JP2008514591A - Benzimidazole derivatives and their use as cannabinoid receptor ligands - Google Patents

Abstract

A compound of formula I or a pharmaceutically acceptable salt thereof: (I) wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in the specification, as well as salts and Pharmaceutical compositions containing the compounds are produced, which are useful for therapy, particularly for the management of pain.
[Chemical 1]

Description

  The present invention relates to therapeutic compounds, pharmaceutical compositions containing these compounds, processes for their preparation and uses thereof. In particular, the present invention relates to compounds that may be effective in the treatment of pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and / or cardiovascular disorders.

Pain management has been studied for many years. Pain in various animal models by the interaction of cannabinoid receptor (eg, CB ₁ receptor, CB ₂ receptor) ligands, including agonists, antagonists and counteracting agents, with CB ₁ and / or CB ₂ receptors It is known to relax. In general, CB ₁ receptors are mostly localized in the central nervous system (CNS), whereas CB ₂ receptors are mainly located in the periphery, the presence of which are cells and tissues derived mainly from the immune system. It is limited to.

Delta ⁹ - CB ₁ receptor agonists, such as tetrahydrocannabinol (Δ ⁹ -THC) and Anadamido are useful in animal antinociceptive models, for example, psychoactive side effects, the possibility of addiction, drug dependence And tends to cause undesirable CNS side effects such as drug resistance. These undesirable side effects are known to be mediated by the CB ₁ receptor present in the CNS. However, CB ₁ agonists exposure to or words CNS acting peripheral site have limited evidence of one way suggesting that can greatly improve the overall in vivo profile in pain management in humans or animals There is.

Accordingly, there is a need for new CB ₁ receptor ligands, such as agonists that are useful in managing pain or treating other related conditions or diseases and that can reduce or minimize undesirable CNS side effects.

The present invention provides CB ₁ receptor ligands that can be useful in the treatment of pain and / or other related conditions or diseases.

The term “C _mn ” or “C _mn group” used alone or as a prefix, refers to a group having m to n carbon atoms.

The term “alkyl” used alone or as a suffix or prefix, refers to a saturated, monovalent linear or branched hydrocarbon group containing from 1 to about 12 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl- 3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl- 2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, Examples include, but are not limited to, C _1-6 alkyl groups such as isopentyl, neopentyl, and hexyl.

The term “cycloalkyl” used alone or as a suffix or prefix, refers to a saturated, monovalent ring-containing hydrocarbon group containing at least 3 to about 12 carbon atoms. Examples of cycloalkyl include, but are not limited to, C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl and cycloheptyl, and saturated cyclic and bicyclic terpenes. Cycloalkyls can be unsubstituted or substituted with one or two suitable substituents. Preferably, the cycloalkyl is a monocyclic ring or a bicyclic ring.

The term “heterocycloalkyl” used alone or as a suffix or prefix, refers to carbon and hydrogen atoms and at least one heteroatom, preferably 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. And a monocyclic or polycyclic ring having no unsaturation. Examples of heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino and pyranyl. A heterocycloalkyl group may be unsubstituted or substituted with one or two suitable substituents. Preferably, the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably a monocyclic ring, containing 2 to 5 carbon atoms and 1 to 3 heteroatoms, A ring referred to herein as C _2-5 heterocycloalkyl.

  The term “alkoxy” used alone or as a suffix or prefix, refers to a group of the general formula —O—R where R is selected from a hydrocarbon group. Typical alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy and propargyloxy.

Halogen includes fluorine, chlorine, bromine and iodine.
“RT” or “rt” means room temperature.

（式中、
Ｒ¹は、Ｃ_1-6アルキル及びＣ_3-6シクロアルキルから選択され、該Ｃ_1-6アルキル及びＣ_3-6シクロアルキルは、場合によりアミノ、シアノ、ハロゲン及びＣ_2-5ヘテロシクロアルキルから選択される１つ又はそれ以上の基によって置換され；
Ｒ²は、−Ｈ及びメチルから選択され；そして
Ｒ³、Ｒ⁴及びＲ⁵は、フルオロ及びメチルから独立に選択される）
の化合物、薬学的に許容されるその塩、ジアステレオマー、エナンチオマー又はそれらの混合物を提供する。 In one aspect, one embodiment of the invention is a compound of formula I:

(Where
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally amino, cyano, halogen and C _2-5 heterocycloalkyl Substituted by one or more groups selected from:
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl)
Or a pharmaceutically acceptable salt, diastereomer, enantiomer or mixture thereof.

Another embodiment of the invention is a compound of formula I, wherein:
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl;
A compound is provided.

Another embodiment of the invention is a compound of formula I, wherein:
R ¹ is selected from methyl, ethyl, propyl, isopropyl, t-butyl, 2,2-dimethyl-1-propyl, cyclopropyl and cyclobutyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl;
A compound is provided.

A further embodiment of the present invention is a compound of formula I, wherein
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are methyl;
A compound is provided.

A further embodiment of the present invention is a compound of formula I, wherein
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl;
R ² is selected from —H and methyl;
R ³ is methyl; and R ⁴ and R ⁵ are fluoro;
A compound is provided.

A still further embodiment of the present invention is a compound of formula I, wherein
R ¹ is selected from methyl, ethyl, propyl, isopropyl, t-butyl, 2,2-dimethyl-1-propyl, cyclopropyl and cyclobutyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are methyl;
A compound is provided.

A still further embodiment of the present invention is a compound of formula I, wherein
R ¹ is selected from methyl, ethyl, propyl, isopropyl, t-butyl, 2,2-dimethyl-1-propyl, cyclopropyl and cyclobutyl;
R ² is selected from —H and methyl;
R ³ is methyl; and R ⁴ and R ⁵ are fluoro;
A compound is provided.

A still further embodiment of the present invention is a compound of formula I, wherein
R ¹ is selected from methyl, ethyl, propyl, isopropyl, t-butyl, 2,2-dimethyl-1-propyl, cyclopropyl and cyclobutyl;
R ² is —H; and R ³ , R ⁴ and R ⁵ are methyl;
A compound is provided.

In another embodiment, R ¹ of formula I is selected from methyl, ethyl, propyl, isopropyl, t-butyl, 2,2-dimethyl-1-propyl, cyclopropyl and cyclobutyl.
In another embodiment, R ² is selected from -H and methyl.
In another embodiment, R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl.

A further embodiment of the invention is a compound of the following formula:

を有する化合物から選択される化合物、及び薬学的に許容されるそれらの塩を提供する。

And pharmaceutically acceptable salts thereof are provided.

  Where a compound of the invention contains one or more asymmetric centers, the compound of the invention exists in the form of an enantiomer or diastereomer and is isolated as an enantiomer or diastereomer form or as a racemic mixture Of course you can. The present invention includes all possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of formula I. Optically active forms of the compounds of the invention are prepared, for example, by chiral chromatographic separation of racemates, by synthesis from optically active starting materials, or by asymmetric synthesis based on the procedures described below. be able to.

  It will also be appreciated that certain compounds of the present invention may exist as geometric isomers, for example E and Z isomers of alkenes. The present invention includes all possible geometric isomers of the compounds of Formula I. It will be understood that the present invention further encompasses tautomers of the compounds of formula I.

  It will be appreciated that certain compounds of the present invention may also exist in unsolvated forms as well as solvated forms, such as hydrates. It will be understood that the invention further encompasses all such solvated forms of the compounds of Formula I.

  Salts of the compounds of formula I are also within the scope of the invention. In general, a pharmaceutically acceptable salt of a compound of the invention can be prepared using, for example, a sufficiently basic compound such as an alkylamine, physiologically acceptable using standard procedures well known in the art. Can be obtained by reaction with a suitable acid which gives the anion to be produced, for example HCl or acetic acid. Also, a compound of the present invention having a proton that preferably forms an acid, such as a carboxylic acid or phenol, is converted to one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as ethoxide or methoxide) or suitable basic. Treatment with an organic amine (such as choline or meglumine) in an aqueous solvent, followed by conventional purification methods to produce the corresponding alkali metal (such as sodium, potassium or lithium) or alkaline earth metal (such as calcium) salt Is possible.

  In one embodiment, the compound of formula I above is a pharmaceutically acceptable salt or solvate thereof, in particular a hydrochloride, hydrobromide, phosphate, acetate, fumarate, It can be converted to an acid addition salt such as maleate, tartrate, citrate, methanesulfonate or p-toluenesulfonate.

The present inventors have now found that the compounds of the present invention have activity as modulators or ligands such as drugs, particularly agonists, partial agonists, counteracting agents or antagonists of the CB ₁ receptor. . More particularly, the compounds of the present invention show selective activity as agonists of the CB ₁ receptor and are particularly useful for treating chronic pain, neuropathic pain, acute pain, cancer pain, rheumatoid arthritis, It is useful for treatment to reduce various pain conditions such as migraine and visceral pain. However, this list should not be interpreted as exhaustive. Furthermore, the compounds of the present invention are also useful in other disease states where B ₁ receptor dysfunction is present or associated. Furthermore, the compounds of the invention can be used for the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders.

  The compounds of the present invention are particularly useful as immunomodulators for collagen diseases and various allergies for skin transplants, organ transplants and similar surgical needs for autoimmune diseases such as arthritis, Useful as anticancer and antiviral agents.

  The compounds of the present invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present in or associated with that paradigm. This may include the use of isotopically labeled compounds of the present invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

  The compounds of the present invention include diarrhea; depression; post-traumatic stress disorder, panic disorder, generalized anxiety disorder, anxiety disorders and stress-related disorders such as social phobia and obsessive compulsive disorder; urinary incontinence; premature ejaculation; Disorders; cough; pulmonary edema; various gastrointestinal disorders such as constipation, functional gastrointestinal disorders (such as irritable bowel syndrome and functional dyspepsia), etc .; Parkinson's disease and other movement disorders; traumatic brain injury; Useful for the treatment of drug addiction, including cardioprotection after infarction; spinal cord injury; and the treatment of alcohol, nicotine, opioids and other drug abuse, and for the treatment of sympathetic nervous system disorders such as hypertension .

  The compounds of the present invention are useful as analgesics for use during general anesthesia and supervised sedation management. Combinations of drugs with different properties are often used to achieve a balance of effects necessary to maintain anesthesia (eg, memory loss, analgesia, muscle relaxation and sedation). This combination includes inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

  Similarly, the scope of the present invention includes the use of any of the compounds described in Formula I above for the manufacture of a medicament for treating any of the conditions discussed above.

  A further aspect of the invention is a method of treating a subject afflicted with any of the conditions discussed above, by administering an effective amount of a compound of formula I above to a patient in need thereof. is there.

  Accordingly, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the treatment as defined above.

  In a further aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for use in a treatment as defined above.

  In the context of this specification, the term “therapy” also includes “prophylaxis” unless specifically stated otherwise. The terms “therapeutic” and “therapeutically” should be construed accordingly. The term “treatment” in connection with the present invention further includes administering an effective amount of a compound of the present invention to alleviate either a preexisting disease state, an acute or chronic condition, or a recurrent condition. Is included. This definition also includes prophylactic treatment to prevent recurrent conditions and continued treatment for chronic diseases.

