [6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea [110 mg, 3- [6-Ethoxy-5-fluoro-1H-benzoimidazol-2-yl) -1H— according to the same method as in Example 257 (a) except that Reference Example 48 (h)] was used. Pyrazol-4-yl] -1,1-diethylurea (65 mg) was prepared. LC-MS (Method E): R _T = 3.13 min, 361 (M + H) ⁺ .

５−メトキシ−２−［４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール（２８２ｍｇ、参考実施例５０（ｄ））を使用する以外は、上記実施例２５７（ａ）と同様の方法に従って、赤色粉末として５−メトキシ−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール（３７３ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝１.６０分、２６０.２２（Ｍ＋Ｈ)⁺、２５８.２３（Ｍ−Ｈ)^-。 (F) 5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole

5-Methoxy-2- [4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole (282 mg, Reference Example 50 (d)) is used. Except for the above, in the same manner as in Example 257 (a), 5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole (373 mg) was produced as a red powder. LC-MS (Method H): R _T = 1.60 min, 260.22 (M + H) ⁺ , 258.23 (M−H) ⁻ .

モルホリン−４−カルボン酸（２,４−ジメトキシ−ベンジル）−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イルメチル］−アミド（参考実施例５９）を使用し、反応生成物をシリカ上のフラッシュクロマトグラフィー［ジクロロメタンからジクロロメタン／メタノール（９：１）を溶離剤とする］に付し、水／アセトンから再結晶化し、ついでジエチルエーテルで磨砕する以外は、上記実施例２５７（ａ）と同様の方法に従って、白色固体としてモルホリン−４−カルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルメチル］−アミド（１６.５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝６.９７分、ＭＳ：３５５.３６（Ｍ＋Ｈ)⁺、３５３.３９（Ｍ−Ｈ)^-。 (G) Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide

Morpholine-4-carboxylic acid (2,4-dimethoxy-benzyl)-[3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H- Using pyrazol-4-ylmethyl] -amide (Reference Example 59), the reaction product is subjected to flash chromatography on silica [dichloromethane to dichloromethane / methanol (9: 1) as eluent] and water. Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H as a white solid, according to the same procedure as in Example 257 (a) except that recrystallized from / acetone and then triturated with diethyl ether. -Benzimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide (16.5 mg) was prepared. LC-MS (Method M): R _T = 6.97 min, MS: 355.36 (M + H) ⁺ , 353.39 (M−H) ⁻ .

３−［３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジエチル−尿素［参考実施例４８（ｊ）］を使用する以外は、上記実施例２５７（ａ）と同様の方法に従って、白色固体として３−［３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジエチル−尿素（６０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝１０.６１分。
¹HNMR（CD₃OD）：δ 1.24（t, 6H）, 3.43（q, 4H）, 6.72（bt, 1H）, 6.98（d, 1H）, 7.26（s, 1H）, 7.47（d, 1H）, 7.91（s, 1H） (H) 3- [3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea

3- [3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea [ 3- [3- (5-Difluoromethoxy-1H-benzoimidazol-2-yl) as a white solid according to the same method as in Example 257 (a) except that Reference Example 48 (j)] was used. -1H-pyrazol-4-yl] -1,1-diethyl-urea (60 mg) was prepared. LC-MS (Method L): R _T = 10.61 min.
¹ HNMR (CD ₃ OD): δ 1.24 (t, 6H), 3.43 (q, 4H), 6.72 (bt, 1H), 6.98 (d, 1H), 7.26 (s, 1H), 7.47 (d, 1H) , 7.91 (s, 1H)

ピペリジン−１−カルボン酸［３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド［参考実施例４８（ｋ）］を使用する以外は、上記実施例２５７（ａ）と同様の方法に従って、白色固体としてピペリジン−１−カルボン酸［３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（５２ｍｇ）を製造した。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.７８分。
¹H NMR(CD₃OD): δ 1.69 (bm, 6H), 3.64 (bm, 4H), 6.82 (bt, 1H), 7.09 (bm, 1H), 7.39 (bm, 1H), 7.61 (bm, 1H),8.05 (bm, 1H) (I) Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-yl] amide [Reference Example 48 (k)] according to the same method as in Example 257 (a) except that piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl] was used as a white solid. ) -1H-pyrazol-4-yl] -amide (52 mg). HPLC (Method E1): R _T = 10.78 min.
¹ H NMR (CD ₃ OD): δ 1.69 (bm, 6H), 3.64 (bm, 4H), 6.82 (bt, 1H), 7.09 (bm, 1H), 7.39 (bm, 1H), 7.61 (bm, 1H ), 8.05 (bm, 1H)

ジクロロメタン（２０ｍＬ）中の３−（６−クロロ−５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［５０ｍｇ、実施例２３３（ｅ）］およびジイソプロピルエチルアミン（４０μＬ）の溶液を、室温で攪拌しながら、塩化シクロプロパンカルボニル（５１μＬ、３当量）で処理した。さらに２０時間攪拌後、反応混合物を蒸発させ、残存物をシリカゲル上のクロマトグラフィー（酢酸エチル／ヘプタン １／１）に付して橙色固体としてビス−アクリル化生成物（６０ｍｇ）を得た。ＭＳ４００（Ｍ＋Ｈ)⁺。ビス−アクリル化生成物をメタノール（５ｍＬ）に溶解し、その後水酸化カリウム溶液（０.５ｍＬ、５Ｎ）で処理し、その後６０℃で１時間攪拌し、その後冷却し、その後蒸発させた。残存物を水（１５ｍＬ）で処理し、水性の混合物のｐＨを５に調整し、その後酢酸エチル（２５ｍＬ）で２回抽出した。合わせた抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させ、残存物をジイソプロピルエーテルで磨砕し、濾過し、沈殿物を６０℃で真空乾燥し、オフホワイトの固体としてシクロプロパンカルボン酸［３−（６−クロロ−５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（１１ｍｇ）を得た。融点２２５〜２２６℃。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.９２分、３３２（Ｍ＋Ｈ)⁺。 [Example 258]
(A) Cyclopropanecarboxylic acid [3- (6-chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

3- (6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [50 mg, Example 233 (e)] and diisopropylethylamine (40 μL) in dichloromethane (20 mL) Was treated with cyclopropanecarbonyl chloride (51 μL, 3 eq) with stirring at room temperature. After stirring for an additional 20 hours, the reaction mixture was evaporated and the residue was chromatographed on silica gel (ethyl acetate / heptane 1/1) to give the bis-acrylated product (60 mg) as an orange solid. MS 400 (M + H) ^<+> . The bis-acrylated product was dissolved in methanol (5 mL) and then treated with potassium hydroxide solution (0.5 mL, 5N), then stirred at 60 ° C. for 1 hour, then cooled and then evaporated. The residue was treated with water (15 mL) and the pH of the aqueous mixture was adjusted to 5, then extracted twice with ethyl acetate (25 mL). The combined extracts are dried over magnesium sulfate and then evaporated, the residue is triturated with diisopropyl ether, filtered, the precipitate is dried in vacuo at 60 ° C., and the cyclopropanecarboxylic acid [3 -(6-Chloro-5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide (11 mg) was obtained. Melting point 225-226 [deg.] C. LC-MS (Method E): R _T = 2.92 min, 332 (M + H) ⁺ .

（ｉ）テトラヒドロフラン（１５ｍＬ）中の３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１Ｈ−ピラゾール−４−イルアミン［３１０ｍｇ、実施例２５６（ｂ）］およびトリエチルアミン（４当量）を塩化シクロプロパンカルボニル（４当量）で処理し、（ii）反応混合物を６０℃で２時間攪拌し、（iii）得られたビス−アシル化生成物を４０℃で１時間メタノール性水酸化カリウム（２０ｍＬ、１.０５ｇＫＯＨ）で処理し、ついで塩化アンモニウム水（２００ｍＬ）で処理し、（iii）混合物を酢酸エチル（１００ｍＬ）で３回抽出し、（iv）合わせた抽出物を蒸発させ、（ｖ）残存物をシリカゲル上のクロマトグラフィー（酢酸エチル／５０〜０％勾配ヘプタン）に付する以外は、上記実施例２５８（ａ）と同様の方法に従って、黄色固体としてシクロプロパンカルボン酸［３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（５０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.０５分、３０８（Ｍ＋Ｈ)⁺。 (B) Cyclopropanecarboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] amide

(I) 3- (1,5,6,7-Tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-ylamine [310 mg, Example 256 in tetrahydrofuran (15 mL) (B)] and triethylamine (4 equivalents) are treated with cyclopropanecarbonyl chloride (4 equivalents), (ii) the reaction mixture is stirred at 60 ° C. for 2 hours, and (iii) the resulting bis-acylated product is Treat with methanolic potassium hydroxide (20 mL, 1.05 g KOH) at 40 ° C. for 1 hour, then with aqueous ammonium chloride (200 mL), (iii) extract the mixture three times with ethyl acetate (100 mL), (iv ) The combined extracts were evaporated and (v) the residue was chromatographed on silica gel (ethyl acetate / 50-0% gradient heptane) except that Example 258 above ) As a yellow solid, cyclopropanecarboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl The amide (50 mg) was prepared. LC-MS (Method E): R _T = 2.05 min, 308 (M + H) ⁺ .

塩化モルホリン−４−カルボニルを使用する以外は、上記実施例２５８（ｂ）と同様の方法に従って、橙色固体としてモルホリン−４−カルボン酸［３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１Ｈ−ピラゾール−４−イル］−アミドを製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.４５分、３５３（Ｍ＋Ｈ)⁺。 (C) Morpholine-4-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] -amide

Except for using morpholine-4-carbonyl chloride, a morpholine-4-carboxylic acid [3- (1,5,6,7-tetrahydro-1, 3-Diaza-s-indasen-2-yl) -1H-pyrazol-4-yl] -amide was prepared. LC-MS (Method E): R _T = 2.45 min, 353 (M + H) ⁺ .

ジイソプロピルエチルアミンの存在下に、３−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［２５７ｍｇ、実施例２３３（ｆ）］を塩化１−ピペリジン−カルボニルで処理し、溶媒としてテトラヒドロフランを使用する以外は、上記実施例２５８（ａ）と同様の方法に従って、白色固体としてピペリジン−１−カルボン酸［３−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（４６.１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝６.４３分、３４１.２８（Ｍ＋Ｈ)⁺。 (D) Piperidine-1-carboxylic acid [3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Treatment of 3- (5-methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [257 mg, Example 233 (f)] with 1-piperidine-carbonyl chloride in the presence of diisopropylethylamine. Then, piperidine-1-carboxylic acid [3- (5-methoxy-1H-benzoimidazol-2-yl) as a white solid was prepared in the same manner as in Example 258 (a) except that tetrahydrofuran was used as the solvent. -1H-pyrazol-4-yl] -amide (46.1 mg) was prepared. LC-MS (Method L): R _T = 6.43 min, 341.28 (M + H) ⁺ .

塩化ジメチルカルバミルを使用する以外は、上記実施例２５８（ｄ）と同様の方法に従って、白色固体として３−［３−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジメチル−尿素を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝７.６４分、３０１.３５（Ｍ＋Ｈ)⁺。 (E) 3- [3- (5-Methoxy-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea

3- [3- (5-Methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole- was obtained as a white solid according to the same method as in Example 258 (d) except that dimethylcarbamyl chloride was used. 4-yl] -1,1-dimethyl-urea was prepared. LC-MS (Method M): R _T = 7.64 min, 301.35 (M + H) ⁺ .

（ｉ）溶媒としてのテトラヒドロフラン（２０ｍｌ）とともに３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［４００ｍｇ、実施例２３３（ｄ）］、塩化１−ピペリジンカルボニル（１.２５ｍｌ）およびジイソプロピルエチルアミン（１.７４ｍｌ）を使用し、反応混合物を周囲温度で４８時間、その後５０℃で２４時間攪拌し、（ii）ビス−アシル化生成物を室温でメタノール／テトラヒドロフラン（１：３、２０ｍｌ）中の１Ｍ水酸化カリウムで処理し、（iii）生成物をシリカ上のフラッシュカラムクロマトグラフィー［酢酸エチル／ヘキサン（１：１ ｖ／ｖ）から酢酸エチル／ヘキサン（３：１ ｖ／ｖ）を溶離剤とする］に付する以外は、上記実施例２５８（ｄ）と同様の方法に従って、白色固体としてピペリジン−１−カルボン酸［３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（４２５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝７.５５分、３５３.３４（Ｍ＋Ｈ)⁺。 (F) Piperidine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

(I) 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [400 mg, Example 233 (d)] with tetrahydrofuran (20 ml) as a solvent Using 1-piperidinecarbonyl chloride (1.25 ml) and diisopropylethylamine (1.74 ml), the reaction mixture is stirred at ambient temperature for 48 hours and then at 50 ° C. for 24 hours, and (ii) the bis-acylated product is Treat with 1M potassium hydroxide in methanol / tetrahydrofuran (1: 3, 20 ml) at room temperature, (iii) flash column chromatography on silica [ethyl acetate / hexane (1: 1 v / v) to acetic acid Ethyl / hexane (3: 1 v / v is used as an eluent)], and the same as Example 258 (d) above According to the method, piperidine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide (425 mg) was prepared as a white solid. . LC-MS (Method L): R _T = 7.55 min, 353.34 (M + H) ⁺ .

３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｈ）］および塩化Ｎ,Ｎ′−ジメチルカルバミルを使用する以外は、上記実施例２５８（ｆ）と同様の方法に従って、白色固体として３−［３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジメチル−尿素（３２ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１０.４０分、３０３.３４（Ｍ＋Ｈ)⁺。 (G) 3- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea

Except using 3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (h)] and N, N'-dimethylcarbamyl chloride Was prepared according to the same method as in Example 258 (f) above as 3- [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] as a white solid. -1,1-dimethyl-urea (32 mg) was prepared. LC-MS (Method M): R _T = 10.40 min, 303.34 (M + H) ⁺ .

３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミノ［実施例２３３（ｊ）］および塩化モルホリン−１−カルボニルを使用する以外は、上記実施例２５８（ｆ）と同様の方法に従って、白色固体としてをモルホリン−４−カルボン酸［３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（１３１ｍｇ）を製造した。ＭＳ：３７９.０８（Ｍ−Ｈ)^-。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.６１分。 (H) Morpholine-4-carboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

The above example except that 3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamino [Example 233 (j)] and morpholine-1-carbonyl chloride are used. According to a method similar to 258 (f), morpholine-4-carboxylic acid [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide as a white solid (131 mg) was produced. MS: 379.08 (M-H) ^- . HPLC (Method E1): R _T = 10.61 min.

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン［実施例２５１（ａ）］および塩化ジエチルカルバミルを使用し、反応生成物を酢酸エチルから酢酸エチル／メタノール（４９：１、ｖ／ｖ）を溶離剤とするフラッシュカラムクロマトグラフィーに付する以外は、上記実施例２５８（ｆ）と同様の方法に従って、オフホワイトの固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ジエチルアミド（２０.９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.４４分、３６７（Ｍ＋Ｈ)⁺。 (I) 3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [Example 251 (a)] and chloride Example 258 (f) above with the exception that diethylcarbamyl was used and the reaction product was subjected to flash column chromatography using ethyl acetate to ethyl acetate / methanol (49: 1, v / v) as the eluent. According to a similar method, 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5 as an off-white solid -Carboxylic acid diethylamide (20.9 mg) was prepared. LC-MS (Method J): R _T = 3.44 min, 367 (M + H) ⁺ .

塩化１−ピロリジンカルボニルを使用し、反応生成物を酢酸エチル、メタノールおよびジクロロメタンで磨砕する以外は、上記実施例２５８（ｉ）と同様の方法に従って、オフホワイトの固体として［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−イル］−ピロリジン−１−イル−メタノン（６８ｍｇ）を製造した。ＭＳ：３６５（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.３２分。 (J) [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidine- 1-yl-methanone

According to a method similar to Example 258 (i) above except that 1-pyrrolidinecarbonyl chloride was used and the reaction product was triturated with ethyl acetate, methanol and dichloromethane [3- (5, 6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1-yl-methanone (68 mg). Manufactured. MS: 365 (M + H) ^<+> . HPLC (Method E1): R _T = 10.32 min.

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン［実施例２５１（ａ）］を使用し、反応生成物を酢酸エチル／ペトロール（５：１、ｖ／ｖ）から１００％酢酸エチルから酢酸エチル／メタノール（１９：１、ｖ／ｖ）を溶離剤とするフラッシュカラムクロマトグラフィーに付する以外は、上記実施例２５８（ｆ）と同様の方法に従って、オフホワイトの固体として［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−イル］−ピペリジン−１−イル−メタノン（９３.３ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝６.７７分、３７９（Ｍ＋Ｈ)⁺。 (K) [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidine- 1-yl-methanone

Using 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [Example 251 (a)] The reaction product is subjected to flash column chromatography eluting with ethyl acetate / petrol (5: 1, v / v) to 100% ethyl acetate to ethyl acetate / methanol (19: 1, v / v). [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro as an off-white solid according to the same method as in Example 258 (f) except above. -Pyrazolo [4,3-c] pyridin-5-yl] -piperidin-1-yl-methanone (93.3 mg) was prepared. LC-MS (Method L): R _T = 6.77 min, 379 (M + H) ⁺ .

塩化１−モルホリンカルボニルを使用し、反応生成物をトルエンおよびジクロロメタンで共沸する以外は、上記実施例２５８（ｋ）と同様の方法に従って、オフホワイトの固体として［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−イル］−モルホリン−４−イル−メタノン（３２ｍｇ）を製造した。ＭＳ：３８１（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝９.３９分。 (L) [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholine- 4-yl-methanone

[3- (5,6-dimethyl) as an off-white solid according to a method similar to Example 258 (k) above except that 1-morpholinecarbonyl chloride is used and the reaction product is azeotroped with toluene and dichloromethane. -1H-Benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4-yl-methanone (32 mg) was prepared. MS: 381 (M + H) ^<+> . HPLC (Method E1): R _T = 9.39 min.

（ｉ）３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン［実施例２５１（ｂ）］および塩化ジエチルカルバミルを使用し、（ii）反応生成物を酢酸エチルから酢酸エチル／メタノール（４７：３、ｖ／ｖ）を溶離剤とするフラッシュカラムクロマトグラフィーに付し、ついでエタノールで磨砕する以外は、上記実施例２５８（ａ）と同様の方法に従って、淡黄色固体として３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ジエチルアミド（３５.６ｍｇ）を製造した。ＭＳ：３８７／３８９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１１.０７分。 (M) 3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide

(I) 3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [Example 251 ( b)] and diethylcarbamyl chloride, and (ii) subjecting the reaction product to flash column chromatography eluting with ethyl acetate to ethyl acetate / methanol (47: 3, v / v) followed by ethanol. 3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1,4,6 as a pale yellow solid according to the same method as in Example 258 (a) except grinding with , 7-Tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide (35.6 mg) was prepared. MS: 387/389 (M + H) ^<+> . HPLC (Method E1): R _T = 11.07 min.

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｃ）］および塩化１−モルホリンカルボニルを使用する以外は、上記実施例２５８（ｐ）と同様の方法に従って、白色固体としてモルホリン−４−カルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（２０６ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝７.３６分、３４１（Ｍ＋Ｈ)⁺。 (N) Morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Example 258 above, except that 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (c)] and 1-morpholinecarbonyl chloride are used. According to a method similar to (p), morpholine-4-carboxylic acid [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide (206 mg) as a white solid ) Was manufactured. LC-MS (Method L): R _T = 7.36 min, 341 (M + H) ⁺ .

塩化１−ピペリジンカルボニルを使用する以外は、上記実施例２５８（ｐ）と同様の方法に従って、白色固体としてピペリジン−１−カルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（１８５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝１０.７９分、３３９（Ｍ＋Ｈ)⁺。 (O) Piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for using 1-piperidinecarbonyl chloride, piperidine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl] as a white solid according to the same method as in Example 258 (p) above. Yl) -1H-pyrazol-4-yl] -amide (185 mg) was prepared. LC-MS (Method M): R _T = 10.79 min, 339 (M + H) ⁺ .

３−［５−（２−モルホリン−４−イル−エトキシ）−１Ｈ−ベンゾイミダゾール−２−イル］−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン［実施例２５１（ｃ）］および塩化ジエチルカルバミルを使用する以外は、上記実施例２５８（ａ
）と同様の方法に従って、白色固体として３−［５−（２−モルホリン−４−イル−エトキシ）−１Ｈ−ベンゾイミダゾール−２−イル］−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ジエチルアミド（２８ｍｇ）を製造した。ＭＳ：４６８.３０（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝９.４７分。 (P) 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine- 5-carboxylic acid diethylamide

3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [implementation] Example 251 (c)] and Example 258 (a) above except that diethylcarbamyl chloride was used.
) As a white solid, 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4 , 3-c] pyridine-5-carboxylic acid diethylamide (28 mg) was prepared. MS: 468.30 (M + H) ^<+> . HPLC (Method E1): R _T = 9.47 min.

３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−４,５,６,７−テトラヒドロ−１Ｈ−ピラゾロ［４,３−ｃ］ピリジン［実施例２５１（ｄ）］および塩化ジエチルカルバミルを使用する以外は、上記実施例２５８（ａ）と同様の方法に従って、白色固体として３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ジエチルアミド（１０３ｍｇ）を製造した。ＭＳ：４０７.１７（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.８１分。 (Q) 3- (5-Trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide

3- (5-Trifluoromethyl-1H-benzimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [Example 251 (d)] and chloride 3- (5-Trifluoromethyl-1H-benzimidazol-2-yl) -1,4,6, as a white solid according to the same method as in Example 258 (a) except that diethylcarbamyl is used. 7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide (103 mg) was prepared. MS: 407.17 (M + H) ^<+> . HPLC (Method E1): R _T = 10.81 min.

塩化ジメチルカルバミルを使用する以外は、上記実施例２５８（ｐ）と同様の方法に従って、３−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジメチル−尿素を製造した。ＭＳ：２９９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝８.２４分。 (R) 3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea

3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazole-4 is prepared according to the same method as in Example 258 (p) except that dimethylcarbamyl chloride is used. -Yl] -1,1-dimethyl-urea was prepared. MS: 299 (M + H) ^<+> . HPLC (Method E1): R _T = 8.24 min.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（２−シアノ−エチル）−アミド［１５０ｍｇ、実施例２４６（ｓ）］およびアジドトリブチルチン（２ｍｌ）の攪拌溶液を９５℃で２４時間加熱した。反応混合物を周囲温度に冷却し、アセトニトリル（２０ｍｌ）、テトラヒドロフラン（１０ｍｌ）および酢酸（２０ｍｌ）とともに２時間攪拌した。反応混合物をイソ−ヘキサン（６×８０ｍｌ）で洗浄し、真空下に濃縮した。残存物を分取ＨＰＬＣに付して茶色固体として２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸［２−（２Ｈ−テトラゾール−５−イル）−エチル］−アミド（３５.９ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝９.８０分、３７４.２１（Ｍ＋Ｈ)⁺。 [Example 259]
2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid [2- (2H-tetrazol-5-yl) -ethyl] -amide

A stirred solution of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-cyano-ethyl) -amide [150 mg, Example 246 (s)] and azidotributyltin (2 ml) Was heated at 95 ° C. for 24 hours. The reaction mixture was cooled to ambient temperature and stirred with acetonitrile (20 ml), tetrahydrofuran (10 ml) and acetic acid (20 ml) for 2 hours. The reaction mixture was washed with iso-hexane (6 × 80 ml) and concentrated under vacuum. The residue was subjected to preparative HPLC to give 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid [2- (2H-tetrazol-5-yl) -ethyl]-as a brown solid Amide (35.9 mg) was obtained. LC-MS (Method L): R _T = 9.80 min, 374.21 (M + H) ⁺ .

テトラヒドロフラン（２０ｍｌ）中の３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［２５０ｍｇ、実施例２３３（ｄ）］の攪拌溶液に、１,１−カルボニルジイミダゾール（７４０ｍｇ）を添加し、反応混合物を還流下に６０時間加熱した。反応混合物を周囲温度に冷却し、溶媒を真空下に除去した。残存物をテトラヒドロフラン（１５ｍｌ）中の２Ｍシクロプロピルアミンに添加した。反応混合物を圧力試験管に移し、還流下に４８時間加熱した。反応混合物を周囲温度に冷却し、酢酸エチルと水の間に分配した。水層を酢酸エチルで３回抽出し、合わせた有機抽出物を塩水で洗浄し、硫酸マグネシウム上に乾燥し、濃縮した。残存物を酢酸エチル／ヘキサン（１：１ ｖ／ｖ）から１００％酢酸エチルを溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、白色固体として１−シクロプロピル−３−［３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−尿素（９５ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝９.４０分、３２５.３２（Ｍ＋Ｈ)⁺。 [Example 260]
(A) 1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea

To a stirred solution of 3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [250 mg, Example 233 (d)] in tetrahydrofuran (20 ml) was added 1 , 1-carbonyldiimidazole (740 mg) was added and the reaction mixture was heated at reflux for 60 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed under vacuum. The residue was added to 2M cyclopropylamine in tetrahydrofuran (15 ml). The reaction mixture was transferred to a pressure test tube and heated at reflux for 48 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate / hexane (1: 1 v / v) to 100% ethyl acetate to give 1-cyclopropyl-3- [3- ( 5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea (95 mg) was obtained. LC-MS (Method M): R _T = 9.40 min, 325.32 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍメチルアミンを使用する以外は、上記実施例２６０（ａ）と同様の方法に従って、白色固体として１−［３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−メチル−尿素（３６ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝７.０８分、２９９.３４（Ｍ＋Ｈ)⁺。 (B) 1- [3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea

1- [3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl] as a white solid according to the same procedure as in Example 260 (a) except that 2M methylamine in tetrahydrofuran was used. ) -1H-pyrazol-4-yl] -3-methyl-urea (36 mg). LC-MS (Method M): R _T = 7.08 min, 299.34 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍ １−メチルピペラジンを使用する以外は、上記実施例２６０（ａ）と同様の方法に従って、白色固体として４−メチル−ピペラジン−１−カルボン酸［３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（２４７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝５.２１分、３６８.３２（Ｍ＋Ｈ)⁺。 (C) 4-Methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for using 2M 1-methylpiperazine in tetrahydrofuran, following the same procedure as in Example 260 (a) above, 4-methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6- Methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide (247 mg) was prepared. LC-MS (Method M): R _T = 5.21 min, 368.32 (M + H) ⁺ .

３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｈ）］およびテトラヒドロフラン中の２Ｍピペリジンを使用する以外は、上記実施例２６０（ａ）と同様の方法に従って、白色固体としてピペリジン−１−カルボン酸［３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（１４０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝８.２９分、３４３.２６（Ｍ＋Ｈ)⁺。 (D) Piperidine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

The above procedure except using 3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (h)] and 2M piperidine in tetrahydrofuran. Piperidine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] as a white solid according to a method similar to Example 260 (a) -The amide (140 mg) was prepared. LC-MS (Method L): R _T = 8.29 min, 343.26 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍメチルアミンを使用する以外は、上記実施例２６０（ｄ）と同様の方法に従って、白色固体として１−［３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−メチル−尿素（６１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝４.８５分、２８９.２６（Ｍ＋Ｈ)⁺。 (E) 1- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea

1- [3- (5-Fluoro-6-methyl-1H-benzimidazol-2-yl) as a white solid according to a method similar to Example 260 (d) above, except that 2M methylamine in tetrahydrofuran was used. ) -1H-pyrazol-4-yl] -3-methyl-urea (61 mg) was prepared. LC-MS (Method L): R _T = 4.85 min, 289.26 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍモルホリンを使用する以外は、上記実施例２６０（ｄ）と同様の方法に従って、白色固体としてモルホリン−４−カルボン酸［３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（４９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝６.２６分、３４５.３３（Ｍ＋Ｈ)⁺。 (F) Morpholine-4-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

The morpholine-4-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazole- 2-yl) -1H-pyrazol-4-yl] -amide (49 mg) was prepared. LC-MS (Method L): R _T = 6.26 min, 345.33 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍ １−メチルピペラジンを使用する以外は、上記実施例３１（ｄ）と同様の方法に従って、白色固体として４−メチル−ピペラジン−１−カルボン酸［３−（５−フルオロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（５８ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｐ）：Ｒ_T＝７.７２分、３５８.１９（Ｍ＋Ｈ)⁺。 (G) 4-Methyl-piperazine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Except for using 2M 1-methylpiperazine in tetrahydrofuran, following the same procedure as in Example 31 (d) above, 4-methyl-piperazine-1-carboxylic acid as a white solid [3- (5-fluoro-6- Methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide (58 mg) was prepared. LC-MS (Method P): R _T = 7.72 min, 358.19 (M + H) ⁺ .

３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｊ）］およびテトラヒドロフラン中の２Ｍメチルアミンを使用する以外は、上記実施例２６０（ａ）と同様の方法に従って、白色固体として１−メチル−３−［３−（５−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−尿素（９９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝６.５１分、３２５（Ｍ＋Ｈ)⁺。 (H) 1-methyl-3- [3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea

The above example except that 3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (j)] and 2M methylamine in tetrahydrofuran were used. According to a method similar to 260 (a), 1-methyl-3- [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -urea ( 99 mg) was produced. LC-MS (Method L): R _T = 6.51 min, 325 (M + H) ⁺ .

３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２６１］およびテトラヒドロフラン中の２Ｍメチルアミンを使用する以外は、上記実施例２６０（ａ）と同様の方法に従って、白色固体として１−［３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−メチル−尿素（４５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝５.８５分、３０５／０７（Ｍ＋Ｈ)⁺。 (I) 1- [3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea

Example 260 above, except that 3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 261] and 2M methylamine in tetrahydrofuran were used. 1- [3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea as a white solid according to the same method as in (a) (45 mg) was produced. LC-MS (Method L): R _T = 5.85 min, 305/07 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍ １−メチルピペラジンを使用する以外は、上記実施例２６０（ｉ）と同様の方法に従って、淡黄色固体として４−メチル−ピペラジン−１−カルボン酸［３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（６０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝６.３５分、３７４（Ｍ＋Ｈ)⁺。 (J) 4-methyl-piperazine-1-carboxylic acid [3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide

4-Methyl-piperazine-1-carboxylic acid [3- (5-chloro-6] was prepared as a pale yellow solid according to the same procedure as in Example 260 (i) except that 2M 1-methylpiperazine in tetrahydrofuran was used. -Methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide (60 mg) was prepared. LC-MS (Method M): R _T = 6.35 min, 374 (M + H) ⁺ .

３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミン［実施例２３３（ｃ）］およびｔ−ブチルアミンを使用する以外は、上記実施例２６０（ａ）と同様の方法に従って、白色固体として１−ｔ−ブチル−３−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−尿素（２１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝５.３８分、３２７（Ｍ＋Ｈ)⁺。 (K) 1-t-butyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea

Example 260 (a) above except that 3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (c)] and t-butylamine were used. ) As a white solid, 1-t-butyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea (21 mg) ) Was manufactured. LC-MS (Method L): R _T = 5.38 min, 327 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍエチルアミンを使用する以外は、上記実施例２６０（ｋ）と同様の方法に従って、白色固体として１−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−エチル−尿素（３９ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｌ）：Ｒ_T＝３.９５分、２９９（Ｍ＋Ｈ)⁺。 (L) 1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-ethyl-urea

1- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H as a white solid according to the same procedure as in Example 260 (k) except that 2M ethylamine in tetrahydrofuran was used. -Pyrazol-4-yl] -3-ethyl-urea (39 mg) was prepared. LC-MS (Method L): R _T = 3.95 min, 299 (M + H) ⁺ .

テトラヒドロフラン中の２Ｍ １−メチルピペラジンを使用する以外は、上記実施例２
６０（ｋ）と同様の方法に従って、白色固体として４−メチル−ピペラジン−１−カルボン酸［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（１１３ｍｇ）を製造した。ＭＳ：３５４（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.２１分。 (M) 4-Methyl-piperazine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide

Example 2 above, except that 2M 1-methylpiperazine in tetrahydrofuran was used.
4-Methyl-piperazine-1-carboxylic acid [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl as a white solid according to the same method as for 60 (k) ] -Amide (113 mg) was prepared. MS: 354 (M + H) ^<+> . HPLC (Method E1): R _T = 10.21 min.

シクロプロピルアミンを使用する以外は、上記実施例２６０（ｋ）と同様の方法に従って、白色固体として１−シクロプロピル−３−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−尿素（８０ｍｇ）を製造した。ＭＳ：３１１（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.３６分。 (N) 1-cyclopropyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea

1-Cyclopropyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) as a white solid according to the same method as in Example 260 (k) except that cyclopropylamine was used. ) -1H-pyrazol-4-yl] -urea (80 mg) was prepared. MS: 311 (M + H) ^<+> . HPLC (Method E1): R _T = 10.36 min.

テトラヒドロフラン中の２Ｍジエチルアミンを使用する以外は、上記実施例２６０（ｋ）と同様の方法に従って、白色固体として３−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジエチル−尿素（６１ｍｇ）を製造した。ＭＳ：３２７（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１１.３６分。 (O) 3- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea

3- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H as a white solid according to a method similar to Example 260 (k) except that 2M diethylamine in tetrahydrofuran was used. -Pyrazol-4-yl] -1,1-diethyl-urea (61 mg) was prepared. MS: 327 (M + H) ^<+> . HPLC (Method E1): R _T = 11.36 min.

テトラヒドロフラン中の２Ｍイソブチルアミンを使用する以外は、上記実施例２６０（
ｋ）と同様の方法に従って、白色固体として１−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−３−イソブチル−尿素（５８ｍｇ）を製造した。ＭＳ：３２７（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.９５分。 (P) 1- [3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -3-isobutyl-urea

Example 260 (above) except that 2M isobutylamine in tetrahydrofuran was used.
k) 1- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -3-isobutyl-urea (58 mg) as a white solid Manufactured. MS: 327 (M + H) ^<+> . HPLC (Method E1): R _T = 10.95 min.

テトラヒドロフラン中の２Ｍ（アミノメチル）シクロプロパンを使用する以外は、上記実施例２６０（ｋ）と同様の方法に従って、白色固体として１−シクロプロピルメチル−３−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イル］−尿素（２９ｍｇ）を製造した。ＭＳ：３２５（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｅ１）：Ｒ_T＝１０.６３分。 (Q) 1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea

1-Cyclopropylmethyl-3- [3- (5,6-dimethyl-) as a white solid according to a method similar to Example 260 (k) above, except that 2M (aminomethyl) cyclopropane in tetrahydrofuran was used. 1H-Benzimidazol-2-yl) -1H-pyrazol-4-yl] -urea (29 mg) was prepared. MS: 325 (M + H) ^<+> . HPLC (Method E1): R _T = 10.63 min.

エタノール（５ｍｌ）中の５−クロロ−６−メチル−２−（４−ニトロ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール［０.３２０ｇ、実施例２４９（ｇ）］および塩化スズ（１.１０ｇ）の攪拌溶液をSmith Creatorマイクロ波中に１４０℃で１０分間加熱した。飽和炭酸水素ナトリウム溶液を使用して反応混合物をｐＨ８に塩基性化し、酢酸エチルで抽出した。有機層を硫酸マグネシウム上に乾燥し、濃縮して淡茶色固体として３−（５−クロロ−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−ピラゾール−４−イルアミンを得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２８分、２４８.１３（Ｍ＋Ｈ)⁺。 [Example 261]
3- (5-Chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine

5-chloro-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzimidazole [0.320 g, Example 249 (g)] and tin chloride (5 ml) in ethanol (5 ml) 1.10 g) of the stirred solution was heated in a Smith Creator microwave at 140 ° C. for 10 minutes. The reaction mixture was basified to pH 8 using saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 3- (5-chloro-6-methyl-1H-benzimidazol-2-yl) -1H-pyrazol-4-ylamine as a light brown solid. LC-MS (Method B): R _T = 2.28 min, 248.13 (M + H) ⁺ .

酢酸（１ｍｌ）および濃塩酸（１ｍｌ）中の３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボニトリル［１００ｍｇ、実施例２３５（ａｎ）］の攪拌懸濁液を８０℃で３０分、その後１００℃で４時間加熱した。反応混合物を周囲温度に冷却し、１６時間攪拌した。その後反応混合物を８０℃で２.５時間、その後１００℃で２時間加熱した。反応混合物を周囲温度に冷却し、飽和炭酸ナトリウム溶液で中和した。得られた白色の沈殿物を濾過により収集し、水層を酢酸エチルで抽出し、沈殿物を添加し、真空下に濃縮した。残存物をメタノールに溶解し、ＭＰ−炭酸レジン（１００ｍｇ）を含む固体相カートリッジに移し、１６時間振とうした。その後反応混合物を濾過し、レジンをメタノールで洗浄し、合わせた有機層を真空下に濃縮した。残存物をジエチルエーテルで磨砕し、メタノールに溶解し、１,４−ジオキサン中の４Ｍ塩化水素で酸性化した。溶媒を真空下に除去し、淡茶色固体として３−（５−エチル−６−メチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボン酸アミド二塩酸塩（５８ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｍ）：Ｒ_T＝９.４０分、３２０（Ｍ＋Ｈ)⁺。 [Example 262]
3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid amide dihydrochloride

3- (5-Ethyl-6-methyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile [100 mg, Example 235 (an) in acetic acid (1 ml) and concentrated hydrochloric acid (1 ml). Was stirred at 80 ° C. for 30 minutes and then at 100 ° C. for 4 hours. The reaction mixture was cooled to ambient temperature and stirred for 16 hours. The reaction mixture was then heated at 80 ° C. for 2.5 hours and then at 100 ° C. for 2 hours. The reaction mixture was cooled to ambient temperature and neutralized with saturated sodium carbonate solution. The resulting white precipitate was collected by filtration, the aqueous layer was extracted with ethyl acetate, the precipitate was added and concentrated in vacuo. The residue was dissolved in methanol and transferred to a solid phase cartridge containing MP-resin carbonate (100 mg) and shaken for 16 hours. The reaction mixture was then filtered, the resin was washed with methanol, and the combined organic layers were concentrated in vacuo. The residue was triturated with diethyl ether, dissolved in methanol and acidified with 4M hydrogen chloride in 1,4-dioxane. The solvent was removed in vacuo to give 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid amide dihydrochloride (58 mg) as a light brown solid. It was. LC-MS (Method M): R _T = 9.40 min, 320 (M + H) ⁺ .

酢酸／濃塩酸（４ｍｌ、１：１ ｖ／ｖ）中の３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボニトリル二塩酸塩［２００ｍｇ、参考実施例６（ａｑ）］の攪拌懸濁液を１００℃で１６時間加熱した。反応混合物を周囲温度に冷却し、濾過した。沈殿物を水で洗浄し、真空下に乾燥し、白色固体として３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール−５−カルボン酸（１９５ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５２分、３０７（Ｍ＋Ｈ)⁺。 [Example 263]
3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carboxylic acid

3- (5,6-Dimethyl-1H-benzimidazol-2-yl) -1H-indazole-5-carbonitrile dihydrochloride [200 mg, reference in acetic acid / concentrated hydrochloric acid (4 ml, 1: 1 v / v) The stirred suspension of Example 6 (aq)] was heated at 100 ° C. for 16 hours. The reaction mixture was cooled to ambient temperature and filtered. The precipitate was washed with water and dried under vacuum to give 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid (195 mg) as a white solid. . LC-MS (Method B): R _T = 2.52 min, 307 (M + H) ⁺ .