  The compounds of the present invention are useful for the treatment of various pain conditions, including but not limited to acute pain, chronic pain, neuropathic pain, back pain, cancer pain and visceral pain.

  In use for the treatment of warm-blooded animals such as humans, the compounds of the present invention are orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, in the form of conventional pharmaceutical compositions. It can be administered by any route including intrathoracic, intravenous, epidural, intrathecal, percutaneous, intraventricular, and by injection into a joint.

  In one embodiment of the invention, the route of administration is oral, intravenous or intramuscular.

  In determining the particular patient's individual dosage regimen and the most appropriate dosage level, the dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician.

  For preparing pharmaceutical compositions from the compounds of the present invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.

  A solid carrier can be one or more substances which also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; It may be a chemical material.

  In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active ingredient is mixed in a suitable proportion with a carrier having the necessary binding properties and compressed into the desired shape and size.

  For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

  Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

  The term “composition” is a formulation of an active ingredient using an encapsulating material as a carrier to provide a capsule, in which the active ingredient (with or without other carriers) is surrounded by the carrier, so that It is also intended to encompass the formulation with which the carrier is associated. Similarly, cachets are included.

  Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

  Liquid form compositions include solutions, suspensions, and emulsions. For example, a sterile aqueous solution or a sterile aqueous propylene glycol solution of the active compound can be a liquid formulation suitable for parenteral administration. Liquid compositions can also be formulated in solutions in aqueous polyethylene glycol solution.

  Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners as necessary. Aqueous suspensions for oral use disperse the finely divided active ingredient in water, along with other suspending agents known in the formulation arts such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose and the like and other suspending agents You can make it.

  The pharmaceutical composition depends on the method of administration, but is preferably 0.05-99% by weight, more preferably 0.10-50% by weight (all weight percentages are based on the total amount of the composition). Including the compounds of the invention.

  The therapeutically effective amount for practicing the present invention is determined from the condition of the disease to be treated or prevented by one skilled in the art using known diagnostic criteria including the age, weight and reactivity of the individual patient. It is decided by judgment.

  Within the scope of the present invention is the use of any of the compounds of formula I as defined above for the manufacture of a medicament.

  Similarly, within the scope of the invention is the use of any of the compounds of formula I for the manufacture of a medicament for treating pain.

  Further, a compound of formula I for the manufacture of a medicament for treating various pain conditions, including but not limited to acute pain, chronic pain, neuropathic pain, back pain, cancer pain and visceral pain Any use of is provided.

  A further aspect of the invention is a method of treating a subject afflicted with any of the conditions discussed above by administering an effective amount of a compound of formula I above to a patient in need thereof. is there.

  Further provided is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

  In particular, there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier for treatment, more particularly for the treatment of pain.

  Further provided is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier for use in any of the conditions discussed above.

  In a further aspect, the present invention provides a process for preparing the compounds of the present invention.

の化合物の製造方法であって、式ＩＩ：

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵は上記に定義した通りである）
の化合物を式ＩＩＩの化合物と反応させることを含む方法を提供する。 In one embodiment, the present invention provides compounds of formula I:

A process for the preparation of a compound of formula II:

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above)
A method comprising reacting a compound of formula III with a compound of formula III is provided.

の化合物の製造方法であって、式ＩＶ：

（式中、
Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵は上記に定義した通りであり；そして、
Ｘは−Ｃｌ、−Ｂｒ及び−Ｉから選択される）
の化合物をＲ¹−Ｃ（＝Ｏ）−Ｘと反応させることを含む方法を提供する。 In another embodiment, the present invention provides compounds of formula I:

Wherein the compound of formula IV:

(Where
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above; and
X is selected from -Cl, -Br and -I)
Wherein R ¹ —C (═O) —X is reacted.

The compounds of the present invention can also be synthesized according to the synthetic route illustrated in Scheme 1.

Biological evaluation
hCB ₁ and hCB ₂ receptor binding
A membrane of human CB ₁ receptor (hCB ₁ ) obtained from Receptor Biology or human CB ₂ receptor (hCB ₂ ) obtained from BioSignal is thawed at 37 ° C. and placed on a 25 gauge pointed needle. Dilute in cannabinoid binding buffer (Tris (50 mM), EDTA (2.5 mM), MgCl ₂ (5 mM) and fatty acid free BSA (0.5 mg / mL), pH 7.4), Aliquots containing protein were dispensed into 96 well plates. The IC ₅₀ of the compounds of the invention in hCB ₁ and hCB ₂ is ³ H-CP55,94
0 was used to evaluate from a 10-point dose response curve performed at 20,000 to 25,000 dpm (0.17-0.21 nM) per well in a final volume of 300 μL. Total binding and non-specific binding were measured in the absence and presence of 0.2 μM HU210, respectively. Vortex the plate, incubate for 60 minutes at room temperature, and wash with 3 mL wash buffer (Tris (50 mM), MgCl) in Unifilters GF / B (previously soaked in 0.1% polyethyleneimine) attached to a Tomtec or Packard harvester. ₂ (5 mM) and BSA (0.5 mg, pH 7.0). The filter was dried at 55 ° C. for 1 hour. After addition of 65 μL / well of MS-20 scintillation fluid, radioactivity (cpm) was counted with TopCount (Packard).

GTPγS binding of hCB ₁ and hCB ₂
A human CB ₁ receptor (hCB ₁ ) obtained from Receptor Biology or a human CB ₂ receptor membrane from BioSignal was thawed at 37 ° C. and passed through a 25-gauge non-pointed needle three times to bind GTPγS. Diluted in buffer (Hepes (50 mM), NaOH (20 mM), NaCl (100 mM), EDTA (1 mM), MgCl ₂ (5 mM), pH 7.4, BSA (0.1%)). EC ₅₀ and E _max of the compounds of the invention were performed in 300 μL using appropriate amounts of membrane protein and 100,000 to 130,000 dpm (0.11 to 0.14 nM) GTPg ³⁵ S per well 10 Evaluated from point dose response curves. Binding at basal and maximal stimulation was measured in the absence and presence of 1 μM (hCB ₂ ) or 10 μM (hCB ₁ ) of Win55, 212-2, respectively. Membranes were pre-incubated with 56.25 μM (hCB ₂ ) or 112.5 μM (hCB ₁ ) GDP for 5 minutes before distributing to plates (final 15 μM (hCB ₂ ) or 30 μM (hCB ₁ ) GDP). Vortex the plate, incubate at room temperature for 60 minutes, and wash with 3 mL wash buffer (Tris (50 mM), MgCl ₂ (5 mM) and Unifilters GF / B (previously soaked in water) attached to a Tomtec or Packard harvester. Filtered with NaCl (50 mM), pH 7.0). The filter was dried at 55 ° C. for 1 hour. After addition of 65 μL / well of MS-20 scintillation fluid, radioactivity (cpm) was counted with TopCount (Packard). Antagonist reversal study: (a) perform an agonist dose response curve in the presence of a constant concentration of antagonist, or (b) perform an antagonist dose response curve in the presence of a constant concentration of agonist. The same method was used except for the above.

Based on the above assay, the dissociation constant (Ki) of a particular compound of the invention for a particular receptor is given by the following formula:
Ki = IC ₅₀ / (1+ [rad] / Kd)
here,
The IC ₅₀ is the concentration of the compound of the invention at which 50% of the substitution is observed;
[Rad] is the concentration of the standard or control radioactive ligand at that time; and Kd is the dissociation constant for the specific receptor of the radioactive ligand;
Was used to determine.

When using the above assay, the Ki for some of the compounds of the present invention against the human CB ₁ receptor ranged between 2.8 nM and 1846 nM. The EC _{50 for} these compounds ranged between 1.8 nM and 682 nM. The E _max of these compounds ranged between 78% and 157%.

  The present invention is further illustrated in more detail by the following examples that describe how to make, purify, analyze, and conduct biological tests of the compounds of the present invention, which are described in the present invention. Should not be construed as limiting.

[Example 1]
N- [4-({[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] -2,2-dimethylpropane Amide

トリメチルアセチルクロリド（４１μＬ、４０.０ｍｇ、０.３３ｍｍｏｌ）を、ＤＭＡＰ（５１.０ｍｇ、０.４２ｍｍｏｌ）及び４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（製造は、以下の工程Ｂ、Ｃ、Ｄ、Ｅ、Ｆ、Ｇ及びＨを参照）（７５.２ｍｇ、０.１７ｍｍｏｌ）のＤＣＭ（１０ｍＬ）溶液に、０℃で加えた。反応混合物を、室温で６時間撹拌し、飽和のＮａＨＣＯ₃水溶液（５ｍＬ）でクエンチし、ＣＨ₂Ｃｌ₂（３×５ｍＬ）で抽出した。集めた有機相をブライン（５ｍＬ）で洗浄し、無水Ｎａ₂ＳＯ₄で乾燥した。生成物を、溶離液としてＥｔＯＡｃを用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：７８.５ｍｇ（８７％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.２５（ｓ，９Ｈ），１.４３−１.５９（ｍ，４Ｈ），１.６４ （ｓ，９Ｈ），２.２３−２.４０（ｍ，１Ｈ），３.２９−３.３９（ｍ，２Ｈ），３.８６−３.９８（ｍ，２Ｈ），４.４５（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.２５（ｄｄ，Ｊ＝８.８３，１.４１Ｈｚ，１Ｈ），７.６１（ｓ，１Ｈ），７.７１（ｓ，４Ｈ），７.７９（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５２７.０；元素分析：計算値：Ｃ₂₈Ｈ₃₈Ｎ₄Ｏ₄Ｓ＋１.５０ＨＣｌ＋０.４０Ｈ₂Ｏ（５８８.６０）：Ｃ，５７.１４；Ｈ，６.９０；Ｎ，９.５２；実測値：Ｃ，５７.１１；Ｈ，６.９１；Ｎ，９.４２。 Step A: N- [4-({[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] -2,2 -Dimethylpropanamide

Trimethylacetyl chloride (41 μL, 40.0 mg, 0.33 mmol) was added to DMAP (51.0 mg, 0.42 mmol) and 4-amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4). -Ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (for preparation see steps B, C, D, E, F, G and H below) (75.2 mg, 0.17 mmol) DCM To the (10 mL) solution was added at 0 ° C. The reaction mixture was stirred at room temperature for 6 hours, quenched with saturated aqueous NaHCO ₃ (5 mL) and extracted with CH ₂ Cl ₂ (3 × 5 mL). The collected organic phase was washed with brine (5 mL) and dried over anhydrous Na ₂ SO ₄ . The product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 78.5 mg (87%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.25 (s, 9H), 1.43-1.59 (m, 4H), 1.64 (s, 9H), 2.23-2.40 (m, 1H), 3.29-3.39 (m, 2H), 3.86-3.98 (m, 2H), 4.45 (d, J = 7.42 Hz, 2H), 7.25 (dd, J = 8.83, 1.41 Hz, 1H), 7.61 (s, 1H), 7.71 (s, 4H), 7.79 (d, MS (ESI) (M + H) ⁺ = 527.0; elemental analysis: calculated: C ₂₈ H ₃₈ N ₄ O ₄ S + 1.50 HCl + 0.40H ₂ O (588.60): C 57.14; H, 6.90; N, 9.52; Found: C, 57.11; H, 6.91; N, 9.42.

４−フルオロ−３−ニトロアニリン（５.０ｇ、３２.０ｍｍｏｌ）を、ＴＥＡ（６.７ｍＬ、４８.０ｍｍｏｌ）を含むＤＣＭ（５０ｍＬ）に０℃で溶解した。アセチルクロリド（２.７５ｍＬ、３８.４ｍｍｏｌ）を滴下しながら加え、溶液を室温で終夜撹拌した。溶液を５％ＫＨＳＯ₄水溶液、飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。生成物をＤＣＭから結晶化した。収量：５.３ｇ（８４％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：２.０４（ｓ，３Ｈ），７.５１（ｄｄ，Ｊ＝１１.２３，９.０８Ｈｚ，１Ｈ），７.８０（ｄｄｄ，Ｊ＝９.０８，４.００，２.９３Ｈｚ，１Ｈ），８.４７（ｄｄ，Ｊ＝７.０３，２.７３Ｈｚ，１Ｈ），１０.３８（ｓ，１Ｈ）。 Step B: N- (4-Fluoro-3-nitrophenyl) acetamide

4-Fluoro-3-nitroaniline (5.0 g, 32.0 mmol) was dissolved in DCM (50 mL) containing TEA (6.7 mL, 48.0 mmol) at 0 ° C. Acetyl chloride (2.75 mL, 38.4 mmol) was added dropwise and the solution was stirred at room temperature overnight. The solution was washed with 5% aqueous KHSO ₄ solution, saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The product was crystallized from DCM. Yield: 5.3 g (84%); ¹ HNMR (400 MHz, chloroform-D) δ: 2.04 (s, 3H), 7.51 (dd, J = 11.23, 9.08 Hz, 1H), 7 .80 (ddd, J = 9.08, 4.00, 2.93 Hz, 1H), 8.47 (dd, J = 7.03, 2.73 Hz, 1H), 10.38 (s, 1H).

Ｎ−（４−フルオロ−３−ニトロフェニル）アセトアミド（５００ｍｇ、２.５２ｍｍｏｌ）及び４−アミノメチルテトラヒドロピラン（３５０ｍｇ、３.０２ｍｍｏｌ）を、ＴＥＡ（０.５２５ｍＬ、３.７８ｍｍｏｌ）を含むＥｔＯＨ（２０ｍＬ）中、７５℃で終夜撹拌した。溶媒を濃縮した。残留物をＥｔＯＡｃに溶解し、５％ＫＨＳＯ₄水溶液、飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。粗生成物を、溶離液としてＥｔＯＡｃを用いたシリカゲルフラッシュクロマトグラフィーで精製した。収量：６１１ｍｇ（８３％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４２（ｍ，２Ｈ），１.７４（ｍ，２Ｈ），１.８９−２.００（ｍ，１Ｈ），２.１８（ｓ，３Ｈ），３.２２（ｄｄ，Ｊ＝６.４４，５.６６Ｈｚ，２Ｈ），３.４２（ｍ，２Ｈ），４.０２（ｍ，２Ｈ），６.８４（ｄ，Ｊ＝９.３７Ｈｚ，１Ｈ），７.２０（ｂｒ.ｓ，１Ｈ），７.８１（ｄｄ，Ｊ＝９.３７，２.５４Ｈｚ，１Ｈ），８.０９（ｄ，Ｊ＝２.５４Ｈｚ，１Ｈ），８.１０−８.１２（ｍ，１Ｈ）。 Step C: N- {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide

N- (4-Fluoro-3-nitrophenyl) acetamide (500 mg, 2.52 mmol) and 4-aminomethyltetrahydropyran (350 mg, 3.02 mmol) were added to EtOH containing TEA (0.525 mL, 3.78 mmol). (20 mL) at 75 ° C. overnight. The solvent was concentrated. The residue was dissolved in EtOAc, washed with 5% aqueous KHSO ₄ solution, saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The crude product was purified by flash chromatography on silica gel using EtOAc as eluent. Yield: 611 mg (83%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.42 (m, 2H), 1.74 (m, 2H), 1.89-2.00 (m, 1H), 2.18 (s, 3H), 3.22 (dd, J = 6.44, 5.66 Hz, 2H), 3.42 (m, 2H), 4.02 (m, 2H), 6.84 ( d, J = 9.37 Hz, 1H), 7.20 (br.s, 1H), 7.81 (dd, J = 9.37, 2.54 Hz, 1H), 8.09 (d, J = 2) .54 Hz, 1H), 8.10-8.12 (m, 1H).

Ｎ−｛３−ニトロ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝アセトアミド（６０５ｍｇ、２.０６ｍｍｏｌ）を、触媒量の１０％Ｐｄ／Ｃを含むＥｔＯＡｃ（５０ｍＬ）に溶解した。溶液を水素雰囲気（４０ｐｓｉ）下、Parr水素化装置を用いて終夜室温で振盪した。溶液をCeliteを通して濾過し、そして溶媒を蒸発させた。収量：３１５ｍｇ（５８％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４０（ｍ，２Ｈ），１.７４（ｍ，２Ｈ），１.８２−１.９１（ｍ，１Ｈ），２.１３（ｓ，３Ｈ），２.９９（ｄ，Ｊ＝６.６４，２Ｈ），３.４２（ｍ，２Ｈ），４.０２（ｄｄ，Ｊ＝１０.９４，３.７１Ｈｚ，２Ｈ），６.８４（ｄ，Ｊ＝９.３７Ｈｚ，１Ｈ），７.２０（ｂｒ.ｓ，１Ｈ），７.８１（ｄｄ，Ｊ＝９.３７，２.５４Ｈｚ，１Ｈ），８.０９（ｄ，Ｊ＝２.５４Ｈｚ，１Ｈ），８.１０−８.１２（ｍ，１Ｈ）。 Step D: N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide

N- {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide (605 mg, 2.06 mmol) was added to EtOAc (50 mL) containing a catalytic amount of 10% Pd / C. Dissolved. The solution was shaken overnight at room temperature using a Parr hydrogenator under a hydrogen atmosphere (40 psi). The solution was filtered through Celite and the solvent was evaporated. Yield: 315 mg (58%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.40 (m, 2H), 1.74 (m, 2H), 1.82-1.91 (m, 1H), 2.13 (s, 3H), 2.99 (d, J = 6.64, 2H), 3.42 (m, 2H), 4.02 (dd, J = 10.94, 3.71 Hz, 2H ), 6.84 (d, J = 9.37 Hz, 1H), 7.20 (br.s, 1H), 7.81 (dd, J = 9.37, 2.54 Hz, 1H), 8.09 (D, J = 2.54 Hz, 1H), 8.10-8.12 (m, 1H).

Ｎ−｛３−アミノ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝アセトアミド（３１５ｍｇ、１.２０ｍｍｏｌ）及びＤＭＡＰ（３０ｍｇ、０.２４０ｍｍｏｌ）をＤＣＭ（２０ｍＬ）に溶解した。トリメチルアセチルクロリド（０.１６０ｍＬ、１.３２ｍｍｏｌ）を滴下しながら加え、溶液を室温で２時間撹拌した。溶液を飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。残留物をＡｃＯＨ（３ｍＬ）に溶解し、マイクロ波装置（Personal Chemistry製）を用いて、１２５℃で１時間加熱した。溶媒を蒸発させた。残留物をＥｔＯＡｃに溶解し、飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。粗生成物を、溶離液としてヘキサン／アセトン＝１／１を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：１３５ｍｇ（３４％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４８−１.５４（ｍ，４Ｈ），１.５６（ｓ，９Ｈ），２.２０（ｓ，３Ｈ），２.２４−２.３５（ｍ，１Ｈ），３.２８−３.３５（ｍ，２Ｈ），３.９６（ｔ，Ｊ＝２.８３Ｈｚ，１Ｈ），３.９９（ｔ，Ｊ＝３.０３Ｈｚ，１Ｈ），４.１９（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.２７（ｄ，Ｊ＝８.５９Ｈｚ，１Ｈ），７.３４（ｂｒ.ｓ，１Ｈ），７.５７（ｄｄ，Ｊ＝８.７９，１.９５Ｈｚ，１Ｈ），７.６７（ｄ，Ｊ＝１.９５Ｈｚ，１Ｈ）。 Step E: N- [2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] acetamide

N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide (315 mg, 1.20 mmol) and DMAP (30 mg, 0.240 mmol) were dissolved in DCM (20 mL). . Trimethylacetyl chloride (0.160 mL, 1.32 mmol) was added dropwise and the solution was stirred at room temperature for 2 hours. The solution was washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The residue was dissolved in AcOH (3 mL) and heated at 125 ° C. for 1 hour using a microwave apparatus (Personal Chemistry). The solvent was evaporated. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The crude product was purified by silica gel flash chromatography using hexane / acetone = 1/1 as eluent. Yield: 135 mg (34%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.48-1.54 (m, 4H), 1.56 (s, 9H), 2.20 (s, 3H), 2.24-2.35 (m, 1H), 3.28-3.35 (m, 2H), 3.96 (t, J = 2.83 Hz, 1H), 3.99 (t, J = 3 0.03 Hz, 1H), 4.19 (d, J = 7.42 Hz, 2H), 7.27 (d, J = 8.59 Hz, 1H), 7.34 (br.s, 1H), 7.57 (Dd, J = 8.79, 1.95 Hz, 1H), 7.67 (d, J = 1.95 Hz, 1H).

Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］アセトアミド（１３５ｍｇ、０.４０９ｍｍｏｌ）を、ＥｔＯＨ／２ＭＨＣｌ＝１／１（４ｍＬ）中に溶解した。溶液をマイクロ波装置（Personal Chemistry製）を用いて、１２０℃で３０分間加熱した。溶媒を蒸発させた。残留物をＥｔＯＡｃに溶解し、２ＭのＮａＯＨ溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。溶媒を蒸発させた。収量：１１７ｍｇ（９９％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４７−１.５２（ｍ，４Ｈ），１.５４（ｓ，９Ｈ），２.２３−２.３１（ｍ，１Ｈ），３.２８−３.３６（ｍ，２Ｈ），３.９６（ｔ，Ｊ＝３.１２Ｈｚ，１Ｈ），３.９７−４.００（ｍ，１Ｈ），４.１３（ｄ，Ｊ＝７.６２Ｈｚ，２Ｈ），６.６６（ｄｄ，Ｊ＝８.４０，２.１５Ｈｚ，１Ｈ），７.０６（ｄ，Ｊ＝２.１５Ｈｚ，１Ｈ），７.１０（ｄ，Ｊ＝８.４０Ｈｚ，１Ｈ）。 Step F: 2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine

N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] acetamide (135 mg, 0.409 mmol) was added to EtOH / 2MHCl = 1/1 ( 4 mL). The solution was heated at 120 ° C. for 30 minutes using a microwave apparatus (Personal Chemistry). The solvent was evaporated. The residue was dissolved in EtOAc, washed with 2M NaOH solution, brine and dried over anhydrous MgSO ₄ . The solvent was evaporated. Yield: 117 mg (99%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.47-1.52 (m, 4H), 1.54 (s, 9H), 2.23-2.31 (m , 1H), 3.28-3.36 (m, 2H), 3.96 (t, J = 3.12 Hz, 1H), 3.97-4.00 (m, 1H), 4.13 (d , J = 7.62 Hz, 2H), 6.66 (dd, J = 8.40, 2.15 Hz, 1H), 7.06 (d, J = 2.15 Hz, 1H), 7.10 (d, J = 8.40 Hz, 1H).