テトラヒドロフラン（５ｍｌ）中の２−（４−アミノ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸メチルエステル［２００ｍｇ、実施例２３３（ｋ）］の攪拌溶液に、ジイソプロピルエチルアミン（５４５μｌ）および塩化イソブチリル（３２７μｌ）を滴加し、反応混合物を３０分間攪拌した。反応混合物を真空下に濃縮し、残存物をテトラヒドロフラン／メタノール（１：３、ｖ／ｖ）中の１Ｍ水酸化カリウム中に溶解し、１時間攪拌した。反応混合物を真空下に濃縮し、残存物を水／メタノール（５ｍｌ）中の１Ｍ水酸化ナトリウムに溶解し、１時間攪拌した。溶媒を真空下に除去し、残存物を酢酸エチルと水との間に分配し、層を分離した。水層を５％クエン酸溶液でｐＨ３〜４に酸性化し、酢酸エチルで抽出し、有機層を塩水で洗浄した。その後有機層を硫酸マグネシウム上に乾燥し、濾過し、濾液を真空下に濃縮して、白色固体として２−（４−イソブチリルアミノ−１Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸（１４０ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｃ）：Ｒ_T＝２.８７分、３１３.３３（Ｍ＋Ｈ)⁺。 [Example 264]
2- (4-Isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid

To a stirred solution of 2- (4-amino-1H-pyrazol-3-yl) -1H-benzimidazole-5-carboxylic acid methyl ester [200 mg, Example 233 (k)] in tetrahydrofuran (5 ml) was added diisopropylethylamine. (545 μl) and isobutyryl chloride (327 μl) were added dropwise and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was dissolved in 1M potassium hydroxide in tetrahydrofuran / methanol (1: 3, v / v) and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in 1M sodium hydroxide in water / methanol (5 ml) and stirred for 1 hour. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water, and the layers were separated. The aqueous layer was acidified with 5% citric acid solution to pH 3-4, extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer is then dried over magnesium sulfate, filtered, and the filtrate is concentrated in vacuo to give 2- (4-isobutyrylamino-1H-pyrazol-3-yl) -1H-benzimidazole- as a white solid. 5-carboxylic acid (140 mg) was obtained. LC-MS (Method C): R _T = 2.87 min, 313.33 (M + H) ⁺ .

メタノール（１ｍｌ）中の３−（５−ニトロ−１Ｈ−ベンゾイミダゾール−２−イル）−１Ｈ−インダゾール［９０.８ｍｇ、参考実施例２３３（ａｓ）］の攪拌溶液を塩化スズ（６１６ｍｇ）で処理した。反応混合物を還流下に１６時間加熱し、その後周囲温度に冷却した。重炭酸ナトリウム水を添加して反応混合物のｐＨを８に調整し、その後この混合物を酢酸エチルで抽出した。有機抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させて油状物を得た。粗生成物を酢酸エチルおよび１０％トリエチルアミンを溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−アミン（８２６ｍｇ）を得た。ＭＳ：２５０.３１（Ｍ＋Ｈ)⁺、２４８.３１（Ｍ−Ｈ)^-。ＨＰＬＣ（方法Ｂ）：Ｒ_T＝２.０３分。 [Example 265]
2- (1H-indazol-3-yl) -3H-benzimidazol-5-amine

A stirred solution of 3- (5-nitro-1H-benzimidazol-2-yl) -1H-indazole [90.8 mg, Reference Example 233 (as)] in methanol (1 ml) was treated with tin chloride (616 mg). did. The reaction mixture was heated under reflux for 16 hours and then cooled to ambient temperature. Aqueous sodium bicarbonate was added to adjust the pH of the reaction mixture to 8, after which the mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and then evaporated to give an oil. The crude product was subjected to flash column chromatography on silica eluting with ethyl acetate and 10% triethylamine to give 2- (1H-indazol-3-yl) -3H-benzimidazol-5-amine (826 mg). Obtained. MS: 250.31 (M + H) +, 248.31 (M-H) -. HPLC (Method B): R _T = 2.03 min.

１−［５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−３,３−ビス−メチルスルファニル−プロペノン［３１８ｍｇ、参考実施例２（ａ）］、ヒドラジン（２ｍＬ）およびエタノール（１２ｍＬ）の混合物を還流温度で１時間加熱した。その後反応混合物を室温に冷却し、その後室温で１夜攪拌し、その後６０℃で２時間加熱し、その後還流温度で３時間加熱し、その後室温で３日間放置し、その後蒸発させた。残存物をジクロロメタンに溶解し、少量の塩水を添加した水でこの溶液を洗浄して分離を促進し、水層をジクロロメタン、その後酢酸エチルで洗浄した。合わせた有機物を硫酸マグネシウム上に乾燥し、その後蒸発させて、無色の固体として５,６−ジメチル−２−（５−メチルスルファニル−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール（９０ｍｇ）を得た。 [Reference Example 1]
(A) 5,6-Dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole

1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-methylsulfanyl-propenone [318 mg, Reference Example 2 ( a)], a mixture of hydrazine (2 mL) and ethanol (12 mL) was heated at reflux for 1 h. The reaction mixture was then cooled to room temperature, then stirred overnight at room temperature, then heated at 60 ° C. for 2 hours, then heated at reflux temperature for 3 hours, then allowed to stand at room temperature for 3 days and then evaporated. The residue was dissolved in dichloromethane and this solution was washed with water with a small amount of brine added to facilitate separation and the aqueous layer was washed with dichloromethane followed by ethyl acetate. The combined organics were dried over magnesium sulfate and then evaporated to give 5,6-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsila) as a colorless solid. Nyl-ethoxymethyl) -1H-benzimidazole (90 mg) was obtained.

(B) 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-methylsulfanyl-propenone [reference implementation Except for using Example 2 (b)], 6-chloro-5-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) was prepared in the same manner as in Reference Example 1 (a) above. -1- (2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(C) 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-ethylsulfanyl-propenone [reference implementation Except for using Example 2 (c)], 6-chloro-5-methyl-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) was prepared in the same manner as in Reference Example 1 (a) above. -1- (2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(D) 3,3-bis-methylsulfanyl-1- [5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone [Reference Example 2 (D)] According to the same method as in Reference Example 1 (a) above, 2- (5-methylsulfanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1- ( 2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(E) 3,3-bis-cyclopropylmethylsulfanyl-1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone [reference implementation Except for using Example 2 (e)], 2- (5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl was prepared in the same manner as in Reference Example 1 (a) above. -1- (2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(F) 1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-ethylsulfanylpropenone [Reference Example 2 (F)] According to the same method as in Reference Example 1 (a) above, 5,6-dimethyl-2- (5-ethylsulfanyl-1H-pyrazol-3-yl) -1- ( 2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(G) 1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis- (pyridin-3-ylmethylsulfanyl) -5,6-dimethyl-2- (5- (pyridin-3-yl) methyl according to the same method as in Reference Example 1 (a) except that propenone [Reference Example 2 (g)] was used. Sulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(H) 1- [5-Fluoro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -3,3-bis-methylsulfanyl-propenone [Reference Example 2 (h )] In accordance with the same method as in Reference Example 1 (a) above, 5-fluoro-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsila Nyl-ethoxymethyl) -1H-benzimidazole was prepared.

(I) 1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-phenethylsulfanyl-propenone [Reference Example 2 5,6-dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1- () according to the same method as in Reference Example 1 (a) except that (i)] is used. 2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(J) 3,3-bis-methylsulfanyl-1- [4-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone [Reference Example 2 (k )] According to the same method as in Reference Example 1 (a) above, 4-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsila Nyl-ethoxymethyl) -1H-benzimidazole was prepared.

(K) 3,3-bis-benzylsulfanyl-1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone [Reference Example 2 2- (5-benzylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1- () according to the same method as in Reference Example 1 (a) except that (o)] is used. 2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(L) 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-3-morpholin-1-yl- Except for using propenone [Reference Example 13], 6-chloro-5-methyl-2- (5-morpholin-4-yl-1H-pyrazole-) was prepared in the same manner as in Reference Example 1 (a) above. 3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(M) 1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis- (thiophen-2-ylmethylsulfanyl) -5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) according to the same procedure as in Reference Example 1 (a) except that propenone [Reference Example 2 (s)] was used. ) -1H-pyrazol-3-yl] -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

ベンゼン（６ｍＬ）中のナトリウムｔ−ブトキシド（３５０ｍｇ）の攪拌懸濁液を−５℃でベンゼン（５ｍＬ）中の１−［５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−エタノン［２４０ｍｇ、参考実施例３（ａ）］の溶液、ついで二硫化炭素（２３０μＬ）で処理した。得られた橙色溶液を−５℃で１時間攪拌し、その後ヨウ化メチル（１８０μＬ）で処理し、その後室温に戻し、その後室温で１夜攪拌した。橙色沈殿物が形成された。反応混合物を氷水に注ぎ込み、その後この混合物をジクロロメタンで抽出した。合わせた有機抽出物を水で洗浄し、その後硫酸ナトリウム上に乾燥し、その後蒸発させて、橙色油状物として得られた１−［５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−３,３−ビス−メチルスルファニル−プロペノン（３１８ｍｇ）をさらに精製することなく使用した。 [Reference Example 2]
(A) 1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-methylsulfanyl-propenone

A stirred suspension of sodium t-butoxide (350 mg) in benzene (6 mL) was added to 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) in benzene (5 mL) at −5 ° C. 1H-Benzimidazol-2-yl] -ethanone [240 mg, Reference Example 3 (a)], followed by treatment with carbon disulfide (230 μL). The resulting orange solution was stirred at −5 ° C. for 1 hour, then treated with methyl iodide (180 μL), then returned to room temperature and then stirred at room temperature overnight. An orange precipitate was formed. The reaction mixture was poured into ice water and then the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, then dried over sodium sulfate and then evaporated to give 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxy) as an orange oil. Methyl) -1H-benzimidazol-2-yl] -3,3-bis-methylsulfanyl-propenone (318 mg) was used without further purification.

(B) 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone [Reference Example 3 (b)] is used. 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] according to the same method as in Reference Example 2 (a) above except for -3,3-bis-methylsulfanyl-propenone was prepared.

(C) 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone [Reference Example 3 (b)] and iodide 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole- is prepared according to the same method as in Reference Example 2 (a) except that ethyl is used. 2-yl] -3,3-bis-ethylsulfanyl-propenone was prepared.

(D) Except using 1- [5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone [Reference Example 3 (c)]. According to the same method as in Reference Example 2 (a), 3,3-bis-methylsulfanyl-1- [5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole -2-yl] -propenone was prepared.

(E) Except for using bromomethylcyclopropane, 3,3-bis-cyclopropylmethylsulfanyl-1- [5,6-dimethyl-1- ( 2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone was prepared.

(F) 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H— according to the same method as in Reference Example 2 (a) except that ethyl iodide was used. Benzimidazol-2-yl] -3,3-bis-ethylsulfanyl-propenone was prepared.

(G) 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H according to the same method as in Reference Example 2 (a) except that 3-picolyl chloride was used. -Benzimidazol-2-yl] -3,3-bis- (pyridin-3-ylmethylsulfanyl) -propenone was prepared.

(H) The above except that 1- [5-fluoro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone [Reference Example 3 (d)] was used. 1- [5-Fluoro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-methyl was prepared in the same manner as in Reference Example 2 (a). Sulfanyl-propenone was prepared.

(I) 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H— according to the same method as in Reference Example 2 (a) except that phenethyl bromide is used. Benzimidazol-2-yl] -3,3-bis-phenethylsulfanyl-propenone was prepared.

(J) 1- [5-Methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone [Reference Example 4 (g)] and ethyl bromide are used. 3,3-bis-ethylsulfanyl-1- [5-methoxy-2- (trimethylsilanyl) ethoxymethyl) -1H-benzimidazole-2 according to the same method as in Reference Example 2 (a) above. -Il] -propenone was prepared.

(K) The above except that 1- [4-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone [Reference Example 3 (e)] is used. 3,3-Bis-methylsulfanyl-1- [4-methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl according to the same method as in Reference Example 2 (a) ] -Propenone was produced.

(L) 1- [5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -pentan-1-one [Reference Example 3 (f)] is used. Except 2- (bis-methylsulfanyl-methylene) -1- (5-methyl-1H-benzoimidazol-2-yl) -pentan-1-one according to the same method as in Reference Example 2 (a) above Manufactured.

(M) 1- [5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -pentan-1-one [Reference Example 3 (f)] and 4 chloride 2- [Bis- (4-methoxy-benzylsulfanyl) -methylene] -1- (5-methyl-1H-benzoate is prepared in the same manner as in Reference Example 2 (a) except that -methoxybenzyl is used. Imidazol-2-yl) -pentan-1-one was prepared.

(N) 3-methyl-1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -butan-1-one [Reference Example 3 (g) ] And benzyl chloride according to the same method as in Reference Example 2 (a) above, 2- (bis-benzylsulfanyl-methylene) -3-methyl-1- [5-methyl-1- (2 -Trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -butan-1-one was prepared.

(O) 3,3-bis-benzylsulfanyl-1- [5,6-dimethyl-1- (2-trimethylsila) according to the same method as in Reference Example 2 (a) except that benzyl chloride was used. Nyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone was prepared.

(P) 1- [1- (2-Trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone [Reference Example 4 (h)] is used together with tetrahydrofuran as a solvent, and the reaction is carried out. Method similar to Reference Example 2 (a) above, except that it is run at room temperature and the reaction product is then subjected to flash chromatography on silica under gradient elution conditions (20-33% ethyl acetate in pentane). 3,3-bis-methanesulfanyl-1- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone prepared as an oil was left at room temperature according to It slowly solidified.

(Q) 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone [Reference Example 3 (b)] and iodide 1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole- is prepared according to the same method as in Reference Example 2 (a) except that methyl is used. 2-yl] -3,3-bis-methylsulfanyl-propenone was prepared.

(R) 1- [5-Methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -propan-1-one [Reference Example 4 (i)] and iodide 1- [5-Methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] was prepared in the same manner as in Reference Example 2 (a) except that methyl was used. 2-Methyl-3- (bis-methanesulfanyl) -1-propenone was prepared.

(S) 1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone [Reference Example 3 (a)] and 2-chloromethyl 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H according to the same method as in Reference Example 2 (a) except that thiophene [Reference Example 14] is used. -Benzimidazol-2-yl] -3,3-bis- (thiophen-2-ylmethylsulfanyl) -propenone was prepared.

(T) 1- [5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -propan-1-one [Reference Example 3 (h)] is used. 1- [5-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -2-methyl according to the same method as in Reference Example 2 (a) above. -3- (Bis-methanesulfanyl) -1-propenone was prepared.

乾燥テトラヒドロフラン（５５ｍＬ）中の５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール［５.０１ｇ、参考実施例４（ａ）］の溶液を−７８℃で、テトラヒドロフランとヘプタンの混合物中のリチウムジイソプロピルアミドの溶液（１１.９ｍＬ、２Ｍ）で１０分間かけて処理した。混合物を１５分間攪拌し、その後ジメチルアセトアミド（２.１５ｍＬ）で１０分間かけて滴下処理した。−７８℃でさらに３０分間攪拌後、反応混合物を氷（５０ｇ）に注ぎ込み、その後全ての氷がとけるまで放置した。この混合物をジクロロメタンで抽出し、抽出物を塩水、その後水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存する橙色油状物（５.９１ｇ）を石油エーテルと酢酸エチルの混合物（４：１、ｖ／ｖ）を溶離剤とするシリカ上のカラムクロマトグラフィーに付し、黄色結晶性固体として１−［５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−エタノン（３.９３ｇ）を得た。 [Reference Example 3]
(A) 1- [5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone

A solution of 5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [5.01 g, Reference Example 4 (a)] in dry tetrahydrofuran (55 mL) at −78 ° C. Treated with a solution of lithium diisopropylamide (11.9 mL, 2M) in a mixture of tetrahydrofuran and heptane for 10 minutes. The mixture was stirred for 15 minutes and then treated dropwise with dimethylacetamide (2.15 mL) over 10 minutes. After stirring for an additional 30 minutes at −78 ° C., the reaction mixture was poured into ice (50 g) and then allowed to stand until all the ice had melted. The mixture was extracted with dichloromethane and the extract was washed with brine then water, then dried over magnesium sulfate and then evaporated. The remaining orange oil (5.91 g) was subjected to column chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (4: 1, v / v) to give 1- [ 5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone (3.93 g) was obtained.

(B) Reference Example 3 (a) above except that 6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 4 (b)] is used. ) To produce 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone.

(C) Reference Example 3 (a) above except that 5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 4 (c)] is used. 1- [5-Trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone was prepared according to a similar method.

(D) Same as Reference Example 3 (a) except that 5-fluoro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 4 (d)] is used. 1- [5-Fluoro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone was prepared according to the method.

(E) Similar to Reference Example 3 (a) except that 4-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 4 (e)] is used. 1- [4-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone was prepared according to the method.

(F) Except using 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 4 (f)] and dimethylvaleramide [Reference Example 8 (a)]. Was prepared according to the same method as in Reference Example 3 (a) above, 1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -pentane-1- Manufactured on.

(G) 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 4 (f)] and dimethylisovaleramide [Reference Example 8 (b)] are used. Except for 3-methyl-1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] according to the same method as in Reference Example 3 (a) above. -Butan-1-one was produced.

(H) Reference Example 3 (a) above except that 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole [Reference Example 4 (f)] and dimethylpropionamide are used. ) To produce 1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propan-1-one.

ジメチルホルムアミド（８０ｍＬ）中の水素化ナトリウム（１.０８ｇ）の攪拌混合物をジメチルホルムアミド（５０ｍＬ）中の５,６−ジメチル−１Ｈ−ベンゾイミダゾール（４.９５ｇ）の溶液で室温で１０分間かけて処理した。さらに１時間攪拌後、その後混合物を塩化２−（トリメチルシラニル）エトキシメチル（６.４ｍＬ）で１５分間かけて処理し、その後１８時間攪拌を続行した。反応混合物をメタノール（１５ｍＬ）および水（１ｍＬ）で処理し、その後蒸発させた。残存物を水（５０ｍＬ）で処理し、その後この混合物をジエチルエーテル（８０ｍＬ、その後５０ｍＬ）で２回抽出した。合わせた有機抽出物を水（５０ｍＬ）で３回洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存する茶色油状物（１０.３ｇ）をヘキサン中の酢酸エチルの混合物（２０％から８０％）を使用し、４０ｍｌ／分でFlashmasterにより精製し、橙色油状物として５,６−ジメチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール（７.５４ｇ）を得た。 [Reference Example 4]
(A) 5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole

A stirred mixture of sodium hydride (1.08 g) in dimethylformamide (80 mL) was added with a solution of 5,6-dimethyl-1H-benzimidazole (4.95 g) in dimethylformamide (50 mL) at room temperature over 10 minutes. Processed. After stirring for an additional hour, the mixture was then treated with 2- (trimethylsilanyl) ethoxymethyl chloride (6.4 mL) for 15 minutes, followed by continued stirring for 18 hours. The reaction mixture was treated with methanol (15 mL) and water (1 mL) and then evaporated. The residue was treated with water (50 mL) and then the mixture was extracted twice with diethyl ether (80 mL then 50 mL). The combined organic extracts were washed 3 times with water (50 mL), then dried over magnesium sulfate and then evaporated. The remaining brown oil (10.3 g) was purified by Flashmaster using a mixture of ethyl acetate in hexane (20% to 80%) at 40 ml / min to give 5,6-dimethyl-1- (2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole (7.54 g) was obtained.

(B) Except for using 6-chloro-5-methyl-1H-benzimidazole [Reference Example 5 (a)], according to the same method as Reference Example 4 (a) above, 6-chloro-5- Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(C) According to the same method as in Reference Example 4 (a) except that 5-trifluoromethyl-1H-benzimidazole [Reference Example 5 (b)] was used, 5-trifluoromethyl-1- (2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(D) 5-Fluoro-1- (2-trimethyl) according to the same method as in Reference Example 4 (a) except that 5-fluoro-1H-benzimidazole [Reference Example 5 (c)] was used. Silanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(E) 4-methyl-1- (2-trimethyl) according to the same method as in Reference Example 4 (a) except that 4-methyl-1H-benzimidazole [Reference Example 5 (d)] was used. Silanyl-ethoxymethyl) -1H-benzimidazole was prepared.

(F) Except that 5-methyl-1H-benzimidazole is used, 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H— is prepared in the same manner as in Reference Example 4 (a) above. Benzimidazole was prepared.

(G) According to the same method as in Reference Example 4 (a) except that 1- (5-methoxy-1H-benzimidazol-2-yl) -ethanone [Reference Example 6 (a)] was used. 1- [5-Methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone was prepared.

(H) Using (1H-benzoimidazol-2-yl) -1-ethanone and performing the reaction in tetrahydrofuran, following the same procedure as in Reference Example 4 (a) above, as a colorless oil 1- [1- (2-Trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -ethanone was prepared.

(I) Same as Reference Example 4 (a) except that 1- (5-methoxy-1H-benzimidazol-2-yl) -propan-1-one [Reference Example 6 (b)] is used. 1- [5-Methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -propan-1-one was prepared according to

ギ酸（３５ｍＬ）および塩酸（３００ｍＬ）の混合物中の５−クロロ−４−メチル−１,２−フェニレンジアミン（７.８ｇ）の溶液を５０℃で３時間加熱し、その後溶液が塩基性になるまで水酸化アンモニウム溶液で処理した。その後反応混合物をジクロロメタンで抽出した。抽出物を蒸発させ、６−クロロ−５−メチル−１Ｈ−ベンゾイミダゾール（７ｇ）を得た。 [Reference Example 5]
(A) 6-chloro-5-methyl-1H-benzimidazole

A solution of 5-chloro-4-methyl-1,2-phenylenediamine (7.8 g) in a mixture of formic acid (35 mL) and hydrochloric acid (300 mL) is heated at 50 ° C. for 3 hours, after which the solution becomes basic. Until treated with ammonium hydroxide solution. The reaction mixture was then extracted with dichloromethane. The extract was evaporated to give 6-chloro-5-methyl-1H-benzimidazole (7 g).

(B) 5-trifluoromethyl-1H-benzimidazole was produced in the same manner as in Reference Example 5 (a) except that 4-trifluoromethyl-1,2-phenylenediamine was used.

(C) Except for using 4-fluoro-o-phenylenediamine, 5-fluoro-1H-benzimidazole was produced in the same manner as in Reference Example 5 (a) above.
(D) 4-Methyl-1H-benzimidazole was produced according to the same method as in Reference Example 5 (a) except that 2,3-diaminotoluene was used.

クロロホルム（８０ｍＬ）中の１−（５−メトキシ−１−ベンゾイミダゾール）−１−エタノン［５.１４ｇ、参考実施例７（ａ）］および二酸化マンガン（９ｇ）の攪拌混合物を６０℃で１８時間加熱し、その後室温に冷却し、その後濾過した。濾液を蒸発させて１−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−エタノン（４.２８ｇ）を得た。 [Reference Example 6]
(A) 1- (5-Methoxy-1H-benzimidazol-2-yl) -ethanone

A stirred mixture of 1- (5-methoxy-1-benzimidazole) -1-ethanone [5.14 g, Reference Example 7 (a)] and manganese dioxide (9 g) in chloroform (80 mL) at 60 ° C. for 18 hours. Heated, then cooled to room temperature and then filtered. The filtrate was evaporated to give 1- (5-methoxy-1H-benzimidazol-2-yl) -ethanone (4.28 g).

１−（５−メトキシ−１−ベンゾイミダゾール）−１−プロパノール［参考実施例７（ｂ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、１−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−プロパン−１−オンを製造した。 (B) 1- (5-Methoxy-1H-benzimidazol-2-yl) -propan-1-one

Except for using 1- (5-methoxy-1-benzimidazole) -1-propanol [Reference Example 7 (b)], 1- (5- Methoxy-1H-benzoimidazol-2-yl) -propan-1-one was prepared.

（５−フルオロ−１Ｈ−インダゾール−３−イル）−メタノール［参考実施例２５（ａ）］を溶媒としてのアセトンとともに使用し、５５℃の反応温度で、反応生成物を４０／６０ペトロールと酢酸エチルの混合物（１：１ ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付する以外は、上記参考実施例６（ａ）と同様の方法に従って、明茶色固体として５−フルオロ−１Ｈ−インダゾール−３−カルバルデヒドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７４分、１６５（Ｍ＋Ｈ)⁺。 (C) 5-Fluoro-1H-indazole-3-carbaldehyde

(5-Fluoro-1H-indazol-3-yl) -methanol [Reference Example 25 (a)] is used with acetone as a solvent, and the reaction product is 40/60 petrol and acetic acid at a reaction temperature of 55 ° C. Except for flash column chromatography on silica eluting with a mixture of ethyl (1: 1 v / v), 5-fluoro as a light brown solid according to the same procedure as in Reference Example 6 (a) above. -1H-indazole-3-carbaldehyde was prepared. LC-MS (Method B): R _T = 2.74 min, 165 (M + H) ⁺ .

（６−フルオロ−１Ｈ−インダゾール−３−イル）−メタノール［参考実施例２５（ｂ）］を溶媒としてのアセトンとともに使用し、５５℃の反応温度で、反応生成物を４０／６０ペトロールと酢酸エチルの混合物（１：１ ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付する以外は、上記参考実施例６（ａ）と同様の方法に従って、明茶色固体として６−フルオロ−１Ｈ−インダゾール−３−カルバルデヒドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７４分、１６５（Ｍ＋Ｈ)⁺。 (D) 6-Fluoro-1H-indazole-3-carbaldehyde

(6-Fluoro-1H-indazol-3-yl) -methanol [Reference Example 25 (b)] was used with acetone as a solvent, and the reaction product was 40/60 petrol and acetic acid at a reaction temperature of 55 ° C. Except for flash column chromatography on silica eluting with a mixture of ethyl (1: 1 v / v), 6-fluoro as a light brown solid according to the same procedure as in Reference Example 6 (a) above. -1H-indazole-3-carbaldehyde was prepared. LC-MS (Method B): R _T = 2.74 min, 165 (M + H) ⁺ .

（５−メチル−１Ｈ−インダゾール−３−イル）−メタノール［参考実施例２５（ｃ）］を溶媒としてのジクロロメタンとともに使用し、４０℃の反応温度で、反応生成物をヘキサンと酢酸エチルの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付する以外は、上記参考実施例６（ａ）と同様の方法に従って
、淡茶色固体として５−メチル−１Ｈ−インダゾール−３−カルバルデヒドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７９分、１６１（Ｍ＋Ｈ)⁺。 (E) 5-methyl-1H-indazole-3-carbaldehyde

(5-Methyl-1H-indazol-3-yl) -methanol [Reference Example 25 (c)] was used with dichloromethane as a solvent, and the reaction product was a mixture of hexane and ethyl acetate at a reaction temperature of 40 ° C. 5-Methyl-1H as a light brown solid according to the same method as in Reference Example 6 (a) except that it was subjected to flash column chromatography on silica using (1: 1, v / v) as an eluent. -Indazole-3-carbaldehyde was prepared. LC-MS (Method B): R _T = 2.79 min, 161 (M + H) ⁺ .

（６−メトキシ−１Ｈ−インダゾール−３−イル）−メタノール［参考実施例２５（ｅ）］を溶媒としてのアセトンとともに使用し、５５℃の反応温度で、反応生成物を４０／６０ペトロールと酢酸エチルの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付する以外は、上記参考実施例６（ａ）と同様の方法に従って、明茶色固体として６−メトキシ−１Ｈ−インダゾール−３−カルバルデヒドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７６分、１７７（Ｍ＋Ｈ)⁺。 (F) 6-methoxy-1H-indazole-3-carbaldehyde

(6-Methoxy-1H-indazol-3-yl) -methanol [Reference Example 25 (e)] was used with acetone as a solvent, and the reaction product was 40/60 petrol and acetic acid at a reaction temperature of 55 ° C. According to a method similar to that of Reference Example 6 (a) above except that the mixture is a flash column chromatography on silica eluting with a mixture of ethyl (1: 1, v / v), 6- Methoxy-1H-indazole-3-carbaldehyde was prepared. LC-MS (Method B): R _T = 2.76 min, 177 (M + H) ⁺ .

（４−フェニル−１Ｈ−ピラゾール−３−イル）−メタノール［参考実施例２５（ｆ）］を溶媒としてのアセトンとともに使用し、６０℃の反応温度で２時間、反応生成物をジクロロメタンとメタノールの混合物（４９：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付する以外は、上記参考実施例６（ａ）と同様の方法に従って、白色固体として４−フェニル−１Ｈ−ピラゾール−３−カルバルデヒドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７６分；２１３（Ｍ＋Ｈ)⁺。 (G) 4-Phenyl-1H-pyrazole-3-carbaldehyde

(4-Phenyl-1H-pyrazol-3-yl) -methanol [Reference Example 25 (f)] was used with acetone as a solvent and the reaction product was mixed with dichloromethane and methanol at a reaction temperature of 60 ° C. for 2 hours. 4-phenyl-1H as a white solid according to the same procedure as in Reference Example 6 (a) above except that the mixture (49: 1, v / v) was subjected to flash column chromatography on silica using eluent. -Pyrazole-3-carbaldehyde was prepared. LC-MS (Method B): R _T = 2.76 min; 213 (M + H) ⁺ .

（５−クロロ−１Ｈ−インダゾール−３−イル）−メタノール［参考実施例２５（ｄ）］を溶媒としてのジクロロメタンとテトラヒドロフランの混合物とともに使用し、還流温度で加熱し、反応生成物をヘキサンと酢酸エチルの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付する以外は、上記参考実施例６（ａ）と同様の方法に従って、淡茶色固体として５−クロロ−１Ｈ−インダゾール−３−カルバルデヒドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８９分、１８１（Ｍ＋Ｈ)⁺。 (H) 5-chloro-1H-indazole-3-carbaldehyde

(5-Chloro-1H-indazol-3-yl) -methanol [Reference Example 25 (d)] is used with a mixture of dichloromethane and tetrahydrofuran as solvent and heated at reflux temperature, the reaction product is hexane and acetic acid According to the same method as in Reference Example 6 (a) above except that the mixture was subjected to flash column chromatography on silica using a mixture of ethyl (1: 1, v / v) as an eluent, 5-5- Chloro-1H-indazole-3-carbaldehyde was prepared. LC-MS (Method B): R _T = 2.89 min, 181 (M + H) ⁺ .

３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル［参考実施例４１（ａ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、茶色固体として３−ホルミル−ピラゾール−４−カルボン酸エチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６５分；１６９（Ｍ＋Ｈ)⁺。 (I) 3-Formyl-pyrazole-4-carboxylic acid ethyl ester

3-Formyl as a brown solid according to the same method as in Reference Example 6 (a) except that 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester [Reference Example 41 (a)] was used. -Pyrazole-4-carboxylic acid ethyl ester was prepared. LC-MS (Method B): R _T = 2.65 min; 169 (M + H) ⁺ .

３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミド［参考実施例４１（ｂ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、ワックス状の橙色固体として３−ホルミル−ピラゾール−４−カルボン酸イソプロピルアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７３分；１８２（Ｍ＋Ｈ)⁺。 (J) 3-formyl-pyrazole-4-carboxylic acid isopropylamide

According to the same method as in Reference Example 6 (a) except that 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide [Reference Example 41 (b)] was used, a waxy orange solid was obtained. 3-Formyl-pyrazole-4-carboxylic acid isopropylamide was prepared. LC-MS (Method B): R _T = 2.73 min; 182 (M + H) ⁺ .

３−ヒドロキシメチル−５−メチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル［参考実施例４１（ｃ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、白色固体として３−ホルミル−５−メチル−ピラゾール−４−カルボン酸エチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８０分；１８３（Ｍ＋Ｈ)⁺。 (K) 3-Formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester

A white solid was prepared in the same manner as in Reference Example 6 (a) except that 3-hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester [Reference Example 41 (c)] was used. 3-formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester was prepared. LC-MS (Method B): R _T = 2.80 min; 183 (M + H) ⁺ .

（１Ｈ−インダゾール−３−イル）−メタノール［参考実施例２５（ｇ）］を溶媒としてのアセトンとともに使用し、反応を還流温度で１６時間実行する以外は上記参考実施例６（ａ）と同様の方法に従って、黄色固体として１Ｈ−インダゾール−３−カルバルデヒ
ドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６３分；１４７.２６（Ｍ＋Ｈ)⁺；１４５.２６（Ｍ−Ｈ)^-。 (L) 1H-indazole-3-carbaldehyde

(1H-indazol-3-yl) -methanol [Reference Example 25 (g)] is used with acetone as a solvent and the reaction is carried out at reflux temperature for 16 hours, similar to Reference Example 6 (a) above. In this manner, 1H-indazole-3-carbaldehyde was produced as a yellow solid. LC-MS (Method B): R _T = 2.63 min; 147.26 (M + H) ⁺ ; 145.26 (M−H) ⁻ .

（ｉ）［４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−メタノール（６６３ｍｇ、参考実施例５３）および酸化マンガン（IV）（２.５４ｇ）を溶媒としてのアセトンとともに使用し、（ii）反応を６５℃で２時間実行し、（iii）反応生成物をペンタンと酢酸エチルの混合物（７０：３０、ｖ／ｖ）を溶離剤とするフラッシュシリカクロマトグラフィーに付する以外は、上記参考実施例６（ａ）と同様の方法に従って、淡黄色油状物として４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルバルデヒド（１９１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝２.１９分、２４８.２４（Ｍ＋Ｈ＋Ｎａ)⁺。 (M) 4-Nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carbaldehyde

(I) [4-Nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -methanol (663 mg, Reference Example 53) and manganese (IV) oxide (2.54 g). Used with acetone as solvent, (ii) the reaction is carried out at 65 ° C. for 2 hours, and (iii) the reaction product is a flash silica eluting with a mixture of pentane and ethyl acetate (70:30, v / v) Except for chromatography, 4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carba was prepared as a pale yellow oil according to the same method as in Reference Example 6 (a) above. Rudehydr (191 mg) was prepared. LC-MS (Method H): R _T = 2.19 min, 248.24 (M + H + Na) ⁺ .

３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸（２−メトキシ−エチル）−アミド［参考実施例４１（ｄ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、黄色油状物として３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸（２−メトキシ−エチル）−アミド（３２５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.１３分、１９８（Ｍ＋Ｈ)⁺。 (N) 3-Formyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide

According to the same method as in Reference Example 6 (a) except that 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide [Reference Example 41 (d)] was used. 3-formyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide (325 mg) was prepared as a yellow oil. LC-MS (Method B): R _T = 2.13 min, 198 (M + H) ⁺ .

３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸プロピルアミド［参考実施例４１（ｅ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、橙色油状物として３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸プロピルアミド（４１４ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４２分、１８２（Ｍ＋Ｈ)⁺。 (O) 3-Formyl-1H-pyrazole-4-carboxylic acid propylamide

According to a method similar to that of Reference Example 6 (a) except that 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid propylamide [Reference Example 41 (e)] was used, 3- Formyl-1H-pyrazole-4-carboxylic acid propylamide (414 mg) was prepared. LC-MS (Method B): R _T = 2.42 min, 182 (M + H) ⁺ .

３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸（テトラヒドロ−ピラン−４−イル）−アミド［参考実施例４１（ｆ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、茶色油状物として３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸（テトラヒドロ−ピラン−４−イル）−アミド（４００ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝２.３４分、２２４.３１（Ｍ＋Ｈ)⁺。 (P) 3-Formyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide

Similar to Reference Example 6 (a) above except that 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide [Reference Example 41 (f)] is used. According to the method, 3-formyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide (400 mg) was prepared as a brown oil. LC-MS (Method N): R _T = 2.34 min, 224.31 (M + H) ⁺ .

３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド［参考実施例４１（ｆ）］を使用する以外は、上記参考実施例６（ａ）と同様の方法に従って、黄色油状物として３−ホルミル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド（１２５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝１.８７分、１７８.３１（Ｍ−Ｈ)^-。 (Q) 3-Formyl-1H-pyrazole-4-carboxylic acid cyclopropylamide

3 as a yellow oil according to the same procedure as in Reference Example 6 (a) except that 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide [Reference Example 41 (f)] was used. -Formyl-1H-pyrazole-4-carboxylic acid cyclopropylamide (125 mg) was prepared. LC-MS (Method H): R _T = 1.87 min, 178.31 (M−H) ⁻ .

４−メトキシ−フェニレンジアミン二塩酸塩（１０ｇ）、Ｌ−乳酸ナトリウム（１０ｇ）および塩酸（６０ｍＬ、４Ｍ）の混合物を７０℃で４８時間加熱した。反応混合物を室温に冷却し、その後水酸化アンモニウムで処理した。得られた沈殿物を濾過し、乾燥して１−（５−メトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−エタノール（５.１４ｇ）を得た。 [Reference Example 7]
(A) 1- (5-Methoxy-1H-benzimidazol-2-yl) -ethanol

A mixture of 4-methoxy-phenylenediamine dihydrochloride (10 g), L-sodium lactate (10 g) and hydrochloric acid (60 mL, 4M) was heated at 70 ° C. for 48 hours. The reaction mixture was cooled to room temperature and then treated with ammonium hydroxide. The resulting precipitate was filtered and dried to give 1- (5-methoxy-1H-benzimidazol-2-yl) -ethanol (5.14 g).

２−ヒドロキシ酪酸を使用する以外は、上記参考実施例７（ａ）と同様の方法に従って、１−（５−メトキシ−１−ベンゾイミダゾール）−１−プロパノールを製造した。 (B) 1- (5-Methoxy-1-benzimidazole) -1-propanol

1- (5-methoxy-1-benzimidazole) -1-propanol was produced according to the same method as in Reference Example 7 (a) except that 2-hydroxybutyric acid was used.

[Reference Example 8]
(A) Dimethylvaleramide A solution of dimethylamine hydrochloride (6.76 g) and triethylamine (30 mL) in dichloromethane (100 mL) was treated dropwise with valeryl chloride (10 g) at 0 ° C. under nitrogen. After stirring overnight at room temperature, the reaction mixture was treated with hydrochloric acid (2N) and dichloromethane. The organic layer was separated, dried over magnesium sulfate and then evaporated to give dimethyl valeramide as a clear oil.
(B) Dimethylisovaleramide was produced according to the same method as in Reference Example 8 (a) except that isovaleryl chloride was used.

[Reference Example 9]
2,3-Diaminopyrazine Liquid ammonia (50 mL) was introduced into a pressure reaction vessel containing a small amount of ice. To this was added bronze (1.17 g), copper (II) iodide (0.224 g) and 2,3-dichloropyrazine (4 g). The sealed reaction vessel was heated at 170 ° C. for 48 hours, then cooled to ambient temperature and then evacuated. The reaction mixture was treated with water (75 mL) and the mixture was extracted with diethyl ether (400 mL) for 4 hours. The combined extracts were evaporated to give 2,3-diaminopyrazine as a white solid (0.3 g). The aqueous layer was continuously extracted with diethyl ether for 18 hours to obtain an additional amount of 2,3-diaminopyrazine (1.24 g).
¹ H-NMR [(CD ₃ ) ₂ SO]: δ 5.87 (s, 4H), 7.15 (s, 2H)

[Reference Example 10]
1H-pyrazole-3-carbaldehyde (i) While maintaining the reaction temperature between 80 ° C. and 110 ° C., dry dimethylformamide (77.6 mL) was added at 80 ° C. while cyanuric chloride (26.6 g) was added little by little. And stirred. The reaction mixture was stirred at 100 ° C. for a further 30 minutes, then cooled and then left at room temperature overnight. The reaction mixture was filtered to obtain dimethylvinylamine.

(Ii) Dimethylvinylamine from (i) is added to dry methanol (260 mL), and then the mixture is treated with pyruvaldehyde dimethyl acetal (51 mL), followed by a solution of sodium methoxide in methanol (30%, 81 mL). The mixture was then stirred at ambient temperature for 2 hours, then at reflux temperature for a further hour, then cooled and then filtered. The filtrate was evaporated to give 1,1-dimethoxy-but-3-en-2-one as a brown oil (96.8 g).

(Iii) A stirred solution of 1,1-dimethoxy-but-3-en-2-one in water (300 mL) was treated dropwise with hydrazine hydrate (21 mL). After standing overnight at room temperature, the reaction mixture was treated with sodium chloride (108 g) and then the mixture was extracted with methyl-t-butyl ether (200 mL, then 100 mL). The combined extracts were dried over magnesium sulfate and then evaporated to give 1H-pyrazole-3-carbaldehyde dimethyl acetal as a light brown oil (18.47 g).

(Iv) A solution of 1H-pyrazole-3-carbaldehyde dimethyl acetal in water (85 mL) was treated with glacial acetic acid (3.7 mL). After 2 days, the mixture was filtered to give 1H-pyrazole-3-carbaldehyde (1.3 g) as a light brown solid.