２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−アミン（９４.３ｍｇ、０.３２８ｍｍｏｌ）及び４−ニトロベンゼンスルホニルクロリド（８８.８ｍｇ、０.３６１ｍｍｏｌ）を、触媒量のＤＭＡＰを含むＤＣＭ（５ｍＬ）中、室温で、終夜撹拌した。溶液を飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。粗生成物を、溶離液としてＥｔＯＡｃを用いたシリカゲルフラッシュクロマトグラフィーで精製した。収量：１２４.８ｍｇ（８１％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝４７３.０７。 Step G: N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -4-nitrobenzenesulfonamide

2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine (94.3 mg, 0.328 mmol) and 4-nitrobenzenesulfonyl chloride (88.8 mg, 0.8. 361 mmol) was stirred in DCM (5 mL) containing a catalytic amount of DMAP at room temperature overnight. The solution was washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The crude product was purified by flash chromatography on silica gel using EtOAc as eluent. Yield: 124.8 mg (81%); MS (ESI) (M + H) ⁺ = 473.07.

Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−４−ニトロベンゼンスルホンアミド（１２４.８ｍｇ、０.２６４ｍｍｏｌ）を、触媒量の１０％Ｐｄ／Ｃを含むＥｔＯＡｃ（５０ｍＬ）に溶解した。溶液を水素雰囲気（４０ｐｓｉ）下、Parr水素化装置を用いて、室温で終夜振盪した。溶液をCeliteを通して濾過し、そして溶媒を蒸発させた。収量：１１６.９ｍｇ（９９％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４４３.０８。 Step H: 4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide

N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -4-nitrobenzenesulfonamide (124.8 mg, 0.264 mmol) was catalyzed. Dissolved in EtOAc (50 mL) containing an amount of 10% Pd / C. The solution was shaken overnight at room temperature under a hydrogen atmosphere (40 psi) using a Parr hydrogenator. The solution was filtered through Celite and the solvent was evaporated. Yield: 116.9 mg (99%); MS (ESI) (M + H) ⁺ = 443.08.

ＤＣＭ（５ｍＬ）中の４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（４０.３ｍｇ、０.０９１ｍｍｏｌ）、イソブチリルクロリド（２１μＬ、２１.３ｍｇ、０.２０ｍｍｏｌ）及びＤＭＡＰ（３０.５ｍｇ、０.２５ｍｍｏｌ）を用いて、実施例１における工程１の手順に従った。生成物を２０〜５０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで、凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：１７.６ｍｇ（３１％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.１５（ｄ，Ｊ＝６.９１Ｈｚ，６Ｈ），１.４０−１.５４（ｍ，４Ｈ），１.５６（ｓ，９Ｈ），２.２３−２.３６（ｍ，１Ｈ），２.５３−２.６３（ｍ，１Ｈ），３.３１−３.３５（ｍ，２Ｈ），３.８６−３.９６（ｍ，２Ｈ），４.３２（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.１０（ｄｄ，Ｊ＝８.７０，１.７９Ｈｚ，１Ｈ），７.４０（ｓ，１Ｈ），７.５４（ｄ，Ｊ＝８.７１Ｈｚ，１Ｈ），７.６３−７.６７（ｍ，４Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝５１３.０；元素分析：計算値：Ｃ₂₇Ｈ₃₆Ｎ₄Ｏ₄Ｓ＋０.９０ ＴＦＡ＋０.９０Ｈ₂Ｏ＋０.３０ＭｅＯＨ（６４１.１２）：Ｃ，５４.５２；Ｈ，６.２７；Ｎ，８.７４；実測値：Ｃ，５４.５２；Ｈ，６.２９；Ｎ，８.７４。 [Example 2]
N- [4-({[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] -2-methylpropanamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (40.3 mg, in DCM (5 mL) The procedure of Step 1 in Example 1 was followed using 0.091 mmol), isobutyryl chloride (21 μL, 21.3 mg, 0.20 mmol) and DMAP (30.5 mg, 0.25 mmol). The product was purified by reverse phase HPLC using 20-50% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. Yield: 17.6 mg (31%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.15 (d, J = 6.91 Hz, 6H), 1.40-1.54 (m, 4H), 1.56 (s, 9H), 2.23-2.36 (m, 1H), 2.55-2.63 (m, 1H), 3.31-3.35 (m, 2H), 3. 86-3.96 (m, 2H), 4.32 (d, J = 7.42 Hz, 2H), 7.10 (dd, J = 8.70, 1.79 Hz, 1H), 7.40 (s , 1H), 7.54 (d, J = 8.71 Hz, 1H), 7.63-7.67 (m, 4H); MS (ESI) (M + H) ⁺ = 513.0; Elemental analysis: calculated value _{: C 27 H 36 N 4 O} 4 S + 0.90 TFA + 0.90H 2 O + 0.30MeOH (641.12): C, 54.52; H, 6.27; N, 8.74; Found: C, 54. 52; H, 6.29 N, 8.74.

ＤＣＭ（１０ｍＬ）中４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（６１.８ｍｇ、０.１４ｍｍｏｌ）、プロピオニルクロリド（１５μＬ、１５.９ｍｇ、０.１７ｍｍｏｌ）及びＤＩＰＥＡ（３９.７ｍｇ、０.３０ｍｍｏｌ）を用いて、実施例１における工程１の手順に従った。生成物を２０〜５０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：３０.３ｍｇ（３５％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.１５（ｔ，Ｊ＝７.６８Ｈｚ，３Ｈ），１.４５−１.５９（ｍ，４Ｈ），１.６４（ｓ，９Ｈ），２.２６−２.３３（ｍ，１Ｈ），２.３７（ｑ，Ｊ＝７.４２Ｈｚ，２Ｈ），３.３０−３.３７（ｍ，２Ｈ），３.９０−３.９３（ｍ，２Ｈ），４.４５（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.２４（ｄｄ，Ｊ＝８.９６，２.０５Ｈｚ，１Ｈ），７.６１（ｄ，Ｊ＝１.７９ Ｈｚ，１Ｈ），７.６４−７.６７（ｍ，２Ｈ），７.６８−７.７３（ｍ，２Ｈ），７.７９（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）； ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４９９.０；元素分析：計算値：Ｃ₂₆Ｈ₃₄Ｎ₄Ｏ₄Ｓ＋１.４０ＴＦＡ＋０.４０Ｈ₂Ｏ＋０.９０ＣＨ₃ＯＨ（６９４.３３）：Ｃ，５１.３８；Ｈ，５.７８；Ｎ，８.０７；実測値：Ｃ，５１.３５；Ｈ，５.８３；Ｎ，８.１１。 Example 3
N- [4-({[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] propanamide

4-amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (61.8 mg, 0 in DCM (10 mL). .1 mmol), propionyl chloride (15 μL, 15.9 mg, 0.17 mmol) and DIPEA (39.7 mg, 0.30 mmol) were used to follow the procedure of Step 1 in Example 1. The product was purified by reverse phase HPLC using 20-50% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. Yield: 30.3 mg (35%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.15 (t, J = 7.68 Hz, 3H), 1.45-1.59 (m, 4H), 1.64 (s, 9H), 2.26-2.33 (m, 1H), 2.37 (q, J = 7.42 Hz, 2H), 3.30-3.37 (m, 2H), 3.90-3.93 (m, 2H), 4.45 (d, J = 7.42 Hz, 2H), 7.24 (dd, J = 8.96, 2.05 Hz, 1H), 7.61 (D, J = 1.79 Hz, 1H), 7.64-7.67 (m, 2H), 7.68-7.73 (m, 2H), 7.79 (d, J = 8.96 Hz) MS (ESI) (M + H) ⁺ = 499.0; Elemental analysis: Calculated: C ₂₆ H ₃₄ N ₄ O ₄ S + 1.40 TFA + 0.40H ₂ O + 0.90 CH ₃ OH (694.33): C, 51.38; H 5.78; N, 8.07; Found: C, 51.35; H, 5.83; N, 8.11.

ＤＣＭ（１０ｍＬ）中４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（６１.８ｍｇ、０.１４ｍｍｏｌ）、２−クロロアセチルクロリド（１４μＬ、１８.９ｍｇ、０.１７ｍｍｏｌ）及びＤＩＰＥＡ（３９.７ｍｇ、０.３０ｍｍｏｌ）を用いて、実施例１における工程１の手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／１〜４を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：５７.７ｍｇ（７９％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.４４−１.６０（ｍ，４Ｈ），１.６４（ｓ，９Ｈ），２.２３−２.４０（ｍ，１Ｈ），３.３１−３.３８（ｍ，２Ｈ），３.８５−３.９７（ｍ，２Ｈ），４.１６（ｓ，２Ｈ），４.４６（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.２６（ｄｄ，Ｊ＝９.０９，１.６６Ｈｚ，１Ｈ），７.６３（ｓ，１Ｈ），７.６６−７.７２（ｍ，２Ｈ），７.７２−７.７７（ｍ，２Ｈ），７.８１（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝５１９.０；元素分析：計算値：Ｃ₂₅Ｈ₃₁ＣｌＮ₄Ｏ₄Ｓ＋１.１０ＨＣｌ＋０.６０ＥｔＯＡｃ（６１２.０４）：Ｃ，５３.７７；Ｈ，６.０８；Ｎ，９.１５；実測値：Ｃ，５３.８１；Ｈ，６.０４；Ｎ，９.１４。 Example 4
N- [4-({[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] -2-chloroacetamide

4-amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (61.8 mg, 0 in DCM (10 mL). .14 mmol), 2-chloroacetyl chloride (14 μL, 18.9 mg, 0.17 mmol) and DIPEA (39.7 mg, 0.30 mmol) were used to follow the procedure of Step 1 in Example 1. The product was purified by silica gel flash chromatography using hexane / EtOAc = 1 / 1-4 as eluent. Yield: 57.7 mg (79%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.44-1.60 (m, 4H), 1.64 (s, 9H), 2.23-2. 40 (m, 1H), 3.31-3.38 (m, 2H), 3.85-3.97 (m, 2H), 4.16 (s, 2H), 4.46 (d, J = 7.42 Hz, 2H), 7.26 (dd, J = 9.09, 1.66 Hz, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 2H), 7. 72-7.77 (m, 2H), 7.81 (d, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 519.0; Elemental analysis: calculated value: C ₂₅ H ₃₁ ClN ₄ O ₄ S + 1.10 HCl + 0.60 EtOAc (612.04): C, 53.77; H, 6.08; N, 9.15; Found: C, 53.81; H, 6.04; N, 9 .14.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（６１.８ｍｇ、０.１４ｍｍｏｌ）、シクロプロパンカルボニルクロリド（１５μＬ、１７.５ｍｇ、０.１７ｍｍｏｌ）及びＤＩＰＥＡ（３９.７ｍｇ、０.３０ｍｍｏｌ）を用いて、実施例１における工程１の手順に従った。生成物を、２０〜５０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：３２.３ｍｇ（３７％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：０.８２−０.８８（ｍ，２Ｈ），０.８９−０.９６（ｍ，２Ｈ），１.４５−１.６０（ｍ，４Ｈ），１.６４（ｓ，９Ｈ），１.６８−１.７９（ｍ，１Ｈ），２.２２−２.４０（ｍ，１Ｈ），３.３０−３.３７（ｍ，２Ｈ），３.９６−３.９８（ｍ，２Ｈ），４.４５（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.２４（ｄｄ，Ｊ＝９.０９，１.９２Ｈｚ，１Ｈ），７.６１（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.６４−７.６８（ｍ，２Ｈ），７.６９−７.７３（ｍ，２Ｈ），７.７８（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝５１１.０；元素分析：計算値：Ｃ₂₇Ｈ₃₄Ｎ₄Ｏ₄Ｓ＋１.５０ＴＦＡ＋０.６０Ｈ₂Ｏ（６９２.５４）：Ｃ，５２.０３；Ｈ，５.３４；Ｎ，８.０９；実測値：Ｃ，５２.０１；Ｈ，５.３１；Ｎ，８.１４。 Example 5
N- [4-({[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] cyclopropanecarboxamide

4-amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (61.8 mg, in DCM (10 mL). The procedure of Step 1 in Example 1 was followed using 0.14 mmol), cyclopropanecarbonyl chloride (15 μL, 17.5 mg, 0.17 mmol) and DIPEA (39.7 mg, 0.30 mmol). The product was purified by reverse phase HPLC using 20-50% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. Yield: 32.3 mg (37%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 0.82-0.88 (m, 2H), 0.89-0.96 (m, 2H), 1. 45-1.60 (m, 4H), 1.64 (s, 9H), 1.68-1.79 (m, 1H), 2.22-2.40 (m, 1H), 3.30- 3.37 (m, 2H), 3.96-3.98 (m, 2H), 4.45 (d, J = 7.42 Hz, 2H), 7.24 (dd, J = 9.09, 1 .92 Hz, 1H), 7.61 (d, J = 1.79 Hz, 1H), 7.64-7.68 (m, 2H), 7.69-7.73 (m, 2H), 7.78 (D, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 511.0; Elemental analysis: Calculated value: C ₂₇ H ₃₄ N ₄ O ₄ S + 1.50 TFA + 0.60 H ₂ O (692.54) ): C, 52.03; H, 5.3 ; N, 8.09; Found: C, 52.01; H, 5.31; N, 8.14.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（６１.８ｍｇ、０.１４ｍｍｏｌ）、シクロブタンカルボニルクロリド（１９μＬ、１９.８ｍｇ、０.１７ｍｍｏｌ）及びＤＩＰＥＡ（３９.７ｍｇ、０.３０ｍｍｏｌ）を用いて、実施例１における工程１の手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／１〜４を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：４９.６ｍｇ（６７％収率）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.４４−１.５９（ｍ，４Ｈ），１.６４（ｓ，９Ｈ），１.８２−１.９１（ｍ，１Ｈ），１.９６−２.０７（ｍ，１Ｈ），２.１２−２.２２（ｍ，２Ｈ），２.２２−２.３８（ｍ，３Ｈ），３.１８−３.２７（ｍ，１Ｈ），３.３１−３.３７（ｍ，２Ｈ），３.９０−３.９２（ｍ，２Ｈ），４.４５（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.２４（ｄｄ，Ｊ＝８.９６，２.０５Ｈｚ，１Ｈ），７.６１（ｄ，Ｊ＝２.０５Ｈｚ，１Ｈ），７.６５−７.６９（ｍ，２Ｈ），７.６９−７.７４（ｍ，２Ｈ），７.７９（ｄ，Ｊ＝９.２２Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝５２５.０；元素分析：計算値：Ｃ₂₈Ｈ₃₆Ｎ₄Ｏ₄Ｓ＋１.３０ＨＣｌ＋０.１０Ｈ₂Ｏ＋０.５０ＥｔＯＡｃ（６１７.９４）：Ｃ，５８.３１；Ｈ，６.７７；Ｎ，９.０７；実測値：Ｃ，５８.２８；Ｈ，６.７３；Ｎ，９.０４。 Example 6
N- [4-({[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] cyclobutanecarboxamide

4-amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (61.8 mg, in DCM (10 mL). The procedure of Step 1 in Example 1 was followed using 0.14 mmol), cyclobutanecarbonyl chloride (19 μL, 19.8 mg, 0.17 mmol) and DIPEA (39.7 mg, 0.30 mmol). The product was purified by silica gel flash chromatography using hexane / EtOAc = 1 / 1-4 as eluent. Yield: 49.6 mg (67% yield); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.44-1.59 (m, 4H), 1.64 (s, 9H), 1.82- 1.91 (m, 1H), 1.96-2.07 (m, 1H), 2.12-2.22 (m, 2H), 2.22-2.38 (m, 3H), 3. 18-3.27 (m, 1H), 3.31-3.37 (m, 2H), 3.90-3.92 (m, 2H), 4.45 (d, J = 7.42 Hz, 2H ), 7.24 (dd, J = 8.96, 2.05 Hz, 1H), 7.61 (d, J = 2.05 Hz, 1H), 7.65-7.69 (m, 2H), 7 .69-7.74 (m, 2H), 7.79 (d, J = 9.22 Hz, 1H); MS (ESI) (M + H) ⁺ = 525.0; Elemental analysis: calculated: C ₂₈ H _{36 N 4 O 4 S + 1.30HCl +} 0.10H 2 O + 0.5 EtOAc (617.94): C, 58.31; H, 6.77; N, 9.07; Found: C, 58.28; H, 6.73; N, 9.04.

Example 7
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -2-methyl Propanamide

イソブチリルクロリド（２５μＬ、２５.２ｍｇ、０.２４ｍｍｏｌ）を、ＤＩＰＥＡ（７５μＬ、５５.９ｍｇ、０.４３ｍｍｏｌ）及び４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（製造は、以下の工程Ｂ、Ｃ、Ｄ、Ｅ、Ｆ、Ｇ及びＨを参照）（８９.６ｍｇ、０.２０ｍｍｏｌ）のＤＣＭ（１０ｍＬ）溶液に０℃で加えた。反応混合物を室温で３時間撹拌し、飽和のＮａＨＣＯ₃水溶液（５ｍＬ）でクエンチし、ＤＣＭ（３×５ｍＬ）を用いて抽出した。集めた有機相をブライン（５ｍＬ）で洗浄し、無水Ｎａ₂ＳＯ₄で乾燥した。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／２を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：８６.４ｍｇ（８４％収率）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.２１（ｄ，Ｊ＝６.９１Ｈｚ，６Ｈ），１.５１−１.６６（ｍ，４Ｈ），１.７０（ｓ，９Ｈ），２.２６−２.４６（ｍ，１Ｈ），２.６１−２.７０（ｍ，１Ｈ），３.２８（ｓ，３Ｈ），３.３４−３.４３（ｍ，２Ｈ），３.９１−４.０３（ｍ，２Ｈ），４.５５（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.３５（ｄｄ，Ｊ＝８.９６，２.０５Ｈｚ，１Ｈ），７.４３−７.５１（ｍ，２Ｈ），７.５６（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.７１−７.７７（ｍ，２Ｈ），７.９２（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５２７.０； 元素分析：計算値：Ｃ₂₈Ｈ₃₈Ｎ₄Ｏ₄Ｓ＋１.５０ＨＣｌ＋０.５０ＭｅＯＨ（５９７.４１）：Ｃ，５７.３０；Ｈ，７.００；Ｎ，９.３８；実測値：Ｃ，５７.３２；Ｈ，６.９０； Ｎ，９.２４。 Step A: N- (4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl)- 2-methylpropanamide

Isobutyryl chloride (25 μL, 25.2 mg, 0.24 mmol) was added to DIPEA (75 μL, 55.9 mg, 0.43 mmol) and 4-amino-N- [2-tert-butyl-1- (tetrahydro-2H— (Pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (see steps B, C, D, E, F, G and H below for preparation) (89.6 mg , 0.20 mmol) in DCM (10 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NaHCO ₃ (5 mL) and extracted with DCM (3 × 5 mL). The collected organic phase was washed with brine (5 mL) and dried over anhydrous Na ₂ SO ₄ . The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/2 as eluent. Yield: 86.4 mg (84% yield); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.21 (d, J = 6.91 Hz, 6H), 1.51-1.66 (m, 4H) ), 1.70 (s, 9H), 2.26-2.46 (m, 1H), 2.61-2.70 (m, 1H), 3.28 (s, 3H), 3.34- 3.43 (m, 2H), 3.91-4.03 (m, 2H), 4.55 (d, J = 7.42 Hz, 2H), 7.35 (dd, J = 8.96, 2 0.05 Hz, 1H), 7.43-7.51 (m, 2H), 7.56 (d, J = 1.79 Hz, 1H), 7.71-7.77 (m, 2H), 7.92 (D, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 527.0; Elemental analysis: calculated: C ₂₈ H ₃₈ N ₄ O ₄ S + 1.50 HCl + 0.50 MeOH (597.41): C, 57.30; H 7.00; N, 9.38; Found: C, 57.32; H, 6.90; N, 9.24.

水素化ナトリウム（４.２２ｇ、６０％、１０６ｍｍｏｌ）を、Ｎ−（４−フルオロ−３−ニトロフェニル）アセトアミド（１３.９ｇ、７０ｍｍｏｌ）（製造は、実施例１の工程Ｂを参照）のＴＨＦ（２００ｍＬ）溶液に、０℃で少しずつ加えた。２０分間撹拌した後、ヨードメタン（１８.５ｇ、１３０ｍｍｏｌ）を加えた。反応混合物を室温で２時間撹拌し、飽和のＮａＨＣＯ₃水溶液（３０ｍＬ）でクエンチし、ＥｔＯＡｃ（３×１００ｍＬ）で以って抽出した。集めた有機相を飽和のＮａＣｌ（２×５０ｍＬ）で洗浄した。濾過し、濃縮した後、標題化合物（１３.１ｇ、８８％）を黄色の固体として得た。¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.９２（ｓ，３Ｈ），３.３０（ｓ，３Ｈ），７.３８（ｓ，１Ｈ），７.５２（ｓ，１Ｈ），７.９５（ｓ，１Ｈ）。 Step B: N- (4-Fluoro-3-nitrophenyl) -N-methylacetamide

Sodium hydride (4.22 g, 60%, 106 mmol) was added to N- (4-fluoro-3-nitrophenyl) acetamide (13.9 g, 70 mmol) (see step 1 of Example 1 for preparation) in THF. To the (200 mL) solution was added in portions at 0 ° C. After stirring for 20 minutes, iodomethane (18.5 g, 130 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO ₃ (30 mL) and extracted with EtOAc (3 × 100 mL). The collected organic phase was washed with saturated NaCl (2 × 50 mL). After filtration and concentration, the title compound (13.1 g, 88%) was obtained as a yellow solid. ¹ HNMR (400 MHz, chloroform-D) δ: 1.92 (s, 3H), 3.30 (s, 3H), 7.38 (s, 1H), 7.52 (s, 1H), 7.95 (S, 1H).