水素化ナトリウム（０.１ｇ）をエタノール（５ｍＬ）に添加し、混合物を１０分間攪拌し、その後３,３−ビス−メタンスルファニル−１−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−プロペノン［０.５ｇ、参考実施例２（ｐ）］で処理し、その後還流温度で６時間加熱した。反応混合物を冷却し、その後ヒドラジン水和物（１.２７ミリモル）で処理し、その後還流温度で４時間加熱した。その後混合物を蒸発させ、残存物を水で磨砕し、濾過した。固体を酢酸エチルを溶離剤とするシリカゲル上のクロマトグラフィーに付し、黄色油状物として２−（５−エトキシ−１Ｈ−ピラゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾールを得た。 [Reference Example 11]
2- (5-Ethoxy-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole

Sodium hydride (0.1 g) was added to ethanol (5 mL) and the mixture was stirred for 10 minutes, after which 3,3-bis-methanesulfanyl-1- [1- (2-trimethylsilanyl-ethoxymethyl)- 1H-benzoimidazol-2-yl] -propenone [0.5 g, Reference Example 2 (p)] was then heated at reflux for 6 hours. The reaction mixture was cooled and then treated with hydrazine hydrate (1.27 mmol) and then heated at reflux for 4 hours. The mixture was then evaporated and the residue was triturated with water and filtered. The solid was chromatographed on silica gel with ethyl acetate as eluent to give 2- (5-ethoxy-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) as a yellow oil. -1H-benzimidazole was obtained.

塩酸ヒドロキシルアミン（１６８ｍｇ）をメタノール中のナトリウムメトキシドの溶液［水素化ナトリウム（１２２ｍｇ）をメタノール（５ｍＬ）に添加することにより製造］に添加した。混合物を１０分間攪拌し、その後３,３−ビス−メタンスルファニル−１−［１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−プロペノン［５００ｍｇ、参考実施例２（ｐ）］で処理し、その後還流下に６時間加熱し、その後冷却し、その後蒸発させた。残存物を水に溶解し、水性の混合物を酢酸エチルで抽出した。抽出物を乾燥し、蒸発させた。残存物を塩化メチレンを溶離剤とするシリカ上のクロマトグラフィーに付し、無色の油状物として２−（５−メチルスルファニル−イソオキサゾール−３−イル）−１−（２−トリメチルシラニル−エトキシメチル）１Ｈ−ベンゾイミダゾール（０.１６ｇ）を得た。 [Reference Example 12]
2- (5-Methylsulfanyl-isoxazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) 1H-benzimidazole

Hydroxylamine hydrochloride (168 mg) was added to a solution of sodium methoxide in methanol [prepared by adding sodium hydride (122 mg) to methanol (5 mL)]. The mixture was stirred for 10 minutes, after which 3,3-bis-methanesulfanyl-1- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -propenone [500 mg, Reference Example] 2 (p)], then heated at reflux for 6 hours, then cooled and then evaporated. The residue was dissolved in water and the aqueous mixture was extracted with ethyl acetate. The extract was dried and evaporated. The residue was chromatographed on silica eluting with methylene chloride to give 2- (5-methylsulfanyl-isoxazol-3-yl) -1- (2-trimethylsilanyl-ethoxy as a colorless oil. Methyl) 1H-benzimidazole (0.16 g) was obtained.

モルホリン（３ｍＬ）中の１−［６−クロロ−５−メチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−３,３−ビス−メタンスルファニル−プロペノン［８００ｍｇ、参考実施例２（ｑ）］の溶液を９５℃で２時間加熱し、その後蒸発させて、１−［６−クロロ−５−メチル−１−（２−トリメチルシラニル−エトキシメチル）−１Ｈ−ベンゾイミダゾール−２−イル］−３−メチルスルファニル−３−モルホリン−１−イル−プロペノンを得た。 [Reference Example 13]
1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3-methylsulfanyl-3-morpholin-1-yl-propenone

1- [6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazol-2-yl] -3,3-bis-methanesulfanyl-propenone in morpholine (3 mL) A solution of [800 mg, Reference Example 2 (q)] was heated at 95 ° C. for 2 hours and then evaporated to give 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl). -1H-Benzimidazol-2-yl] -3-methylsulfanyl-3-morpholin-1-yl-propenone was obtained.

攪拌棒、分圧均一化滴下漏斗および注入／排出アダプターを備えた三つ口フラスコに、チオフェン（１０ｍＬ）および塩酸水（５.５ｍＬ）を添加した。塩化水素ガス［硫酸（３０ｍＬ）を乾燥塩化ナトリウム（５０ｇ）上に滴下することにより発生］を反応混合物を通して０℃で激しく攪拌しながらバブリングした。その後この混合物をホルムアルデヒド溶液（３７％、１２.５ｍＬ）で滴下処理し、攪拌を４５分間続行した。層を分離し、水層をジエチルエーテル（１０ｍＬ）で３回抽出した。その後有機層を水（１０ｍＬ）で２回、その後飽和炭酸水素ナトリウム（１０ｍＬ）で２回洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を２０ｍｍＨｇでヒートガンを使用して蒸留し、得られた２−クロロメチル−チオフェンをさらに精製することなく直接使用した。 [Reference Example 14]
2-Chloromethyl-thiophene

Thiophene (10 mL) and aqueous hydrochloric acid (5.5 mL) were added to a three-necked flask equipped with a stir bar, a partial pressure homogenizing dropping funnel and an injection / discharge adapter. Hydrogen chloride gas [generated by dropwise addition of sulfuric acid (30 mL) onto dry sodium chloride (50 g)] was bubbled through the reaction mixture at 0 ° C. with vigorous stirring. The mixture was then treated dropwise with formaldehyde solution (37%, 12.5 mL) and stirring was continued for 45 minutes. The layers were separated and the aqueous layer was extracted 3 times with diethyl ether (10 mL). The organic layer was then washed twice with water (10 mL) and then twice with saturated sodium bicarbonate (10 mL), then dried over magnesium sulfate and then evaporated. The residue was distilled using a heat gun at 20 mm Hg and the resulting 2-chloromethyl-thiophene was used directly without further purification.

水素化ナトリウム（１９.２ｇ）およびトルエン（４００ｍＬ）の混合物を８０℃でｔ−ブタノール（３０.８ｇ）で少しずつ処理した。２時間後、反応混合物を室温に冷却し、ジメチルホルムアミド（４０ｍＬ）、二硫化炭素（１２ｍＬ）および２−アセチル−１−（テトラヒドロピラン−２−イル）−ベンゾイミダゾール（５１ｇ、参考実施例１６）の混合物で９０分間かけて滴下処理した。添加後、赤色の反応混合物を８０℃で３０分間攪拌し、その後室温に冷却し、その後ヨウ化メチル（５０ｍＬ）で処理した。この混合物を８０℃で３０分間攪拌し、その際沈殿の形成が開始された。反応混合物を室温に冷却し、その後濾過した。濾液を濃縮し、得られた粘稠な赤色油状物をメタノール（３００ｍＬ）に溶解した。この溶液をｐ−トルエンスルホン酸（２ｇ）および水（４ｍＬ）で処理し、その後還流温度で１３時間加熱し、その後アイスバス中に冷却した。得られた固体を濾過し、その後イソプロピルエーテルで洗浄し、ビス（メチルチオ）−３,３−（ベンゾイミダゾール−２−イル）−１−プロパ−２−エン−２−オン（１１.２ｇ）を得た。融点２２４℃。 [Reference Example 15]
Bis (methylthio) -3,3- (benzimidazol-2-yl) -1-prop-2-en-2-one

A mixture of sodium hydride (19.2 g) and toluene (400 mL) was treated in portions with t-butanol (30.8 g) at 80 ° C. After 2 hours, the reaction mixture was cooled to room temperature and dimethylformamide (40 mL), carbon disulfide (12 mL) and 2-acetyl-1- (tetrahydropyran-2-yl) -benzimidazole (51 g, Reference Example 16). The mixture was added dropwise over 90 minutes. After the addition, the red reaction mixture was stirred at 80 ° C. for 30 minutes, then cooled to room temperature and then treated with methyl iodide (50 mL). The mixture was stirred at 80 ° C. for 30 minutes, whereupon precipitate formation began. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated and the resulting viscous red oil was dissolved in methanol (300 mL). This solution was treated with p-toluenesulfonic acid (2 g) and water (4 mL), then heated at reflux for 13 hours and then cooled in an ice bath. The resulting solid was filtered and then washed with isopropyl ether to give bis (methylthio) -3,3- (benzimidazol-2-yl) -1-prop-2-en-2-one (11.2 g). Obtained. Mp 224 ° C.

ジヒドロピラン（２０.５ｍＬ）をジクロロメタン（２８０ｍＬ）中の２−アセチルベンゾイミダゾール（３２ｇ）およびｐ−トルエンスルホン酸（２ｇ）の溶液に還流下に滴加した。反応混合物をこの温度で２４時間攪拌し、その後冷却し、不溶性の物質を濾去した。濾液を濃縮し、琥珀色油状物（５１.８ｇ）として２−アセチル−１−（テトラヒドロピラン−２−イル）−ベンゾイミダゾールを得た。ＴＬＣ：（ジクロロメタン：メタノール、９７：３）Ｒ_F＝０.８０。 [Reference Example 16]
2-Acetyl-1- (tetrahydropyran-2-yl) -benzimidazole

Dihydropyran (20.5 mL) was added dropwise at reflux to a solution of 2-acetylbenzimidazole (32 g) and p-toluenesulfonic acid (2 g) in dichloromethane (280 mL). The reaction mixture was stirred at this temperature for 24 hours, then cooled and insoluble material was filtered off. The filtrate was concentrated to give 2-acetyl-1- (tetrahydropyran-2-yl) -benzimidazole as an amber oil (51.8 g). TLC: (dichloromethane: methanol, 97: 3) R _F = 0.80.

メタノール（５０ｍｌ）中の４,５,６,７−テトラヒドロ−１Ｈ−インダゾール−３−カルボン酸エチルエステル［０.６０６ｇ、参考実施例１８（ａ）］の溶液を水酸化ナトリウム（０.５００ｇ）で処理した。混合物を１６時間還流し、その後冷却し、その後蒸発させた。残存する白色固体を塩酸（３０ｍｌ、２Ｎ）で処理し、得られた溶液を酢酸エチル（５０ｍｌ）で３回抽出した。合わせた有機抽出物を硫酸ナトリウム上に乾燥し、その後蒸発させて、白色固体として４,５,６,７−テトラヒドロ−１Ｈ−インダゾール−３−カルボン酸（０.４２４ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４４分；１６７（Ｍ＋Ｈ)⁺。 [Reference Example 17]
(A) 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

A solution of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester [0.606 g, Reference Example 18 (a)] in methanol (50 ml) was added to sodium hydroxide (0.500 g). Was processed. The mixture was refluxed for 16 hours, then cooled and then evaporated. The remaining white solid was treated with hydrochloric acid (30 ml, 2N) and the resulting solution was extracted three times with ethyl acetate (50 ml). The combined organic extracts were dried over sodium sulfate and then evaporated to give 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.424 g) as a white solid. LC-MS (Method B): R _T = 2.44 min; 167 (M + H) ⁺ .

５−イソプロピル−１Ｈ−ピラゾール−３−カルボン酸エチルエステル［参考実施例１８（ｂ）］を使用する以外は、上記実施例１７（ａ）と同様の方法に従って、白色固体（０.９７３ｇ）として製造した５−イソプロピル−１Ｈ−ピラゾール−３−カルボン酸をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４３分；１５５（Ｍ＋Ｈ)⁺。 (B) 5-Isopropyl-1H-pyrazole-3-carboxylic acid

As a white solid (0.973 g) according to the same method as in Example 17 (a) except that 5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester [Reference Example 18 (b)] was used. The prepared 5-isopropyl-1H-pyrazole-3-carboxylic acid was used without further purification. LC-MS (Method B): R _T = 2.43 min; 155 (M + H) ⁺ .

５−エチル−１Ｈ−ピラゾール−３−カルボン酸エチルエステル［参考実施例１８（ｃ）］を使用する以外は、上記参考実施例１７（ａ）と同様の方法に従って、白色固体として５−イソプロピル−１Ｈ−ピラゾール−３−カルボン酸を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３４分；１４１（Ｍ＋Ｈ)⁺。 (C) 5-ethyl-1H-pyrazole-3-carboxylic acid

According to a method similar to that of Reference Example 17 (a) except that 5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester [Reference Example 18 (c)] was used, 5-isopropyl- 1H-pyrazole-3-carboxylic acid was prepared. LC-MS (Method B): R _T = 2.34 min; 141 (M + H) ⁺ .

３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル［参考実施例４２］を使用する以外は、上記参考実施例１７（ａ）と同様の方法に従って、白色固体として製造した３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７５分；１９９（Ｍ＋Ｈ)⁺。 (D) 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid

3 produced as a white solid according to the same method as in Reference Example 17 (a) except that 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester [Reference Example 42] was used. -T-Butyloxymethyl-1H-pyrazole-4-carboxylic acid was used without further purification. LC-MS (Method B): R _T = 2.75 min; 199 (M + H) ⁺ .

１,４,６,７−テトラヒドロ−ピラノ［４,３−ｃ］ピラゾール−３−カルボン酸エチルエステル［参考実施例１８（ｅ）］を使用する以外は、上記参考実施例１７（ａ）と同様の方法に従って、白色固体として１,４,６,７−テトラヒドロ−ピラノ［４,３−ｃ］ピラゾール−３−カルボン酸（２６１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝１.９８分、１６９（Ｍ＋Ｈ)⁺。 (E) 1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid

Reference Example 17 (a) above, except that 1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid ethyl ester [Reference Example 18 (e)] was used. In a similar manner, 1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid (261 mg) was prepared as a white solid. LC-MS (Method B): R _T = 1.98 min, 169 (M + H) ⁺ .

１,４,５,６−テトラヒドロ−シクロペンタピラゾール−３−カルボン酸エチルエステル［参考実施例１８（ｆ）］を使用する以外は、上記参考実施例１７（ａ）と同様の方法に従って、白色固体として１,４,５,６−テトラヒドロ−シクロペンタピラゾール−３−カルボン酸（０.６４１ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.１３分、１５３.２２（Ｍ＋Ｈ)⁺。 (F) 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid

According to the same method as in Reference Example 17 (a) except that 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester [Reference Example 18 (f)] was used, 1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid (0.641 g) was prepared as a solid. LC-MS (Method B): R _T = 2.13 min, 153.22 (M + H) ⁺ .

酢酸（１５０ｍｌ）中のオキソ−（２−オキソ−シクロヘキシル）−酢酸エチルエステル［７.５ｇ、参考実施例１９（ａ）］の溶液をヒドラジン１水和物（１.６５ｍｌ）で滴下処理した。混合物を８時間還流し、その後冷却し、その後蒸発させた。残存物を酢酸エチル（２００ｍｌ）と飽和重炭酸ナトリウム溶液（２００ｍｌ）の間に分配し、有機層を硫酸ナトリウム上に乾燥し、その後蒸発させた。残存する橙色油状物を酢酸エチルとヘキサンの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、橙色油状物として得られた４,５,６,７−テトラヒドロ−１Ｈ−インダゾール−３−カルボン酸エチルエステル（６０６ｍｇ）を放置して固体化した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７９分；１９５（Ｍ＋Ｈ)⁺。 [Reference Example 18]
(A) 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester

A solution of oxo- (2-oxo-cyclohexyl) -acetic acid ethyl ester [7.5 g, Reference Example 19 (a)] in acetic acid (150 ml) was treated dropwise with hydrazine monohydrate (1.65 ml). The mixture was refluxed for 8 hours, then cooled and then evaporated. The residue was partitioned between ethyl acetate (200 ml) and saturated sodium bicarbonate solution (200 ml) and the organic layer was dried over sodium sulfate and then evaporated. The remaining orange oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 1, v / v) to give 4,5,6, 7-Tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (606 mg) was allowed to solidify. LC-MS (Method B): R _T = 2.79 min; 195 (M + H) ⁺ .

５−メチル−２,４−ジオキソ−ヘキサン酸エチルエステル［２.００ｇ、参考実施例１９（ｂ）］を使用する以外は、上記参考実施例１８（ａ）と同様の方法に従って、明黄色油状物として製造した５−イソプロピル−１Ｈ−ピラゾール−３−カルボン酸エチルエステルをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７９分；１８３（Ｍ＋Ｈ)⁺。 (B) 5-Isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester

A light yellow oil was obtained in the same manner as in Reference Example 18 (a) except that 5-methyl-2,4-dioxo-hexanoic acid ethyl ester [2.00 g, Reference Example 19 (b)] was used. The 5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester prepared as product was used without further purification. LC-MS (Method B): R _T = 2.79 min; 183 (M + H) ⁺ .

２,４−ジオキソ−ヘキサン酸エチルエステル［参考実施例１９（ｃ）］を使用し、反応生成物である橙色油状物を酢酸エチルとヘキサンの混合物（８：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュクロマトグラフィーに付する以外は、上記参考実施例１８（ａ）と同様の方法に従って、黄色油状物として５−エチル−１Ｈ−ピラゾール−３−カルボン酸エチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６４分；１６９（Ｍ＋Ｈ)⁺。 (C) 5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester

Using 2,4-dioxo-hexanoic acid ethyl ester [Reference Example 19 (c)], the orange oil as the reaction product was eluted with a mixture of ethyl acetate and hexane (8: 1, v / v). 5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester was produced as a yellow oil according to the same method as in Reference Example 18 (a) except that flash chromatography on silica was used. LC-MS (Method B): R _T = 2.64 min; 169 (M + H) ⁺ .

３−エトキシオキサリル−４−オキソ−ピペリジン−１−カルボン酸ｔ−ブチルエステル［参考実施例１９（ｄ）］を使用する以外は、上記参考実施例１８（ａ）と同様の方法に従って、黄色油状物として１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−３,５−ジカルボン酸５−ｔ−ブチルエステル３−エチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７３分；２９６（Ｍ＋Ｈ)⁺。 (D) 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid 5-t-butyl ester 3-ethyl ester

According to a method similar to that of Reference Example 18 (a) except that 3-ethoxyoxalyl-4-oxo-piperidine-1-carboxylic acid t-butyl ester [Reference Example 19 (d)] was used, a yellow oily oil was obtained. As a product, 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid 5-t-butyl ester 3-ethyl ester was produced. LC-MS (Method B): R _T = 2.73 min; 296 (M + H) ⁺ .

テトラヒドロ−４Ｈ−ピラン−４−オンを使用する以外は、上記参考実施例１８（ａ）と同様の方法に従って、白色固体として１,４,６,７−テトラヒドロ−ピラノ［４,３−ｃ］ピラゾール−３−カルボン酸エチルエステル（３８５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４３分、１９７（Ｍ＋Ｈ)⁺。 (E) 1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid ethyl ester

Except that tetrahydro-4H-pyran-4-one is used, 1,4,6,7-tetrahydro-pyrano [4,3-c] is obtained as a white solid according to the same method as in Reference Example 18 (a) above. Pyrazole-3-carboxylic acid ethyl ester (385 mg) was prepared. LC-MS (Method B): R _T = 2.43 min, 197 (M + H) ⁺ .

オキソ−（２−オキソ−シクロペンチル）−酢酸エチルエステル［参考実施例１９（ｅ）］を使用する以外は、上記参考実施例１８（ａ）と同様の方法に従って、黄色固体として１,４,５,６−テトラヒドロ−シクロペンタピラゾール−３−カルボン酸エチルエステル（２.０６ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５６分、１８５（Ｍ＋Ｈ)⁺。 (F) 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester

According to the same method as Reference Example 18 (a) except that oxo- (2-oxo-cyclopentyl) -acetic acid ethyl ester [Reference Example 19 (e)] was used, 1,4,5 as a yellow solid , 6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester (2.06 g) was prepared. LC-MS (Method B): R _T = 2.56 min, 185 (M + H) ⁺ .

エタノール（１００ｍｌ）中のナトリウム（１.７５ｇ）の溶液をジエチルオキサレート（９.４１ｍｌ）およびシクロヘキサノン（７.１８ｍｌ）の混合物で処理した。混合物を６０℃に５時間加熱し、その後冷却し、その後蒸発させて茶色泡状物（１６.６３５ｇ）としてオキソ−（２−オキソ−シクロヘキシル）−酢酸エチルエステルを得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１０分；１９７（Ｍ−Ｈ)^-。 [Reference Example 19]
(A) Oxo- (2-oxo-cyclohexyl) -acetic acid ethyl ester

A solution of sodium (1.75 g) in ethanol (100 ml) was treated with a mixture of diethyl oxalate (9.41 ml) and cyclohexanone (7.18 ml). The mixture was heated to 60 ° C. for 5 hours, then cooled and then evaporated to give oxo- (2-oxo-cyclohexyl) -acetic acid ethyl ester as a brown foam (16.635 g). LC-MS (Method B): R _T = 3.10 min; 197 (M−H) ⁻ .

３−メチル−２−ブタノンを使用する以外は、上記実施例１９（ａ）と同様の方法に従って、白色固体として５−メチル−２,４−ジオキソ−ヘキサン酸エチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４７分；１８７（Ｍ＋Ｈ)⁺。 (B) 5-methyl-2,4-dioxo-hexanoic acid ethyl ester

Except for using 3-methyl-2-butanone, 5-methyl-2,4-dioxo-hexanoic acid ethyl ester was produced as a white solid according to the same method as in Example 19 (a) above. LC-MS (Method B): R _T = 3.47 min; 187 (M + H) ⁺ .

２−ブタノンを使用する以外は、上記参考実施例１９（ａ）と同様の方法に従って、茶色油状物として製造した２,４−ジオキソ−ヘキサン酸エチルエステルをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.２８分；１７３（Ｍ＋Ｈ)⁺。 (C) 2,4-Dioxo-hexanoic acid ethyl ester

Except for using 2-butanone, 2,4-dioxo-hexanoic acid ethyl ester produced as a brown oil was used without further purification according to the same method as in Reference Example 19 (a) above. LC-MS (Method B): R _T = 3.28 min; 173 (M + H) ⁺ .

Ｎ−Ｂｏｃピペリドンを使用する以外は、上記参考実施例１９（ａ）と同様の方法に従って、茶色油状物として製造した３−エトキシオキサリル−４−オキソ−ピペリジン−１−カルボン酸ｔ−ブチルエステルをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４３分；２４４（Ｍ−ｔＢｕ)⁺。 (D) 3-Ethoxyoxalyl-4-oxo-piperidine-1-carboxylic acid t-butyl ester

Except for using N-Boc piperidone, 3-ethoxyoxalyl-4-oxo-piperidine-1-carboxylic acid t-butyl ester produced as a brown oil was prepared in the same manner as in Reference Example 19 (a) above. Used without further purification. LC-MS (Method B): R _T = 3.43 min; 244 (M-tBu) ⁺ .

シクロペンタノンを使用する以外は、上記実施例１９（ａ）と同様の方法に従って、黄色固体としてオキソ−（２−オキソ−シクロペンチル）−酢酸エチルエステル（９.９９ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１２分、１８５（Ｍ＋Ｈ)⁺。 (E) Oxo- (2-oxo-cyclopentyl) -acetic acid ethyl ester

Except for the use of cyclopentanone, oxo- (2-oxo-cyclopentyl) -acetic acid ethyl ester (9.99 g) was prepared as a yellow solid according to the same method as in Example 19 (a) above. LC-MS (Method B): R _T = 3.12 min, 185 (M + H) ⁺ .

テトラヒドロフラン（４ｍｌ）および水（１.５ｍｌ）中の５−メトキシ−３−（２−メトキシカルボニル−ビニル）−インダゾール−１−カルボン酸ｔ−ブチルエステル［２８２ｍｇ、参考実施例２１（ａ）］の溶液を水中の四酸化オスミウムの溶液（５４μＬ、４重量％）および過ヨウ素酸ナトリウム（４００ｍｇ）で処理した。反応混合物を周囲温度で１６時間攪拌し、その後濾過した。濾液を蒸発させ、残存物を酢酸エチルと水との間に分配した。有機層を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルとペトロールの混合物（１：９、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、白色固体として３−ホルミル−５−メトキシ−インダゾール−１−カルボン酸ｔ−ブチルエステル（１６２ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９７分；２７７（Ｍ＋Ｈ)⁺。 [Reference Example 20]
(A) 3-Formyl-5-methoxy-indazole-1-carboxylic acid t-butyl ester

Of 5-methoxy-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester [282 mg, Reference Example 21 (a)] in tetrahydrofuran (4 ml) and water (1.5 ml). The solution was treated with a solution of osmium tetroxide in water (54 μL, 4% by weight) and sodium periodate (400 mg). The reaction mixture was stirred at ambient temperature for 16 hours and then filtered. The filtrate was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol (1: 9, v / v) to give 3-formyl-5-methoxy-indazole-1-carbon as a white solid. Acid t-butyl ester (162 mg) was obtained. LC-MS (Method B): R _T = 2.97 min; 277 (M + H) ⁺ .

４−フルオロ−３−（２−メトキシカルボニル−ビニル）−インダゾール−１−カルボン酸ｔ−ブチルエステル［参考実施例２１（ｂ）］を使用する以外は、上記参考実施例２０（ａ）と同様の方法に従って、明茶色固体として４−フルオロ−１Ｈ−インダゾール−３−カルバルデヒドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６３分；１６５（Ｍ＋Ｈ)⁺。 (B) 4-Fluoro-1H-indazole-3-carbaldehyde

Similar to Reference Example 20 (a) except that 4-fluoro-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester [Reference Example 21 (b)] is used. According to the method, 4-fluoro-1H-indazole-3-carbaldehyde was produced as a light brown solid. LC-MS (Method B): R _T = 2.63 min; 165 (M + H) ⁺ .

４−クロロ−３−（２−メトキシカルボニル−ビニル）−インダゾール−１−カルボン酸ｔ−ブチルエステル［参考実施例２１（ｃ）］を使用する以外は、上記参考実施例２０（ａ）と同様の方法に従って、茶色油状物として４−クロロ−３−ホルミル−インダゾール−１−カルボン酸ｔ−ブチルエステル（０.２１７ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４９分；２８３（Ｍ＋Ｈ)⁺。 (C) 4-chloro-3-formyl-indazole-1-carboxylic acid t-butyl ester

Similar to Reference Example 20 (a) except that 4-chloro-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester [Reference Example 21 (c)] is used. According to the method of 4-chloro-3-formyl-indazole-1-carboxylic acid t-butyl ester (0.217 g) as a brown oil. LC-MS (Method B): R _T = 3.49 min; 283 (M + H) ⁺ .

５−エトキシ−３−（２−メトキシカルボニル−ビニル）−インダゾール−１−カルボン酸ｔ−ブチルエステル［参考実施例２１（ｄ）］を使用する以外は、上記参考実施例２０（ａ）と同様の方法に従って、茶色油状物として５−エトキシ−３−ホルミル−インダゾール−１−カルボン酸ｔ−ブチルエステルを製造した。ＴＬＣ（酢酸エチル：ヘキサン、１：９、ｖ／ｖ）：Ｒ_F＝０.２５。
¹H NMR (400MHz, CDCl₃): δ 1.38(3H, t), 1.67(9H, s), 4.05(2H, q), 7.12(1H, d),
7.60(1H, s), 7.98(1H, d), 10.20(1H, s) (D) 5-Ethoxy-3-formyl-indazole-1-carboxylic acid t-butyl ester

Same as Reference Example 20 (a) except using 5-ethoxy-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester [Reference Example 21 (d)]. According to the method, 5-ethoxy-3-formyl-indazole-1-carboxylic acid t-butyl ester was produced as a brown oil. TLC (ethyl acetate: hexane, 1: 9, v / v): R _F = 0.25.
¹ H NMR (400MHz, CDCl ₃ ): δ 1.38 (3H, t), 1.67 (9H, s), 4.05 (2H, q), 7.12 (1H, d),
7.60 (1H, s), 7.98 (1H, d), 10.20 (1H, s)

ジオキサン（１５ｍｌ）中の３−ヨード−５−メトキシ−インダゾール−１−カルボン酸ｔ−ブチルエステル［０.５００ｇ、参考実施例２２（ａ）］の溶液を窒素雰囲気下に、トリエチルアミン（１.８６ｍｌ）、ついでアクリル酸メチル（１.２０ｍｌ）、トリフェニルホスフィン（０.１０５ｇ）、および酢酸パラジウム（II）（６０ｍｇ）で処理した。得られた混合物を５０℃で１６時間加熱し、その後周囲温度に冷却し、その後蒸発させた。残存物を酢酸エチルと水との間に分配した。有機層を塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルと４０／６０ペトロールの混合物（１：９、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、５−メトキシ−３−（２−メトキシカルボニル−ビニル）−インダゾール−１−カルボン酸ｔ−ブチルエステル（２８２ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３３分；３３３（Ｍ＋Ｈ)⁺。 [Reference Example 21]
(A) 5-methoxy-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester

A solution of 3-iodo-5-methoxy-indazole-1-carboxylic acid t-butyl ester [0.50 g, Reference Example 22 (a)] in dioxane (15 ml) was added to a triethylamine (1.86 ml) under a nitrogen atmosphere. ), Followed by treatment with methyl acrylate (1.20 ml), triphenylphosphine (0.105 g), and palladium (II) acetate (60 mg). The resulting mixture was heated at 50 ° C. for 16 hours, then cooled to ambient temperature and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40/60 petrol (1: 9, v / v) to give 5-methoxy-3- (2-methoxycarbonyl-vinyl ) -Indazole-1-carboxylic acid t-butyl ester (282 mg) was obtained. LC-MS (Method B): R _T = 3.33 min; 333 (M + H) ⁺ .

(B) 4-fluoro-3-iodo-indazole-1-carboxylic acid t-butyl ester [Reference Example 22 (b)] was used except in the same manner as in Reference Example 21 (a) above. 4-Fluoro-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester was prepared as a light brown solid. LC-MS (Method B): R _T = 3.39 min; 321 (M + H) ⁺ .

(C) 4-chloro-3-iodo-indazole-1-carboxylic acid t-butyl ester [Reference Example 22 (c)] was used according to the same method as in Reference Example 21 (a) above, except that 4-Chloro-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester was prepared as a brown solid. LC-MS (Method B): R _T = 3.48 min; 339 (M + H) ⁺ .

(D) Except for using 5-ethoxy-3-iodo-indazole-1-carboxylic acid t-butyl ester [Reference Example 22 (d)], according to the same method as Reference Example 21 (a) above, 5-Ethoxy-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid t-butyl ester was prepared as an off-white solid. LC-MS (Method B): R _T = 3.41 min; 347 (M + H) ⁺ .

アセトニトリル（６ｍｌ）中の３−ヨード−５−メトキシ−１Ｈ−インダゾール［１.４８ｇ、参考実施例２３（ａ）］の溶液をトリエチルアミン（０.９８ｍｌ）およびＮ,Ｎ−ジメチルアミノピリジン（０.１３２ｇ）で処理した。混合物を０℃に冷却し、その後アセトニトリル（６ｍｌ）中のジ−ｔ−ブチルジカーボネート（１.４１ｇ）の溶液で処理した。周囲温度で１時間攪拌後、反応混合物を蒸発させ、残存物を酢酸エチルと水との間に分配した。ｐＨを２に調整し、有機層を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存する橙色油状物を酢酸エチルとペトロールの混合物（１：４、ｖ／ｖ）を溶離剤とするフラッシュカラムクロマトグラフィーに付し、黄色固体として３−ヨード−５−メトキシ−インダゾール−１−カルボン酸ｔ−ブチルエステル（１.７２ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４５分；３７５（Ｍ＋Ｈ)⁺。 [Reference Example 22]
(A) 3-Iodo-5-methoxy-indazole-1-carboxylic acid t-butyl ester

A solution of 3-iodo-5-methoxy-1H-indazole [1.48 g, Reference Example 23 (a)] in acetonitrile (6 ml) was added to triethylamine (0.98 ml) and N, N-dimethylaminopyridine (0. 132 g). The mixture was cooled to 0 ° C. and then treated with a solution of di-t-butyl dicarbonate (1.41 g) in acetonitrile (6 ml). After stirring for 1 hour at ambient temperature, the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The pH was adjusted to 2 and the organic layer was dried over magnesium sulfate and then evaporated. The remaining orange oil was subjected to flash column chromatography eluting with a mixture of ethyl acetate and petrol (1: 4, v / v) to give 3-iodo-5-methoxy-indazole-1-carboxylic acid as a yellow solid. Acid t-butyl ester (1.72 g) was obtained. LC-MS (Method B): R _T = 3.45 min; 375 (M + H) ⁺ .

４−フルオロ−３−ヨード−１Ｈ−インダゾール［参考実施例２３（ｂ）］を使用する以外は、上記参考実施例２２（ａ）と同様の方法に従って、明茶色固体として４−フルオロ−３−ヨード−インダゾール−１−カルボン酸ｔ−ブチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４８分；３６３（Ｍ＋Ｈ)⁺。 (B) 4-Fluoro-3-iodo-indazole-1-carboxylic acid t-butyl ester

Except for using 4-fluoro-3-iodo-1H-indazole [Reference Example 23 (b)], 4-Fluoro-3-as a light brown solid according to the same method as Reference Example 22 (a) above. Iodo-indazole-1-carboxylic acid t-butyl ester was prepared. LC-MS (Method B): R _T = 3.48 min; 363 (M + H) ⁺ .

４−クロロ−３−ヨード−１Ｈ−インダゾール［参考実施例２３（ｃ）］を使用する以外は、上記参考実施例２２（ａ）と同様の方法に従って、茶色固体として４−クロロ−３−ヨード−インダゾール−１−カルボン酸ｔ−ブチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３９分；３８１（Ｍ＋Ｈ)⁺。 (C) 4-chloro-3-iodo-indazole-1-carboxylic acid t-butyl ester

4-Chloro-3-iodo as a brown solid according to the same procedure as in Reference Example 22 (a) except that 4-chloro-3-iodo-1H-indazole [Reference Example 23 (c)] was used. -Indazole-1-carboxylic acid t-butyl ester was prepared. LC-MS (Method B): R _T = 3.39 min; 381 (M + H) ⁺ .

５−エトキシ−３−ヨード−１Ｈ−インダゾール［参考実施例２３（ｄ）］を使用する以外は、上記参考実施例２２（ａ）と同様の方法に従って、オフホワイトの固体として５−エトキシ−３−ヨード−インダゾール−１−カルボン酸ｔ−ブチルエステルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４９分；３８９（Ｍ＋Ｈ)⁺。 (D) 5-Ethoxy-3-iodo-indazole-1-carboxylic acid t-butyl ester

Except for using 5-ethoxy-3-iodo-1H-indazole [Reference Example 23 (d)], 5-ethoxy-3 as an off-white solid was prepared in the same manner as Reference Example 22 (a) above. -Iodo-indazole-1-carboxylic acid t-butyl ester was prepared. LC-MS (Method B): R _T = 3.49 min; 389 (M + H) ⁺ .

ジメチルホルムアミド（８ｍｌ）中の５−メトキシ−１Ｈ−インダゾール［０.８１５ｇ、参考実施例２４（ａ）］の溶液をヨウ素（２.８０ｇ）および水酸化カリウム（１.１６ｇ）で処理した。混合物を周囲温度で１時間攪拌し、その後１０％重亜硫酸ナトリウム水溶液（２００ｍｌ）に注ぎ込み、その後酢酸エチルで３回抽出した。合わせた有機抽出物を水、その後塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させて、黄色固体として３−ヨード−５−メトキシ−１Ｈ−インダゾール（１.４８ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９６分；２７５（Ｍ＋Ｈ)⁺。 [Reference Example 23]
(A) 3-Iodo-5-methoxy-1H-indazole

A solution of 5-methoxy-1H-indazole [0.815 g, Reference Example 24 (a)] in dimethylformamide (8 ml) was treated with iodine (2.80 g) and potassium hydroxide (1.16 g). The mixture was stirred at ambient temperature for 1 hour, then poured into 10% aqueous sodium bisulfite (200 ml) and then extracted three times with ethyl acetate. The combined organic extracts were washed with water followed by brine, then dried over magnesium sulfate and then evaporated to give 3-iodo-5-methoxy-1H-indazole (1.48 g) as a yellow solid. LC-MS (Method B): R _T = 2.96 min; 275 (M + H) ⁺ .

４−フルオロ−１Ｈ−インダゾール［参考実施例２４（ｂ）］を使用する以外は、上記参考実施例２３（ａ）と同様の方法に従って、赤色固体として４−フルオロ−３−ヨード−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.０６分；２８１（Ｍ＋Ｈ)⁺。 (B) 4-Fluoro-3-iodo-1H-indazole

4-Fluoro-3-iodo-1H-indazole as a red solid according to the same method as Reference Example 23 (a) except that 4-fluoro-1H-indazole [Reference Example 24 (b)] was used. Manufactured. LC-MS (Method B): R _T = 3.06 min; 281 (M + H) ⁺ .

４−クロロ−１Ｈ−インダゾール［参考実施例２４（ｃ）］を使用する以外は、上記参考実施例２３（ａ）と同様の方法に従って、明茶色固体として４−クロロ−３−ヨード−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９７分；２６３（Ｍ＋Ｈ)⁺。 (C) 4-chloro-3-iodo-1H-indazole

Except for using 4-chloro-1H-indazole [Reference Example 24 (c)], 4-chloro-3-iodo-1H— as a light brown solid was prepared in the same manner as in Reference Example 23 (a) above. Indazole was produced. LC-MS (Method B): R _T = 2.97 min; 263 (M + H) ⁺ .

５−エトキシ−１Ｈ−インダゾール［参考実施例３７］を使用する以外は、上記参考実施例２３（ａ）と同様の方法に従って、明茶色固体として５−エトキシ−３−ヨード−１Ｈ−インダゾールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９７分；２６３（Ｍ＋Ｈ)⁺。 (D) 5-Ethoxy-3-iodo-1H-indazole

Except for using 5-ethoxy-1H-indazole [Reference Example 37], 5-ethoxy-3-iodo-1H-indazole is produced as a light brown solid in the same manner as in Reference Example 23 (a) above. did. LC-MS (Method B): R _T = 2.97 min; 263 (M + H) ⁺ .

ジクロロメタン（１０ｍｌ）中の４−メトキシ−２−メチルアニリン（２ｍｌ）の溶液をトリエチルアミン（３.２７ｍｌ）で処理した。混合物を０℃に冷却し、その後無水酢酸（２.３８ｍｌ）で処理し、その後周囲温度で１時間攪拌し、その後０℃に冷却した際に、桃色固体が沈殿した。この固体を濾過し、その後冷ジクロロメタンで洗浄し、その後酢酸（５５ｍｌ）および濃塩酸（２０ｍｌ）に溶解した。この溶液を−５℃に冷却し、その後水（２０ｍｌ）中の亜硝酸ナトリウム（２.６８ｇ）の溶液で処理し、その後その温度で１時間攪拌し、その後水（１００ｍｌ）で処理した。この混合物を０℃で１０分間激しく攪拌した後、黄色固体が沈殿した。この固体を濾過し、その後水で洗浄し、その後トルエン（１３ｍｌ）に溶解した。この溶液を８０℃に１.５時間加熱し、その後冷却し、その後１Ｎ炭酸ナトリウム水溶液で洗浄した。有機層を２Ｎ塩酸水で３回抽出し、酸性の抽出物を冷却し、その後５Ｎ水酸化ナトリウム水溶液を添加して塩基性にした。水層を酢酸エチルで３回抽出し、合わせた有機層を硫酸マグネシウム上に乾燥し、その後蒸発させて、黄色固体として５−メトキシ−１Ｈ−インダゾール（０.４１０ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝１.３２分；１４９（Ｍ＋Ｈ)⁺。 [Reference Example 24]
(A) 5-methoxy-1H-indazole

A solution of 4-methoxy-2-methylaniline (2 ml) in dichloromethane (10 ml) was treated with triethylamine (3.27 ml). The mixture was cooled to 0 ° C., then treated with acetic anhydride (2.38 ml), then stirred at ambient temperature for 1 hour, and then cooled to 0 ° C. to precipitate a pink solid. This solid was filtered and then washed with cold dichloromethane and then dissolved in acetic acid (55 ml) and concentrated hydrochloric acid (20 ml). The solution was cooled to −5 ° C. and then treated with a solution of sodium nitrite (2.68 g) in water (20 ml), then stirred at that temperature for 1 hour and then treated with water (100 ml). After the mixture was vigorously stirred at 0 ° C. for 10 minutes, a yellow solid precipitated. This solid was filtered, then washed with water and then dissolved in toluene (13 ml). The solution was heated to 80 ° C. for 1.5 hours, then cooled and then washed with 1N aqueous sodium carbonate. The organic layer was extracted 3 times with 2N aqueous hydrochloric acid, the acidic extract was cooled and then made basic by adding 5N aqueous sodium hydroxide. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and then evaporated to give 5-methoxy-1H-indazole (0.410 g) as a yellow solid. LC-MS (Method B): R _T = 1.32 min; 149 (M + H) ⁺ .

テトラフルオロホウ酸（８.２ｍｌ、水中４８重量％）に、３−フルオロ−２−メチルアニリン（２.７ｍｌ）を添加した。混合物を０℃に冷却した際に形成した沈殿物を水（８ｍｌ）を添加して溶解した。その後水（２.７ｍｌ）中の亜硝酸ナトリウム（１.３８ｇ）の溶液を滴加し、その後混合物を周囲温度に戻し、その後さらに１時間攪拌した。沈殿した固体を濾過し、その後ジエチルエーテルで洗浄し、その後３０分間吸引下に乾燥した。得られたテトラフルオロホウ酸塩をクロロホルム（４５ｍｌ）中の酢酸カリウム（３.９２ｇ）および１８−クラウン−６（０.２６４ｇ）の懸濁液に添加した。周囲温度で３時間攪拌後、輝橙色混合物を濾過し、不溶性の物質をジクロロメタンで洗浄し、その後４０／６０ペトロールと酢酸エチルの混合物（３：１ ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、オフホワイトの固体として４−フルオロ−１Ｈ−インダゾール（０.６７５ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７０分；１３７（Ｍ＋Ｈ)⁺。 (B) 4-Fluoro-1H-indazole

To tetrafluoroboric acid (8.2 ml, 48% by weight in water) was added 3-fluoro-2-methylaniline (2.7 ml). The precipitate formed when the mixture was cooled to 0 ° C. was dissolved by adding water (8 ml). A solution of sodium nitrite (1.38 g) in water (2.7 ml) was then added dropwise, after which the mixture was allowed to return to ambient temperature and then stirred for an additional hour. The precipitated solid was filtered, then washed with diethyl ether and then dried under suction for 30 minutes. The resulting tetrafluoroborate was added to a suspension of potassium acetate (3.92 g) and 18-crown-6 (0.264 g) in chloroform (45 ml). After stirring for 3 hours at ambient temperature, the bright orange mixture is filtered, the insoluble material is washed with dichloromethane and then on silica eluting with a mixture of 40/60 petrol and ethyl acetate (3: 1 v / v). Flash column chromatography gave 4-fluoro-1H-indazole (0.675 g) as an off-white solid. LC-MS (Method B): R _T = 2.70 min; 137 (M + H) ⁺ .

３−クロロ−２−メチルアニリンを使用する以外は、上記参考実施例２４（ａ）と同様の方法に従って、赤色固体（０.８０７ｇ）として製造した４−クロロ−１Ｈ−インダゾールをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９０分；１５５（Ｍ＋Ｈ)⁺。 (C) 4-Chloro-1H-indazole

Purify 4-chloro-1H-indazole produced as a red solid (0.807 g) according to the same method as in Reference Example 24 (a) except that 3-chloro-2-methylaniline is used. We used without. LC-MS (Method B): R _T = 2.90 min; 155 (M + H) ⁺ .

無水テトラヒドロフラン（１５ｍｌ）中の５−フルオロ−１Ｈ−インダゾール−３−カルボン酸［０.６８０ｇ、参考実施例２６（ａ）］の溶液を０℃で水素化リチウムアルミニウム（０.７１６ｇ）で少しずつ処理し、その後周囲温度で２時間攪拌し、その後飽和硫酸ナトリウム水で処理した。塩酸（１Ｎ）を添加して反応混合物を酸性化し、その後酢酸エチル（３０ｍｌ）で３回抽出した。合わせた有機抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存した暗茶色油状物を４０／６０ペトロールと酢酸エチルの混合物（１：１〜１：３ ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、茶色固体として（５−フルオロ−１Ｈ−インダゾール−３−イル）−メタノール（０.１４４ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４０分；１６７（Ｍ＋Ｈ)⁺。 [Reference Example 25]
(A) (5-Fluoro-1H-indazol-3-yl) -methanol

A solution of 5-fluoro-1H-indazole-3-carboxylic acid [0.680 g, Reference Example 26 (a)] in anhydrous tetrahydrofuran (15 ml) was added in portions with lithium aluminum hydride (0.716 g) at 0 ° C. Treated, then stirred at ambient temperature for 2 hours and then treated with saturated aqueous sodium sulfate. Hydrochloric acid (1N) was added to acidify the reaction mixture and then extracted three times with ethyl acetate (30 ml). The combined organic extracts were dried over magnesium sulfate and then evaporated. The remaining dark brown oil was subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (1: 1 to 1: 3 v / v) as a brown solid (5- Fluoro-1H-indazol-3-yl) -methanol (0.144 g) was obtained. LC-MS (Method B): R _T = 2.40 min; 167 (M + H) ⁺ .

６−フルオロ−１Ｈ−インダゾール−３−カルボン酸［参考実施例２６（ｂ）］を使用する以外は、上記参考実施例２５（ａ）と同様の方法に従って、暗灰色固体として（６−フルオロ−１Ｈ−インダゾール−３−イル）−メタノール（０.２６５ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４０分、１６５（Ｍ−Ｈ）。 (B) (6-Fluoro-1H-indazol-3-yl) -methanol

Except that 6-fluoro-1H-indazole-3-carboxylic acid [Reference Example 26 (b)] is used, (6-Fluoro-) as a dark gray solid is prepared in the same manner as in Reference Example 25 (a) above. 1H-indazol-3-yl) -methanol (0.265 g) was prepared. LC-MS (Method B): R _T = 2.40 min, 165 (M−H).

５−メチル−１Ｈ−インダゾール−３−カルボン酸［参考実施例２６（ｃ）］を使用する以外は、上記参考実施例２５（ａ）と同様の方法に従って、茶色油状物として（５−メチル−１Ｈ−インダゾール−３−イル）−メタノール（０.５１１ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４５分；１６３（Ｍ＋Ｈ)⁺。 (C) (5-Methyl-1H-indazol-3-yl) -methanol

According to the same method as in Reference Example 25 (a) except that 5-methyl-1H-indazole-3-carboxylic acid [Reference Example 26 (c)] was used, (5-methyl- 1H-indazol-3-yl) -methanol (0.511 g) was prepared. LC-MS (Method B): R _T = 2.45 min; 163 (M + H) ⁺ .

５−クロロ−１Ｈ−インダゾール−３−カルボン酸［参考実施例２６（ｄ）］を使用する以外は、上記参考実施例２５（ａ）と同様の方法に従って、暗茶色油状物として製造した（５−クロロ−１Ｈ−インダゾール−３−イル）−メタノールを放置して固体化した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５１分；１８５（Ｍ＋Ｈ)⁺。 (D) (5-Chloro-1H-indazol-3-yl) -methanol

Prepared as a dark brown oil in the same manner as in Reference Example 25 (a) except that 5-chloro-1H-indazole-3-carboxylic acid [Reference Example 26 (d)] was used (5 -Chloro-1H-indazol-3-yl) -methanol solidified on standing. LC-MS (Method B): R _T = 2.51 min; 185 (M + H) ⁺ .

６−メトキシ−１Ｈ−インダゾール−３−カルボン酸［参考実施例２６（ｅ）］を使用する以外は、上記参考実施例２５（ａ）と同様の方法に従って、茶色固体として（６−メトキシ−１Ｈ−インダゾール−３−イル）−メタノール（０.２６５ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３７分；１７９（Ｍ＋Ｈ)⁺。 (E) (6-Methoxy-1H-indazol-3-yl) -methanol

Except that 6-methoxy-1H-indazole-3-carboxylic acid [Reference Example 26 (e)] is used, (6-methoxy-1H) as a brown solid according to the same method as Reference Example 25 (a) above -Indazol-3-yl) -methanol (0.265 g) was prepared. LC-MS (Method B): R _T = 2.37 min; 179 (M + H) ⁺ .

４−フェニル−１Ｈ−ピラゾール−３−カルボン酸［参考実施例４７］を使用し、反応生成物をジクロロメタンとメタノールの混合物（９：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付する以外は、上記参考実施例２５（ａ）と同様の方法に従って、（４−フェニル−１Ｈ−ピラゾール−３−イル）−メタノールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５１分；１７５（Ｍ＋Ｈ)⁺。 (F) (4-Phenyl-1H-pyrazol-3-yl) -methanol

A flash column on silica using 4-phenyl-1H-pyrazole-3-carboxylic acid [Reference Example 47] and eluting the reaction product with a mixture of dichloromethane and methanol (9: 1, v / v). (4-Phenyl-1H-pyrazol-3-yl) -methanol was produced according to the same method as in Reference Example 25 (a) except that it was subjected to chromatography. LC-MS (Method B): R _T = 2.51 min; 175 (M + H) ⁺ .

インダゾール−３−カルボン酸を使用し、反応生成物をｎ−ヘキサンと酢酸エチルの混合物（１：１）から酢酸エチルを溶離剤とするシリカ上のカラムクロマトグラフィーに付する以外は、上記参考実施例２５（ａ）と同様の方法に従って、淡黄色固体として（１Ｈ−インダゾール−３−イル）−メタノールを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１７分；１４９.２１（Ｍ＋Ｈ)⁺。 (G) (1H-indazol-3-yl) -methanol

The above reference procedure was performed except that indazole-3-carboxylic acid was used and the reaction product was subjected to column chromatography on silica using a mixture of n-hexane and ethyl acetate (1: 1) as the eluent. (1H-indazol-3-yl) -methanol was prepared as a pale yellow solid according to the same method as in Example 25 (a). LC-MS (Method B): R _T = 3.17 min; 149.21 (M + H) ⁺ .

水（２０ｍｌ）中の５−フルオロイサチン（２ｇ）および水酸化ナトリウム（０.５０９ｇ）の溶液を５０℃に３０分間加熱し、その後冷却し、その後亜硝酸ナトリウム（０.８３６ｇ）で処理した。温度を５℃より下に維持しながら、この混合物を１０分間かけて水（２００ｍｌ）中の濃硫酸（２.２６ｇ）の溶液に０℃で添加した。さらに１５分後、濃塩酸（１０.５ｍｌ）中の塩化スズ（II）（５.５１ｇ）の溶液を添加し、得られた混合物を５℃でさらに３０分間維持した。その後混合物を周囲温度に戻しながらさらに１時間攪拌し、その後濾過した。明茶色のペースト状物を酢酸エチルに溶解し、溶液を硫酸マグネシウム上に乾燥し、その後蒸発させて、明茶色固体として製造した５−フルオロ−１Ｈ−インダゾール−３−カルボン酸（０.８６３ｇ）をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５１分；１８１（Ｍ＋Ｈ)⁺。 [Reference Example 26]
(A) 5-Fluoro-1H-indazole-3-carboxylic acid

A solution of 5-fluoroisatin (2 g) and sodium hydroxide (0.509 g) in water (20 ml) was heated to 50 ° C. for 30 minutes, then cooled and then treated with sodium nitrite (0.836 g). . This mixture was added to a solution of concentrated sulfuric acid (2.26 g) in water (200 ml) at 0 ° C. over 10 minutes while maintaining the temperature below 5 ° C. After an additional 15 minutes, a solution of tin (II) chloride (5.51 g) in concentrated hydrochloric acid (10.5 ml) was added and the resulting mixture was maintained at 5 ° C. for an additional 30 minutes. The mixture was then stirred for an additional hour while returning to ambient temperature and then filtered. The light brown paste was dissolved in ethyl acetate and the solution was dried over magnesium sulfate and then evaporated to give 5-fluoro-1H-indazole-3-carboxylic acid (0.863 g) prepared as a light brown solid. Was used without further purification. LC-MS (Method B): R _T = 2.51 min; 181 (M + H) ⁺ .

６−フルオロ−１Ｈ−インドール−２,３−ジオン［参考実施例２７（ａ）］を使用する以外は、上記参考実施例２６（ａ）と同様の方法に従って、明茶色固体として６−フルオロ−１Ｈ−インダゾール−３−カルボン酸（１.９６２ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５０分；１８１（Ｍ＋Ｈ)⁺。 (B) 6-Fluoro-1H-indazole-3-carboxylic acid

Except that 6-fluoro-1H-indole-2,3-dione [Reference Example 27 (a)] is used, 6-Fluoro- 1H-indazole-3-carboxylic acid (1.962 g) was prepared. LC-MS (Method B): R _T = 2.50 min; 181 (M + H) ⁺ .

５−メチルイサチンを使用する以外は、上記参考実施例２６（ａ）と同様の方法に従って、明茶色固体として５−メチル−１Ｈ−インダゾール−３−カルボン酸を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５３分；１７７（Ｍ＋Ｈ)⁺。 (C) 5-methyl-1H-indazole-3-carboxylic acid

5-Methyl-1H-indazole-3-carboxylic acid was produced as a light brown solid according to the same method as in Reference Example 26 (a) except that 5-methylisatin was used. LC-MS (Method B): R _T = 2.53 min; 177 (M + H) ⁺ .

５−クロロイサチンを使用する以外は、上記参考実施例２６（ａ）と同様の方法に従って、明茶色固体として５−クロロ−１Ｈ−インダゾール−３−カルボン酸を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５８分；１７１（Ｍ＋Ｈ)⁺。 (D) 5-chloro-1H-indazole-3-carboxylic acid

Except for using 5-chloroisatin, 5-chloro-1H-indazole-3-carboxylic acid was produced as a light brown solid according to the same method as in Reference Example 26 (a) above. LC-MS (Method B): R _T = 2.58 min; 171 (M + H) ⁺ .

６−メトキシ−１Ｈ−インドール−２,３−ジオン［２.５０ｇ、参考実施例２７（ｂ）］を使用する以外は、上記参考実施例２６（ａ）と同様の方法に従って、明茶色固体として６−メトキシ−１Ｈ−インダゾール−３−カルボン酸を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４５分；１９３（Ｍ＋Ｈ)⁺。 (E) 6-methoxy-1H-indazole-3-carboxylic acid

As a light brown solid according to the same method as in Reference Example 26 (a) except that 6-methoxy-1H-indole-2,3-dione [2.50 g, Reference Example 27 (b)] was used. 6-methoxy-1H-indazole-3-carboxylic acid was prepared. LC-MS (Method B): R _T = 2.45 min; 193 (M + H) ⁺ .

激しく攪拌したポリリン酸（１００ｇ）に７５℃でＮ−（３−フルオロ−フェニル）−２−ヒドロキシイミノ−アセトアミド［１０.３０４ｇ、参考実施例２８（ａ）］を３０分間かけて少しずつ添加した。得られた混合物を８０℃で１５分間攪拌し、その後氷に注ぎ込み、その後１６時間放置し、その後濾過し、茶色のペースト状物を得た。濾液を酢酸エチルで４回抽出した。合わせた有機画分を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物および上記濾過からの茶色のペースト状物を合わせ、水酸化ナトリウム水（１Ｎ）で処理した。混合物を濾過し、塩酸水（２Ｎ）を添加して濾液を酸性化した。得られた茶色固体を濾過し、その後水酸化ナトリウム水（１Ｎ）で処理した。この混合物を濾過し、塩酸水（２Ｎ）を添加して濾液を酸性化し、その後濾過した。合わせた酸性の水性濾液を酢酸エチルで４回抽出し、その後硫酸マグネシウム上に乾燥し、その後蒸発させて、淡橙色固体として６−フルオロ−１Ｈ−インドール−２,３−ジオン（１.８６１ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４９分；１６６（Ｍ＋Ｈ)⁺。 [Reference Example 27]
(A) 6-Fluoro-1H-indole-2,3-dione

N- (3-Fluoro-phenyl) -2-hydroxyimino-acetamide [10.304 g, Reference Example 28 (a)] was added in portions over 30 minutes to vigorously stirred polyphosphoric acid (100 g) at 75 ° C. . The resulting mixture was stirred at 80 ° C. for 15 minutes, then poured into ice, then allowed to stand for 16 hours, and then filtered to obtain a brown paste. The filtrate was extracted 4 times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and then evaporated. The residue and the brown paste from the above filtration were combined and treated with aqueous sodium hydroxide (1N). The mixture was filtered and aqueous hydrochloric acid (2N) was added to acidify the filtrate. The resulting brown solid was filtered and then treated with aqueous sodium hydroxide (1N). The mixture was filtered, aqueous hydrochloric acid (2N) was added to acidify the filtrate and then filtered. The combined acidic aqueous filtrates were extracted four times with ethyl acetate, then dried over magnesium sulfate and then evaporated to give 6-fluoro-1H-indole-2,3-dione (1.861 g) as a pale orange solid. Got. LC-MS (Method B): R _T = 2.49 min; 166 (M + H) ⁺ .

２−ヒドロキシイミノ−Ｎ−（３−メトキシ−フェニル）−アセトアミド［７.２０ｇ、参考実施例２８（ｂ）］を使用する以外は、上記参考実施例２７（ａ）と同様の方法に従って、茶色固体として６−メトキシ−１Ｈ−インドール−２,３−ジオンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４９分；１７８（Ｍ＋Ｈ)⁺。 (B) 6-methoxy-1H-indole-2,3-dione

According to the same method as in Reference Example 27 (a) except that 2-hydroxyimino-N- (3-methoxy-phenyl) -acetamide [7.20 g, Reference Example 28 (b)] was used, brown 6-methoxy-1H-indole-2,3-dione was prepared as a solid. LC-MS (Method B): R _T = 2.49 min; 178 (M + H) ⁺ .

水（２５ｍｌ）中の抱水クロラール（０.８１９ｇ）の混合物を硫酸ナトリウム（５.１０ｇ）、３−フルオロアニリン（０.４３ｍｌ）、濃塩酸（０.３ｍｌ）、および塩酸ヒドロキシルアミン（０.９３８ｇ）で処理した。混合物を８０℃に２時間加温し、その後放冷し、その後濾過した。固体を水で洗浄し、その後１６時間風乾し、淡黄褐色固体としてＮ−（３−フルオロ−フェニル）−２−ヒドロキシイミノ−アセトアミド（０.７５６ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５１分；１８１（Ｍ＋Ｈ)⁺。 [Reference Example 28]
(A) N- (3-Fluoro-phenyl) -2-hydroxyimino-acetamide

A mixture of chloral hydrate (0.819 g) in water (25 ml) was added to sodium sulfate (5.10 g), 3-fluoroaniline (0.43 ml), concentrated hydrochloric acid (0.3 ml), and hydroxylamine hydrochloride (0. 938 g). The mixture was warmed to 80 ° C. for 2 hours, then allowed to cool and then filtered. The solid was washed with water and then air dried for 16 hours to give N- (3-fluoro-phenyl) -2-hydroxyimino-acetamide (0.756 g) as a light tan solid. LC-MS (Method B): R _T = 2.51 min; 181 (M + H) ⁺ .

ｍ−アニシジン（０.５ｍｌ）を使用する以外は、上記参考実施例２８（ａ）と同様の方法に従って、茶色固体として２−ヒドロキシイミノ−Ｎ−（３−メトキシ−フェニル）−アセトアミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４４分；１９５（Ｍ＋Ｈ)⁺。 (B) 2-Hydroxyimino-N- (3-methoxy-phenyl) -acetamide

2-Hydroxyimino-N- (3-methoxy-phenyl) -acetamide was produced as a brown solid according to the same method as in Reference Example 28 (a) except that m-anisidine (0.5 ml) was used. . LC-MS (Method B): R _T = 2.44 min; 195 (M + H) ⁺ .

エタノール（５ｍｌ）中の５−エチル−２−ニトロ−アニリン［２００ｍｇ、参考実施例３０（ａ）］および塩化スズ（２.７５ｇ）の攪拌溶液をＳｍｉｔｈ Ｃｒｅａｔｏｒマイクロ波中に１４０℃で１０分間加熱した。飽和炭酸水素ナトリウム溶液を添加して反応混合物をｐＨ８に塩基性化し、その後酢酸エチルで抽出した。有機抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させて淡橙色固体として得られた４−エチル−フェニレンジアミン（１４０ｍｇ）をさらに精製することなく使用した。ＭＳ：１３７.２（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｈ）：Ｒ_T＝２.９１分。 [Reference Example 29]
(A) 4-ethyl-phenylenediamine

A stirred solution of 5-ethyl-2-nitro-aniline [200 mg, Reference Example 30 (a)] and tin chloride (2.75 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140 ° C. for 10 minutes. did. Saturated sodium bicarbonate solution was added to basify the reaction mixture to pH 8 and then extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and then evaporated to give 4-ethyl-phenylenediamine (140 mg) obtained as a pale orange solid without further purification. MS: 137.2 (M + H) ^<+> . HPLC (Method H): R _T = 2.91 min.

４−メトキシ−５−メチル−２−ニトロ−フェニルアミン［５８２ｍｇ、参考実施例３１（ｉ）］を使用する以外は、上記参考実施例２９（ａ）と同様の方法に従って、明茶色固体として４−メトキシ−５−メチル−ベンゼン−１,２−ジアミン（４５４ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝２.３９分、１５３.２０（Ｍ＋Ｈ)⁺。 (B) 4-methoxy-5-methyl-benzene-1,2-diamine

4 as a light brown solid according to the same procedure as in Reference Example 29 (a) except that 4-methoxy-5-methyl-2-nitro-phenylamine [582 mg, Reference Example 31 (i)] was used. -Methoxy-5-methyl-benzene-1,2-diamine (454 mg) was prepared. LC-MS (Method K): R _T = 2.39 min, 153.20 (M + H) ⁺ .

４−［２−（３,４−ジニトロ−フェノキシ）−エチル］−モルホリン［参考実施例６７］を使用する以外は、上記参考実施例２９（ａ）と同様の方法に従って、淡茶色油状物として４−（２−モルホリン−４−イル−エトキシ）−ベンゼン−１,２−ジアミン（１７０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝２.２分、２３８.２１（Ｍ＋Ｈ)⁺。 (C) 4- (2-morpholin-4-yl-ethoxy) -benzene-1,2-diamine

According to the same method as in Reference Example 29 (a) except that 4- [2- (3,4-dinitro-phenoxy) -ethyl] -morpholine [Reference Example 67] was used, 4- (2-morpholin-4-yl-ethoxy) -benzene-1,2-diamine (170 mg) was prepared. LC-MS (Method N): R _T = 2.2 min, 238.21 (M + H) ⁺ .

メタノール（２０ｍｌ）中の４−エチル−２−ニトロ−アニリン［４８４ｍｇ、参考実施例３１（ｂ）］の攪拌溶液を塩化スズ（５.０９ｇ）で処理し、その後還流下に１６時間加熱し、その後周囲温度に冷却した。重炭酸ナトリウム水を添加して反応混合物のｐＨをｐＨ８に調整し、その後この混合物を酢酸エチルで抽出した。有機抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させて、オフホワイトの固体として４−エチル−５−メチル−フェニレンジアミン（３７４ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝１.８０分；１５１.２５（Ｍ＋Ｈ)⁺。 [Reference Example 30]
(A) 4-Ethyl-5-methyl-phenylenediamine

A stirred solution of 4-ethyl-2-nitro-aniline [484 mg, Reference Example 31 (b)] in methanol (20 ml) was treated with tin chloride (5.09 g) and then heated at reflux for 16 hours, It was then cooled to ambient temperature. Aqueous sodium bicarbonate was added to adjust the pH of the reaction mixture to pH 8, and then the mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and then evaporated to give 4-ethyl-5-methyl-phenylenediamine (374 mg) as an off-white solid. LC-MS (Method B): R _T = 1.80 min; 151.25 (M + H) ⁺ .

４−イソプロピル−５−メチル−２−ニトロ−アニリン［参考実施例３１（ｃ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、明茶色固体として４−イソプロピル−５−メチル−フェニレンジアミンを製造した。ＬＣ−ＭＳ（方法Ｃ）：Ｒ_T＝３.３０分；１６５.１６（Ｍ＋Ｈ)⁺。 (B) 4-Isopropyl-5-methyl-phenylenediamine

Except for using 4-isopropyl-5-methyl-2-nitro-aniline [Reference Example 31 (c)], 4-isopropyl-as a light brown solid according to the same method as Reference Example 30 (a) above. 5-methyl-phenylenediamine was prepared. LC-MS (Method C): R _T = 3.30 min; 165.16 (M + H) ⁺ .

４−ブロモ−５−メチル−２−ニトロ−アニリン［参考実施例３１（ｄ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、オフホワイトの固体として４−ブロモ−５−メチル−フェニレンジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６３分；２０３.２２（Ｍ＋Ｈ)⁺。 (C) 4-Bromo-5-methyl-phenylenediamine

Except for using 4-bromo-5-methyl-2-nitro-aniline [Reference Example 31 (d)], 4-bromo as an off-white solid according to the same procedure as Reference Example 30 (a) above. -5-methyl-phenylenediamine was prepared. LC-MS (Method B): R _T = 2.63 min; 203.22 (M + H) ⁺ .

４−ｎ−プロピル−２−ニトロ−アニリン［参考実施例３１（ｅ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、オフホワイトの固体として４−ｎ−プロピル−フェニレンジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.０７分、１５１.３０（Ｍ＋Ｈ)⁺。 (D) 4-n-propyl-phenylenediamine

Except for using 4-n-propyl-2-nitro-aniline [Reference Example 31 (e)], 4-n-propyl as an off-white solid was prepared in the same manner as Reference Example 30 (a) above. -Phenylenediamine was produced. LC-MS (Method B): R _T = 2.07 min, 151.30 (M + H) ⁺ .

４−ブロモ−２−ニトロ−アニリンを使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、黄色固体として４−ブロモ−フェニレンジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝１.７７分；１８７.２２（Ｍ＋Ｈ)⁺。 (E) 4-Bromo-phenylenediamine

4-Bromo-phenylenediamine was produced as a yellow solid according to the same method as in Reference Example 30 (a) except that 4-bromo-2-nitro-aniline was used. LC-MS (Method B): R _T = 1.77 min; 187.22 (M + H) ⁺ .

４′−アミノ−３′−ニトロ−ビフェニル−３−カルボニトリル［参考実施例３４（ａ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、オフホワイトの固体として３′,４′−ジアミノビフェニル−３−カルボニトリルを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７２分；２１０.３（Ｍ＋Ｈ)⁺。 (F) 3 ', 4'-diaminobiphenyl-3-carbonitrile

As an off-white solid, following the same procedure as in Reference Example 30 (a) except that 4'-amino-3'-nitro-biphenyl-3-carbonitrile [Reference Example 34 (a)] was used. 3 ', 4'-Diaminobiphenyl-3-carbonitrile was prepared. LC-MS (Method B): R _T = 2.72 min; 210.3 (M + H) ⁺ .

２−ニトロ−４−ピリジン−３−イル−フェニルアミン［参考実施例３４（ｂ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、オフホワイトの固体として４−（ピリジン−３−イル）ベンゼン−１,２−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝０.３７分；１８６.３（Ｍ＋Ｈ)⁺。 (G) 4- (Pyridin-3-yl) benzene-1,2-diamine

According to a method similar to that of Reference Example 30 (a) except that 2-nitro-4-pyridin-3-yl-phenylamine [Reference Example 34 (b)] was used, 4- (Pyridin-3-yl) benzene-1,2-diamine was prepared. LC-MS (Method B): R _T = 0.37 min; 186.3 (M + H) ⁺ .

２−メチル−５−ニトロ−ビフェニル−４−イルアミン［参考実施例３４（ｃ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、オフホワイトの固体と
して６−メチルビフェニル−３,４−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３６分；１９９.２５（Ｍ＋Ｈ)⁺。 (H) 6-methylbiphenyl-3,4-diamine

According to a method similar to that of Reference Example 30 (a) except that 2-methyl-5-nitro-biphenyl-4-ylamine [Reference Example 34 (c)] was used, 6-methyl as an off-white solid. Biphenyl-3,4-diamine was prepared. LC-MS (Method B): R _T = 2.36 min; 199.25 (M + H) ⁺ .

３−ニトロビフェニル−４−イルアミン［参考実施例３４（ｄ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、黄色固体としてビフェニル−３,４−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２５分；１８５.３（Ｍ＋Ｈ)⁺。 (I) Biphenyl-3,4-diamine

Biphenyl-3,4-diamine was produced as a yellow solid according to the same method as in Reference Example 30 (a) except that 3-nitrobiphenyl-4-ylamine [Reference Example 34 (d)] was used. . LC-MS (Method B): R _T = 2.25 min; 185.3 (M + H) ⁺ .

２′−フルオロ−３−ニトロ−ビフェニル−４−イルアミン［参考実施例３４（ｅ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、白色固体として２′−フルオロビフェニル−３,４−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７３分；２０３.３１（Ｍ＋Ｈ)⁺。 (J) 2'-fluorobiphenyl-3,4-diamine

According to the same procedure as in Reference Example 30 (a) except that 2'-fluoro-3-nitro-biphenyl-4-ylamine [Reference Example 34 (e)] was used, 2'-Fluoro as a white solid. Biphenyl-3,4-diamine was prepared. LC-MS (Method B): R _T = 2.73 min; 203.31 (M + H) ⁺ .

４−ベンゾ［１,３］ジオキソ−５−イル−２−ニトロフェニルアミン［参考実施例３４（ｆ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、白色固体として４−ベンゾ［１,３］ジオキソール−５−イルベンゼン−１,２−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６６分；２２９.３（Ｍ＋Ｈ)⁺。 (K) 4-Benzo [1,3] dioxol-5-ylbenzene-1,2-diamine

A white solid was prepared in the same manner as in Reference Example 30 (a) except that 4-benzo [1,3] dioxo-5-yl-2-nitrophenylamine [Reference Example 34 (f)] was used. 4-Benzo [1,3] dioxol-5-ylbenzene-1,2-diamine was produced. LC-MS (Method B): R _T = 2.66 min; 229.3 (M + H) ⁺ .

２′−メトキシ−３−ニトロ−ビフェニル−４−イルアミン［参考実施例３４（ｇ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、白色固体として２′−メトキシビフェニル−３,４−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７４分；２１５.３３（Ｍ＋Ｈ)⁺。 (L) 2'-methoxybiphenyl-3,4-diamine

According to the same procedure as in Reference Example 30 (a) except that 2'-methoxy-3-nitro-biphenyl-4-ylamine [Reference Example 34 (g)] was used, 2'-methoxy as a white solid was used. Biphenyl-3,4-diamine was prepared. LC-MS (Method B): R _T = 2.74 min; 215.33 (M + H) ⁺ .

４′−クロロ−３−ニトロ−ビフェニル−４−イル−アミン［参考実施例３４（ｈ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、白色固体として４′−クロロビフェニル−３,４−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８５分；２１９.３（Ｍ＋Ｈ)⁺。 (M) 4'-chlorobiphenyl-3,4-diamine

4'-Chloro-3-nitro-biphenyl-4-yl-amine [Reference Example 34 (h)] was used in the same manner as Reference Example 30 (a) above except that 4 ' -Chlorobiphenyl-3,4-diamine was prepared. LC-MS (Method B): R _T = 2.85 min; 219.3 (M + H) ⁺ .

４′−メチル−３−ニトロ−ビフェニル−４−イル−アミン［参考実施例３４（ｉ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、白色固体として４′−メチルビフェニル−３,４−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３９分、１９９.２５（Ｍ＋Ｈ)⁺。 (N) 4'-methylbiphenyl-3,4-diamine

4'-Methyl-3-nitro-biphenyl-4-yl-amine [Reference Example 34 (i)] was used in the same manner as Reference Example 30 (a) above except that 4 ' -Methylbiphenyl-3,4-diamine was prepared. LC-MS (Method B): R _T = 2.39 min, 199.25 (M + H) ⁺ .

４−ベンジルオキシ−１,２−ジニトロベンゼン［参考実施例３５（ａ）］を使用する
以外は、上記参考実施例３０（ａ）と同様の方法に従って、白色固体として４−ベンジルオキシベンゼン−１,２−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３４分、２１５.３３（Ｍ＋Ｈ)⁺。 (O) 4-Benzyloxybenzene-1,2-diamine

4-Benzyloxybenzene-1 as a white solid according to the same method as in Reference Example 30 (a) except that 4-benzyloxy-1,2-dinitrobenzene [Reference Example 35 (a)] was used. 2-diamine was prepared. LC-MS (Method B): R _T = 2.34 min, 215.33 (M + H) ⁺ .

５,６−ジニトロ−ベンゾ［１,３］ジオキソール［参考実施例５６（ｂ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、油脂状の固体としてベンゾ［１,３］ジオキソール−５,６−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝０.４３分、１５３.１８（Ｍ＋Ｈ)⁺。 (P) Benzo [1,3] dioxol-5,6-diamine

Except for the use of 5,6-dinitro-benzo [1,3] dioxole [Reference Example 56 (b)], benzo [1 as an oily solid was prepared in the same manner as Reference Example 30 (a) above. , 3] dioxol-5,6-diamine was prepared. LC-MS (Method B): R _T = 0.43 min, 153.18 (M + H) ⁺ .

４,５−ジメトキシ−２−ニトロアニリンを使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、油脂状の固体として４,５−ジメトキシベンゼン−１,２−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝０.４３分、１６９.２４（Ｍ＋Ｈ)⁺。 (Q) 4,5-dimethoxybenzene-1,2-diamine

Except for using 4,5-dimethoxy-2-nitroaniline, 4,5-dimethoxybenzene-1,2-diamine was produced as an oily solid according to the same method as in Reference Example 30 (a) above. . LC-MS (Method B): R _T = 0.43 min, 169.24 (M + H) ⁺ .

４,５−ジエチル−２−ニトロアニリン［参考実施例３１（ｆ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、製造した４,５−ジエチルベンゼン−１,２−ジアミンをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２１分、１６５.２４（Ｍ＋Ｈ)⁺。 (R) 4,5-diethylbenzene-1,2-diamine

4,5-Diethylbenzene-1,2 prepared according to the same method as in Reference Example 30 (a) except that 4,5-diethyl-2-nitroaniline [Reference Example 31 (f)] was used. -The diamine was used without further purification. LC-MS (Method B): R _T = 2.21 min, 165.24 (M + H) ⁺ .

４−エトキシ−５−エチル−２−ニトロアニリン［参考実施例３１（ｇ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、４−エトキシ−５−エチル−ベンゼン−１,２−ジアミンを製造した。 (S) 4-Ethoxy-5-ethyl-benzene-1,2-diamine

4-Ethoxy-5-ethyl-2-benzene according to the same method as Reference Example 30 (a) except that 4-ethoxy-5-ethyl-2-nitroaniline [Reference Example 31 (g)] was used. -1,2-diamine was produced.

１−エトキシ−２−エチル−４−ニトロベンゼン［参考実施例３２（ｈ）］を使用し、反応生成物をシリカゲル上のクロマトグラフィー（ヘプタン、酢酸エチル勾配２５〜３５％）に付する以外は、上記参考実施例３０（ａ）と同様の方法に従って、油状物として４−エトキシ−３−エチル−フェニルアミン（０.６ｇ）を製造した。ＧＳ−ＭＳ単一ピーク、Ｒ_T＝７.１７分、１６５（Ｍ）⁺。 (T) 4-Ethoxy-3-ethyl-phenylamine

Except for using 1-ethoxy-2-ethyl-4-nitrobenzene [Reference Example 32 (h)] and subjecting the reaction product to chromatography on silica gel (heptane, ethyl acetate gradient 25-35%). 4-Ethoxy-3-ethyl-phenylamine (0.6 g) was produced as an oil according to the same method as in Reference Example 30 (a) above. GS-MS single peak, R _T = 7.17 min, 165 (M) ⁺ .

１−メトキシ−２−メチル−４−ニトロベンゼン［２.７ｇ、参考実施例５６（ａ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、４−メトキシ−３−メチル−フェニルアミン（２.０７ｇ）を製造した。Ｒ_F＝０.５［酢酸エチル／ｎ−ペンタン、１：１、ｖ／ｖ］。 (U) 4-methoxy-3-methyl-phenylamine

According to the same method as in Reference Example 30 (a) except that 1-methoxy-2-methyl-4-nitrobenzene [2.7 g, Reference Example 56 (a)] was used, 4-methoxy-3- Methyl-phenylamine (2.07 g) was prepared. R _F = 0.5 [ethyl acetate / n-pentane, 1: 1, v / v].

４−エトキシ−２−ニトロアニリン（１.５ｇ）を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、茶色油状物として４−エトキシ−ベンゼン−１,２−ジアミン（１.０２ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝０.５０および３.８８分、１５３.３０（Ｍ＋Ｈ)⁺。 (V) 4-Ethoxy-benzene-1,2-diamine

According to the same method as in Reference Example 30 (a) except that 4-ethoxy-2-nitroaniline (1.5 g) was used, 4-ethoxy-benzene-1,2-diamine (1 0.02 g) was produced. LC-MS (Method J): R _T = 0.50 and 3.88 min, 153.30 (M + H) ⁺ .

４−フルオロ−５−メチル−２−ニトロ−フェニルアミン［参考実施例３１（ｊ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、黄色固体として４−フルオロ−５−メチル−ベンゼン−１,２−ジアミン（１.２７ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝１.９３分、１４１.２５（Ｍ＋Ｈ)⁺。 (W) 4-fluoro-5-methyl-benzene-1,2-diamine

According to the same method as in Reference Example 30 (a) except that 4-fluoro-5-methyl-2-nitro-phenylamine [Reference Example 31 (j)] was used, 4-fluoro- 5-Methyl-benzene-1,2-diamine (1.27 g) was prepared. LC-MS (Method J): R _T = 1.93 min, 141.25 (M + H) ⁺ .

４−アミノ−Ｎ−ベンジル−３−ニトロ−ベンゼンスルホンアミド［参考実施例６１］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、黄色フィルム状物として３,４−ジアミノ−Ｎ−ベンジル−ベンゼンスルホンアミド（０.３５０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝２.８７分、２７８.２８（Ｍ＋Ｈ)⁺。 (X) 3,4-diamino-N-benzyl-benzenesulfonamide

Except that 4-amino-N-benzyl-3-nitro-benzenesulfonamide [Reference Example 61] was used, a yellow film-like product was obtained according to the same method as Reference Example 30 (a) above. Diamino-N-benzyl-benzenesulfonamide (0.350 g) was prepared. LC-MS (Method K): R _T = 2.87 min, 278.28 (M + H) ⁺ .

４−ジフルオロメトキシ−２−ニトロ−フェニルアミン［参考実施例３１（ｋ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、淡茶色固体として４−ジフルオロメトキシ−ベンゼン−１,２−ジアミン（２.７０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝２.４５分、１７５（Ｍ＋Ｈ)⁺。 (Y) 4-difluoromethoxy-benzene-1,2-diamine

4-Difluoromethoxy-benzene as a light brown solid according to the same method as in Reference Example 30 (a) except that 4-difluoromethoxy-2-nitro-phenylamine [Reference Example 31 (k)] was used. -1,2-diamine (2.70 g) was prepared. LC-MS (Method N): R _T = 2.45 min, 175 (M + H) ⁺ .

５−エチル−４−メトキシ−２−ニトロ−フェニルアミン［２.４ｇ、参考実施例３１（ｌ）］を使用する以外は、上記参考実施例３０（ａ）と同様の方法に従って、黒色固体として４−エチル−５−メトキシ−ベンゼン−１,２−ジアミン（１.６ｇ）を製造した。ＬＣ−ＭＳ（方法１、酢酸アンモニウム、５分）：Ｒ_T＝３.５０分、１６７.１７（Ｍ＋Ｈ)⁺。 (Z) 4-Ethyl-5-methoxy-benzene-1,2-diamine [200 mg, Reference Example 30 (z)]

A black solid was prepared according to the same method as Reference Example 30 (a) except that 5-ethyl-4-methoxy-2-nitro-phenylamine [2.4 g, Reference Example 31 (l)] was used. 4-Ethyl-5-methoxy-benzene-1,2-diamine (1.6 g) was prepared. LC-MS (Method 1, ammonium acetate, 5 min): R _T = 3.50 min, 167.17 (M + H) ⁺ .