４−アミノメチルピラン（１０.０ｇ、８６.５ｍｍｏｌ）を、ＥｔＯＨ（３００ｍＬ）中のＮ−（４−フルオロ−３−ニトロフェニル）−Ｎ−メチルアセトアミド（１５.６ｇ、７３.３ｍｍｏｌ）及びＴＥＡ（１５.３ｍＬ、１１.１ｇ、１１０ｍｍｏｌ）の混合物に、室温で加えた。反応混合物を、還流下で６時間加熱した。エタノールを蒸発させた後、残留物をＥｔＯＡｃ（４００ｍＬ）に溶解し、水（３×５０ｍＬ）、飽和のＮａＣｌ（３×５０ｍＬ）で洗浄し、Ｎａ₂ＳＯ₄で乾燥した。濾過し、濃縮した後、標題の化合物（２１.７ｇ、９６％）を橙赤色固体として得た。¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.３８−１.５２（ｍ，２Ｈ），１.７２−１.８１（ｍ，２Ｈ），１.９０（ｓ，３Ｈ），１.９３−２.０２（ｍ，１Ｈ），３.２３（ｓ，３Ｈ），３.２３−３.２７（ｍ，２Ｈ），３.３６−３.４９（ｍ，２Ｈ），４.０１−４.０７（ｍ，２Ｈ），６.９１（ｄ，Ｊ＝９.１８Ｈｚ，１Ｈ），７.２９（ｄｄ，Ｊ＝９.０８，２.６４Ｈｚ，１Ｈ），８.０５（ｄ，Ｊ＝２.３４Ｈｚ，１Ｈ），８.２２（ｔ，Ｊ＝５.３７Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝３０９.１２。 Step C: N-methyl-N- {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide

4-Aminomethylpyran (10.0 g, 86.5 mmol) was added to N- (4-fluoro-3-nitrophenyl) -N-methylacetamide (15.6 g, 73.3 mmol) and TEA in EtOH (300 mL). To a mixture of (15.3 mL, 11.1 g, 110 mmol) was added at room temperature. The reaction mixture was heated at reflux for 6 hours. After evaporating the ethanol, the residue was dissolved in EtOAc (400 mL), washed with water (3 × 50 mL), saturated NaCl (3 × 50 mL) and dried over Na ₂ SO ₄ . After filtration and concentration, the title compound (21.7 g, 96%) was obtained as an orange solid. ¹ HNMR (400 MHz, chloroform-D) δ: 1.38-1.52 (m, 2H), 1.72-1.81 (m, 2H), 1.90 (s, 3H), 1.93- 2.02 (m, 1H), 3.23 (s, 3H), 3.23-3.27 (m, 2H), 3.36-3.49 (m, 2H), 4.01-4. 07 (m, 2H), 6.91 (d, J = 9.18 Hz, 1H), 7.29 (dd, J = 9.08, 2.64 Hz, 1H), 8.05 (d, J = 2) .34 Hz, 1H), 8.22 (t, J = 5.37 Hz, 1H); MS (ESI) (M + H) ⁺ = 309.12.

Ｎ−メチル−Ｎ−｛３−ニトロ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝アセトアミド（２１.７ｇ、７０.５ｍｍｏｌ）を、酢酸エチル（５００ｍＬ）中、１０％Ｐｄ／Ｃ（１.０ｇ）を触媒として用い、３０〜４０ｐｓｉの水素圧下、Parr振盪器内において、室温で１８時間水素化した。Celiteを通して濾過し、濃縮した後、紫色の固体（１９.６ｇ、１００％）を得た。¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.３５−１.５０（ｍ，２Ｈ），１.６７（ｓ，１Ｈ），１.７３−１.８１（ｍ，２Ｈ），１.８８（ｓ，３Ｈ），１.８８−１.９９（ｍ，１Ｈ），３.０４（ｄ，Ｊ＝６.６４Ｈｚ，２Ｈ），３.２０（ｓ，３Ｈ），３.３３−３.４８（ｍ，４Ｈ），３.９７−４.０８（ｍ，２Ｈ），６.５４（ｄ，Ｊ＝１.７６Ｈｚ，１Ｈ），６.６０−６.６３（ｍ，２Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝２７８.７。 Step D: N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} -N-methylacetamide

N-methyl-N- {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide (21.7 g, 70.5 mmol) in 10% ethyl acetate (500 mL) Pd / C (1.0 g) was used as a catalyst and hydrogenated for 18 hours at room temperature in a Parr shaker under 30-40 psi hydrogen pressure. After filtration through Celite and concentration, a purple solid (19.6 g, 100%) was obtained. ¹ HNMR (400 MHz, chloroform-D) δ: 1.35-1.50 (m, 2H), 1.67 (s, 1H), 1.73-1.81 (m, 2H), 1.88 ( s, 3H), 1.88-1.99 (m, 1H), 3.04 (d, J = 6.64 Hz, 2H), 3.20 (s, 3H), 3.33-3.48 ( m, 4H), 3.97-4.08 (m, 2H), 6.54 (d, J = 1.76 Hz, 1H), 6.60-6.63 (m, 2H); MS (ESI) (M + H) ^<+> = 278.7.

トリメチルアセチルクロリド（３.３ｍＬ、３.２０ｇ、２６.５ｍｍｏｌ）を、Ｎ−｛３−アミノ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝−Ｎ−メチルアセトアミド（７.０１ｇ、２５.３ｍｍｏｌ）及びＤＩＰＥＡ（５.３ｍＬ、３.９２ｇ、３０.４ｍｍｏｌ）のジクロロメタン（１７０ｍＬ）溶液に、０℃で滴下しながら加えた。得られた混合物を室温で４時間撹拌した。溶媒を蒸発させた後、残留物を酢酸（７５ｍＬ）に溶解し、次いで、１５本の密封した試験管に分けた。混合物を、マイクロ波装置（Personal Chemistry Smith Synthesizer製）を用いて、１５０℃で２.５時間加熱した。集めた反応混合物を蒸発させ、次いでＥｔＯＡｃ（４００ｍＬ）に溶解し、２ＮのＮａＯＨ水溶液（２×２０ｍＬ）、ブライン（２×２０ｍＬ）で洗浄し、そして、Ｎａ₂ＳＯ₄で乾燥した。濾過し、蒸発させた後、残留物を、シリカゲル上で、溶離液としてＥｔＯＡｃ／ＭｅＯＨ＝１０／１を用いたＭＰＬＣにより精製し、標題の化合物（７.３１ｇ、８４％）を白色固体として得た。ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝３４４.１５。 Step E: N- [2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylacetamide

Trimethylacetyl chloride (3.3 mL, 3.20 g, 26.5 mmol) was added to N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} -N-methylacetamide (7 To a solution of .01 g, 25.3 mmol) and DIPEA (5.3 mL, 3.92 g, 30.4 mmol) in dichloromethane (170 mL) was added dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 4 hours. After evaporation of the solvent, the residue was dissolved in acetic acid (75 mL) and then divided into 15 sealed test tubes. The mixture was heated at 150 ° C. for 2.5 hours using a microwave apparatus (Personal Chemistry Smith Synthesizer). The collected reaction mixture was evaporated, then dissolved in EtOAc (400 mL), washed with 2N aqueous NaOH (2 × 20 mL), brine (2 × 20 mL) and dried over Na ₂ SO ₄ . After filtration and evaporation, the residue was purified by MPLC on silica gel using EtOAc / MeOH = 10/1 as eluent to give the title compound (7.31 g, 84%) as a white solid. It was. MS (ESI) (M + H) ^<+> = 344.15.

Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルアセトアミド（４.５７ｇ、１３.３ ｍｍｏｌ）を塩酸（３７％、１００ｍＬ）に溶解し、９０〜１００℃で終夜加熱した。濃縮後、残留物をＥｔＯＡｃに溶解し、２ＮのＮａＯＨ溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。溶媒を蒸発させた。収量：４.０１ｇ（１００％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４６−１.５４（ｍ，４Ｈ），１.５４（ｓ，９Ｈ），２.１６−２.３７（ｍ，１Ｈ），２.８７（ｓ，３Ｈ），３.２３−３.３８（ｍ，２Ｈ），３.９１−４.０２（ｍ，２Ｈ），４.１３（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），６.６１（ｄｄ，Ｊ＝８.５９，２.１５Ｈｚ，１Ｈ），６.９９（ｄ，Ｊ＝２.１５Ｈｚ，１Ｈ），７.１１（ｄ，Ｊ＝８.５９Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝３０２.０６。 Step F: 2-tert-butyl-N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine

N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylacetamide (4.57 g, 13.3 mmol) was added to hydrochloric acid ( 37%, 100 mL) and heated at 90-100 ° C. overnight. After concentration, the residue was dissolved in EtOAc, washed with 2N NaOH solution, brine and dried over anhydrous MgSO ₄ . The solvent was evaporated. Yield: 4.01 g (100%); ¹ H NMR (400 MHz, chloroform-D) δ: 1.46-1.54 (m, 4H), 1.54 (s, 9H), 2.16-2.37 (M, 1H), 2.87 (s, 3H), 3.23-3.38 (m, 2H), 3.91-4.02 (m, 2H), 4.13 (d, J = 7 .42 Hz, 2H), 6.61 (dd, J = 8.59, 2.15 Hz, 1H), 6.99 (d, J = 2.15 Hz, 1H), 7.11 (d, J = 8. 59 Hz, 1H); MS (ESI) (M + H) ⁺ = 302.06.

４−ニトロベンゼンスルホニルクロリド（１.０６ｇ、４.８ｍｍｏｌ）を、２−ｔｅｒｔ−ブチル−Ｎ−メチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イル−メチル）−１Ｈ−ベンゾイミダゾール−５−アミン（１.２１ｇ、４.０ｍｍｏｌ）、ＤＩＰＥＡ（０.９８ｍＬ、０.７２ｇ、５.６ｍｍｏｌ）及びＤＭＡＰ（０.１０ｇ、０.８ｍｍｍｏｌ）のＤＣＭ（２０ｍＬ）溶液に加えた。混合物を室温で終夜撹拌し、飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。粗生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／１を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：１.９１ｇ（９８％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.５１−１.５７（ｍ，１３Ｈ），２.２４−２.３４（ｍ，１Ｈ），３.２７（ｓ，３Ｈ），３.３０−３.３８（ｍ，２Ｈ），３.９９（ｔ，Ｊ＝２.９３Ｈｚ，１Ｈ），４.０２（ｔ，Ｊ＝３.０３Ｈｚ，１Ｈ），４.２０（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.１９−７.２３（ｍ，２Ｈ），７.２９−７.３３（ｍ，１Ｈ），７.７７（ｄ，Ｊ＝８.９８Ｈｚ，２Ｈ），８.３０（ｄ，Ｊ＝８.７９Ｈｚ，２Ｈ）。 Step G: N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methyl-4-nitrobenzenesulfonamide

4-Nitrobenzenesulfonyl chloride (1.06 g, 4.8 mmol) was added to 2-tert-butyl-N-methyl-1- (tetrahydro-2H-pyran-4-yl-methyl) -1H-benzimidazol-5-amine. (1.21 g, 4.0 mmol), DIPEA (0.98 mL, 0.72 g, 5.6 mmol) and DMAP (0.10 g, 0.8 mmol) in DCM (20 mL). The mixture was stirred at room temperature overnight, washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The crude product was purified by silica gel flash chromatography using hexane / EtOAc = 1/1 as eluent. Yield: 1.91 g (98%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.51-1.57 (m, 13H), 2.24-2.34 (m, 1H), 3.27 (S, 3H), 3.30-3.38 (m, 2H), 3.99 (t, J = 2.93 Hz, 1H), 4.02 (t, J = 3.03 Hz, 1H), 4 .20 (d, J = 7.42 Hz, 2H), 7.19-7.23 (m, 2H), 7.29-7.33 (m, 1H), 7.77 (d, J = 8. 98 Hz, 2H), 8.30 (d, J = 8.79 Hz, 2H).

Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチル−４−ニトロベンゼンスルホンアミド（１.９１ｇ、３.９３ｍｍｏｌ）を、触媒量の１０％Ｐｄ／Ｃを含むＥｔＯＡｃ（２００ｍＬ）に溶解した。溶液を水素雰囲気（４０ｐｓｉ）下で、Parr水素化装置を用いて室温で終夜振盪した。溶液をCeliteを通して濾過し、溶媒を蒸発させた。収量：１.８０ｇ（１００％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４５７.０１。 Step H: 4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide

N- [2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methyl-4-nitrobenzenesulfonamide (1.91 g, 3.93 mmol ) Was dissolved in a catalytic amount of 10% Pd / C in EtOAc (200 mL). The solution was shaken overnight at room temperature using a Parr hydrogenator under a hydrogen atmosphere (40 psi). The solution was filtered through Celite and the solvent was evaporated. Yield: 1.80 g (100%); MS (ESI) (M + H) ⁺ = 457.01.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（８９.６ｍｇ、０.２０ｍｍｏｌ）、プロピオニルクロリド（２１μＬ、２１.８ｍｇ、０.２４ｍｍｏｌ）及びＤＩＰＥＡ（７５μＬ、５５.９ｍｇ、０.４３ｍｍｏｌ）を用いて、実施例７における工程Ａの手順に従った。生成物を２０〜５０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：６８.２ｍｇ（６８％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.２１（ｔ，Ｊ＝７.５５Ｈｚ，３Ｈ），１.５１−１.６５（ｍ，４Ｈ），１.７０（ｓ，９Ｈ），２.３３−２.４２（ｍ，１Ｈ），２.４３（ｑ，Ｊ＝７.４２Ｈｚ，２Ｈ），３.２７（ｓ，３Ｈ），３.３４−３.４４（ｍ，２Ｈ），３.９４−３.９８（ｍ，２Ｈ），４.５４（ｄ，Ｊ＝７.６８Ｈｚ，２Ｈ），７.３４（ｄｄ，Ｊ＝９.０９，１.９２Ｈｚ，１Ｈ），７.４５−７.５０（ｍ，２Ｈ），７.５６（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.６９−７.７９（ｍ，２Ｈ），７.９０（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５１３.０；元素分析：計算値：Ｃ₂₇Ｈ₃₆Ｎ₄Ｏ₂Ｓ＋１.８０ＴＦＡ＋０.２０Ｈ₂Ｏ＋０.２０ＭｅＣＮ（７２９.７３）：Ｃ，５１.０２；Ｈ，５.３６；Ｎ，８.０６；実測値：Ｃ，５０.９６；Ｈ，５.３０；Ｎ，８.０２。 Example 8
N- (4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzoimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) propanamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (10 mL) in DCM (10 mL). The procedure of Step A in Example 7 was followed using 89.6 mg, 0.20 mmol), propionyl chloride (21 μL, 21.8 mg, 0.24 mmol) and DIPEA (75 μL, 55.9 mg, 0.43 mmol). . The product was purified by reverse phase HPLC using 20-50% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. Yield: 68.2 mg (68%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.21 (t, J = 7.55 Hz, 3H), 1.51-1.65 (m, 4H), 1.70 (s, 9H), 2.33-2.42 (m, 1H), 2.43 (q, J = 7.42 Hz, 2H), 3.27 (s, 3H), 3.34- 3.44 (m, 2H), 3.94-3.98 (m, 2H), 4.54 (d, J = 7.68 Hz, 2H), 7.34 (dd, J = 9.09, 1 .92 Hz, 1H), 7.45-7.50 (m, 2H), 7.56 (d, J = 1.79 Hz, 1H), 7.69-7.79 (m, 2H), 7.90 (D, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 513.0; elemental analysis: calculated value: C ₂₇ H ₃₆ N ₄ O ₂ S + 1.80 TFA + 0.20H ₂ O + 0.20 MeCN (729) .73): C, 51.02; H, 5.36; N, 8.06; Found: C, 50.96; H, 5.30; N, 8.02.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（８９.６ｍｇ、０.２０ｍｍｏｌ）、ブチリルクロリド（２５μＬ、２５.２ｍｇ、０.２４ｍｍｏｌ）及びＤＩＰＥＡ（７５μＬ、５５.９ｍｇ、０.４３ｍｍｏｌ）を用いて、実施例７における工程Ａの手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／２を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：９８.３ｍｇ（９５％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.０１（ｔ，Ｊ＝７.４２Ｈｚ，３Ｈ），１.５０−１.６６（ｍ，４Ｈ），１.７０（ｓ，９Ｈ），１.７１−１.７８（ｍ，２Ｈ），２.３１−２.４６（ｍ，３Ｈ），３.２８（ｓ，３Ｈ），３.３４−３.４３（ｍ，２Ｈ），３.９１−４.０１（ｍ，２Ｈ），４.５５（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.３４（ｄｄ，Ｊ＝８.９６，２.０５Ｈｚ，１Ｈ），７.４４−７.５０（ｍ，２Ｈ），７.５６（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.７０−７.７７（ｍ，２Ｈ），７.９１（ｄ，Ｊ＝９.２２Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５２７.０；元素分析：計算値：Ｃ₂₈Ｈ₃₈Ｎ₄Ｏ₄Ｓ＋１.５０ＨＣｌ＋０.５０ＭｅＯＨ（５９７.４１）：Ｃ，５７.３０；Ｈ，７.００；Ｎ，９.３８；実測値：Ｃ，５７.２９；Ｈ，６.９３；Ｎ，９.２３。 Example 9
N- (4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) butanamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (10 mL) in DCM (10 mL). 89.6 mg, 0.20 mmol), butyryl chloride (25 μL, 25.2 mg, 0.24 mmol) and DIPEA (75 μL, 55.9 mg, 0.43 mmol), followed the procedure of Step A in Example 7. It was. The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/2 as eluent. Yield: 98.3 mg (95%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.01 (t, J = 7.42 Hz, 3H), 1.50-1.66 (m, 4H), 1.70 (s, 9H), 1.71-1.78 (m, 2H), 2.31-2.46 (m, 3H), 3.28 (s, 3H), 3.34-3. 43 (m, 2H), 3.91-4.01 (m, 2H), 4.55 (d, J = 7.42 Hz, 2H), 7.34 (dd, J = 8.96, 2.05 Hz) , 1H), 7.44-7.50 (m, 2H), 7.56 (d, J = 1.79 Hz, 1H), 7.70-7.77 (m, 2H), 7.91 (d , J = 9.22 Hz, 1H); MS (ESI) (M + H) ⁺ = 527.0; Elemental analysis: calculated: C ₂₈ H ₃₈ N ₄ O ₄ S + 1.50 HCl + 0.50 MeOH (597.41): C, 57.30; H, 7. 0; N, 9.38; Found: C, 57.29; H, 6.93; N, 9.23.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（８９.６ｍｇ、０.２０ｍｍｏｌ）、３，３−ジメチルブチリルクロリド（３３μＬ、３１.８ｍｇ、０.２４ｍｍｏｌ）及びＤＩＰＥＡ（７５μＬ、５５.９ｍｇ、０.４３ｍｍｏｌ）を用いて、実施例７における工程Ａの手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／２を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：１０７.６ｍｇ（９９％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.０９（ｓ，９Ｈ），１.５０−１.６７（ｍ，４Ｈ），１.７０（ｓ，９Ｈ），２.２８（ｓ，２Ｈ），２.３２−２.４９（ｍ，１Ｈ），３.２８（ｓ，３Ｈ），３.３４−３.４４（ｍ，２Ｈ），３.９２−４.０６（ｍ，２Ｈ），４.５４（ｄ，Ｊ＝７.６８Ｈｚ，２Ｈ），７.３５（ｄｄ，Ｊ＝８.９６，２.０５Ｈｚ，１Ｈ），７.４４−７.５３（ｍ，２Ｈ），７.５６（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.７０−７.７８（ｍ，２Ｈ），７.９０（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５５５.０；元素分析：計算値：Ｃ₃₀Ｈ₄₂Ｎ₄Ｏ₄Ｓ＋１.３０ＨＣｌ＋０.４０Ｈ₂Ｏ＋１.００ＭｅＯＨ（６４１.４０）：Ｃ，５８.０５；Ｈ，７.５６；Ｎ，８.７４；実測値：Ｃ，５８.０８；Ｈ，７.５５；Ｎ，８.７３。 Example 10
N- (4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -3,3 -Dimethylbutanamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (10 mL) in DCM (10 mL). 89.6 mg, 0.20 mmol), 3,3-dimethylbutyryl chloride (33 μL, 31.8 mg, 0.24 mmol) and DIPEA (75 μL, 55.9 mg, 0.43 mmol) using the steps in Example 7. The procedure of A was followed. The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/2 as eluent. Yield: 107.6 mg (99%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.09 (s, 9H), 1.50-1.67 (m, 4H), 1.70 (s, 9H), 2.28 (s, 2H), 2.32-2.49 (m, 1H), 3.28 (s, 3H), 3.34-3.44 (m, 2H), 3.92 -4.06 (m, 2H), 4.54 (d, J = 7.68 Hz, 2H), 7.35 (dd, J = 8.96, 2.05 Hz, 1H), 7.44-7. 53 (m, 2H), 7.56 (d, J = 1.79 Hz, 1H), 7.70-7.78 (m, 2H), 7.90 (d, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 555.0; elemental analysis: calculated: C ₃₀ H ₄₂ N ₄ O ₄ S + 1.30HCl + 0.40H ₂ O + 1.00 MeOH (641.40): C, 58.05; H, 7.56; N, 8.74; Found: C, 58.08; H, 7.55; N, 8.73.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（６９.８ｍｇ、０.１５ｍｍｏｌ）、２−クロロアセチルクロリド（１４μＬ、２０.３ｍｇ、０.１８ｍｍｏｌ）及びＤＩＰＥＡ（５７μＬ、４２.３ｍｇ、０.３３ｍｍｏｌ）を用いて、実施例７における工程Ａの手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／２を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：８０.０ｍｇ（１００％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.５１−１.６６（ｍ，４Ｈ），１.７０（ｓ，９Ｈ），２.３１−２.４９（ｍ，１Ｈ），３.２９（ｓ，３Ｈ），３.３４−３.４３（ｍ，２Ｈ），３.９０−４.０３（ｍ，２Ｈ），４.２２（ｓ，２Ｈ），４.５５（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.３５（ｄｄ，Ｊ＝９.０９，１.９２Ｈｚ，１Ｈ），７.４６−７.５４（ｍ，２Ｈ），７.５７（ｄ，Ｊ＝２.０５Ｈｚ，１Ｈ），７.７３−７.８０（ｍ，２Ｈ），７.９２（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５３３.０；元素分析：計算値：Ｃ₂₆Ｈ₃₃ＣｌＮ₄Ｏ₄Ｓ＋０.９０ ＨＣｌ＋０.８０ＭｅＯＨ（５９１.５４）：Ｃ，５４.４２；Ｈ，６.３２；Ｎ，９.４７；実測値：Ｃ，５４.５３；Ｈ，６.１３；Ｎ，９.２２。 Example 11
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -2-chloro Acetamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (10 mL) in DCM (10 mL). 69.8 mg, 0.15 mmol), 2-chloroacetyl chloride (14 μL, 20.3 mg, 0.18 mmol) and DIPEA (57 μL, 42.3 mg, 0.33 mmol) using the procedure of Step A in Example 7. Followed. The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/2 as eluent. Yield: 80.0 mg (100%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.51-1.66 (m, 4H), 1.70 (s, 9H), 2.31-2. 49 (m, 1H), 3.29 (s, 3H), 3.34-3.43 (m, 2H), 3.90-4.03 (m, 2H), 4.22 (s, 2H) 4.55 (d, J = 7.42 Hz, 2H), 7.35 (dd, J = 9.09, 1.92 Hz, 1H), 7.46-7.54 (m, 2H), 7. 57 (d, J = 2.05 Hz, 1H), 7.73-7.80 (m, 2H), 7.92 (d, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 533.0; Elemental analysis: Calculated: C ₂₆ H ₃₃ ClN ₄ O ₄ S + 0.90 HCl + 0.80 MeOH (591.54): C, 54.42; H, 6.32; N, 9.47; : C, 54.53 H, 6.13; N, 9.22.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（６９.８ｍｇ、０.１５ｍｍｏｌ）、シクロプロパンカルボニルクロリド（１６μＬ、１８.８ｍｇ、０.１８ｍｍｏｌ）及びＤＩＰＥＡ（５７μＬ、４２.３ｍｇ、０.３３ｍｍｏｌ）を用いて、実施例７における工程Ａの手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／２を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：７５.２ｍｇ（９６％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：０.８７−０.９３（ｍ，２Ｈ），０.９５−１.０３（ｍ，２Ｈ），１.５２−１.６５（ｍ，４Ｈ），１.７０（ｓ，９Ｈ），１.７６−１.８６（ｍ，１Ｈ），２.２８−２.４８（ｍ，１Ｈ），３.２８（ｓ，３Ｈ），３.３４−３.４３（ｍ，２Ｈ），３.９５−３.９７（ｍ，２Ｈ），４.５４（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.３４（ｄｄ，Ｊ＝８.９６，２.０５Ｈｚ，１Ｈ），７.４２−７.５０（ｍ，２Ｈ），７.５５（ｄ，Ｊ＝１.５４Ｈｚ，１Ｈ），７.６８−７.７９（ｍ，２Ｈ），７.９０（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５２５.０；元素分析：計算値：Ｃ₂₈Ｈ₃₆Ｎ₄Ｏ₄Ｓ＋１.３０ＨＣｌ＋０.８０ＭｅＯＨ（５９７.７２）：Ｃ，５７.８７；Ｈ，６.８３；Ｎ，９.３７；実測値：Ｃ，５７.９０；Ｈ，６.６９；Ｎ，９.３０。 Example 12
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) cyclopropanecarboxamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (10 mL) in DCM (10 mL). 69.8 mg, 0.15 mmol), cyclopropanecarbonyl chloride (16 μL, 18.8 mg, 0.18 mmol) and DIPEA (57 μL, 42.3 mg, 0.33 mmol) were used for the procedure of Step A in Example 7. I followed. The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/2 as eluent. Yield: 75.2 mg (96%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 0.87-0.93 (m, 2H), 0.95-1.03 (m, 2H), 1. 52-1.65 (m, 4H), 1.70 (s, 9H), 1.76-1.86 (m, 1H), 2.28-2.48 (m, 1H), 3.28 ( s, 3H), 3.34-3.43 (m, 2H), 3.95-3.97 (m, 2H), 4.54 (d, J = 7.42 Hz, 2H), 7.34 ( dd, J = 8.96, 2.05 Hz, 1H), 7.42-7.50 (m, 2H), 7.55 (d, J = 1.54 Hz, 1H), 7.68-7.79. (M, 2H), 7.90 (d, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 525.0; Elemental analysis: calculated value: C ₂₈ H ₃₆ N ₄ O ₄ S + 1. 30HCl + 0.80 MeOH (597.72): , 57.87; H, 6.83; N, 9.37; Found: C, 57.90; H, 6.69; N, 9.30.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（６９.８ｍｇ、０.１５ｍｍｏｌ）、シクロブタンカルボニルクロリド（２１μＬ、２１.３ｍｇ、０.１８ｍｍｏｌ）及びＤＩＰＥＡ（５７μＬ、４２.３ｍｇ、０.３３ｍｍｏｌ）を用いて、実施例７における工程Ａの手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／２を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：８０.１ｍｇ（９９％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.５２−１.６４（ｍ，４Ｈ），１.６９（ｓ，９Ｈ），１.８７−１.９７（ｍ，１Ｈ），２.０１−２.１０（ｍ，１Ｈ），２.１８−２.２７（ｍ，３Ｈ），２.２９−２.３７（ｍ，２Ｈ），２.３７−２.４５（ｍ，１Ｈ），３.２７（ｓ，３Ｈ）３.３４−３.４３（ｍ，２Ｈ），３.９６−３.９８（ｍ，２Ｈ），４.５３（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.３２（ｄｄ，Ｊ＝８.９６，２.０５Ｈｚ，１Ｈ），７.４４−７.５０（ｍ，２Ｈ），７.５４（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.７１−７.８０（ｍ，２Ｈ），７.８８（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５３９.０；元素分析：計算値：Ｃ₂₉Ｈ₃₈Ｎ₄Ｏ₄Ｓ＋１.０ＨＣｌ＋０.７０ＭｅＯＨ（５９７.６０）：Ｃ，５９.６９；Ｈ，７.０５；Ｎ，９.３８；実測値：Ｃ，５９.７５；Ｈ，６.９０；Ｎ，９.２９。 Example 13
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) cyclobutanecarboxamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (10 mL) in DCM (10 mL). 69.8 mg, 0.15 mmol), cyclobutane carbonyl chloride (21 μL, 21.3 mg, 0.18 mmol) and DIPEA (57 μL, 42.3 mg, 0.33 mmol), followed the procedure of Step A in Example 7. It was. The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/2 as eluent. Yield: 80.1 mg (99%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.52-1.64 (m, 4H), 1.69 (s, 9H), 1.87-1. 97 (m, 1H), 2.01-2.10 (m, 1H), 2.18-2.27 (m, 3H), 2.29-2.37 (m, 2H), 2.37- 2.45 (m, 1H), 3.27 (s, 3H) 3.34-3.43 (m, 2H), 3.96-3.98 (m, 2H), 4.53 (d, J = 7.42 Hz, 2H), 7.32 (dd, J = 8.96, 2.05 Hz, 1H), 7.44-7.50 (m, 2H), 7.54 (d, J = 1. 79 Hz, 1H), 7.71-7.80 (m, 2H), 7.88 (d, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 539.0; Elemental analysis: calculation _{value: C 29 H 38 N 4 O} 4 S + 1.0HCl + 0.70 eOH (597.60): C, 59.69; H, 7.05; N, 9.38; Found: C, 59.75; H, 6.90; N, 9.29.