５−エチル−４−メトキシ−２−ニトロ−フェニルアミン［３.６ｇ、参考実施例３１（ｌ）］を使用し、反応を２４時間実施する以外は、上記参考実施例３０（ａ）と同様の方法に従って、茶色油状物として３−エチル−４−メトキシ−フェニルアミン（２.５ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.０４分、１５２.２（Ｍ＋Ｈ)⁺。 (Aa) 3-ethyl-4-methoxy-phenylamine

Same as Reference Example 30 (a) above except that 5-ethyl-4-methoxy-2-nitro-phenylamine [3.6 g, Reference Example 31 (l)] is used and the reaction is carried out for 24 hours. According to the method, 3-ethyl-4-methoxy-phenylamine (2.5 g) was produced as a brown oil. LC-MS (Method J): R _T = 2.04 min, 152.2 (M + H) ⁺ .

メタノール（１５ｍｌ）中のナトリウムメトキシド（０.３５ｇ）の攪拌溶液をメタノール（１５ｍｌ）中の４−エチル−２−ニトロ−Ｎ−アセチル−アニリン［１ｇ、参考実施例３２（ａ）］の溶液で処理した。反応混合物を室温で２４時間攪拌し、その後氷水に注ぎ込んだ。得られた沈殿物を濾過し、その後乾燥して５−エチル−２−ニトロ−アニリン（６５０ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１１分；１６７.２（Ｍ＋Ｈ)⁺。 [Reference Example 31]
(A) 5-ethyl-2-nitro-aniline

A stirred solution of sodium methoxide (0.35 g) in methanol (15 ml) was added to a solution of 4-ethyl-2-nitro-N-acetyl-aniline [1 g, Reference Example 32 (a)] in methanol (15 ml). Was processed. The reaction mixture was stirred at room temperature for 24 hours and then poured into ice water. The resulting precipitate was filtered and then dried to give 5-ethyl-2-nitro-aniline (650 mg). LC-MS (Method B): R _T = 3.11 min; 167.2 (M + H) ⁺ .

４−エチル−５−メチル−２−ニトロ−Ｎ−アセチル−アニリン［１ｇ、参考実施例３２（ｂ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、橙色固体として４−エチル−５−メチル−２−ニトロ−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１６分；１８１.１４（Ｍ＋Ｈ)⁺。 (B) 4-ethyl-5-methyl-2-nitro-aniline

An orange solid was prepared according to the same procedure as in Reference Example 31 (a) except that 4-ethyl-5-methyl-2-nitro-N-acetyl-aniline [1 g, Reference Example 32 (b)] was used. 4-ethyl-5-methyl-2-nitro-aniline was prepared as LC-MS (Method B): R _T = 3.16 min; 181.14 (M + H) ⁺ .

４−イソプロピル−５−メチル−２−ニトロ−Ｎ−アセチル−アニリン［１ｇ、参考実施例３２（ｃ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、橙色固体として４−イソプロピル−５−メチル−２−ニトロ−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.２６分；１９５.３（Ｍ＋Ｈ)⁺。 (C) 4-Isopropyl-5-methyl-2-nitro-aniline

An orange solid according to the same method as in Reference Example 31 (a) except that 4-isopropyl-5-methyl-2-nitro-N-acetyl-aniline [1 g, Reference Example 32 (c)] was used. 4-isopropyl-5-methyl-2-nitro-aniline was prepared as LC-MS (Method B): R _T = 3.26 min; 195.3 (M + H) ⁺ .

４−ブロモ−５−メチル−２−ニトロ−Ｎ−アセチル−アニリン［１ｇ、参考実施例３２（ｄ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、茶色固体として４−ブロモ−５−メチル−２−ニトロ−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.２４分；２３１.２（Ｍ＋Ｈ)⁺。 (D) 4-Bromo-5-methyl-2-nitro-aniline

According to the same method as in Reference Example 31 (a) except that 4-bromo-5-methyl-2-nitro-N-acetyl-aniline [1 g, Reference Example 32 (d)] was used, a brown solid was obtained. 4-Bromo-5-methyl-2-nitro-aniline was prepared as LC-MS (Method B): R _T = 3.24 min; 231.2 (M + H) ⁺ .

２−ニトロ−４−プロピル−Ｎ−アセチル−アニリンを使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、橙色固体として４−ｎ−プロピル−２−ニトロ−アニリンを製造した。ＬＣ−ＭＳ（方法Ｃ）：Ｒ_T＝３.４６分；１８１.２（Ｍ＋Ｈ)⁺。 (E) 4-n-propyl-2-nitro-aniline

4-n-propyl-2-nitro-aniline was produced as an orange solid according to the same method as in Reference Example 31 (a) except that 2-nitro-4-propyl-N-acetyl-aniline was used. . LC-MS (Method C): R _T = 3.46 min; 181.2 (M + H) ⁺ .

４,５−ジエチル−２−ニトロ−Ｎ−アセチル−アニリン［参考実施例３２（ｆ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、４,５−ジエチル−２−ニトロ−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.２７分；１９５.２２（Ｍ＋Ｈ)⁺。 (F) 4,5-diethyl-2-nitro-aniline

4,5-Diethyl-2-nitro-N-acetyl-aniline [Reference Example 32 (f)] was used according to the same method as Reference Example 31 (a) except that 4,5-diethyl-2-nitro-N-acetyl-aniline was used. 2-Nitro-aniline was prepared. LC-MS (Method B): R _T = 3.27 min; 195.22 (M + H) ⁺ .

Ｎ−（４−エトキシ−５−エチル−２−ニトロフェニル）アセトアミド［０.２ｇ、参考実施例３２（ｇ）］をメタノール（２５ｍＬ）に溶解し、水素化ナトリウム（１００ｍｇ、鉱油中の５０％分散液、２ミリモル）を添加した。混合物を周囲温度で１夜攪拌し、塩化アンモニア水（３ｍＬ）を添加し、混合物を蒸発させた。残存物をシリカゲル上のクロマトグラフィー（２５〜５０％酢酸エチル勾配を含むヘプタン）に付し、赤色固体として４−エトキシ−５−エチル−２−ニトロフェニルアミン（０.１ｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝３.４分、２１１（Ｍ＋Ｈ)⁺。 (G) 4-Ethoxy-5-ethyl-2-nitrophenylamine

N- (4-Ethoxy-5-ethyl-2-nitrophenyl) acetamide [0.2 g, Reference Example 32 (g)] was dissolved in methanol (25 mL) and sodium hydride (100 mg, 50% in mineral oil). Dispersion, 2 mmol) was added. The mixture was stirred overnight at ambient temperature, aqueous ammonia chloride (3 mL) was added and the mixture was evaporated. The residue was chromatographed on silica gel (heptane containing a 25-50% ethyl acetate gradient) to give 4-ethoxy-5-ethyl-2-nitrophenylamine (0.1 g) as a red solid. LC-MS (Method E): R _T = 3.4 min, 211 (M + H) ⁺ .

Ｎ−（５−クロロ−４−メトキシ−２−ニトロフェニル）アセトアミド（８.０ｇ、参考実施例３２（ｉ））をメタノール（１５０ｍＬ）中のナトリウムメトキシド（２.０ｇ、０.０３７モル）の溶液に添加し、混合物を周囲温度で４時間攪拌した。反応混合物を氷水（７５０ｍＬ）に添加し、１５分間攪拌し、水性の混合物を濾過した。沈殿物を水で洗浄し、真空下に６０℃で乾燥し、橙色固体として５−クロロ−４−メトキシ−２−ニトロフェニルアミン（６.５２ｇ）を得た。融点１２８〜１２９℃。 (H) 5-chloro-4-methoxy-2-nitrophenylamine

N- (5-chloro-4-methoxy-2-nitrophenyl) acetamide (8.0 g, Reference Example 32 (i)) was added to sodium methoxide (2.0 g, 0.037 mol) in methanol (150 mL). And the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was added to ice water (750 mL), stirred for 15 minutes and the aqueous mixture was filtered. The precipitate was washed with water and dried at 60 ° C. under vacuum to give 5-chloro-4-methoxy-2-nitrophenylamine (6.52 g) as an orange solid. Mp 128-129 ° C.

Ｎ−（４−メトキシ−５−メチル−２−ニトロ−フェニル）−アセトアミド［２.５３ｇ、参考実施例３２（ｊ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、輝橙色固体として４−メトキシ−５−メチル−２−ニトロ−フェニルアミン（２.０５ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.４６分、１８３.２９（Ｍ＋Ｈ)⁺。 (I) 4-methoxy-5-methyl-2-nitro-phenylamine

The same method as Reference Example 31 (a) above, except that N- (4-methoxy-5-methyl-2-nitro-phenyl) -acetamide [2.53 g, Reference Example 32 (j)] was used. To 4-methoxy-5-methyl-2-nitro-phenylamine (2.05 g) as a bright orange solid. LC-MS (Method J): R _T = 3.46 min, 183.29 (M + H) ⁺ .

Ｎ−（４−フルオロ−５−メチル−２−ニトロ−フェニル）−アセトアミド［２.５３ｇ、参考実施例３２（ｋ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、橙色固体として４−フルオロ−５−メチル−２−ニトロ−フェニルアミン（２.２５ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.５３分、１７１.２８（Ｍ＋Ｈ)⁺。 (J) 4-fluoro-5-methyl-2-nitro-phenylamine

The same method as Reference Example 31 (a) above, except that N- (4-fluoro-5-methyl-2-nitro-phenyl) -acetamide [2.53 g, Reference Example 32 (k)] was used. Prepared 4-fluoro-5-methyl-2-nitro-phenylamine (2.25 g) as an orange solid. LC-MS (Method J): R _T = 3.53 min, 171.28 (M + H) ⁺ .

Ｎ−（４−ジフルオロメトキシ−２−ニトロ−フェニル）−アセトアミド［参考実施例３２（ｌ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、橙色固体として４−ジフルオロメトキシ−２−ニトロ−フェニルアミン（１０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.８６分、２０５（Ｍ＋Ｈ)⁺。 (K) 4-difluoromethoxy-2-nitro-phenylamine

Except that N- (4-difluoromethoxy-2-nitro-phenyl) -acetamide [Reference Example 32 (l)] was used, an orange solid was prepared as an orange solid according to the same method as Reference Example 31 (a) above. Difluoromethoxy-2-nitro-phenylamine (10 g) was prepared. LC-MS (Method N): R _T = 3.86 min, 205 (M + H) ⁺ .

Ｎ−（５−エチル−４−メトキシ−２−ニトロ−フェニル）−アセトアミド［２.４ｇ、参考実施例３２（ｍ）］を使用する以外は、上記参考実施例３１（ａ）と同様の方法に従って、茶色固体として５−エチル−４−メトキシ−２−ニトロ−フェニルアミン（１.９ｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝４.１４分、１９７.０９（Ｍ＋Ｈ)⁺。 (L) 5-ethyl-4-methoxy-2-nitro-phenylamine

The same method as Reference Example 31 (a) above, except that N- (5-ethyl-4-methoxy-2-nitro-phenyl) -acetamide [2.4 g, Reference Example 32 (m)] was used. According to the procedure, 5-ethyl-4-methoxy-2-nitro-phenylamine (1.9 g) was produced as a brown solid. LC-MS (Method K): R _T = 4.14 min, 197.09 (M + H) ⁺ .

無水酢酸（８ｍＬ）および酢酸（４ｍＬ）中の４−エチル−Ｎ−アセチル−アニリン［３ｇ、参考実施例３３（ａ）］の攪拌溶液を−５℃で酢酸（１.７５ｍＬ）および濃硝酸（１.２２ｍＬ）の混合物で滴下処理した。混合物を０℃に加温し、その後０℃で２時間攪拌し、その後水に注ぎ込んだ。この混合物を蒸発させ、残存した油状物を酢酸エチルと水との間に分配した。有機層を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存した油状物を酢酸エチルと石油エーテルの混合物（２：５）を溶離剤とするシリカ上のフラッシュカラムクロマトフラフィーに付し、橙色固体として４−エチル−２−ニトロ−Ｎ−アセチル−アニリン（１.４ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９５分；２０９.２（Ｍ＋Ｈ)⁺。 [Reference Example 32]
(A) 4-ethyl-2-nitro-N-acetyl-aniline

A stirred solution of 4-ethyl-N-acetyl-aniline [3 g, Reference Example 33 (a)] in acetic anhydride (8 mL) and acetic acid (4 mL) was added at −5 ° C. with acetic acid (1.75 mL) and concentrated nitric acid ( 1.22 mL) of the mixture. The mixture was warmed to 0 ° C., then stirred at 0 ° C. for 2 hours and then poured into water. The mixture was evaporated and the remaining oil was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The remaining oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (2: 5) to give 4-ethyl-2-nitro-N-acetyl-aniline as an orange solid ( 1.4 g) was obtained. LC-MS (Method B): R _T = 2.95 min; 209.2 (M + H) ⁺ .

３−メチル−４−エチル−Ｎ−アセチルアニリンを使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、橙色固体として４−エチル−５−メチル−２−ニトロ−Ｎ−アセチル−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.０３分；２２３.２５（Ｍ＋Ｈ)⁺。 (B) 4-ethyl-5-methyl-2-nitro-N-acetyl-aniline

Except that 3-methyl-4-ethyl-N-acetylaniline is used, 4-ethyl-5-methyl-2-nitro-N-acetyl is obtained as an orange solid according to the same method as in Reference Example 32 (a) above. -Aniline was produced. LC-MS (Method B): R _T = 3.03 min; 223.25 (M + H) ⁺ .

３−メチル−４−イソプロピル−Ｎ−アセチルアニリン［参考実施例３３（ｂ）］を使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、橙色固体として４−イソプロピル−５−メチル−２−ニトロ−Ｎ−アセチル−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１５分；２３１.３６（Ｍ＋Ｈ)⁺。 (C) 4-Isopropyl-5-methyl-2-nitro-N-acetyl-aniline

According to the same method as in Reference Example 32 (a) except that 3-methyl-4-isopropyl-N-acetylaniline [Reference Example 33 (b)] was used, 4-isopropyl-5- Methyl-2-nitro-N-acetyl-aniline was prepared. LC-MS (Method B): R _T = 3.15 min; 231.36 (M + H) ⁺ .

３−メチル−４−ブロモ−Ｎ−アセチルアニリン［参考実施例３３（ｃ）］を使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、橙色固体として４−ブロモ−５−メチル−２−ニトロ−Ｎ−アセチル−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.０６分；２７４.２（Ｍ＋Ｈ)⁺。 (D) 4-Bromo-5-methyl-2-nitro-N-acetyl-aniline

According to a method similar to that of Reference Example 32 (a) except that 3-methyl-4-bromo-N-acetylaniline [Reference Example 33 (c)] was used, 4-bromo-5-5- Methyl-2-nitro-N-acetyl-aniline was prepared. LC-MS (Method B): R _T = 3.06 min; 274.2 (M + H) ⁺ .

３,４−ジエチル−Ｎ−アセチルアニリン［参考実施例３３（ｄ）］を使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、橙色固体として４,５−ジエチル−２−ニトロ−Ｎ−アセチル−アニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１８分；２３７.４（Ｍ＋Ｈ)⁺。 (F) 4,5-diethyl-2-nitro-N-acetyl-aniline

Except for using 3,4-diethyl-N-acetylaniline [Reference Example 33 (d)], in the same manner as in Reference Example 32 (a) above, 4,5-Diethyl-2- Nitro-N-acetyl-aniline was prepared. LC-MS (Method B): R _T = 3.18 min; 237.4 (M + H) ⁺ .

Ｎ−（４−エトキシ−３−エチル−フェニル）アセトアミド［３.１ｇ、参考実施例３３（ｅ）］を無水酢酸（５ｍＬ）に溶解し、酢酸中の硝酸の溶液（４ｍＬ中９５％硝酸０.５ｍＬ）を添加し、混合物を周囲温度で１夜攪拌した。混合物を水（１００ｍＬ）で希釈し、水性の混合物を酢酸エチル（１００ｍＬ）で抽出した。合わせた抽出物を蒸発させ、残存物をシリカゲル上のクロマトグラフィー（ヘプタン／酢酸エチル ９／１）に付し、輝黄色固体としてＮ−（４−エトキシ−５−エチル−２−ニトロフェニル）アセトアミド（３.０ｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝３.２７分、２５３（Ｍ＋Ｈ)⁺。 (G) N- (4-Ethoxy-5-ethyl-2-nitrophenyl) acetamide

N- (4-Ethoxy-3-ethyl-phenyl) acetamide [3.1 g, Reference Example 33 (e)] was dissolved in acetic anhydride (5 mL) and a solution of nitric acid in acetic acid (95% nitric acid in 4 mL 0%). 0.5 mL) was added and the mixture was stirred overnight at ambient temperature. The mixture was diluted with water (100 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane / ethyl acetate 9/1) to give N- (4-ethoxy-5-ethyl-2-nitrophenyl) acetamide as a light yellow solid. (3.0 g) was obtained. LC-MS (Method E): R _T = 3.27 min, 253 (M + H) ⁺ .

無水酢酸（３０ｍＬ）中の１−エトキシ−２−エチルベンゼン（３.５ｇ、参考実施例５１）の溶液を氷水バス中に冷却した。酢酸（２５ｍＬ）中の硝酸（９０％〜３０％過剰１.４ｍＬ）の溶液を滴加し、混合物を周囲温度で１夜攪拌した。反応混合物を氷水（３００ｍＬ）に注ぎ込み、水性の混合物を酢酸エチル（２×２００ｍＬ）で抽出した。合わせた抽出物を蒸発させ、残存物をシリカゲル上のクロマトグラフィー（５〜１０％勾配の酢酸エチルを含むヘプタン）に付し、透明な液体として１−エトキシ−２−エチル−４−ニトロベンゼン（１.４ｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝３.７５分、１９６（Ｍ＋Ｈ)⁺。 (H) 1-ethoxy-2-ethyl-4-nitrobenzene

A solution of 1-ethoxy-2-ethylbenzene (3.5 g, Reference Example 51) in acetic anhydride (30 mL) was cooled in an ice water bath. A solution of nitric acid (90% to 30% excess 1.4 mL) in acetic acid (25 mL) was added dropwise and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into ice water (300 mL) and the aqueous mixture was extracted with ethyl acetate (2 × 200 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane containing a 5-10% gradient of ethyl acetate) to give 1-ethoxy-2-ethyl-4-nitrobenzene (1 0.4 g) was obtained. LC-MS (Method E): R _T = 3.75 min, 196 (M + H) ⁺ .

酢酸（２０ｍＬ）および無水酢酸（３５ｍＬ）の混合物中のＮ−（３−クロロ−４−メトキシフェニル）アセトアミド（６.８５ｇ、参考実施例）の溶液を−５℃に冷却し、反応温度を０℃より下に保持しながら酢酸（４ｍＬ）中の発煙硝酸（３ｍＬ）の溶液を滴加した。混合物を０℃で３０分間攪拌し、その時点で黄色沈殿物が形成した。さらに０℃で
１.５時間後、混合物を水（１００ｍＬ）に注ぎ込み、水性の混合物を１５分間激しく攪拌し、濾過した。黄色の沈殿物を水で洗浄し、真空下に６０℃で乾燥し、黄色固体として生成物（８.０ｇ）を得た。融点１５２〜１５３℃。ＭＳ：２４５（Ｍ＋Ｈ)⁺。 (I) N- (5-chloro-4-methoxy-2-nitrophenyl) acetamide

A solution of N- (3-chloro-4-methoxyphenyl) acetamide (6.85 g, Reference Example) in a mixture of acetic acid (20 mL) and acetic anhydride (35 mL) was cooled to −5 ° C. and the reaction temperature was reduced to 0. A solution of fuming nitric acid (3 mL) in acetic acid (4 mL) was added dropwise, keeping below C. The mixture was stirred at 0 ° C. for 30 minutes, at which point a yellow precipitate formed. After an additional 1.5 hours at 0 ° C., the mixture was poured into water (100 mL) and the aqueous mixture was stirred vigorously for 15 minutes and filtered. The yellow precipitate was washed with water and dried under vacuum at 60 ° C. to give the product (8.0 g) as a yellow solid. Mp 152-153 ° C. MS: 245 (M + H) ^<+> .

Ｎ−（４−メトキシ−３−メチル−フェニル）−アセトアミド［２.６５ｇ、参考実施例３３（ｆ）］を使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、橙色固体としてＮ−（４−メトキシ−５−メチル−２−ニトロ−フェニル）−アセトアミド（２.５３ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.３０分、２２５.２９（Ｍ＋Ｈ)⁺、２２３.２９（Ｍ−Ｈ)^-。 (J) N- (4-methoxy-5-methyl-2-nitro-phenyl) -acetamide

An orange solid according to the same procedure as in Reference Example 32 (a) above except that N- (4-methoxy-3-methyl-phenyl) -acetamide [2.65 g, Reference Example 33 (f)] was used. As N- (4-methoxy-5-methyl-2-nitro-phenyl) -acetamide (2.53 g). LC-MS (Method J): R _T = 3.30 min, 225.29 (M + H) ⁺ , 223.29 (M−H) ⁻ .

Ｎ−（４−フルオロ−３−メチル−フェニル）−アセトアミド［２.６５ｇ、参考実施例３３（ｇ）］を使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、黄色固体としてＮ−（４−フルオロ−５−メチル−２−ニトロ−フェニル）−アセトアミド（２.２５ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.３１分、２１１.２６（Ｍ−Ｈ)^-。 (K) N- (4-Fluoro-5-methyl-2-nitro-phenyl) -acetamide

A yellow solid according to the same procedure as in Reference Example 32 (a) above except that N- (4-fluoro-3-methyl-phenyl) -acetamide [2.65 g, Reference Example 33 (g)] was used. N- (4-Fluoro-5-methyl-2-nitro-phenyl) -acetamide (2.25 g) was prepared as LC-MS (Method J): R _T = 3.31 min, 211.26 (M−H) ⁻ .

Ｎ−（４−ジフルオロメトキシ−フェニル）−アセトアミド［参考実施例３３（ｈ）］を使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、黄色固体としてＮ−（４−ジフルオロメトキシ−２−ニトロ−フェニル）−アセトアミド（４５０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝３.７２分、ＭＳ：２４５（Ｍ−Ｈ)^-。 (L) N- (4-Difluoromethoxy-2-nitro-phenyl) -acetamide

Except for using N- (4-difluoromethoxy-phenyl) -acetamide [Reference Example 33 (h)], N- (4-Difluoro as a yellow solid was prepared in the same manner as Reference Example 32 (a) above. Methoxy-2-nitro-phenyl) -acetamide (450 mg) was prepared. LC-MS (Method K): R _T = 3.72 min, MS: 245 (M−H) ⁻ .

Ｎ−（３−エチル−４−メトキシ−フェニル）−アセトアミド［２.９ｇ、参考実施例３３（ｉ）］を使用する以外は、上記参考実施例３２（ａ）と同様の方法に従って、黄色固体としてＮ−（５−エチル−４−メトキシ−２−ニトロ−フェニル）−アセトアミド（
２.４ｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝４.０４分、ＭＳ：２３９.１６（Ｍ＋Ｈ)⁺。 (M) N- (5-Ethyl-4-methoxy-2-nitro-phenyl) -acetamide

A yellow solid according to the same procedure as in Reference Example 32 (a) above except that N- (3-ethyl-4-methoxy-phenyl) -acetamide [2.9 g, Reference Example 33 (i)] was used. As N- (5-ethyl-4-methoxy-2-nitro-phenyl) -acetamide (
2.4 g) was produced. LC-MS (Method K): R _T = 4.04 min, MS: 239.16 (M + H) ⁺ .

ジクロロメタン（４０ｍＬ）中の４−エチルアニリン（２ｇ）およびトリエチルアミン（１３.９１ｍＬ）の攪拌溶液を０℃で窒素下に無水酢酸（４.６７ｍＬ）で滴下処理した。混合物を周囲温度に加温し、その後室温で１６時間攪拌し、その後（ｉ）１０％クエン酸（４０ｍＬ）、(ii）水（４０ｍＬ）および（iii）塩水（４０ｍＬ）で洗浄した。有機層を硫酸マグネシウム上に乾燥し、その後蒸発させて、淡橙色固体として得られた４−エチル−Ｎ−アセチル−アニリン（２.３６ｇ）をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８０分；１６４.２（Ｍ＋Ｈ)⁺。 [Reference Example 33]
(A) 4-ethyl-N-acetyl-aniline

A stirred solution of 4-ethylaniline (2 g) and triethylamine (13.91 mL) in dichloromethane (40 mL) was treated dropwise with acetic anhydride (4.67 mL) at 0 ° C. under nitrogen. The mixture was warmed to ambient temperature and then stirred at room temperature for 16 hours, then washed with (i) 10% citric acid (40 mL), (ii) water (40 mL) and (iii) brine (40 mL). The organic layer was dried over magnesium sulfate and then evaporated and 4-ethyl-N-acetyl-aniline (2.36 g) obtained as a pale orange solid was used without further purification. LC-MS (Method B): R _T = 2.80 min; 164.2 (M + H) ⁺ .

３−メチル−４−イソプロピルアニリンを使用する以外は、上記参考実施例３３（ａ）と同様の方法に従って、橙色固体として３−メチル−４−イソプロピル−Ｎ−アセチルアニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９７分；１９２.３（Ｍ＋Ｈ)⁺。 (B) 3-Methyl-4-isopropyl-N-acetylaniline

3-Methyl-4-isopropyl-N-acetylaniline was produced as an orange solid according to the same method as in Reference Example 33 (a) except that 3-methyl-4-isopropylaniline was used. LC-MS (Method B): R _T = 2.97 min; 192.3 (M + H) ⁺ .

３−メチル−４−ブロモアニリンを使用する以外は、上記参考実施例３３（ａ）と同様の方法に従って、茶色固体として３−メチル−４−ブロモ−Ｎ−アセチルアニリンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８８分；２２８.１２（Ｍ＋Ｈ)⁺。 (C) 3-methyl-4-bromo-N-acetylaniline

3-Methyl-4-bromo-N-acetylaniline was produced as a brown solid according to the same method as in Reference Example 33 (a) except that 3-methyl-4-bromoaniline was used. LC-MS (Method B): R _T = 2.88 min; 228.12 (M + H) ⁺ .

３,４−ジエチルアニリンを使用する以外は、上記参考実施例３３（ａ）と同様の方法に従って、製造した３,４−ジエチル−Ｎ−アセチルアニリンをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.０３分；１９２.３０（Ｍ＋Ｈ)⁺。 (D) 3,4-diethyl-N-acetylaniline

Except for using 3,4-diethylaniline, the produced 3,4-diethyl-N-acetylaniline was used without further purification according to the same method as in Reference Example 33 (a) above. LC-MS (Method B): R _T = 3.03 min; 192.30 (M + H) ⁺ .

ピリジン（５ｍＬ）中の４−エトキシ−３−エチル−フェニルアミン［０.６ｇ、参考実施例３０（ｔ）］の溶液に無水酢酸（１ｍＬ）を添加し、混合物を周囲温度で１８時間攪拌した。反応混合物を水（１００ｍＬ）に希釈し、水性の混合物を酢酸エチル（１００ｍＬ）で２回抽出した。合わせた抽出物を蒸発させて桃色泡状物としてＮ−（４−エトキシ−３−エチル−フェニル）アセトアミド（０.６ｇ）を得た。ＧＣ−ＭＳ単一ピーク、Ｒ_T＝９.１６分、ＭＳ ２０７（Ｍ)⁺。 (E) N- (4-Ethoxy-3-ethyl-phenyl) acetamide

Acetic anhydride (1 mL) was added to a solution of 4-ethoxy-3-ethyl-phenylamine [0.6 g, Reference Example 30 (t)] in pyridine (5 mL) and the mixture was stirred at ambient temperature for 18 hours. . The reaction mixture was diluted in water (100 mL) and the aqueous mixture was extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated to give N- (4-ethoxy-3-ethyl-phenyl) acetamide (0.6 g) as a pink foam. GC-MS single peak, R _T = 9.16 min, MS 207 (M) ⁺ .

４−メトキシ−３−メチル−フェニルアミン（２.０７ｇ、参考実施例３０（ｕ））を使用し、反応生成物を酢酸エチルとｎ−ペンタンの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュクロマトグラフィーに付し、淡桃色結晶性固体としてＮ−（４−メトキシ−３−メチル−フェニル）−アセトアミド（２.６５ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.９４分、１８０.３０（Ｍ＋Ｈ)⁺。 (F) N- (4-Methoxy-3-methyl-phenyl) -acetamide

Using 4-methoxy-3-methyl-phenylamine (2.07 g, Reference Example 30 (u)), the reaction product was eluted with a mixture of ethyl acetate and n-pentane (1: 1, v / v). Flash chromatography on silica as an agent produced N- (4-methoxy-3-methyl-phenyl) -acetamide (2.65 g) as a pale pink crystalline solid. LC-MS (Method J): R _T = 2.94 min, 180.30 (M + H) ⁺ .

４−フルオロ−３−メチルアニリンを使用する以外は、上記参考実施例３３（ａ）と同様の方法に従って、橙色固体としてＮ−（４−フルオロ−３−メチル−フェニル）−アセトアミド（３.８２ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.０８分、１６８.２４（Ｍ＋Ｈ)⁺。 (G) N- (4-Fluoro-3-methyl-phenyl) -acetamide

N- (4-Fluoro-3-methyl-phenyl) -acetamide (3.82 g) as an orange solid according to the same method as in Reference Example 33 (a) except that 4-fluoro-3-methylaniline was used. ) Was manufactured. LC-MS (Method J): R _T = 3.08 min, 168.24 (M + H) ⁺ .

４−ジフルオロメトキシアニリンを使用する以外は、上記参考実施例３３（ａ）と同様の方法に従って、橙色固体としてＮ−（４−ジフルオロメトキシ−フェニル）−アセトアミド（５.９０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝３.６２分、２０２（Ｍ＋Ｈ)⁺。 (H) N- (4-Difluoromethoxy-phenyl) -acetamide

N- (4-Difluoromethoxy-phenyl) -acetamide (5.90 g) was produced as an orange solid according to the same method as in Reference Example 33 (a) except that 4-difluoromethoxyaniline was used. LC-MS (Method K): R _T = 3.62 min, 202 (M + H) ⁺ .

３−エチル−４−メトキシ−フェニルアニリン［２.５ｇ、参考実施例３０（ａａ）］を使用する以外は、上記参考実施例３３（ａ）と同様の方法に従って、明茶色固体としてＮ−（３−エチル−４−メトキシ−フェニル）−アセトアミド（２.９ｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝３.９２分、１９４.１６（Ｍ＋Ｈ)⁺。 (I) N- (3-Ethyl-4-methoxy-phenyl) -acetamide

Except for the use of 3-ethyl-4-methoxy-phenylaniline [2.5 g, Reference Example 30 (aa)], N- ( 3-Ethyl-4-methoxy-phenyl) -acetamide (2.9 g) was prepared. LC-MS (Method K): R _T = 3.92 min, 194.16 (M + H) ⁺ .

テトラヒドロフラン（４ｍＬ）中の３−シアノフェニルボロン酸（８１２ｍｇ）およびテトラキス（トリフェニルホスフィン）パラジウム（１５０ｍｇ）の攪拌溶液を窒素雰囲気下にテトラヒドロフラン（１０ｍＬ）中の４−ブロモ−２−ニトロアニリンで処理した。反応混合物を８５℃で４８時間加熱し、その後周囲温度に冷却し、その後酢酸エチルと水との間に分配した。有機層を塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルとヘキサンの混合物（１：２、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、黄色固体として４′−アミノ−３′−ニトロ−ビフェニル−３−カルボニトリル（２２４ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.２１分、２４０.３（Ｍ＋Ｈ)⁺。 [Reference Example 34]
(A) 4'-amino-3'-nitro-biphenyl-3-carbonitrile

Treat a stirred solution of 3-cyanophenylboronic acid (812 mg) and tetrakis (triphenylphosphine) palladium (150 mg) in tetrahydrofuran (4 mL) with 4-bromo-2-nitroaniline in tetrahydrofuran (10 mL) under a nitrogen atmosphere. did. The reaction mixture was heated at 85 ° C. for 48 hours, then cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 2, v / v) to give 4'-amino-3'-nitro-biphenyl-3 as a yellow solid. -Carbonitrile (224 mg) was obtained. LC-MS (Method B): R _T = 3.21 min, 240.3 (M + H) ⁺ .

ピリジン−３−ボロン酸を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、黄色固体として２−ニトロ−４−ピリジン−３−イル−フェニルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.０９分、２１６.２４（Ｍ＋Ｈ)⁺。 (B) 2-Nitro-4-pyridin-3-yl-phenylamine

2-Nitro-4-pyridin-3-yl-phenylamine was produced as a yellow solid according to the same method as in Reference Example 34 (a) except that pyridine-3-boronic acid was used. LC-MS (Method B): R _T = 2.09 min, 216.24 (M + H) ⁺ .

フェニルボロン酸および４−ブロモ−５−メチル−２−ニトロ−アニリン［参考実施例３１（ｄ）］を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、橙色固体として２−メチル−５−ニトロ−ビフェニル−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３０分、ＭＳ：２２９.２３（Ｍ＋Ｈ)⁺。 (C) 2-methyl-5-nitro-biphenyl-4-ylamine

2 as an orange solid according to the same procedure as in Reference Example 34 (a) above except that phenylboronic acid and 4-bromo-5-methyl-2-nitro-aniline [Reference Example 31 (d)] are used. -Methyl-5-nitro-biphenyl-4-ylamine was prepared. LC-MS (Method B): R _T = 3.30 min, MS: 229.23 (M + H) ⁺ .

フェニルボロン酸を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、赤色固体として３−ニトロフェニル−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４３分、２１５.０６（Ｍ＋Ｈ)⁺。 (D) 3-nitrophenyl-4-ylamine

3-Nitrophenyl-4-ylamine was produced as a red solid according to the same method as in Reference Example 34 (a) except that phenylboronic acid was used. LC-MS (Method B): R _T = 3.43 min, 215.06 (M + H) ⁺ .

２−フルオロフェニルボロン酸を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、赤色固体として２′−フルオロ−３−ニトロ−ビフェニル−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３３分、２３３.３（Ｍ＋Ｈ)⁺。 (E) 2'-fluoro-3-nitro-biphenyl-4-ylamine

2′-Fluoro-3-nitro-biphenyl-4-ylamine was produced as a red solid according to the same method as in Reference Example 34 (a) except that 2-fluorophenylboronic acid was used. LC-MS (Method B): R _T = 3.33 min, 233.3 (M + H) ⁺ .

３,４−メチレンジオキシフェニルボロン酸を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、橙色固体として４′−ベンゾ［１,３］ジオキソ−５−イル−２−ニトロフェニルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.２３分、２５９.３（Ｍ＋Ｈ)⁺。 (F) 4'-benzo [1,3] dioxo-5-yl-2-nitrophenylamine

According to the same method as in Reference Example 34 (a) except that 3,4-methylenedioxyphenylboronic acid was used, 4′-benzo [1,3] dioxo-5-yl-2- Nitrophenylamine was prepared. LC-MS (Method B): R _T = 3.23 min, 259.3 (M + H) ⁺ .

２−メトキシフェニルボロン酸を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、橙色固体として２′−メトキシ−３−ニトロ−ビフェニル−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３０分、２４５.３（Ｍ＋Ｈ)⁺。 (G) 2'-methoxy-3-nitro-biphenyl-4-ylamine

2′-methoxy-3-nitro-biphenyl-4-ylamine was produced as an orange solid according to the same method as in Reference Example 34 (a) except that 2-methoxyphenylboronic acid was used. LC-MS (Method B): R _T = 3.30 min, 245.3 (M + H) ⁺ .

４−クロロフェニルボロン酸を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、橙色固体として４′−クロロ−３−ニトロ−ビフェニル−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.４５分、２４９.２７（Ｍ＋Ｈ)⁺。 (H) 4'-chloro-3-nitro-biphenyl-4-ylamine

4'-Chloro-3-nitro-biphenyl-4-ylamine was produced as an orange solid according to the same method as in Reference Example 34 (a) except that 4-chlorophenylboronic acid was used. LC-MS (Method B): R _T = 3.45 min, 249.27 (M + H) ⁺ .

４−メチルフェニルボロン酸を使用する以外は、上記参考実施例３４（ａ）と同様の方法に従って、橙色固体として４′−メチル−３−ニトロ−ビフェニル−４−イルアミンを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３３分、２２９.２（Ｍ＋Ｈ)⁺。 (I) 4'-methyl-3-nitro-biphenyl-4-ylamine

4'-Methyl-3-nitro-biphenyl-4-ylamine was produced as an orange solid according to the same method as in Reference Example 34 (a) except that 4-methylphenylboronic acid was used. LC-MS (Method B): R _T = 3.33 min, 229.2 (M + H) ⁺ .

ジメチルホルムアミド（３０ｍＬ）中の３,４−ジニトロフェノール（１ｇ）の攪拌溶液を臭化ベンジル（７２３μＬ）および炭酸カリウム（１.１３ｇ）で処理した。反応混合物を周囲温度で２４時間攪拌し、その後酢酸エチルと水との間に分配した。有機層を塩
水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルとヘキサンの混合物（１：４、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、黄色固体として４−ベンジルオキシ−１,２−ジニトロベンゼン（１.３０ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３１分。
¹H NMR [(CD₃)₂CO, ppm]: δ 5.28 (s, 2H), 7.26-7.42 (m, 6H), 7.57 (d, 1H), 8.12
(d, 1H) [Reference Example 35]
(A) 4-Benzyloxy-1,2-dinitrobenzene

A stirred solution of 3,4-dinitrophenol (1 g) in dimethylformamide (30 mL) was treated with benzyl bromide (723 μL) and potassium carbonate (1.13 g). The reaction mixture was stirred at ambient temperature for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 4, v / v) to give 4-benzyloxy-1,2-dinitrobenzene (1 .30 g) was obtained. LC-MS (Method B): R _T = 3.31 min.
¹ H NMR [(CD ₃ ) ₂ CO, ppm]: δ 5.28 (s, 2H), 7.26-7.42 (m, 6H), 7.57 (d, 1H), 8.12
(d, 1H)

溶媒としてのアセトンとともに２−エチルフェノール（５ｍｌ）およびヨードメタン（２.６ｍｌ）を使用し、密封した圧力容器中に７０℃で２４時間加熱する以外は、上記参考実施例３５（ａ）と同様の方法に従って、黄色油状物として製造した１−エチル−２−メトキシ−ベンゼン（５.６ｇ）をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝３.８３分。
¹H NMR (d₆ アセトン) : δ 6.95 (m ,2H), 6.75 (d , 1H), 6.68 (t, 1H), 3.67 (s, 3H), 2.44 (q, 2H) 0.95 (t, 3H) (B) 1-ethyl-2-methoxy-benzene

Similar to Reference Example 35 (a) above except that 2-ethylphenol (5 ml) and iodomethane (2.6 ml) are used with acetone as solvent and heated in a sealed pressure vessel at 70 ° C. for 24 hours. According to the method, 1-ethyl-2-methoxy-benzene (5.6 g) prepared as a yellow oil was used without further purification. LC-MS (Method K): R _T = 3.83 min.
¹ H NMR (d ₆ acetone): δ 6.95 (m, 2H), 6.75 (d, 1H), 6.68 (t, 1H), 3.67 (s, 3H), 2.44 (q, 2H) 0.95 (t, 3H)

方法Ａ ジクロロメタン（２００ｍｌ）中の４,５−ジメチルフェニレンジアミン（４.３２ｇ）およびジイソプロピルエチルアミン（３０ｍｌ）の攪拌溶液を０℃で塩化４−ニトロピラゾール−３−カルボン酸（５ｇ）で少しずつ処理した。反応混合物を周囲温度に加温し、３０分間攪拌した。溶媒を真空下に除去し、油状の残存物を酢酸エチルと水との間に分配した。有機層を硫酸マグネシウム上に乾燥し、濃縮した。残存した油状物を酢酸エチルおよびメタノール（１０％）から再結晶化し、橙色固体として４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４,５−ジメチルフェニル）アミド（６.５８ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３６分、２７６.０９（Ｍ＋Ｈ)⁺。 [Reference Example 36]
(A) 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl) amide

Method A A stirred solution of 4,5-dimethylphenylenediamine (4.32 g) and diisopropylethylamine (30 ml) in dichloromethane (200 ml) was treated portionwise with 4-nitropyrazole-3-carboxylic acid chloride (5 g) at 0 ° C. did. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The solvent was removed in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated. The remaining oil was recrystallized from ethyl acetate and methanol (10%) and 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl) amide (6.58 g) as an orange solid. ) LC-MS (Method B): R _T = 2.36 min, 276.09 (M + H) ⁺ .

Method B Polyphosphoric acid (500 g) was added to a 1 L flask equipped with an overhead stirrer and heated to 70 ° C. under nitrogen. A blended mixture of 4-nitro-3-pyrazolecarboxylic acid (50 g) and 1,2-diamino-4,5-dimethylbenzene (43.4 g) was added and the mixture was heated to 180 ° C. After 1 hour at this temperature, the reaction mixture was cooled to 130 ° C. and poured into ice water (2.5 kg). The mixture was stirred with an overhead stirrer and then treated with aqueous ammonium hydroxide (350 mL, 30%) until the pH was 2.1. After stirring for an additional 15 minutes, the mixture was filtered and the filtered solid was washed three times with water (200 mL) and then dried under vacuum to give 4-nitro-1H-pyrazole-3-carboxylic acid (2 -Amino-4,5-dimethylphenyl) amide was obtained.

４−エチル−５−メチル−フェニレンジアミン［参考実施例３０（ａ）］を使用する以外は、上記参考実施例３６（ａ）方法Ａと同様の方法に従って、暗赤色固体として４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−エチル−５−メチルフェニル）アミドを製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８９分、２９０.２４（Ｍ＋Ｈ)⁺。 (B) 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethyl-5-methylphenyl) amide

4-Nitro-1H as a dark red solid according to the same procedure as Reference Example 36 (a) Method A above except that 4-ethyl-5-methyl-phenylenediamine [Reference Example 30 (a)] is used. -Pyrazole-3-carboxylic acid (2-amino-4-ethyl-5-methylphenyl) amide was prepared. LC-MS (Method B): R _T = 2.89 min, 290.24 (M + H) ⁺ .

４−クロロ−５−メトキシベンジル−１,２−ジアミン［１ｇ、参考実施例４９（ｂ）］、ジイソプロピルエチルアミン（４.１ｍＬ、４当量）、ジクロロメタン（５０ｍＬ）およびジクロロメタン（２５ｍＬ）中の塩化４−ニトロピラゾール−３−カルボニル（１ｇ、５.８ミリモル）を使用し、反応混合物を周囲温度で１８時間攪拌する以外は、上記参考実施例３６（ａ）方法Ａと同様の方法に従って、４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−５−クロロ−４−メトキシフェニル）アミドとビス−アクリル化物質との混合物を製造した。ＭＳ３１０（Ｍ^-）および４４９（Ｍ^-）。本物質をさらに精製することなく実施例２０（ｃ）に使用した。 (C) 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-5-chloro-4-methoxyphenyl) amide

4-Chloro-5-methoxybenzyl-1,2-diamine [1 g, Reference Example 49 (b)], diisopropylethylamine (4.1 mL, 4 eq), dichloromethane (50 mL) and dichloromethane (25 mL) in chloride 4 4-Nitropyrazole-3-carbonyl (1 g, 5.8 mmol) was used according to a method similar to that of Reference Example 36 (a) Method A above except that the reaction mixture was stirred at ambient temperature for 18 hours. A mixture of nitro-1H-pyrazole-3-carboxylic acid (2-amino-5-chloro-4-methoxyphenyl) amide and bis-acrylated material was prepared. MS 310 (M ⁻ ) and 449 (M ⁻ ). This material was used in Example 20 (c) without further purification.

４−メトキシ−１,２−フェニレンジアミン（８８０ｍｇ）および塩化４−ニトロピラゾール−３−カルボン酸［乾燥ジクロロメタン（７０ｍｌ）中の４−ニトロピラゾール−３−カルボン酸（１ｇ）の溶液を窒素下に塩化オキサリル（１.１１ｍｌ）およびジメチルホルムアミドで処理し、１夜攪拌後、蒸発させ、その後反応混合物をトルエン（１０ｍｌ）で３回共沸させることにより製造］を使用する以外は上記参考実施例３６（ａ）方法Ａと同様の方法に従って、４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−メトキシ−フェニル）−アミド（８００ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.６７分、２７８.２５（Ｍ＋Ｈ)⁺、２７６.２８（Ｍ−Ｈ)^-。 (D) 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl) -amide

4-Methoxy-1,2-phenylenediamine (880 mg) and 4-nitropyrazole-3-carboxylic acid chloride [solution of 4-nitropyrazole-3-carboxylic acid (1 g) in dry dichloromethane (70 ml) under nitrogen. The above Reference Example 36 except that it is treated with oxalyl chloride (1.11 ml) and dimethylformamide, stirred overnight, evaporated and then azeotroped with toluene (10 ml) three times. (A) According to the same method as Method A, 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl) -amide (800 mg) was prepared. LC-MS (Method J): R _T = 2.67 min, 278.25 (M + H) ⁺ , 276.28 (M−H) ⁻ .

４−エトキシ−ベンゼン−１,２−ジアミン［１.２５ｇ、参考実施例３０（ｖ）］を使用し、反応生成物を最初酢酸エチル、その後酢酸エチルとメタノール（９：１、ｖ／ｖ）の混合物を溶離剤とするシリカ上のフラッシュクロマトグラフィーに付する以外は、上記参考実施例３６（ｄ）と同様の方法に従って、黒色固体として４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−エトキシ−フェニル）−アミド（８２４ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.９０分、２９２.２７（Ｍ＋Ｈ)⁺、２９０.３０（Ｍ−Ｈ)^-。 (E) 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethoxy-phenyl) -amide

4-Ethoxy-benzene-1,2-diamine [1.25 g, Reference Example 30 (v)] was used and the reaction product was first ethyl acetate, then ethyl acetate and methanol (9: 1, v / v). 4-nitro-1H-pyrazole-3-carboxylic acid (2) as a black solid according to the same method as in Reference Example 36 (d) except that the mixture was -Amino-4-ethoxy-phenyl) -amide (824 mg) was prepared. LC-MS (Method J): R _T = 2.90 min, 292.27 (M + H) ⁺ , 290.30 (M−H) ⁻ .

４−フルオロ−５−メチル−ベンゼン−１,２−ジアミン［参考実施例３０（ｗ）］を使用する以外は、上記参考実施例３６（ｄ）と同様の方法に従って、赤色油状物として４
−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−フルオロ−５−メチル−フェニル）−アミド（２.１２ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.０２分、２８０.２５（Ｍ＋Ｈ)⁺。 (F) 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-fluoro-5-methyl-phenyl) -amide

According to a method similar to that of Reference Example 36 (d) except that 4-fluoro-5-methyl-benzene-1,2-diamine [Reference Example 30 (w)] was used, 4
-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-fluoro-5-methyl-phenyl) -amide (2.12 g) was prepared. LC-MS (Method J): R _T = 3.02 min, 280.25 (M + H) ⁺ .

４−トリフルオロメトキシ−ベンゼン−１,２−ジアミン［参考実施例３０（ｘ）］を使用する以外は、上記参考実施例３６（ｄ）と同様の方法に従って、赤色固体として４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−トリフルオロメトキシ−フェニル）−アミド（０.８５０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.３４分、３３２.２１（Ｍ＋Ｈ)⁺。 (G) 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-trifluoromethoxy-phenyl) -amide

4-Nitro-1H as a red solid according to the same procedure as in Reference Example 36 (d) except that 4-trifluoromethoxy-benzene-1,2-diamine [Reference Example 30 (x)] was used. -Pyrazole-3-carboxylic acid (2-amino-4-trifluoromethoxy-phenyl) -amide (0.850 g) was prepared. LC-MS (Method J): R _T = 3.34 min, 332.21 (M + H) ⁺ .

４−トリフルオロメチル−ベンゼン−１,２−ジアミン［参考実施例３０（ｙ）］を使用する以外は、上記参考実施例３６（ｄ）と同様の方法に従って、赤色固体として４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−トリフルオロメチル−フェニル）−アミド（０.２５０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３５分、３１６.１４（Ｍ＋Ｈ)⁺。 (H) 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-trifluoromethyl-phenyl) -amide

4-Nitro-1H as a red solid according to the same method as Reference Example 36 (d) above except that 4-trifluoromethyl-benzene-1,2-diamine [Reference Example 30 (y)] was used. -Pyrazole-3-carboxylic acid (2-amino-4-trifluoromethyl-phenyl) -amide (0.250 g) was prepared. LC-MS (Method B): R _T = 3.35 min, 316.14 (M + H) ⁺ .

４−クロロ−５−メチル−ベンゼン−１,２−ジアミンを使用する以外は、上記参考実
施例３６（ｄ）と同様の方法に従って、黄色固体として４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸（２−アミノ−４−クロロ−５−メチル−フェニル）−アミド（０.３００ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７２分、２９６.１０（Ｍ＋Ｈ)⁺。 (I) 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-chloro-5-methyl-phenyl) -amide

4-Nitro-1H-pyrazole-3-carboxylic acid as a yellow solid according to the same method as in Reference Example 36 (d) except that 4-chloro-5-methyl-benzene-1,2-diamine was used. (2-Amino-4-chloro-5-methyl-phenyl) -amide (0.300 g) was prepared. LC-MS (Method B): R _T = 2.72 min, 296.10 (M + H) ⁺ .

メチル−３,４−ジアミノベンゾエートを使用する以外は、上記参考実施例３６（ｄ）と同様の方法に従って、褐色泡状固体として３−アミノ−４−［（４−ニトロ−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−安息香酸メチルエステル（２.５１ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８３分、３０６.２１（Ｍ＋Ｈ)⁺。 (J) 3-Amino-4-[(4-nitro-1H-pyrazole-3-carbonyl) -amino] -benzoic acid methyl ester

Except for using methyl-3,4-diaminobenzoate, 3-amino-4-[(4-nitro-1H-pyrazole-3) as a brown foamy solid was prepared in the same manner as in Reference Example 36 (d) above. -Carbonyl) -amino] -benzoic acid methyl ester (2.51 g) was prepared. LC-MS (Method B): R _T = 2.83 min, 306.21 (M + H) ⁺ .

アセトン（１０ｍｌ）中の５−ヒドロキシ−１Ｈ−インダゾール［０.５ｇ、参考実施例３８］の溶液を炭酸カリウム（２.５６ｇ）その後ヨードエタン（０.２９６ｍｌ）で処理した。混合物を４時間還流し、その後冷却し、蒸発させた。残存物を酢酸エチルと水との間に分配し、水層を酢酸エチルでさらに２回抽出した。合わせた有機画分を硫酸マグネシウム上に乾燥し、その後蒸発させて得られた茶色の残存物を酢酸エチルとヘキサンの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、オフホワイトの固体として５−エトキシ−１Ｈ−インダゾール（０.３８ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６８分；１６３（Ｍ＋Ｈ)⁺。 [Reference Example 37]
5-Ethoxy-1H-indazole

A solution of 5-hydroxy-1H-indazole [0.5 g, Reference Example 38] in acetone (10 ml) was treated with potassium carbonate (2.56 g) followed by iodoethane (0.296 ml). The mixture was refluxed for 4 hours, then cooled and evaporated. The residue was partitioned between ethyl acetate and water, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic fractions are dried over magnesium sulfate and then evaporated to give a brown residue on a flash column on silica eluting with a mixture of ethyl acetate and hexane (1: 1, v / v). Chromatography gave 5-ethoxy-1H-indazole (0.38 g) as an off-white solid. LC-MS (Method B): R _T = 2.68 min; 163 (M + H) ⁺ .

ジクロロメタン（７.５ｍｌ）中の５−メトキシ−１Ｈ−インダゾール［０.４１０ｇ、参考実施例２４（ａ）］の溶液をジクロロメタン中の三臭化ホウ素の溶液（７.５ｍｌ、１Ｍ）で処理した。その後混合物を還流下に４時間加熱し、その後０℃に冷却し、その後水（２ｍｌ）で滴下処理した。１０％炭酸水素ナトリウム水を添加して、この混合物のＰＨを７〜８に調整した。その後混合物を酢酸エチルで３回抽出した。合わせた抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させた。残存した茶色油状物を酢酸エチルとヘキ
サンの混合物（１：１、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、黄色固体として５−ヒドロキシ−１Ｈ−インダゾール（０.３１０ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝１.９６分；１３５（Ｍ＋Ｈ)⁺。 [Reference Example 38]
5-hydroxy-1H-indazole

A solution of 5-methoxy-1H-indazole [0.410 g, Reference Example 24 (a)] in dichloromethane (7.5 ml) was treated with a solution of boron tribromide in dichloromethane (7.5 ml, 1M). . The mixture was then heated under reflux for 4 hours, then cooled to 0 ° C. and then treated dropwise with water (2 ml). 10% aqueous sodium bicarbonate was added to adjust the pH of this mixture to 7-8. The mixture was then extracted 3 times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated. The remaining brown oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 1, v / v) to give 5-hydroxy-1H-indazole (0. 310 g) was obtained. LC-MS (Method B): R _T = 1.96 min; 135 (M + H) ⁺ .

ジメチルホルムアミド（１００ｍｌ）中の４,５−ジメチルベンゼン−１,２−ジアミン（０.８４１ｇ）および１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−３,５−ジカルボン酸５−ｔ−ブチルエステル［１.５ｇ、参考実施例４０（ａ）］の溶液にジイソプロピルエチルアミン（１.０８ｍｌ）および２−（１Ｈ−９−アザベンゾトリアゾール−１−イル）−１,１,３,３−テトラメチルウロニウムヘキサフルオロホスフェート（２.３５ｇ）を添加した。混合物を１.５時間攪拌し、酢酸エチルで希釈し、その後塩水で６回洗浄した。有機層を硫酸マグネシウム上に乾燥し、真空下に濃縮し、淡茶色固体を得た。その後固体をメタノールで磨砕し、オフホワイトの固体として１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−３,５−ジカルボン酸,３−（２−アミノ−４,５−ジメチルフェニル）アミド，５−ｔ−ブチルエステル（０.９９ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９４分；３８６（Ｍ＋Ｈ)⁺。 [Reference Example 39]
(A) 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid, 3- (2-amino-4,5-dimethylphenyl) amide, 5-t- Butyl ester

4,5-Dimethylbenzene-1,2-diamine (0.841 g) and 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid in dimethylformamide (100 ml) Diisopropylethylamine (1.08 ml) and 2- (1H-9-azabenzotriazol-1-yl) -1,1 were added to a solution of acid 5-t-butyl ester [1.5 g, Reference Example 40 (a)]. 1,3,3-tetramethyluronium hexafluorophosphate (2.35 g) was added. The mixture was stirred for 1.5 hours, diluted with ethyl acetate and then washed 6 times with brine. The organic layer was dried over magnesium sulfate and concentrated under vacuum to give a light brown solid. The solid is then triturated with methanol and 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid, 3- (2-amino-4, as an off-white solid. 5-Dimethylphenyl) amide, 5-t-butyl ester (0.99 g) was obtained. LC-MS (Method B): R _T = 2.94 min; 386 (M + H) ⁺ .

４−｛［（２,４−ジメトキシ−ベンジル）−（モルホリン−４−カルボニル）−アミノ］−メチル｝−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸［５３４ｍｇ、参考実施例４０（ｂ）］を使用する以外は、上記参考実施例３９（ａ）と同様の方法に従って、黄色油状物としてモルホリン−４−カルボン酸［３−（２−アミノ−４,５−ジメチル−フェニルカルバモイル）−１−（テトラヒドロ−ピラン−
２−イル）−１Ｈ−ピラゾール−４−イルメチル］−（２,４−ジメトキシ−ベンジル）−アミド（１.６６ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.８１分、６０７.７１（Ｍ＋Ｈ)⁺。 (B) Morpholine-4-carboxylic acid [3- (2-amino-4,5-dimethyl-phenylcarbamoyl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-ylmethyl]-(2 , 4-Dimethoxy-benzyl) -amide

4-{[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid [534 mg The morpholine-4-carboxylic acid [3- (2-amino-4,5] as a yellow oil was prepared in the same manner as in Reference Example 39 (a) except that Reference Example 40 (b)] was used. -Dimethyl-phenylcarbamoyl) -1- (tetrahydro-pyran-
2-yl) -1H-pyrazol-4-ylmethyl]-(2,4-dimethoxy-benzyl) -amide (1.66 g) was prepared. LC-MS (Method B): R _T = 2.81 min, 607.71 (M + H) ⁺ .

４−クロロ−５−メチル−１,２−フェニレンジアミンを使用する以外は、上記参考実施例３９（ａ）と同様の方法に従って、茶色固体として３−（２−アミノ−４−クロロ−５−メチル−フェニルカルバモイル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル（４１１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.６６分、４０６／４０８（Ｍ＋Ｈ)⁺。 (C) 3- (2-Amino-4-chloro-5-methyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester

According to the same method as in Reference Example 39 (a) except that 4-chloro-5-methyl-1,2-phenylenediamine was used, 3- (2-amino-4-chloro-5-5- Methyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester (411 mg) was prepared. LC-MS (Method J): R _T = 3.66 min, 406/408 (M + H) ⁺ .

４−（２−モルホリン−４−イル−エトキシ）−ベンゼン−１,２−ジアミン［参考実施例２９（ｃ）］を使用する以外は、上記参考実施例３９（ａ）と同様の方法に従って、茶色固体として３−［２−アミノ−４−（２−モルホリン−４−イル−エトキシ）−フェニルカルバモイル］−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル（４００ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.３３分、４８５.１８（Ｍ−Ｈ)^-。 (D) 3- [2-Amino-4- (2-morpholin-4-yl-ethoxy) -phenylcarbamoyl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5- Carboxylic acid t-butyl ester

According to the same method as in Reference Example 39 (a) except that 4- (2-morpholin-4-yl-ethoxy) -benzene-1,2-diamine [Reference Example 29 (c)] was used, 3- [2-Amino-4- (2-morpholin-4-yl-ethoxy) -phenylcarbamoyl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5 as a brown solid Carboxylic acid t-butyl ester (400 mg) was prepared. LC-MS (Method N): R _T = 3.33 min, 485.18 (M−H) ⁻ .

１,４,６,７−テトラヒドロ−ピラノ［４,３−ｃ］ピラゾール−３−カルボン酸［参考実施例１７（ｅ）］を使用する以外は、上記参考実施例３９（ａ）と同様の方法に従って、クリーム色の固体として１,４,６,７−テトラヒドロ−ピラノ［４,３−ｃ］ピラゾール−３−カルボン酸（２−アミノ−４,５−ジメチル−フェニル）−アミド（１１６ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.３２分、２８７（Ｍ＋Ｈ)⁺。 (E) 1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid (2-amino-4,5-dimethyl-phenyl) -amide

Similar to Reference Example 39 (a) above, except that 1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid [Reference Example 17 (e)] was used. According to method, 1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole-3-carboxylic acid (2-amino-4,5-dimethyl-phenyl) -amide (116 mg) as a cream solid Manufactured. LC-MS (Method B): R _T = 2.32 min, 287 (M + H) ⁺ .

４−トリフルオロメチル−１,２−フェニレンジアミンを使用する以外は、上記参考実施例３９（ａ）と同様の方法に従って、茶色固体として３−（２−アミノ−４−トリフルオロメチル−フェニルカルバモイル）−１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−５−カルボン酸ｔ−ブチルエステル（１.００ｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.７５分、４２４.１０（Ｍ−Ｈ)^-。 (F) 3- (2-Amino-4-trifluoromethyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester

3- (2-Amino-4-trifluoromethyl-phenylcarbamoyl) as a brown solid according to the same method as in Reference Example 39 (a) except that 4-trifluoromethyl-1,2-phenylenediamine was used. ) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid t-butyl ester (1.00 g) was prepared. LC-MS (Method N): R _T = 3.75 min, 424.10 (M−H) ⁻ .

メタノール（３０ｍｌ）および水（１０ｍｌ）中の１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−３,５−ジカルボン酸５−ｔ−ブチルエステル３−エチルエステル［５.１０５ｇ、参考実施例１８（ｄ）］および水酸化リチウム１水和物（０.８７０ｇ）の溶液を５５℃で２.５時間攪拌した。混合物を飽和硫酸水素カリウム水溶液で酸性化し、酢酸エチルで３回抽出した。有機抽出物を合わせ、硫酸マグネシウム上に乾燥し、真空下に濃縮して、淡黄色固体として１,４,６,７−テトラヒドロ−ピラゾロ［４,３−ｃ］ピリジン−３,５−ジカルボン酸５−ｔ−ブチルエステル（４.４４２ｇ）を得た。ＭＳ：２６８（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｇ）：Ｒ_T＝２.８６分。 [Reference Example 40]
(A) 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid 5-t-butyl ester

1,4,6,7-Tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid 5-t-butyl ester 3-ethyl ester in methanol (30 ml) and water (10 ml) [5. 105 g, Reference Example 18 (d)] and lithium hydroxide monohydrate (0.870 g) were stirred at 55 ° C. for 2.5 hours. The mixture was acidified with saturated aqueous potassium hydrogen sulfate and extracted three times with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid as a pale yellow solid. 5-t-butyl ester (4.442 g) was obtained. MS: 268 (M + H) ^<+> . HPLC (Method G): R _T = 2.86 min.

４−｛［（２,４−ジメトキシ−ベンジル）−（モルホリン−４−カルボニル）−アミノ］−メチル｝−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸エチルエステル［５９４ｍｇ、参考実施例４８（ｉ）］を使用する以外は、上記参考実施例４０（ａ）と同様の方法に従って、白色綿毛状固体として４−｛［（２,４−ジメトキシ−ベンジル）−（モルホリン−４−カルボニル）−アミノ］−メチル｝−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸（５３４ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７１分、４８９.２１（Ｍ＋Ｈ)⁺。 (B) 4-{[(2,4-Dimethoxy-benzyl)-(morpholine-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carvone acid

4-{[(2,4-Dimethoxy-benzyl)-(morpholine-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester 4-{[(2,4-dimethoxy-benzyl)-as a white fluffy solid according to the same procedure as in Reference Example 40 (a) except that [594 mg, Reference Example 48 (i)] was used. (Morpholine-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid (534 mg) was prepared. LC-MS (Method B): R _T = 2.71 min, 489.21 (M + H) ⁺ .

ジクロロメタン（２５ｍｌ）中の３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル［３.４６ｇ、参考実施例４２］の溶液をトリフルオロ酢酸（２５ｍｌ）で処理した。混合物を１.５時間攪拌し、その後濃縮した。残存物を飽和炭酸ナトリウム溶液と酢酸エチルとの間に分配した。有機層を硫酸マグネシウム上に乾燥し、その後蒸発させて、茶色固体として得られた３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル（２.４９ｇ）をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５４分；１７１（Ｍ＋Ｈ)⁺。 [Reference Example 41]
(A) 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester

A solution of 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester [3.46 g, Reference Example 42] in dichloromethane (25 ml) was treated with trifluoroacetic acid (25 ml). The mixture was stirred for 1.5 hours and then concentrated. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was dried over magnesium sulfate and then evaporated to give 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.49 g) obtained as a brown solid without further purification. LC-MS (Method B): R _T = 2.54 min; 171 (M + H) ⁺ .

３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミド［参考実施例４４（ａ）］を使用する以外は、上記参考実施例４１（ａ）と同様の方法に従って、淡黄色固体として製造した３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミドをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４３分；１８４（Ｍ＋Ｈ)⁺。 (B) 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide

A pale yellow solid was prepared in the same manner as in Reference Example 41 (a) except that 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide [Reference Example 44 (a)] was used. The 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide prepared as was used without further purification. LC-MS (Method B): R _T = 2.43 min; 184 (M + H) ⁺ .

３−ｔ−ブチルオキシメチル−５−メチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル［参考実施例４３］を使用する以外は、上記参考実施例４１（ａ）と同様の方法に従って、橙色固体として製造した３−ヒドロキシメチル−５−メチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステルをさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.５８分；１８５（Ｍ＋Ｈ)⁺。 (C) 3-hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

According to the same method as in Reference Example 41 (a) except that 3-t-butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester [Reference Example 43] was used, an orange solid was obtained. 3-hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester prepared as was used without further purification. LC-MS (Method B): R _T = 2.58 min; 185 (M + H) ⁺ .

３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸（２−メトキシ−エチル）−アミド［参考実施例４４（ｂ）］を使用する以外は、上記参考実施例４１（ａ）と同様の方法に従って、橙色油状物として３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸（２−メトキシ−エチル）−アミド（３９８ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝１.６６分、２２２（Ｍ＋Ｎａ)⁺。 (D) 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide

Same as Reference Example 41 (a) except using 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide [Reference Example 44 (b)]. According to the method, 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide (398 mg) was obtained as an orange oil. LC-MS (Method B): R _T = 1.66 min, 222 (M + Na) ⁺ .

３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸プロピルアミド［参考実施例４４（ｃ）］を使用する以外は、上記参考実施例４１（ａ）と同様の方法に従って、橙色油状物として３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸プロピルアミド（７３１ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.０９分、２０６（Ｍ＋Ｎａ)⁺。 (E) 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid propylamide

According to the same method as in Reference Example 41 (a) except that 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid propylamide [Reference Example 44 (c)] was used, an orange oily substance was obtained. As a result, 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid propylamide (731 mg) was obtained. LC-MS (Method B): R _T = 2.09 min, 206 (M + Na) ⁺ .

３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸（テトラヒドロ−ピラン−４−イル）−アミド［参考実施例４４（ｄ）］を使用する以外は、上記参考実施例４１（ａ）と同様の方法に従って、橙色油状物として３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸（テトラヒドロ−ピラン−４−イル）−アミド（４.１０ｇ）を得た。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝１.８９分、２２６（Ｍ＋Ｈ)⁺。 (F) 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide

Reference Example 41 (a) above, except using 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide [Reference Example 44 (d)] According to the same method, 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide (4.10 g) was obtained as an orange oil. LC-MS (Method N): R _T = 1.89 min, 226 (M + H) ⁺ .

３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド［参考実施例４４（ｅ）］を使用する以外は、上記参考実施例４１（ａ）と同様の方法に従って、白色泡状物として３−ヒドロキシメチル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド（２.４８ｇ）を得た。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝１.８５分、１８０.１５（Ｍ−Ｈ)^-。 (G) 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide

According to the same method as in Reference Example 41 (a) except that 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide [Reference Example 44 (e)] was used, white foam As a product, 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide (2.48 g) was obtained. LC-MS (Method N): R _T = 1.85 min, 180.15 (M−H) ⁻ .

トルエン（５０ｍｌ）中のジメチルホルムアミドアセタール（３.４７ｍｌ）および４−ｔ−ブトキシ−３−オキソ−酪酸エチルエステル［３.５２ｇ、参考実施例４３］の溶液を６５℃で２時間加熱した。その後混合物を濃縮し、残存物を酢酸（３ｍｌ）に再溶解した。混合物にヒドラジン水和物（０.９３ｍｌ）を添加し、周囲温度で２時間全体を攪拌した。混合物を再び真空下に濃縮し、残存物を酢酸エチルと５％炭酸水素ナトリウム水溶液との間に分配した。有機層を硫酸マグネシウム上に乾燥し、その後濃縮して得られた茶色油状物を酢酸エチルとペトロールの混合物（３：７、ｖ／ｖ）を溶離剤とするシリカ上のフラッシュカラムクロマトグラフィーに付し、黄色固体として３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル（３.４６ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７９分；２２７（Ｍ＋Ｈ)⁺。 [Reference Example 42]
3-t-Butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester

A solution of dimethylformamide acetal (3.47 ml) and 4-t-butoxy-3-oxo-butyric acid ethyl ester [3.52 g, Reference Example 43] in toluene (50 ml) was heated at 65 ° C. for 2 hours. The mixture was then concentrated and the residue was redissolved in acetic acid (3 ml). To the mixture was added hydrazine hydrate (0.93 ml) and the whole was stirred at ambient temperature for 2 hours. The mixture was again concentrated in vacuo and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic layer is dried over magnesium sulfate and then concentrated, and the resulting brown oil is subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol (3: 7, v / v). Then, 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.46 g) was obtained as a yellow solid. LC-MS (Method B): R _T = 2.79 min; 227 (M + H) ⁺ .

ジメチルホルムアミド（５０ｍｌ）中の水素化ナトリウム（４.４４ｇ、鉱油中の６０％分散液）の懸濁液を０℃でエチル−４−クロロアセトアセテート（５ｍｌ）、その後ｔ−ブチルアルコール（７.０８ｍｌ）で滴下処理した。この混合物を０℃で２時間、その後さらに２時間周囲温度で維持し、その後２Ｎ塩酸／氷に注ぎ込み、その後酢酸エチルで４回抽出した。合わせた抽出物を飽和炭酸水素ナトリウム水溶液、その後水、その後塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。得られた黄色油状物を酢酸エチルとペトロールの混合物（１：９、ｖ／ｖ）を溶離剤とするフラッシュカラムクロマトグラフィーに付し、黄色油状物として４−ｔ−ブトキシ−３−オキソ−酪酸エチルエステル（５.２０ｇ）を得た。ＴＬＣ（シリカ、１：４、ｖ／ｖ酢酸エチル／ペトロール）：Ｒ_F＝０.５１。
NMR (400MHz, CDCl₃): δ 1.21(9H, s), 1.28(3H, t), 3.55(2H, s), 4.19(2H, q) [Reference Example 43]
4-t-Butoxy-3-oxo-butyric acid ethyl ester

A suspension of sodium hydride (4.44 g, 60% dispersion in mineral oil) in dimethylformamide (50 ml) was stirred at 0 ° C. with ethyl-4-chloroacetoacetate (5 ml) followed by t-butyl alcohol (7. 08 ml). The mixture was maintained at ambient temperature for 2 hours at 0 ° C. and then for another 2 hours, then poured into 2N hydrochloric acid / ice and then extracted 4 times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate, then water, then brine, then dried over magnesium sulfate and then evaporated. The resulting yellow oil was subjected to flash column chromatography using a mixture of ethyl acetate and petrol (1: 9, v / v) as eluent to give 4-t-butoxy-3-oxo-butyric acid as a yellow oil. Ethyl ester (5.20 g) was obtained. TLC (silica, 1: 4, v / v ethyl acetate / petrol): R _F = 0.51.
NMR (400MHz, CDCl ₃ ): δ 1.21 (9H, s), 1.28 (3H, t), 3.55 (2H, s), 4.19 (2H, q)

ジメチルホルムアミド（１３０ｍｌ）中の３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸［１.５２０ｇ、参考実施例１７（ｄ）］、ヒドロキシベンザトリアゾール（３.１１０ｇ）およびジイソプロピルエチルアミン（４.０１０ｍｌ）の溶液にイソプロピルアミン（１.９６０ｍｌ）ついで塩酸１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（４.４２０ｇ）を添加した。混合物を７０℃で２.５時間加熱し、その後酢酸エチルで希釈し、その後水、その後塩水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させた。残存物を酢酸エチルとペトロールの混合物で磨砕し、オフホワイトの固体として、３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸イソプロピルアミド（６５２ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９９分；２４０（Ｍ＋Ｈ)⁺。 [Reference Example 44]
(A) 3-t-Butyloxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide

3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acid [1.520 g, Reference Example 17 (d)], hydroxybenztriazole (3.110 g) and diisopropylethylamine (4) in dimethylformamide (130 ml) To a solution of .010 ml) was added isopropylamine (1.960 ml) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.420 g). The mixture was heated at 70 ° C. for 2.5 hours, then diluted with ethyl acetate, then washed with water, then brine, then dried over magnesium sulfate and then evaporated. The residue was triturated with a mixture of ethyl acetate and petrol to give 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide (652 mg) as an off-white solid. LC-MS (Method B): R _T = 2.99 min; 240 (M + H) ⁺ .

２−メトキシエチルアミンを使用する以外は、上記参考実施例４４（ａ）と同様の方法に従って、橙色油状物として３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸（２−メトキシ−エチル）−アミド（８１１ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４３分、２７８（Ｍ＋Ｎａ)⁺。 (B) 3-t-Butyloxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide

3-t-Butyloxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) as an orange oil according to the same method as in Reference Example 44 (a) except that 2-methoxyethylamine was used. ) -Amide (811 mg) was prepared. LC-MS (Method B): R _T = 2.43 min, 278 (M + Na) ⁺ .

ｎ−プロピルアミンを使用する以外は、上記参考実施例４４（ａ）と同様の方法に従って、橙色油状物として３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸プロピルアミド（１.１２ｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.６５分、２６２（Ｍ＋Ｎａ)⁺。 (C) 3-t-Butyloxymethyl-1H-pyrazole-4-carboxylic acid propylamide

Except that n-propylamine is used, 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid propylamide (1.12 g) is obtained as an orange oil according to the same method as in Reference Example 44 (a) above. ) Was manufactured. LC-MS (Method B): R _T = 2.65 min, 262 (M + Na) ⁺ .

テトラヒドロピラン−４−イルアミンを使用する以外は、上記参考実施例４４（ａ）と同様の方法に従って、橙色油状物として３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール
−４−カルボン酸（テトラヒドロ−ピラン−４−イル）−アミド（５.５０ｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.０５分、２８２（Ｍ＋Ｎａ)⁺。 (D) 3-t-Butyloxymethyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl) -amide

Except that tetrahydropyran-4-ylamine is used, 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran) is obtained as an orange oil according to the same method as in Reference Example 44 (a) above. -4-yl) -amide (5.50 g) was prepared. LC-MS (Method N): R _T = 3.05 min, 282 (M + Na) ⁺ .

シクロプロピルアミンを使用する以外は、上記参考実施例４４（ａ）と同様の方法に従って、橙色油状物として３−ｔ−ブチルオキシメチル−１Ｈ−ピラゾール−４−カルボン酸シクロプロピルアミド（３.２７ｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝２.２４分、２３８.３８（Ｍ＋Ｎａ)⁺。 (E) 3-t-Butyloxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide

Except for the use of cyclopropylamine, 3-t-butyloxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide (3.27 g) was obtained as an orange oil according to the same method as in Reference Example 44 (a) above. ) Was manufactured. LC-MS (Method H): R _T = 2.24 min, 238.38 (M + Na) ⁺ .

酢酸（３ｍｌ）中の２−アセチル−４−ｔ−ブトキシ−３−オキソ−酪酸エチルエステル［０.３２５、参考実施例４６］の溶液に、ヒドラジン水和物（７１μＬ）を添加した。混合物を周囲温度で１６時間攪拌し、その後蒸発させて酢酸を除去した。残存物を酢酸エチルに溶解し、溶液を５％炭酸水素ナトリウム溶液その後水で洗浄し、その後硫酸マグネシウム上に乾燥し、その後蒸発させ、黄色油状物として得られた３−ｔ−ブチルオキシメチル−５−メチル−１Ｈ−ピラゾール−４−カルボン酸エチルエステル（０.２５８ｇ）をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.２２分；２４１（Ｍ＋Ｈ)⁺。 [Reference Example 45]
3-t-Butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

To a solution of 2-acetyl-4-t-butoxy-3-oxo-butyric acid ethyl ester [0.325, Reference Example 46] in acetic acid (3 ml) was added hydrazine hydrate (71 μL). The mixture was stirred at ambient temperature for 16 hours and then evaporated to remove acetic acid. The residue was dissolved in ethyl acetate and the solution was washed with 5% sodium bicarbonate solution followed by water, then dried over magnesium sulfate and then evaporated to give 3-t-butyloxymethyl- 5-Methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.258 g) was used without further purification. LC-MS (Method B): R _T = 3.22 min; 241 (M + H) ⁺ .

ジクロロメタン（６ｍｌ）中の乾燥塩化マグネシウム（０.４７１ｇ）の懸濁液を４−ｔ−ブトキシ−３−オキソ−酪酸エチルエステル［１.００ｇ、参考実施例４３］で処理した。この混合物を０℃に冷却し、その後ピリジン（０.８０ｍｌ）で処理し、その後０℃で１５分間攪拌し、その後塩化アセチル（０.３５２ｍｌ）で処理した。０℃でさらに１５分間、その後周囲温度で１時間攪拌後、反応混合物を飽和塩化アンモニウム水溶液で処理し、その後酢酸エチルで２回抽出した。合わせた抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させて、黄色油状物として得られた２−アセチル−４−ｔ−ブトキシ−３−オキソ−酪酸エチルエステル（１.１５ｇ）をさらに精製することなく使用した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１６分；２４３（Ｍ−Ｈ)^-。 [Reference Example 46]
2-acetyl-4-t-butoxy-3-oxo-butyric acid ethyl ester

A suspension of dry magnesium chloride (0.471 g) in dichloromethane (6 ml) was treated with 4-tert-butoxy-3-oxo-butyric acid ethyl ester [1.00 g, Reference Example 43]. The mixture was cooled to 0 ° C. and then treated with pyridine (0.80 ml), then stirred at 0 ° C. for 15 minutes and then treated with acetyl chloride (0.352 ml). After stirring at 0 ° C. for a further 15 minutes and then at ambient temperature for 1 hour, the reaction mixture was treated with saturated aqueous ammonium chloride and then extracted twice with ethyl acetate. The combined extracts are dried over magnesium sulfate and then evaporated to further purify 2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester (1.15 g) obtained as a yellow oil. Used without. LC-MS (Method B): R _T = 3.16 min; 243 (M−H) ⁻ .

ｔ−ブタノール（１５ｍｌ）および水（２５ｍｌ）中の３−メチル−４−フェニルピラゾール（１.００ｇ）の溶液を６０℃で過マンガン酸カリウム（５.４７ｇ）で少しずつ処理した。その後温度をゆっくりと９０℃に上昇させ、その温度を５時間維持した。その後混合物を冷却し、セライトのパッドを通して濾過した。濾液を濃縮し、５Ｎ水酸化ナトリウム水溶液を添加してｐＨを１０〜１４に調整した。この混合物を酢酸エチルで２回洗浄した。その後水層をｐＨ３〜５に酸性化し、その後酢酸エチルで４回抽出した。合わせた抽出物を硫酸マグネシウム上に乾燥し、その後蒸発させて白色固体として得られた４−フェニル−１Ｈ−ピラゾール−３−カルボン酸（０.５１２ｇ）をさらに精製することなく使用した。ＭＳ：１８９（Ｍ＋Ｈ)⁺。ＨＰＬＣ（方法Ｂ）：Ｒ_T＝２.４８分。 [Reference Example 47]
4-Phenyl-1H-pyrazole-3-carboxylic acid

A solution of 3-methyl-4-phenylpyrazole (1.00 g) in t-butanol (15 ml) and water (25 ml) was treated in portions with potassium permanganate (5.47 g) at 60 ° C. The temperature was then slowly raised to 90 ° C. and maintained for 5 hours. The mixture was then cooled and filtered through a pad of celite. The filtrate was concentrated and 5N aqueous sodium hydroxide solution was added to adjust the pH to 10-14. This mixture was washed twice with ethyl acetate. The aqueous layer was then acidified to pH 3-5 and then extracted four times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to give 4-phenyl-1H-pyrazole-3-carboxylic acid (0.512 g) obtained as a white solid without further purification. MS: 189 (M + H) ^<+> . HPLC (Method B): R _T = 2.48 min.

テトラヒドロフラン（２０ｍＬ）中の３−（５−エトキシ−６−エチル−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イルアミン［０.３ｇ、参考実施例４９（ａ）］およびトリエチルアミン（０.８ｍＬ、過剰量）の溶液を塩化シクロプロパンカルボニル（０.３ｇ、２.４ミリモル）で滴下処理した。この混合物を４８時間攪拌し、その後重炭酸ナトリウム水溶液（１００ｍＬ）で希釈し、その後酢酸エチル（１００ｍＬ）で２回抽出した。合わせた抽出物を蒸発させ、残存物をテトラヒドロフラン（５０ｍＬ）に溶解した。この溶液をエタノール（１０ｍＬ）中の水酸化カリウム（１.１ｇ）の溶液で処理し、混合物を２時間攪拌し、その後水（１００ｍＬ）に注ぎ込み、その後酢酸エチル（１００ｍＬ）で２回抽出した。合わせた抽出物を蒸発させ、残存物をヘプタンと酢酸エチルの混合物（１／１、ｖ／ｖ）を溶離剤とするシリカゲル上のクロマトグラフィーに付し、オフホワイトの固体としてシクロプロパンカルボン酸［３−（５−エトキシ−６−エチル−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（０.３ｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.９９分、４２４（Ｍ＋Ｈ)⁺。 [Reference Example 48]
(A) Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide

3- (5-Ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-ylamine [0.3 g, in tetrahydrofuran (20 mL). A solution of Reference Example 49 (a)] and triethylamine (0.8 mL, excess) was treated dropwise with cyclopropanecarbonyl chloride (0.3 g, 2.4 mmol). The mixture was stirred for 48 hours, then diluted with aqueous sodium bicarbonate (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was dissolved in tetrahydrofuran (50 mL). This solution was treated with a solution of potassium hydroxide (1.1 g) in ethanol (10 mL) and the mixture was stirred for 2 hours, then poured into water (100 mL) and then extracted twice with ethyl acetate (100 mL). The combined extracts are evaporated and the residue is chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1/1, v / v) to give cyclopropanecarboxylic acid [ 3- (5-Ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide (0.3 g) was obtained. LC-MS (Method E): R _T = 2.99 min, 424 (M + H) ⁺ .

（ｉ）テトラヒドロフラン（１０ｍＬ）中の３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イルアミン［３０２ｍｇ、参考実施例４９（ｄ）］およびトリエチルアミン（０.９４ｇ、１０当量）を塩化４−メチルピペラジン−１−カルボニル（９３０ｍｇ、４.６７ミリモル）で処理し、（ii）混合物を４５℃で４時間、その後５５℃で１時間攪拌し、（iii）冷却した反応混合物を重炭酸ナトリウム水（２００ｍＬ）で処理し、この混合物を酢酸エチル（１００ｍＬ）で３回抽出し、（iv）合わせた抽出物を蒸発させ、残存物をシリカゲル上にクロマトグラフィー（酢酸エチル／５〜２０％メタノール勾配）する以外は上記参考実施例４８（ａ）と同様の方法に従って、紫色固体として４−メチルピペラジン−１−カルボン酸［３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（１８９ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｆ）：Ｒ_T＝２.２８分、４５０（Ｍ＋Ｈ)⁺。 (B) 4-methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1- (tetrahydropyran-2-yl ) -1H-pyrazol-4-yl] amide

(I) 3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1- (tetrahydropyran-2-yl) -1H- in tetrahydrofuran (10 mL) Pyrazol-4-ylamine [302 mg, Reference Example 49 (d)] and triethylamine (0.94 g, 10 eq) were treated with 4-methylpiperazine-1-carbonyl chloride (930 mg, 4.67 mmol) (ii ) The mixture was stirred at 45 ° C. for 4 hours and then at 55 ° C. for 1 hour, (iii) The cooled reaction mixture was treated with aqueous sodium bicarbonate (200 mL) and the mixture was extracted three times with ethyl acetate (100 mL). (Iv) The combined extracts were evaporated and the residue was chromatographed on silica gel (ethyl acetate / 5-20% methanol gradient), except in Reference Example 48 (a) above. ) As a purple solid, 4-methylpiperazine-1-carboxylic acid [3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1- (Tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide (189 mg) was obtained. LC-MS (Method F): R _T = 2.28 min, 450 (M + H) ⁺ .

塩化ジメチルカルバミル（４当量）を使用する以外は、上記参考実施例４８（ｂ）と同様の方法に従って、ベージュ色泡状物として１,１−ジメチル−３−［３−（１,５,６,７−テトラヒドロ−ｓ−インダセン−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］尿素を製造した。ＬＣ−ＭＳ（方法Ｆ）：Ｒ_T＝３.２２
分、３９５（Ｍ＋Ｈ)⁺。 (C) 1,1-dimethyl-3- [3- (1,5,6,7-tetrahydro-s-indasen-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazole-4 -Il] urea

Except that dimethylcarbamyl chloride (4 equivalents) was used, 1,1-dimethyl-3- [3- (1,5, 6,7-Tetrahydro-s-indasen-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] urea was prepared. LC-MS (Method F): R _T = 3.22
Min, 395 (M + H) ⁺ .

６−エトキシ−５−フルオロ−２［４−アミノ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール［０.４５ｇ、参考実施例４９（ｅ）］を使用し、反応生成物をシリカゲル上のクロマトグラフィー（ヘプタン／酢酸エチル、７／３、ｖ／ｖ）に付する以外は上記参考実施例４８（ａ）と同様の方法に従って、シクロプロパンカルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（９０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝８.１分、４１４（Ｍ＋Ｈ)⁺。 (D) Cyclopropanecarboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide

6-Ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole [0.45 g, Reference Example 49 (e) And the reaction product is chromatographed on silica gel (heptane / ethyl acetate, 7/3, v / v) according to the same procedure as in Reference Example 48 (a) above, except that cyclopropanecarboxylic acid is The acid [3- (6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide (90 mg) was prepared. LC-MS (Method G): R _T = 8.1 min, 414 (M + H) ⁺ .

６−エトキシ−５−フルオロ−２［４−アミノ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール［０.４５ｇ、参考実施例４９（ｅ）］および塩化テトラヒドロピラン−４−カルボニル（０.１３５ｇ）を使用し、反応生成物をシリカゲル上のクロマトグラフィー（ヘプタン／酢酸エチル、７／３、ｖ／ｖ）に付する以外は、上記参考実施例４８（ａ）と同様の方法に従って、テトラヒドロピラン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（１２０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝８.０５分、４５８（Ｍ＋Ｈ)⁺。 (E) Tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl Amides

6-Ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole [0.45 g, Reference Example 49 (e) And tetrahydropyran-4-carbonyl chloride (0.135 g) and the reaction product is chromatographed on silica gel (heptane / ethyl acetate, 7/3, v / v). According to a method similar to Example 48 (a), tetrahydropyran-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide (120 mg) was prepared. LC-MS (Method G): R _T = 8.05 min, 458 (M + H) ⁺ .

（ｉ）テトラヒドロフラン（４ｍＬ）中の６−エトキシ−５−フルオロ−２［４−アミノ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール［９０ｍｇ、参考実施例４９（ｅ）］およびジイソプロピルエチルアミン（１６８ｍｇ）を塩化モルホリン−４−カルボニル（１９４ｍｇ）で周囲温度で２日間処理し、（ii）反応生成物をシリカゲル上のクロマトグラフィー（ヘプタン／酢酸エチル、２／１、ｖ／ｖ）に付する以外は、上記参考実施例４８（ａ）と同様の方法に従って、モルホリン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（１４０ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝７.８５分、４５９（Ｍ＋Ｈ)⁺。 (F) Morpholine-4-carboxylic acid [3- (6-Ethoxy-5-fluoro-1H-benzoimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] Amide

(I) 6-ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole [90 mg, in tetrahydrofuran (4 mL), Reference Example 49 (e)] and diisopropylethylamine (168 mg) were treated with morpholine-4-carbonyl chloride (194 mg) at ambient temperature for 2 days and (ii) the reaction product was chromatographed on silica gel (heptane / ethyl acetate). 2/1, v / v) According to the same method as in Reference Example 48 (a), morpholine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzo Imidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide (140 mg) It was. LC-MS (Method G): R _T = 7.85 min, 459 (M + H) ⁺ .

塩化ピペリジン−１−カルボニル（１９１ｍｇ）を使用する以外は、上記参考実施例４８（ｆ）と同様の方法に従って、ピペリジン−４−カルボン酸［３−（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］アミド（１２７ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝８.２分、４５７（Ｍ＋Ｈ)⁺。 (G) Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzoimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] Amide

Piperidine-4-carboxylic acid [3- (6-ethoxy-5-fluoro-1H-benzoate] was prepared in the same manner as in Reference Example 48 (f) except that piperidine-1-carbonyl chloride (191 mg) was used. Imidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] amide (127 mg) was prepared. LC-MS (Method G): R _T = 8.2 min, 457 (M + H) ⁺ .

塩化ジエチルカルバミル（１７５ｍｇ）を使用する以外は、上記参考実施例４８（ｆ）と同様の方法に従って、３−［（６−エトキシ−５−フルオロ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジエチル尿素（１１０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝７.９分、４４５（Ｍ＋Ｈ)⁺。 (H) 3-[(6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl urea

3-[(6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1 according to the same method as in Reference Example 48 (f) except that diethylcarbamyl chloride (175 mg) was used. -(Tetrahydropyran-2-yl) -1H-pyrazol-4-yl] -1,1-diethylurea (110 mg) was prepared. LC-MS (Method G): R _T = 7.9 min, 445 (M + H) ⁺ .

（ｉ）４−［（２,４−ジメトキシ−ベンジルアミノ）−メチル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸エチルエステル（８２９ｍｇ、参考実施例６０）および塩化４−モルホリンカルボニル（０.９６ｍｌ）を使用し、（ii）反応生成物を酢酸エチルを溶離剤とするシリカ上のフラッシュクロマトグラフィーに付する以外は、上記参考実施例４８（ａ）と同様の方法に従って、無色の油状物として４−｛［（２,４−ジメトキシ−ベンジル）−（モルホリン−４−カルボニル）−アミノ］−メチル｝−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸（５９５ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９６分、５１７.３０（Ｍ＋Ｈ)⁺。 (I) 4-{[(2,4-Dimethoxy-benzyl)-(morpholine-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carbon acid

(I) 4-[(2,4-Dimethoxy-benzylamino) -methyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (829 mg, Reference Example 60) And 4-morpholinecarbonyl chloride (0.96 ml) and (ii) subjecting the reaction product to flash chromatography on silica using ethyl acetate as the eluent with Reference Example 48 (a) above. According to a similar method, 4-{[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl)- 1H-pyrazole-3-carboxylic acid (595 mg) was prepared. LC-MS (Method B): R _T = 2.96 min, 517.30 (M + H) ⁺ .

３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イルアミン［参考実施例４９（ｇ）］および塩化ジエチルカルバミルを使用する以外は、上記参考実施例４８（ａ）と同様の方法に従って、淡茶色固体として３−［３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イル］−１,１−ジエチル−尿素（２２０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｋ）：Ｒ_T＝４.０２分、４４７.２７（Ｍ−Ｈ)^-。 (J) 3- [3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl -Urea

3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-ylamine [Reference Example 49 (g)] and diethylcarbayl chloride Except for using a mill, 3- [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1- (tetrahydro as a light brown solid, according to the same method as in Reference Example 48 (a) above. -Pyran-2-yl) -1H-pyrazol-4-yl] -1,1-diethyl-urea (220 mg) was prepared. LC-MS (Method K): R _T = 4.02 min, 447.27 (M−H) ⁻ .

塩化ピペリジン−１−カルボニルを使用する以外は、上記参考実施例４８（ｊ）と同様の方法に従って、淡茶色固体としてピペリジン−１−カルボン酸［３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イル］−アミド（２２０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝４.０７分、４５９.２８（Ｍ−Ｈ)^-。 (K) Piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-yl] -amide

Except for using piperidine-1-carbonyl chloride, piperidine-1-carboxylic acid [3- (5-difluoromethoxy-1H-benzimidazole- 2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-yl] -amide (220 mg) was prepared. LC-MS (Method N): R _T = 4.07 min, 459.28 (M−H) ⁻ .

エタノール（１００ｍＬ）中の５−エトキシ−６−エチル−２−［４−ニトロ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール［０.８ｇ、参考実施例５０（ａ）］の溶液をＰｄ／Ｃ（０.１ｇ、１０％）で処理し、混合物を大気圧（バルーン）で４日間水素化した。触媒を濾去し、濾液を蒸発させ、残存物をシリカゲル上のクロマトグラフィー（０〜５％メタノール勾配を含む酢酸エチル）に付し、固体として３−（５−エトキシ−６−エチル−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イルアミン（０.３ｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.１５分、３５６（Ｍ＋Ｈ)⁺。 [Reference Example 49]
(A) 3- (5-Ethoxy-6-ethyl-1H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-ylamine

5-ethoxy-6-ethyl-2- [4-nitro-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole [0.8 g, in ethanol (100 mL), The solution of Reference Example 50 (a)] was treated with Pd / C (0.1 g, 10%) and the mixture was hydrogenated at atmospheric pressure (balloon) for 4 days. The catalyst is filtered off, the filtrate is evaporated and the residue is chromatographed on silica gel (ethyl acetate with 0-5% methanol gradient) to give 3- (5-ethoxy-6-ethyl-1H— as a solid. Benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-ylamine (0.3 g) was obtained. LC-MS (Method E): R _T = 2.15 min, 356 (M + H) ⁺ .

５−クロロ−４−メトキシ−２−ニトロフェニルアミン［参考実施例３１（ｈ）］を使用し、反応生成物をシリカゲル上のクロマトグラフィー（４０％〜０％ヘプタン勾配を含む酢酸エチル）に付し、橙色固体として４−クロロ−５−メトキシベンゼン−１,２−ジアミン（１.０ｇ）を製造した。ＭＳ：１７３（Ｍ＋Ｈ)⁺。 (B) 4-chloro-5-methoxybenzene-1,2-diamine

The reaction product is chromatographed on silica gel (ethyl acetate with a 40% to 0% heptane gradient) using 5-chloro-4-methoxy-2-nitrophenylamine [Reference Example 31 (h)]. 4-chloro-5-methoxybenzene-1,2-diamine (1.0 g) was produced as an orange solid. MS: 173 (M + H) ^<+> .

４−エトキシ−５−エチル−２−ニトロフェニルアミン［参考実施例３１（ｇ）］を使用し、反応生成物を酢酸エチルを溶離剤とするシリカゲル上のクロマトグラフィーに付する以外は、上記参考実施例４９（ａ）と同様の方法に従って、暗色の固体として４−エトキシ−５−エチル−ベンゼン−１,２−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝８.４３４分、１８０（Ｍ＋Ｈ)⁺。 (C) 4-Ethoxy-5-ethyl-benzene-1,2-diamine

Reference above, except that 4-ethoxy-5-ethyl-2-nitrophenylamine [Reference Example 31 (g)] was used and the reaction product was chromatographed on silica gel with ethyl acetate as the eluent. In the same manner as in Example 49 (a), 4-ethoxy-5-ethyl-benzene-1,2-diamine was produced as a dark solid. LC-MS (Method E): R _T = 8.434 min, 180 (M + H) ⁺ .

（ｉ）エタノール（１２０ｍＬ）中の２−［４−ニトロ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン［４.１ｇ、参考実施例５０（ｂ）］および５％Ｐｄ／Ｃ（３２０ｍｇ）を使用し、（ii）６０ｐｓｉで１８時間Ｐａｒｒ水素化装置を使用する以外は、上記参考実施例４９（ａ）と同様の方法に従って、茶色固体として３−（１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセン−２−イル）−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−４−イルアミン（３６８ｍｇ）を製造した。ＬＣ（方法Ｇ）：Ｒ_T＝３.０７９分、３２４（Ｍ＋Ｈ)⁺および３４６（Ｍ＋Ｎａ)⁺。 (D) 3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-ylamine

(I) 2- [4-Nitro-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1,5,6,7-tetrahydro-1,3- in ethanol (120 mL) The above reference except that diaza-s-indacene [4.1 g, Reference Example 50 (b)] and 5% Pd / C (320 mg) were used and (ii) a Parr hydrogenator at 60 psi for 18 hours. According to a method similar to that in Example 49 (a), 3- (1,5,6,7-tetrahydro-1,3-diaza-s-indasen-2-yl) -1- (tetrahydropyran-2) as a brown solid -Il) -1H-pyrazol-4-ylamine (368 mg) was prepared. LC (Method G): R _T = 3.079 min, 324 (M + H) ⁺ and 346 (M + Na) ⁺ .

６−エトキシ−５−フルオロ−２−［４−ニトロ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ベンゾイミダゾール［１.２ｇ、参考実施例５０（ｃ）］を使用する以外は上記参考実施例４９（ａ）と同様の方法に従って、６−エトキシ−５−フルオロ−２［４−アミノ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール（１.２ｇ）を製造した。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝６.７４分、３４６（Ｍ＋Ｈ)⁺。 (E) 6-Ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole

Reference above except that 6-ethoxy-5-fluoro-2- [4-nitro-1- (tetrahydropyran-2-yl) -1H-benzimidazole [1.2 g, Reference Example 50 (c)] is used. According to a method similar to that in Example 49 (a), 6-ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole (1.2 g) was produced. LC-MS (Method G): R _T = 6.74 min, 346 (M + H) ⁺ .

Ｎ^*１^*−ベンジル−４−メタンスルホニル−ベンゼン−１,２−ジアミン［参考実施例６５］を使用する以外は、上記参考実施例４９（ａ）と同様の方法に従って、白色固体として４−メタンスルホニル−ベンゼン−１,２−ジアミンを製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝０.９８分、１８７.３２（Ｍ＋Ｈ)⁺。 (F) 4-Methanesulfonyl-benzene-1,2-diamine

According to the same method as in Reference Example 49 (a) except that N ^* 1 ^* -benzyl-4-methanesulfonyl-benzene-1,2-diamine [Reference Example 65] was used, 4- Methanesulfonyl-benzene-1,2-diamine was prepared. LC-MS (Method J): R _T = 0.98 min, 187.32 (M + H) ⁺ .

５−ジフルオロメトキシ−２−［４−ニトロ−１−（テトラヒドロ−ピラン−２−イル
）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール［参考実施例５０（ｅ）］を使用する以外は、上記参考実施例４９（ａ）と同様の方法に従って、淡茶色固体として３−（５−ジフルオロメトキシ−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イルアミン（７３０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.２７分、３５０.２９（Ｍ＋Ｈ)⁺。 (G) 3- (5-Difluoromethoxy-1H-benzimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-ylamine

Other than using 5-difluoromethoxy-2- [4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole [Reference Example 50 (e)] Was prepared according to the same method as in Reference Example 49 (a) above as 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1- (tetrahydro-pyran-2-yl)- 1H-pyrazol-4-ylamine (730 mg) was prepared. LC-MS (Method N): R _T = 3.27 min, 350.29 (M + H) ⁺ .

ジメチルホルムアミド（１０ｍＬ）中の４−エトキシ−５−エチル−ベンゼン−１,２−ジアミン［０.１８ｇ、参考実施例３０（ｓ）］、４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルバルデヒド［０.２２５ｇ、参考実施例６（ｍ）］および重亜硫酸ナトリウム（０.１２ｇ、１.２ミリモル）の混合物を１２０℃で１時間加熱した。混合物を冷却し、水（１００ｍＬ）を添加し、水性の混合物を酢酸エチル（５０ｍＬ）で２回抽出した。合わせた抽出物を蒸発させ、残存物をシリカゲル上のクロマトグラフィー（２０〜０％ヘプタン勾配を含む酢酸エチル）に付し、固体として５−エトキシ−６−エチル−２−［４−ニトロ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール（２００ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｅ）：Ｒ_T＝２.８５分、３８６（Ｍ＋Ｈ)⁺。 [Reference Example 50]
(A) 5-Ethoxy-6-ethyl-2- [4-nitro-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole

4-Ethoxy-5-ethyl-benzene-1,2-diamine [0.18 g, Reference Example 30 (s)] in dimethylformamide (10 mL), 4-nitro-1- (tetrahydro-pyran-2-yl ) -1H-pyrazole-3-carbaldehyde [0.225 g, Reference Example 6 (m)] and sodium bisulfite (0.12 g, 1.2 mmol) were heated at 120 ° C. for 1 hour. The mixture was cooled, water (100 mL) was added and the aqueous mixture was extracted twice with ethyl acetate (50 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (ethyl acetate with a 20-0% heptane gradient) to give 5-ethoxy-6-ethyl-2- [4-nitro-1 as a solid. -(Tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole (200 mg) was obtained. LC-MS (Method E): R _T = 2.85 min, 386 (M + H) ⁺ .

インダン−５,６−ジアミン（１.０５ｇ、Sui Xiong Cai et al., J. Med. Chem., 1997, 40, 730〜738ページに記載された通り製造）および４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルバルデヒド［２.５ｇ、参考実施例６（ｍ）］を使用する以外は、上記参考実施例５０（ａ）と同様の方法に従って、製造した２−［４−ニトロ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１,５,６,７−テトラヒドロ−１,３−ジアザ−ｓ−インダセンをさらに精製することなく使用した。 (B) 2- [4-Nitro-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1,5,6,7-tetrahydro-1,3-diaza-s-indacene

Indan-5,6-diamine (1.05 g, prepared as described in Sui Xiong Cai et al., J. Med. Chem., 1997, 40, pages 730-738) and 4-nitro-1- (tetrahydro -Pyran-2-yl) -1H-pyrazole-3-carbaldehyde [2.5 g, Reference Example 6 (m)], except that it was prepared according to the same method as Reference Example 50 (a) above. 2- [4-nitro-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1,5,6,7-tetrahydro-1,3-diaza-s-indacene was further purified Used without.

４−エトキシ−５−フルオロ−ベンゼン−１,２−ジアミン（２.２ｇ、Uchida, et al,Chem. Pharm. Bull. 1989, volume 37, 1517から1523ページの方法に従って製造）を使用する以外は、上記参考実施例５０（ａ）と同様の方法に従って、６−エトキシ−５−フルオロ−２−［４−ニトロ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ベンゾイミダゾールを製造した。ＬＣ−ＭＳ（方法Ｇ）：Ｒ_T＝８.１分、３７６（Ｍ＋Ｈ)⁺。 (C) 6-Ethoxy-5-fluoro-2- [4-nitro-1- (tetrahydropyran-2-yl) -1H-benzimidazole

Except using 4-ethoxy-5-fluoro-benzene-1,2-diamine (2.2 g, manufactured according to the method of Uchida, et al, Chem. Pharm. Bull. 1989, volume 37, pages 1517 to 1523) According to the same method as in Reference Example 50 (a), 6-ethoxy-5-fluoro-2- [4-nitro-1- (tetrahydropyran-2-yl) -1H-benzimidazole was produced. LC-MS (Method G): R _T = 8.1 min, 376 (M + H) ⁺ .

４−メトキシ−１,２−フェニレンジアミン（１１７ｍｇ）を使用する以外は、参考実施例５０（ａ）と同様の方法に従って、深赤色油状物として５−メトキシ−２−［４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール（２８２ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝２.０２分、３４４.２１（Ｍ＋Ｈ)⁺、３４２.２４（Ｍ−Ｈ)^-。 (D) 5-methoxy-2- [4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole

Except that 4-methoxy-1,2-phenylenediamine (117 mg) was used, 5-methoxy-2- [4-nitro-1- (Tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole (282 mg) was prepared. LC-MS (Method H): R _T = 2.02 min, 344.21 (M + H) ⁺ , 342.24 (M−H) ⁻ .

ジフルオロメトキシ−ベンゼン−１,２−ジアミン［参考実施例３０（ｙ）］および４−ニトロ−１−（テトラヒドロピラン−２−イル）−１Ｈ−ピラゾール−３−カルバルデヒド［参考実施例６（ｍ）］を使用する以外は、上記参考実施例５０（ａ）と同様の方法に従って、淡茶色固体として５−ジフルオロメトキシ−２−［４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−１Ｈ−ベンゾイミダゾール（９１０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｎ）：Ｒ_T＝３.４０分、３８０.２２（Ｍ＋Ｈ)⁺。 (E) 5-difluoromethoxy-2- [4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -1H-benzimidazole

Difluoromethoxy-benzene-1,2-diamine [Reference Example 30 (y)] and 4-nitro-1- (tetrahydropyran-2-yl) -1H-pyrazole-3-carbaldehyde [Reference Example 6 (m )] According to the same method as in Reference Example 50 (a) above, as a light brown solid, 5-difluoromethoxy-2- [4-nitro-1- (tetrahydro-pyran-2-yl)- 1H-pyrazol-3-yl] -1H-benzimidazole (910 mg) was prepared. LC-MS (Method N): R _T = 3.40 min, 380.22 (M + H) ⁺ .

[Reference Example 51]
1-Ethoxy-2-ethylbenzene To a solution of 2-ethylphenol (6.9 g, 56.5 mmol), triphenylphosphine (15.7 g, 60 mmol) and ethanol (6 mL, excess) in tetrahydrofuran (100 mL). DIAD (12.1 g, 60 mmol) was added dropwise. After stirring for 18 hours, the mixture was evaporated and the residue was chromatographed on silica gel (heptane / ethyl acetate 9/1) to give 1-ethoxy-2-ethylbenzene (7.2 g) as a clear liquid. . GC-MS showed a single peak. R _T = 5.6 minutes. MS 150 (M +).

[Reference Example 52]
N- (3-Chloro-4-methoxyphenyl) acetamide A solution of 3-chloro-4-methoxyphenylamine (6.3 g) and triethylamine (4.04 g) in dichloromethane (100 mL) was cooled in an ice bath, Acetyl chloride (3.45 g) was added dropwise and the mixture was stirred overnight at ambient temperature. The reaction mixture was extracted with water (2 × 30 mL) and brine (2 × 30 mL), and the organic layer was dried over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was evaporated to give N- (3-chloro-4-methoxyphenyl) acetamide (7.45 g) as a dark oil that solidified on standing. MS: 200 (M + H) ^<+> .

テトラヒドロフラン（２０ｍｌ）中の４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸メチルエステル［５００ｍｇ、参考実施例５４（ａ）］の攪拌溶液を窒素下に−７８℃でテトラヒドロフラン中の水素化ジイソブチルアルミニウムの溶液（８.８２ｍｌ、１Ｍ）で滴下処理した。反応混合物を室温で１.５時間攪拌した。反応混合物をジエチルエーテル（１００ｍｌ）に溶解し、水（１５０ｍｌ）でクエンチングした。得られた懸濁液をセライトを通して濾過し、有機層を濾液から収集し、その後硫酸マグネシウム上に乾燥し、その後蒸発させ、桃色油状物として［４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−イル］−メタノール（３４９ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝２.０８分、２５０.２９（Ｍ＋Ｈ＋Ｎａ)⁺。 [Reference Example 53]
[4-Nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -methanol

A stirred solution of 4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid methyl ester [500 mg, Reference Example 54 (a)] in tetrahydrofuran (20 ml) under nitrogen. Treated dropwise at −78 ° C. with a solution of diisobutylaluminum hydride in tetrahydrofuran (8.82 ml, 1M). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was dissolved in diethyl ether (100 ml) and quenched with water (150 ml). The resulting suspension was filtered through celite and the organic layer was collected from the filtrate and then dried over magnesium sulfate and then evaporated to give [4-nitro-1- (tetrahydro-pyran-2- Yl) -1H-pyrazol-3-yl] -methanol (349 mg). LC-MS (Method H): R _T = 2.08 min, 250.29 (M + H + Na) ⁺ .

クロロホルム（３０ｍｌ）中の４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸メチルエステル（１.３ｇ、参考実施例５５）およびｐ−トルエンスルホン酸（１４４ｍｇ）の懸濁液を０℃で３,４−ジヒドロピラン（１.０４ｍｌ）で滴下処理した。反応混合物を１夜かけて室温に戻した。反応混合物を飽和重炭酸ナトリウム（４０ｍｌ）および水（３×４０ｍｌ）で洗浄した。合わせた水層をジクロロメタン（３×６０ｍｌ）で抽出した。有機層を合わせ、硫酸マグネシウム上に乾燥し、濃縮して粘稠な茶色油状物として４−ニトロ−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸メチルエステル（２.２３ｇ）を得た。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝２.７９分、２７８.２１（Ｍ＋Ｈ＋Ｎａ)⁺。 [Reference Example 54]
(A) 4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid methyl ester

A suspension of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3 g, Reference Example 55) and p-toluenesulfonic acid (144 mg) in chloroform (30 ml) at 3.4 ° C. -Treated dropwise with dihydropyran (1.04 ml). The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (40 ml) and water (3 × 40 ml). The combined aqueous layer was extracted with dichloromethane (3 × 60 ml). The organic layers were combined, dried over magnesium sulfate and concentrated to 4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid methyl ester (2 0.23 g) was obtained. LC-MS (Method H): R _T = 2.79 min, 278.21 (M + H + Na) ⁺ .

４−ホルミル−１Ｈ−ピラゾール−３−カルボン酸エチルエステル（１００ｍｇ、参考実施例５７）を使用する以外は、上記参考実施例５４（ａ）と同様の方法に従って、粘稠な黄色油状物として４−ホルミル−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸エチルエステル（１７０ｍｇ）を製造した。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.２９分、２７５.３０（Ｍ＋Ｈ＋Ｎａ)⁺。 (B) 4-Formyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester

4 as a viscous yellow oil according to the same procedure as in Reference Example 54 (a) except that 4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg, Reference Example 57) was used. -Formyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (170 mg) was prepared. LC-MS (Method J): R _T = 3.29 min, 275.30 (M + H + Na) ⁺ .

ジクロロメタン中の４−ニトロ−３−ピラゾールカルボン酸（１ｇ）の攪拌溶液を窒素
下に０℃で塩化オキサリル（１.１１ｍｌ）ついでジメチルホルムアミド（５滴）で処理した。反応混合物を室温に加温し、１夜攪拌した。メタノール（１０ｍｌ）を添加し、反応混合物を１夜攪拌した。溶媒を減圧下に除去し、トルエンで２回共沸し、淡緑色固体として４−ニトロ−１Ｈ−ピラゾール−３−カルボン酸メチルエステル（１.３ｇ）を得た。ＬＣ−ＭＳ（方法Ｈ）：Ｒ_T＝１.９４分、１７０.２３（Ｍ−Ｈ)^-。 [Reference Example 55]
4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester

A stirred solution of 4-nitro-3-pyrazolecarboxylic acid (1 g) in dichloromethane was treated with oxalyl chloride (1.11 ml) and then dimethylformamide (5 drops) at 0 ° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred overnight. Methanol (10 ml) was added and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and azeotroped twice with toluene to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3 g) as a pale green solid. LC-MS (Method H): R _T = 1.94 min, 170.23 (M−H) ⁻ .

酢酸（１４０ｍｌ）およびジクロロメタン（１５０ｍｌ）中の２−メチルアニソール（２.５ｍｌ）を１５℃に冷却した。反応温度を４０℃より下に保持しながら濃硝酸（２０ｍｌ）をゆっくり添加した。反応混合物を周囲温度で３０分間攪拌し、０℃に冷却後、発煙硝酸（５０ｍｌ）を滴加した。反応混合物をゆっくろ周囲温度に戻し、さらに４日間攪拌した。反応混合物を氷水（６００ｍｌ）に注ぎ込み、有機層を水（２×４０ｍｌ）および飽和炭酸水素ナトリウム（２×４０ｍｌ）で洗浄し、硫酸マグネシウム上に乾燥し、濃縮した。残存した深赤色固体をイソヘキサン／酢酸エチル（９：１）から（７：３）を溶離剤とするシリカ上のフラッシュシリカクロマトグラフィーに付し、オフホワイトの固体として１−メトキシ−２−メチル−４−ニトロベンゼン（２.７０ｇ）を得た。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.７４分、１６８.２７（Ｍ＋Ｈ)⁺。 [Reference Example 56]
(A) 1-methoxy-2-methyl-4-nitrobenzene

2-Methylanisole (2.5 ml) in acetic acid (140 ml) and dichloromethane (150 ml) was cooled to 15 ° C. Concentrated nitric acid (20 ml) was slowly added while maintaining the reaction temperature below 40 ° C. The reaction mixture was stirred at ambient temperature for 30 minutes, cooled to 0 ° C. and fuming nitric acid (50 ml) was added dropwise. The reaction mixture was slowly returned to ambient temperature and stirred for an additional 4 days. The reaction mixture was poured into ice water (600 ml) and the organic layer was washed with water (2 × 40 ml) and saturated sodium bicarbonate (2 × 40 ml), dried over magnesium sulfate and concentrated. The remaining deep red solid was subjected to flash silica chromatography on silica eluting with isohexane / ethyl acetate (9: 1) to (7: 3) to give 1-methoxy-2-methyl- 4-Nitrobenzene (2.70 g) was obtained. LC-MS (Method J): R _T = 3.74 min, 168.27 (M + H) ⁺ .

１,２−メチレンジオキシベンゼンを使用する以外は、上記参考実施例５６（ａ）と同様の方法に従って、橙色固体として５,６−ジニトロ−ベンゾ［１,３］ジオキソールを製造した。ＨＰＬＣ（方法Ｃ）：Ｒ_T＝２.９９分；４９０.２４（２Ｍ＋１）。 (B) 5,6-dinitro-benzo [1,3] dioxole

Except for the use of 1,2-methylenedioxybenzene, 5,6-dinitro-benzo [1,3] dioxole was produced as an orange solid according to the same method as in Reference Example 56 (a) above. HPLC (Method C): R _T = 2.99 min; 490.24 (2M + 1).

オキシ塩化リン（５.０７ｍｌ）を０℃で窒素下にジメチルホルムアミド（８.４ｍｌ）に滴加した。ピルビン酸エチルセミカルバジド（４.３ｇ、参考実施例５８）を攪拌溶液に０℃で窒素陽圧下に少しずつ添加した。反応混合物を６０℃で２.５時間加熱し、周囲温度に冷却後、ゆっくり氷（３０ｇ）に注ぎ込んだ。温度を０℃に維持しながら、６.２５Ｍ水酸化ナトリウム溶液で反応混合物のｐＨをｐＨ１２に調整した。水性の反応混合物を６０℃に５分間加熱し、０℃に冷却した。１Ｍ塩酸でｐＨをｐＨ６に再調整した。１時間後に形成して得られた沈殿物を濾過により収集し、淡黄色固体として４−ホルミル−１Ｈ−ピラゾール−３−カルボン酸エチルエステル（１.０２ｇ）を得た。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.５５分、１６９.２７（Ｍ＋Ｈ)⁺、１６７.３０（Ｍ−Ｈ)^-。 [Reference Example 57]
4-Formyl-1H-pyrazole-3-carboxylic acid ethyl ester

Phosphorus oxychloride (5.07 ml) was added dropwise to dimethylformamide (8.4 ml) at 0 ° C. under nitrogen. Ethyl pyruvate semicarbazide (4.3 g, Reference Example 58) was added to the stirred solution little by little at 0 ° C. under positive nitrogen pressure. The reaction mixture was heated at 60 ° C. for 2.5 hours, cooled to ambient temperature and then poured slowly into ice (30 g). While maintaining the temperature at 0 ° C., the pH of the reaction mixture was adjusted to pH 12 with 6.25 M sodium hydroxide solution. The aqueous reaction mixture was heated to 60 ° C. for 5 minutes and cooled to 0 ° C. The pH was readjusted to pH 6 with 1M hydrochloric acid. The precipitate that formed after 1 hour was collected by filtration to give 4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.02 g) as a pale yellow solid. LC-MS (Method J): R _T = 2.55 min, 169.27 (M + H) ⁺ , 167.30 (M−H) ⁻ .

水（２５０ｍｌ）中の塩酸セミカルバジド（１１.１ｇ）および酢酸ナトリウム（８.２ｇ）の攪拌溶液をピルビン酸エチル（１０.９ｍｌ）で１回に処理した。得られた白色沈殿物を濾過により収集し、白色粉末としてピルビン酸エチルセミカルバジド（１６.５９ｇ）を得た。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.３８分、１７４.３１（Ｍ＋Ｈ)⁺、１７２.３２（Ｍ−Ｈ)^-。 [Reference Example 58]
Pyruvate ethyl semicarbazide

A stirred solution of semicarbazide hydrochloride (11.1 g) and sodium acetate (8.2 g) in water (250 ml) was treated once with ethyl pyruvate (10.9 ml). The resulting white precipitate was collected by filtration to give ethyl pyruvate semicarbazide (16.59 g) as a white powder. LC-MS (Method J): R _T = 2.38 min, 174.31 (M + H) ⁺ , 172.32 (M−H) ⁻ .

酢酸（５ｍｌ）中の［３３２ｍｇ、参考実施例３９（ｂ）］の攪拌溶液を１２０℃で５分間Personal Chemistry Smith Creatorマイクロ波中に加熱した。五回の反応からの混合物を合わせ、溶媒を真空下に除去し、暗黄色油状物としてモルホリン−４−カルボン酸（２,４−ジメトキシ−ベンジル）−［３−（５,６−ジメチル−１Ｈ−ベンゾイミダゾール−２−イル）−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−４−イルメチル］−アミド（１.２２ｇ）を得た。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝２.７０分、５８９.６３（Ｍ＋Ｈ)⁺。 [Reference Example 59]
Morpholine-4-carboxylic acid (2,4-dimethoxy-benzyl)-[3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H- Pyrazol-4-ylmethyl] -amide

A stirred solution of [332 mg, Reference Example 39 (b)] in acetic acid (5 ml) was heated in a Personal Chemistry Smith Creator microwave at 120 ° C. for 5 minutes. The mixtures from the five reactions were combined, the solvent removed in vacuo and morpholine-4-carboxylic acid (2,4-dimethoxy-benzyl)-[3- (5,6-dimethyl-1H as a dark yellow oil. -Benzimidazol-2-yl) -1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-ylmethyl] -amide (1.22 g) was obtained. LC-MS (Method J): R _T = 2.70 min, 589.63 (M + H) ⁺ .

テトラヒドロフラン（２５ｍｌ）中の４−［（２,４−ジメトキシ−ベンジルアミノ）−メチル］−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸エチルエステル［１ｇ、参考実施例５４（ｂ）］の攪拌溶液を２,４−ジメトキシベンジルアミン（０.５９６ｍｌ）で処理した。１２時間攪拌後、ナトリウムトリアセトキシボロハイドライド（１.６８ｇ）を反応混合物に添加し、反応混合物をさらに１時間攪拌した後、酢酸エチル（２００ｍｌ）と飽和炭酸水素ナトリウム（２００ｍｌ）との間に分配した。水層を酢酸エチル（１００ｍｌ）で２回抽出し、合わせた有機層を硫酸マグネシウム上に乾燥し、その後真空下に濃縮して、黄色油状物として４−｛［（２,４−ジメトキシ−ベンジル）−（モルホリン−４−カルボニル）−アミノ］−メチル｝−１−（テトラヒドロ−ピラン−２−イル）−１Ｈ−ピラゾール−３−カルボン酸エチルエステル（１.６６ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.２７分、４０４.１７（Ｍ＋Ｈ)⁺。 [Reference Example 60]
4-{[(2,4-Dimethoxy-benzyl)-(morpholine-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester

4-[(2,4-Dimethoxy-benzylamino) -methyl] -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester [1 g, reference implementation in tetrahydrofuran (25 ml) The stirred solution of Example 54 (b)] was treated with 2,4-dimethoxybenzylamine (0.596 ml). After stirring for 12 hours, sodium triacetoxyborohydride (1.68 g) was added to the reaction mixture and the reaction mixture was stirred for an additional hour before being partitioned between ethyl acetate (200 ml) and saturated sodium bicarbonate (200 ml). did. The aqueous layer was extracted twice with ethyl acetate (100 ml) and the combined organic layers were dried over magnesium sulfate and then concentrated in vacuo to give 4-{[(2,4-dimethoxy-benzyl as a yellow oil. )-(Morpholin-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester (1.66 g) was obtained. LC-MS (Method B): R _T = 2.27 min, 404.17 (M + H) ⁺ .

エタノール（３０ｍｌ）中の（４−ベンジルスルファモイル−２−ニトロ−フェニル）−カルバミン酸エチルエステル（１.５０ｇ、参考実施例６２）の攪拌懸濁液に２Ｍ水酸化ナトリウム溶液（５.９３ｍｌ）を添加し、反応混合物を７５℃で２時間加熱した。反応混合物を周囲温度に冷却し、氷水に注ぎ込み、２Ｍ塩酸（３０ｍｌ）でｐＨ３に酸性化した。得られた沈殿物を濾過により収集し、真空下に乾燥して黄色固体として４−アミノ−Ｎ−ベンジル−３−ニトロ−ベンゼンスルホンアミ（１.０１ｇ）を得た。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.４１分、３０８.２２（Ｍ＋Ｈ)⁺。 [Reference Example 61]
4-Amino-N-benzyl-3-nitro-benzenesulfonamide

To a stirred suspension of (4-benzylsulfamoyl-2-nitro-phenyl) -carbamic acid ethyl ester (1.50 g, Reference Example 62) in ethanol (30 ml) was added 2M sodium hydroxide solution (5.93 ml). ) And the reaction mixture was heated at 75 ° C. for 2 h. The reaction mixture was cooled to ambient temperature, poured into ice water and acidified to pH 3 with 2M hydrochloric acid (30 ml). The resulting precipitate was collected by filtration and dried under vacuum to give 4-amino-N-benzyl-3-nitro-benzenesulfonami (1.01 g) as a yellow solid. LC-MS (Method J): R _T = 3.41 min, 308.22 (M + H) ⁺ .

ジクロロメタン（５０ｍｌ）中の（４−クロロスルホニル−２−ニトロ−フェニル）−カルバミン酸エチルエステル（２ｇ、参考実施例６３）の攪拌溶液に０℃で窒素雰囲気下にジイソプロピルエチルアミン（２.７１ｍｌ）およびベンジルアミン（０.８５０ｍｌ）を添加した。反応混合物を周囲温度に加温し、１２時間攪拌した。その後反応混合物を水（２×２０ｍｌ）および塩水（２×２０ｍｌ）で洗浄し、硫酸マグネシウム上に乾燥し、濾過し、濾液を真空下に濃縮して茶色固体として標題化合物（２.２９ｇ）を得た。ＬＣ−ＭＳ（方法Ｊ）：Ｒ_T＝３.８３分、３８０.１２（Ｍ＋Ｈ)⁺。 [Reference Example 62]
(4-Benzylsulfamoyl-2-nitro-phenyl) -carbamic acid ethyl ester

To a stirred solution of (4-chlorosulfonyl-2-nitro-phenyl) -carbamic acid ethyl ester (2 g, Reference Example 63) in dichloromethane (50 ml) was added diisopropylethylamine (2.71 ml) and nitrogen atmosphere at 0 ° C. under nitrogen atmosphere. Benzylamine (0.850 ml) was added. The reaction mixture was warmed to ambient temperature and stirred for 12 hours. The reaction mixture was then washed with water (2 × 20 ml) and brine (2 × 20 ml), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the title compound (2.29 g) as a brown solid. Obtained. LC-MS (Method J): R _T = 3.83 min, 380.12 (M + H) ⁺ .

濃硫酸（２５ｍｌ）中の（４−クロロスルホニル−フェニル）−カルバミン酸エチルエステル（５ｇ、参考実施例６４）の攪拌懸濁液に０℃で濃硫酸中の硝酸ナトリウム（１.６１ｇ）の懸濁液を滴加し、反応混合物を３時間攪拌した。その後反応混合物を氷に注ぎ込み、得られた沈殿物を濾過により収集し、真空下に乾燥し、黄色固体として（４−クロロスルホニル−２−ニトロ−フェニル）−カルバミン酸エチルエステル（４.８０ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.３２分、３０７.０８（Ｍ−Ｈ)^-。 [Reference Example 63]
(4-Chlorosulfonyl-2-nitro-phenyl) -carbamic acid ethyl ester

A stirred suspension of (4-chlorosulfonyl-phenyl) -carbamic acid ethyl ester (5 g, Reference Example 64) in concentrated sulfuric acid (25 ml) was suspended at 0 ° C. with sodium nitrate (1.61 g) in concentrated sulfuric acid. The turbid solution was added dropwise and the reaction mixture was stirred for 3 hours. The reaction mixture was then poured into ice and the resulting precipitate was collected by filtration, dried under vacuum and (4-chlorosulfonyl-2-nitro-phenyl) -carbamic acid ethyl ester (4.80 g) as a yellow solid. Got. LC-MS (Method B): R _T = 3.32 min, 307.08 (M−H) ⁻ .

クロロスルホン酸（２０ｍｌ）の攪拌溶液に０℃でＮ−フェニルウレタン（９.９０ｇ）を温度が２０℃を超えないような速度で添加した。その後反応混合物を６０℃で３時間加熱し、周囲温度に冷却し、慎重に氷に注ぎ込んだ。得られた沈殿物を濾過により収集し、真空下に乾燥してオフホワイトの固体として（４−クロロスルホニル−フェニル）−カルバミン酸エチルエステル（１４.５０ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝３.１１分、２８４.２３（Ｍ＋Ｈ)⁺。 [Reference Example 64]
(4-Chlorosulfonyl-phenyl) -carbamic acid ethyl ester

N-phenylurethane (9.90 g) was added to a stirred solution of chlorosulfonic acid (20 ml) at 0 ° C. at a rate such that the temperature did not exceed 20 ° C. The reaction mixture was then heated at 60 ° C. for 3 hours, cooled to ambient temperature and carefully poured onto ice. The resulting precipitate was collected by filtration and dried under vacuum to give (4-chlorosulfonyl-phenyl) -carbamic acid ethyl ester (14.50 g) as an off-white solid. LC-MS (Method B): R _T = 3.11 min, 284.23 (M + H) ⁺ .

エタノール中のベンジル−（４−メタンスルホニル−２−ニトロ−フェニル）−アミン（０.３００ｇ、参考実施例６６）および塩化スズ（１.８６ｇ）の攪拌溶液をSmith
Creatorマイクロ波中に１４０℃で１０分間加熱した。飽和炭酸水素ナトリウム溶液を使用して反応混合物をｐＨ８に塩基性化し、酢酸エチルで抽出した。有機層を硫酸マグネシウム上に乾燥し、濃縮して淡茶色固体としてＮ^*１^*−ベンジル−４−メタンスルホニル−ベンゼン−１,２−ジアミン（０.２５５ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.７４分、２７５.２０（Ｍ−Ｈ)^-。 [Reference Example 65]
N ^* 1 ^* -benzyl-4-methanesulfonyl-benzene-1,2-diamine

A stirred solution of benzyl- (4-methanesulfonyl-2-nitro-phenyl) -amine (0.300 g, Reference Example 66) and tin chloride (1.86 g) in ethanol was added to Smith.
Heated in a Creator microwave at 140 ° C. for 10 minutes. The reaction mixture was basified to pH 8 using saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give N ^* 1 ^* -benzyl-4-methanesulfonyl-benzene-1,2-diamine (0.255 g) as a light brown solid. LC-MS (Method B): R _T = 2.74 min, 275.20 (M−H) ⁻ .

エタノールおよび水（３：２）（３０ｍｌ）中の（４−フルオロ−２−ニトロフェニル）メチルスルホン（０.５０ｇ）および炭酸水素ナトリウム（０.５７５ｇ）の攪拌懸濁液にベンジルアミン（０.３７４ｍｌ）を添加し、反応混合物を１６時間攪拌した。その後反応混合物を氷水に注ぎ込み、得られた沈殿物を濾過により収集し、真空下に乾燥して黄色固体としてベンジル−（４−メタンスルホニル−２−ニトロ−フェニル）−アミン（０.６６０ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.９７分、３０７.０４（Ｍ＋Ｈ)⁺。 [Reference Example 66]
Benzyl- (4-methanesulfonyl-2-nitro-phenyl) -amine

To a stirred suspension of (4-fluoro-2-nitrophenyl) methylsulfone (0.50 g) and sodium bicarbonate (0.575 g) in ethanol and water (3: 2) (30 ml) was added benzylamine (0. 374 ml) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was then poured into ice water and the resulting precipitate was collected by filtration and dried under vacuum to give benzyl- (4-methanesulfonyl-2-nitro-phenyl) -amine (0.660 g) as a yellow solid. Obtained. LC-MS (Method B): R _T = 2.97 min, 307.04 (M + H) ⁺ .

ジメチルホルムアミド（３ｍｌ）中の３,４−ジニトロフェノール（２５０ｍｇ）、塩酸４−（２−クロロエチル）モルホリン（２５２ｍｇ）および炭酸カリウム（３７５ｍｇ）の混合物をPersonal Chemistry Smith Creatorマイクロ波中に１２０℃で２０分間加熱した。反応混合物を酢酸エチルと水との間に分配し、有機層を硫酸マグネシウム上に乾燥し、濾過し、濾液を真空下に濃縮し、黄色油状物として４−［２−（３,４−ジニトロ−フェノキシ）−エチル］−モルホリン（３１９ｍｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.１３分、２９８（Ｍ＋Ｈ)⁺。 [Reference Example 67]
4- [2- (3,4-Dinitro-phenoxy) -ethyl] -morpholine

A mixture of 3,4-dinitrophenol (250 mg), 4- (2-chloroethyl) morpholine hydrochloride (252 mg) and potassium carbonate (375 mg) in dimethylformamide (3 ml) was placed in a Personal Chemistry Smith Creator microwave at 120 ° C. for 20 minutes. Heated for minutes. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give 4- [2- (3,4-dinitro as a yellow oil. -Phenoxy) -ethyl] -morpholine (319 mg) was obtained. LC-MS (Method B): R _T = 2.13 min, 298 (M + H) ⁺ .

水中の５−シアノインドール（３.９３ｇ）および亜硝酸ナトリウム（１９.０７ｇ）の懸濁液に６Ｍ塩酸をｐＨが２より小さくなるまでゆっくり添加した。その後懸濁液を周囲温度で３時間攪拌した。その後混合物を酢酸エチルで抽出し、硫酸マグネシウム上に乾燥し、濾過し、濾液を真空下に濃縮して、淡茶色固体として３−ホルミル−１Ｈ−インダゾール−５−カルボニトリル（４.５ｇ）を得た。ＬＣ−ＭＳ（方法Ｂ）：Ｒ_T＝２.４７分、１７２.２９（Ｍ＋Ｈ)⁺。 [Reference Example 68]
3-Formyl-1H-indazole-5-carbonitrile

To a suspension of 5-cyanoindole (3.93 g) and sodium nitrite (19.07 g) in water was slowly added 6M hydrochloric acid until the pH was below 2. The suspension was then stirred for 3 hours at ambient temperature. The mixture was then extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give 3-formyl-1H-indazole-5-carbonitrile (4.5 g) as a light brown solid. Obtained. LC-MS (Method B): R _T = 2.47 min, 172.29 (M + H) ⁺ .

In vitro test procedures SYK in vitro test procedure 1. Inhibitory action of compounds on SYK kinase The inhibitory action of compounds on SYK kinase was measured using a time-resolved fluorescence test.
The catalytic domain of SYK kinase (residues A340-N635) was expressed as a fusion protein in yeast cells and purified to homogeneity. Kinase activity was measured in 50 mM Tris-HCl buffer pH 7.0 containing 50 mM NaCl, 5 mM MgCl ₂ , 5 mM MnCl ₂ , 1 μM adenosine triphosphate and 10 μM synthetic peptide biotin- (β-alanine) ₃ -DEEDYEIPP-NH ₂ . . The enzymatic reaction is performed by the addition of a buffer containing 133 mM EDTA, pH 7.0 containing monoclonal phospho-specific antibody conjugated to 0.4 M KF, streptavidin-DL665 conjugate and europium cryptate (Eu-K). Stopped. The characteristics of the two fluorophores XL-665 and Eu-K are described in G. Mathis et al., Anticancer Research, 1997, 17, p. 3011-3014. The specific long-term signal of XL-665 generated only when the synthetic peptide is phosphorylated by SYK was measured on a Packard Discovery Microplate analyzer or LJL Biosystems Analyst AD microplate reader. Inhibition of SYK activity using the compounds of the present invention was expressed as% inhibition of control activity observed in the absence of test compound. Certain compounds of the invention inhibit SYK activity with an IC ₅₀ in the range of 10 micromolar to 0.1 nanomolar. Preferred compounds of the present invention inhibit SYK activity with an IC ₅₀ in the range of 5000 nmol to 0.1 nmol. Particularly preferred compounds of the invention inhibit SYK activity with an IC ₅₀ in the range of 1000 nanomolar to 0.1 nanomolar. More preferred compounds of the invention inhibit SYK activity with an IC ₅₀ in the range of 10 nanomolar to 0.1 nanomolar.

2. Antigen-induced degranulation of rat basophilic leukemia (RBL) cells measured by [ ³ H] 5-hydroxytryptamine (serotonin) release 2.1 Cell culture, RBL-2H3 cell labeling and assay performance.
Method A: For each 24-well culture plate to be set up, 6 × 10 ⁶ RBL-2H3 cells were washed, 25 μl of 1 mCi / mL [ ³ H] serotonin (0.5 μCi / ml final concentration) and anti-DNP IgE Resuspended in 15 ml DMEM-10 containing 1 μg / mL (15 ml). 0.5 ml of cell suspension was added to each well of a 24-well plate. Cells were incubated at 37 ° C. for 2 days to confluence. The medium was gently aspirated from each well and then the cells were washed with test buffer. Next, a final volume of 200 ml of test buffer (
Appropriate concentrations of test compound + or-) were added to each of triplicate wells. DNP (antigen) 100 ng / ml is then added to all wells (except for negative control wells, except for measuring spontaneous [ ³ H] -serotonin release in the absence of receptor cross-linking) did. The cells were incubated at 37 ° C. for 30 minutes and the reaction was stopped by transferring 100 μl of supernatant from each sample to a liquid scintillation microtiter plate on ice. 200 μl of scintillant-40 was then added to the microtiter plate and the plate was read on a top count liquid scintillation counter.

Method B: RBL-2H3 cells were maintained in T75 flasks at 37 ° C. and 5% CO ₂ and passaged every 3-4 days. To harvest cells, the flasks were washed once with 5 ml trypsin EDTA, then 5 ml trypsin was added to each flask and incubated for 2 minutes at room temperature. The cells were transferred to a test tube containing 14 ml of medium, centrifuged at 1100 rpm at room temperature for 5 minutes and resuspended at 2 × 10 ⁵ / ml. Cells were sensitized by adding 1 μl of DNP-specific IgE (1 mg / ml stock solution) to each 10 ml of cells. 200 μl of cells were added to each well of a flat bottom 96-well plate (40,000 cells / well) and the plates were incubated overnight at 37 ° C., 5% CO ₂ . The next day, compounds were prepared to 10 mM in 100% DMSO. Each compound was then diluted to 1: 100 test buffer beneficial insect and then further diluted in 1% DMSO test buffer to a final concentration of 0.03-30 μM. 80 μl of test buffer (Hank's Balanced salt solution, Ca ⁺⁺ / Mg ⁺⁺ , 2 mg / ml glucose, 0.03% BSA) was added to each well followed by 10 μl of diluted compound. Thereafter, it was incubated for 5 minutes. 10 μl of DNP-HSA (100 ng / ml) was added to each well and incubated for 30 minutes at 37 ° C. (in the absence of CO ₂ ). As one control, buffer was added instead of DNP-HSA to a set of wells to measure the test background. After 30 minutes of incubation, the supernatant was transferred to a new 96-well plate. 50 μL of supernatant was added to each well of the test plate. Substrate solution (0.4 M citric acid, 5 mM PNAG in 0.2 M Na ₂ HPO ₄ ) was added to each well and incubated for 90 minutes at 37 ° C. The reaction was stopped by adding 50 μl of 0.4 M glycine solution and the plate was read at 405 nm on a Molecular Devices SpectraMax 250 plate reader.

2.2 Calculation method A
(i) The mean ± SEM of each set of triplicate wells was calculated.
(ii) The maximum response was positive control wells containing antigen (10 ng / ml) but no compound.
(iii) The minimum response was a control well containing neither antigen nor compound.
(iv) These numbers were the maximum (100%) and minimum (0%) values, respectively, and the data was normalized to be the percent of maximum response.
(v) Dose response curves were plotted and compound IC ₅₀ calculated.

Method B
(i) The mean ± SD of each set of triplicate wells was calculated.
(ii) The maximum response was positive control wells containing antigen (100 ng / ml) but no compound.
(iii) The minimum response was a control well containing neither antigen nor compound.
(iv) These numbers were taken as maximum (100%) and minimum (0%) values, respectively, and exponential data were calculated as percent of maximum response (labeled as% control).
(v) Dose response curves were plotted and the compound IC ₅₀ was calculated by prism graph pad software and nonlinear least squares regression analysis.

B. In vitro test procedure for KDR 1. Inhibitory action of compounds on KDR The inhibitory action of compounds is measured in the assay of substrate phosphorylation by the in vitro enzyme KDR by the frass plate method (96-well plate, NEN). The protoplasmic domain of the human KDR enzyme is cloned into the baculovirus expression vector pFastBac in the form of a GST fusion. The protein is expressed in SF21 cells and purified to approximately 60% homogeneity. The kinase activity of KDR is measured in 20 mM MOPS, 10 mM MgCl2, 10 mM MnCl2, 1 mM DTT, 2.5 mM EGTA, 10 mM β-glycerophosphate, pH 7.2, in the presence of 10 mM MgCl2, 100 μM Na3VO4, 1 mM NaF. 10 μL of compound is added to 70 μl of kinase buffer containing 100 ng of KDR enzyme at 4 ° C. The reaction is started by adding 20 μl of a solution containing 2 μg of substrate (PLγγ fragment SH2-SH3 expressed in the form of GST fusion protein), 2 μCi γ33P [ATP] and 2 μM cold ATP. After 1 hour incubation at 37 ° C., the reaction is quenched by adding 1 volume (100 μl) of 200 mM EDTA. Remove the incubation buffer and wash the wells 3 times with 300 μl PBS. The radioactivity of each well is measured using a TopCount NXT instrument (Packard). Background noise is determined by measuring radioactivity in quadruplicate wells containing only radioactive ATP and substrate. Activity controls contain all reagents (γ33P- [ATP], KDR and substrate PLCγ) and are measured in quadruplicate wells in the absence of compound.

Inhibition of KDR activity of compounds of the invention is expressed as a percentage of inhibition of control activity measured in the absence of compound. Compound SU5614 (Calbiochem) is included in each plate as an inhibition control. The IC ₅₀ of the compound is calculated by plotting a dose response curve. IC ₅₀ corresponds to the concentration of compound that induces 50% inhibition of kinase activity. Certain compounds of the invention inhibit KDR activity with IC ₅₀ ranging from 100 micromolar to 10 nanomolar. Preferred compounds of the invention inhibit KDR activity with IC ₅₀ ranging from 3000 nanomolar to 10 nanomolar. Particularly preferred compounds of the present invention inhibit KDR activity with an IC ₅₀ in the range of 300 nanomolar to 10 nanomolar.

II) Cell activity against endothelial cells 1) Inhibition of VEGF-dependent proliferation of HDMEC The anti-KDR activity of the molecule is assessed by [14C] -thymidine incorporation into HDMEC (human skin microvascular endothelial cells) in response to VEGF. HDEC (Promocell, passages 5-7) on day 1 at 37 ° C. under 5% CO ₂ and 5000 per well in Cytostar (Amersham) 96 well plate pre-coated with binding factor (AF, Cascad Biologics) Inoculate in 100 μl. On day 2, complete medium (basic medium supplemented with 5% FCS and growth factor) is replaced with minimal medium (basal medium supplemented with 5% FCS) and cells are incubated for 24 hours. On day 3, the medium is replaced with 200 μl of fresh medium with or without 100 ng / ml VEGF (R & D Systems) with or without the compound of the invention and 0.1 μCi [14C] -thymidine. Cells are incubated for 4 days at 37 ° C., 5% CO ₂ . [14C] -Thymidine incorporation is then quantified by measuring radioactivity. The test is performed in 3 wells. The final concentration of DMSO in the test is 0.1%. The percent inhibition is calculated as follows: [Cpm (+ VEGF) -cpm (+ VEGF + cpd) / cpm (+ VEGF) -cpm (BM5% FCS)] × 100.

2) Inhibition of TF (tissue factor) production by endothelial cells in response to VEGF Endothelial cells are inoculated to 2000 wells in a 96-well plate pre-coated with a binding factor. After incubating for 8 hours, the medium is changed and the cells are preincubated with the compound in the basal medium (0.1% DMSO final concentration) for 16 hours. TF (tissue factor) synthesis is induced by the addition of a final concentration of VEGF (100 mg / ml). The cells are washed and lysed after 6 hours of incubation. Tissue factor is then detected by an Imubind ELISA test.

3) Effect of molecules on VEGF-dependent growth of HDMEC Cytostar (Amersham) 96-well plate pre-coated with binding factor (AF, Cascad Biologics) at 37 ° C. and 5% CO _{2 on} day 1 HDMEC (5000 per well) Inoculate the complete medium inside. The whole medium is then removed and the cells are incubated in 200 μl of complete medium containing the molecules of the invention and [14C] -thymidine (0.1 μCi). [14C] -thymidine incorporation is measured using a Wallac counter after incubation for 3 days. The percent inhibition is calculated as follows: [Cpm (CM) −cpm (CM + cpd) / cpm (CM)] × 100.
Table 5 below shows the results obtained in the above tests of the products shown as examples of the present invention.

The pharmacological results obtained in the above tests on the products shown in the examples of the present invention are shown in Table 6 below, and the degree of activity of the products is indicated by the + sign according to the range of activities shown in the table, That is:
+: Activity higher than 3 micromolar,
++: 0.3-3 micromolar activity,
+++: Activity lower than 0.3 micromolar.

C. ITK In Vitro Test Procedure 1. Inhibitory Effect of Compounds on ITK Kinase The inhibitory effect of compounds on ITK kinase was measured using a fluorescence polarization test.
ITK kinase was generated using a baculovirus expression system.

1.1 Test method The test measures the autophosphorylation of ITK kinase. The test is designed based on the fluorescence polarization method. Incubate enzyme with ATP and compound. After incubation, a specific signal that is inversely proportional to enzyme phosphorylation is generated by adding a mixture containing a fluorescently labeled phosphopeptide tracer and an anti-phosphotyrosine antibody (CoreHTS tyrosine kinase test kit, P2837, Panvera). Phosphorylated ITK generated from the kinase reaction specifically competes with the antibody and releases a fluorescently labeled tracer. Inhibition of ITK kinase results in an increase in FP values.

1.2 Test conditions The test is performed in a BD Black 384 shallow dish well plate. For enzyme reactions, the final reagent concentration / well was 16.5 nM ITK enzyme, 50 μM ATP, 20 mM Hepes (pH 7.5), 0.15 M NaCl, 3 mM MgCl ₂ , 1 mM MnCl ₂ , 0.01% Triton X-100, 1 mM DTT, 5% glycerol and 0.1% γ-globulin. Incubation time: 45 minutes. That is: 25 ° C. Reaction volume: 10 μL. For the immune reaction, add 10 μL of stop detection mix containing 10 mM EDTA, 1: 2 dilution of antibody and 1: 4 dilution of tracer in 1 × dilution buffer (Panvera). Incubation time: 90 minutes at 37 ° C, then 60 minutes at room temperature.

1.3 Test procedure:
1. Add 5.0 μL of ATP solution to each well of a black 384 shallow dish well plate. 2. Add 1.0 μL of compound or 1% DMSO in TBS buffer.
3. Start the reaction by adding 5.0 μL of enzyme solution.
4. Incubate at 25 ° C for 45 minutes.
5. Add 10 μl of stop detection solution.
6. Incubate at 37 ° C. for 90 minutes, then at room temperature for 60 minutes.
7. Read by LJL Acquest in FP mode using fluorescent filter set with FL dichroic mirror (E _x = 485 nm, E _m = 535 nm). Integration time: 200,000 μs. G factor device dependency [G factor = (S _{tracer only-} S _buffer ) / (S _{tracer only} + S _buffer )]

Suppression of ITK activity using the compounds of the present invention was expressed as% inhibition of control activity measured in the absence of test compound. Compound IC ₅₀ values are calculated by plotting a dose response curve. IC ₅₀ corresponds to the concentration of compound that induces 50% inhibition of kinase activity. Certain compounds of the present invention inhibit ITK activity with an IC ₅₀ in the range of 100 micromolar to 1 micromolar.

In Vivo Test Procedure A. In Vivo Test Procedure for SYK 1. Inhibition of Antigen-Dependent Passive Skin Anaphylaxis Compounds of the invention were evaluated in a passive skin anaphylaxis (PCA) model in Balb / c mice. The model used in these in vivo studies mimics the relevant properties of mast cell driven antigen-dependent activation and functional response. These studies showed that the compounds of the invention inhibit the increase in edema observed in sensitized mouse ears after antigen exposure.

Sensitization and induction protocol Balb / c mice were sensitized in the right ear on day 0 with monoclonal anti-DNPIgE (25 μg) administered intradermally into the auricle. The left ear served as a control by injecting PBS. Sixteen to twenty hours after sensitization, mice were challenged with 150 μg of DNP-albumin administered iv.

Protocol for administration and calculation of results The test drug was administered orally 15-60 minutes prior to induction of DNP-albumin antigen. Compound doses were administered between 3 and 100 mg / kg in half log division. A control set of mice received only the solvent and then treated similarly. The thickness of the ear was measured at t = 0, 15, 30 or 60 minutes after DNP-antigen induction using a digital caliper and expressed in units of mm × 0.01. Ear thickness at t = 0 was recorded for use as a baseline. Substantial increases in both left and right ears were calculated by subtracting the t = 0 value from the t = 15, 30 or 60 minute value. Next,% inhibition of ear edema was calculated as [control ear thickness− (right ear thickness−left ear thickness)] / control ear thickness × 100 for each time point measured.

result
(i) The compound showed a dose-dependent suppression of ear edema after oral administration of 3-100 mg / kg. Inhibition of ear edema was observed at t = 15, 30 and 60 minutes after antigen challenge.
These results indicate that the compounds of the present invention inhibit mast cell activation and functional response when administered orally in a mouse model of passive cutaneous anaphylaxis.

2. Antigen-induced degranulation of rat basophilic leukemia (RBL) cells as measured by [ ³ H] 5-hydroxytryptamine (serotonin) release 2.1 Cell culture, labeling of RBL-2H3 cells and testing.
Method A: 6 × 10 ⁶ RBL-2H for each 24-well culture plate to be set up
3 cells were washed and resuspended in 15 ml of DMEM-10 containing 25 μl of 1 mCi / mL [ ³ H] serotonin (0.5 μCi / ml final concentration) and anti-DNP IgE 1 μg / mL (15 ml). 0.5 ml of cell suspension was added to each well of a 24-well plate. Cells were incubated at 37 ° C. for 2 days to confluence. The medium was gently aspirated from each well and then the cells were washed with test buffer. A final volume of 200 ml of test buffer (with appropriate concentration of test compound + or-) was then added to each of triplicate wells. DNP (antigen) 100 ng / ml is then added to all wells (except for negative control wells, ie to measure spontaneous [ ³ H] -serotonin release in the absence of receptor cross-linking) did. The cells were incubated at 37 ° C. for 30 minutes and the reaction was stopped by transferring 100 μl of supernatant from each sample to a liquid scintillation microtiter plate on ice. 200 μl of scintillant-40 was then added to the microtiter plate and the plate was read on a top count liquid scintillation counter.

Method B: RBL-2H3 cells were maintained in T75 flasks at 37 ° C. and 5% CO ₂ and passaged every 3-4 days. To harvest cells, the flasks were washed once with 5 ml trypsin EDTA, then 5 ml trypsin was added to each flask and incubated for 2 minutes at room temperature. The cells were transferred to a test tube containing 14 ml of medium, centrifuged at 1100 rpm at room temperature for 5 minutes and resuspended at 2 × 10 ⁵ / ml. Cells were sensitized by adding 1 μl of DNP-specific IgE (1 mg / ml stock solution) to each 10 ml of cells. 200 μl of cells were added to each well of a flat bottom 96-well plate (40,000 cells / well) and the plates were incubated overnight at 37 ° C., 5% CO ₂ . The next day, compounds were prepared to 10 mM in 100% DMSO. Each compound was then diluted 1: 100 in test buffer and then further diluted in 1% DMSO test buffer to a final concentration of 0.03-30 μM. 80 μl of test buffer (Hank's Balanced salt solution, Ca ⁺⁺ / Mg ⁺⁺ , 2 mg / ml glucose, 0.03% BSA) was added to each well followed by 10 μl of diluted compound. Thereafter, it was incubated for 5 minutes. 10 μl of DNP-HSA (100 ng / ml) was added to each well and incubated for 30 minutes at 37 ° C. (in the absence of CO ₂ ). As one control, buffer was added instead of DNP-HSA to a set of wells to measure the background of the test. After 30 minutes of incubation, the supernatant was transferred to a new 96-well plate. 50 μL of supernatant was added to each well of the test plate. Substrate solution (0.4 M citric acid, 5 mM PNAG in 0.2 M Na ₂ HPO ₄ ) was added to each well and incubated for 90 minutes at 37 ° C. The reaction was stopped by adding 50 μl of 0.4 M glycine solution, and the Molecular
Plates were read at 405 nm on a Devices SpectraMax 250 plate reader.

2.2 Calculation method A
(i) The mean ± SEM of each set of triplicate wells was calculated.
(ii) The maximum response was positive control wells containing antigen (10 ng / ml) but no compound.
(iii) The minimum response was a control well containing neither antigen nor compound.
(iv) These numbers were the maximum (100%) and minimum (0%) values, respectively, and the data was normalized to be the percent of maximum response.
(v) Dose response curves were plotted and compound IC ₅₀ calculated.

Method B
(i) The mean ± SD of each set of triplicate wells was calculated.
(ii) The maximum response was positive control wells containing antigen (100 ng / ml) but no compound.
(iii) The minimum response was a control well containing neither antigen nor compound.
(iv) These numbers were taken as maximum (100%) and minimum (0%) values, respectively, and exponential data were calculated as percent of maximum response (labeled as% control).
(v) Dose response curves were plotted and compound IC ₅₀ was calculated by Prism GraphPad software and nonlinear least squares regression analysis.

Claims (25)

Formula (Ix):

[Where:
X, Y, Z and W each represents CH ;
A ₅ represents H or alkyl;
R ¹ is shows a 3-indazolyl group;
R ² and R ³ may be the same or different and may be H, cyano, hydroxy, nitro, alkenyl, alkynyl, cycloalkyl, aryl , —C (═O) R ⁴ , —C (═O) NY ¹ Y ² , —C (═O) OR ⁴ , —N (R ⁵ ) C (═O) R ⁴ , —N (R ⁵ ) C (═O) NY ¹ Y ² , —N (R ⁵ ) C (= O) OR ⁴ , —N (R ⁵ ) SO ₂ R ⁴ , —N (R ⁵ ) SO ₂ NY ¹ Y ² , —OCF ₂ H, —OCF ₃ , —OC (═O) R ⁴ , —OC ( = O) NY ¹ Y ² , -S (O) nR ⁴ , -S (O) _n NY ¹ Y ² or -S (O) _n OR ⁴ , provided that R ² and R ³ are simultaneously H Absent;
R ⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl,- C (═O) NY ³ Y ⁴ , —C (═O) OR ⁵ , —N (R ⁵ ) C (═O) NY ¹ Y ² , —NY ¹ Y ² , —OR ⁵ , or —NY ³ Y Substituted with one or more substituents selected from ^4- substituted alkyls ;
R ⁵ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
n is zero or an integer of 1 or 2;
Y ¹ and Y ² are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or optionally cyano, aryl, heteroaryl, hydroxy, —C (═O) OR ⁵ , -C (= O) NY ³ Y ⁴ , -NY ³ Y ⁴ and -OR ⁵ is an alkyl substituted with one or more groups selected from, or the group -NY ¹ Y ² is May form a cyclic amine;
Y ³ and Y ⁴ are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —NY ³ Y ⁴ may form a cyclic amine;
here,
All alkyl, A alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, halogen atoms and optionally substituted by hydroxyl heteroaryl and heteroarylalkyl groups, cyano, alkyl, alkoxy, acylamino present in the radicals (NH- CO - alkyl), - C (= O) OR 5, -C (= O) R 5, hydroxyalkyl, carboxyalkyl, S (O) _n - _{alkyl, S (O) n -NH 2} , S (O) _n -NH _{(alkyl), S (O) n -N} ( _{alkyl) 2, CF 3, OCF 3} , NO 2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= O) - Substituted with one or more groups selected from the group NY ³ Y ⁴ and NY ³ Y ⁴ , alkyl, aryl and heteroaryl The latter radicals containing alkenyl are themselves groups 1 or 1 optionally selected from halogen atoms and alkyl groups, free, salt-formated or esterified carboxyl groups and acylamino groups NH-C (O) R ⁵ Replaced with more than]
Or a pharmaceutically acceptable salt or solvate thereof. Compound is
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanone;
2- (1H-indazol-3-yl) -3H-benzimidazol-4-ol;
3- (5- (3-cyano) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (pyrid-3-yl) -1H-benzimidazol-2-yl) -1H-indazole;
3- (5-phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (2-fluoro) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (5,6-methylenedioxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (2-methoxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (4-chloro) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
3- (5- (4-methyl) phenyl-1H-benzimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carbonitrile;
3- (5-methoxycarbonyl-1H-benzoimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-sulfonic acid benzylamide;
3- (5-methanesulfonyl-1H-benzoimidazol-2-yl) -1H-indazole;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -phenyl-methanol;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, methylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, dimethylamide;
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, isopropylamide;
[2 (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, benzamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-cyano-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [2- (2H-tetrazol-5-yl) -ethyl] -amide;
3- (5-nitro-1H-benzimidazol-2-yl) -1H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide; or
N- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -isobutyramide,
Claim 1 Symbol placement compound or a pharmaceutically acceptable salt or solvate thereof, it is. Compound is
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-2-ylmethyl) -amide;
N- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -isobutyramide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methylpiperazino) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (cyclohexylmethyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (2-furfuryl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N-benzyl-N-methylamide; or methyl 2- (1H-indazol-3-yl) -3H-benzimidazol-5- Carboxylate,
Claim 1 Symbol placement compound or a pharmaceutically acceptable salt or solvate thereof, it is. Compound is
2- (1H-indazol-3-yl) -3H-benzimidazol-4-ol;
3- (5- (3,4-methylenedioxy) phenyl-1H-benzimidazol-2-yl) -1H-indazole; or
[2- (Indazol-3-yl) -1H-benzimidazol-5-yl] -carboxylic acid, ethylamide,
Claim 1 Symbol placement compound or a pharmaceutically acceptable salt or solvate thereof, it is. Compound is
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-ethoxy-propyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (naphthalen-1-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-dimethylamino-benzylamide;
4-([[2- (1H-indazol-3-yl) -1H-benzimidazol-5-carbonyl] -amino] -methyl) -piperidine-1-carboxylic acid tert-butyl ester;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-bromo-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [1,3] dioxol-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-phenoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-isopropoxy-propyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1-methyl-1H-pyrazol-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-isopropyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (3-acetylamino-phenoxy) -propyl] -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid ([2,2 '] bithiophenyl-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-cyano-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (5-chloro-benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (1-methyl-1H-benzimidazol-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chloro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-sulfamoylbenzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (3-ethoxy-propyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-bromo-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (naphthalen-1-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-dimethylamino-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-nitro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-bromo-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-methoxy-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (benzo [b] thiophen-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 4-phenoxy-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-trifluoromethoxy-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-trifluoromethyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid (furan-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2-nitro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 3-chloro-benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid phenylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid benzylamide;
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid phenethyl-amide;
3- (6-phenyl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (2,4-dichloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-Naphthalen-1-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (4-Fluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Chloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-methoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-Chloro-4-fluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3,5-dichloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-thianthren-1-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-biphenyl-4-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-p-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-m-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-o-tolyl-1H-benzimidazol-2-yl) -2H-indazole;
3- (6-thiophen-3-yl-1H-benzoimidazol-2-yl) -2H-indazole;
3- [6- (3-trifluoromethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-trifluoromethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-Chloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-methoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3,5-dimethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3,4-dimethyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-Benzo [1,3] dioxole-5-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (4-tert-butyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-hex-1-enyl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (3,4-dimethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenol;
4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenol;
3- [6- (3,4-dichloro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-trifluoromethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
1- [4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl] -ethanone;
3- (6-Benzo [b] thiophen-2-yl-1H-benzimidazol-2-yl) -2H-indazole;
3- [6- (3,4,5-trimethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
1- [5- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -thiophen-2-yl] -ethanone;
1- [3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl] -ethanone;
3- [6- (4-Benzyloxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (2-Fluoro-biphenyl-4-yl) -1H-benzimidazol-2-yl] -2H-indazole;
3- (6-Benzo [b] thiophen-3-yl-1H-benzimidazol-2-yl) -2H-indazole;
[3- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl] -methanol;
3- [6- (4-Ethylsulfanyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (2,4-difluoro-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (3-trifluoromethoxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Fluoro-2-methyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- [2- (4-Fluoro-phenyl) -vinyl] -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- [2- (4-Chloro-phenyl) -vinyl] -1H-benzimidazol-2-yl] -2H-indazole;
3- [4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl] -propionic acid;
[4- [2- (2H-indazol-3-yl) -3H-benzimidazol-5-yl] -phenyl] -methanol;
3- (6-furan-2-yl-1H-benzoimidazol-2-yl) -2H-indazole;
3- [6- (3-Benzyloxy-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Isopropyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
3- [6- (4-Methanesulfonyl-phenyl) -1H-benzimidazol-2-yl] -2H-indazole;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-acetylamino-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid methylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid isopropylamide;
[2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl] -morpholin-4-yl-methanone;
[2- (1H-indazol-3-yl) -1H-benzimidazol-5-yl]-(4-methyl-piperazin-1-yl) -methanone;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzyl-methyl-amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-nitro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,6-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,4-difluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (4'-chloro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3 ', 5'-dichloro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (4'-fluoro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2,4-dichloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-fluoro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide;
4- [2- (1H-indazol-3-yl) -1H-benzimidazol-5-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl) amide; or
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide,
Claim 1 Symbol placement compound or a pharmaceutically acceptable salt or solvate thereof, it is. Compound is
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl) amide; or
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide,
Claim 1 Symbol placement compound or a pharmaceutically acceptable salt or solvate thereof, it is. Compound is
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid (pyridin-2-ylmethyl) -amide;
2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide; or
N- [2- (1H- indazol-3-yl)-1H-benzimidazol-5-yl] - isobutyramide, the compound of claim 1 Symbol mounting a or a pharmaceutically acceptable salt or solvate, object. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 7 together with one or more pharmaceutically acceptable carriers or excipients. Therapeutic agent of the disease in treated patients in need of inflammatory diseases comprising a pharmaceutically effective amount of a compound according to any one of claims 1-7. A therapeutic agent for the disease in a patient in need of treatment for cancer, comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 7 . A therapeutic agent for a disease in a patient in need of treatment for chronic obstructive pulmonary disease, comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 7 . The inhibitory agent in a patient in need of angiogenesis inhibition which comprises a pharmaceutically effective amount of a compound according to any one of claims 1-7. The therapeutic agent according to claim 10, wherein the cancer to be treated is skin cancer. Therapeutic agent for the treatment the disease in a patient in need of asthma containing a pharmaceutically effective amount of a compound according to claim 1-7 Neu deviation or claim. A therapeutic agent for the disease in a patient in need of treatment for psoriasis, comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 7 . A therapeutic agent for the disease in a patient in need of treatment for joint inflammation, comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 7 . A therapeutic agent for a disease in a patient in need of treatment for inflammatory bowel disease, comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 7 . Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of cancer. 19. Use according to claim 18 , wherein the cancer is resistant to cytotoxic agents. Cancer is breast cancer, gastric cancer, ovarian cancer, colon cancer, lung cancer, intracranial carcinoma, laryngeal cancer, cancer of the lymphatic system, cancer of the genitourinary tract including bladder and prostate, according to claim 18 which is selected from bone cancer and pancreatic cancer Use of. 21. Use according to claim 20 , wherein the cancer is breast cancer, colon cancer or lung cancer. Kinase inhibitor which comprises, as an active ingredient a compound according to any one of claims 1-7. A KDR inhibitor comprising the compound according to any one of claims 1 to 7 as an active ingredient. A tie2 inhibitor containing the compound of formula (I) according to any one of claims 1 to 7 as an active ingredient. Breast cancer treated is stomach cancer, ovarian cancer, claim 10 colon cancer, lung cancer, intracranial carcinoma, laryngeal cancer, cancer of the lymphatic system, cancer of the genitourinary tract, bladder, prostate, a carcinoma and pancreatic cancer bone The therapeutic agent described.