ＤＣＭ（１０ｍＬ）中、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（３５.７ｍｇ、０.０７５ｍｍｏｌ）、２−フルオロアセチルクロリド（８.７ｍｇ、０.０９ｍｍｏｌ）及びＤＩＰＥＡ（２９μＬ、２１.３ｍｇ、０.１７ｍｍｏｌ）を用いて、実施例７における工程Ａの手順に従った。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／２を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：１７.０ｍｇ（４４％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.４７−１.６０（ｍ，４Ｈ），１.６４（ｓ，９Ｈ），２.２６−２.４３（ｍ，１Ｈ），３.２４（ｓ，３Ｈ），３.２９−３.３８（ｍ，２Ｈ），３.９１−３.９４（ｍ，２Ｈ），４.４８（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），４.９４（ｄ，Ｊ＝４６.８７Ｈｚ，２Ｈ），７.２７（ｄｄ，Ｊ＝８.８９，１.８６Ｈｚ，１Ｈ），７.４４−７.４９（ｍ，２Ｈ），７.５０（ｄ，Ｊ＝１.７６Ｈｚ，１Ｈ），７.７６−７.８０（ｍ，２Ｈ），７.８３（ｄ，Ｊ＝８.７９Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５１７.０；元素分析：計算値：Ｃ₂₆Ｈ₃₃ＦＮ₄Ｏ₄Ｓ＋０.８０ＴＦＡ＋０.３０Ｈ₂Ｏ＋０.７０ＥｔＯＡｃ（６７４.９４）：Ｃ，５４.１０；Ｈ，５.９７；Ｎ，８.３０；実測値：Ｃ，５４.０９；Ｈ，６.０１；Ｎ，８.２８。 Example 14
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -2-fluoro Acetamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (10 mL) in DCM (10 mL). 35.7 mg, 0.075 mmol), 2-fluoroacetyl chloride (8.7 mg, 0.09 mmol) and DIPEA (29 μL, 21.3 mg, 0.17 mmol), followed the procedure of Step A in Example 7. It was. The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/2 as eluent. Yield: 17.0 mg (44%); ¹ H NMR (600 MHz, methanol-D ₄ ) δ: 1.47-1.60 (m, 4H), 1.64 (s, 9H), 2.26-2. 43 (m, 1H), 3.24 (s, 3H), 3.29-3.38 (m, 2H), 3.91-3.94 (m, 2H), 4.48 (d, J = 7.42 Hz, 2H), 4.94 (d, J = 46.87 Hz, 2H), 7.27 (dd, J = 8.89, 1.86 Hz, 1H), 7.44-7.49 (m , 2H), 7.50 (d, J = 1.76 Hz, 1H), 7.76-7.80 (m, 2H), 7.83 (d, J = 8.79 Hz, 1H); MS (ESI ) (M + H) ⁺ = 517.0; Elemental analysis: Calculated: C ₂₆ H ₃₃ FN ₄ O ₄ S + 0.80TFA + 0.30H ₂ O + 0.70 EtOAc (674.94): C, 54.10; H, 5.97 N, 8.30; Found: C, 54.09; H, 6.01; N, 8.28.

ＤＩＰＥＡ（１１４μＬ、８５.３ｍｇ、０.６６ｍｍｏｌ）を、４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（１３７.０ｍｇ、０.３０ｍｍｏｌ）及び２−シアノ−２−メチルプロパン酸（３７.３ｍｇ、０.３３ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液に加えた。２０分間撹拌した後、ＨＡＴＵ（１３６.９ｍｇ、０.３６ｍｍｏｌ）を、０℃で加えた。反応混合物を室温で２日間撹拌し、水（１００ｍＬ）でクエンチし、ＥｔＯＡｃ（３×５０ｍＬ）で抽出した。集めた有機相をブライン溶液で洗浄し、Ｎａ₂ＳＯ₄で乾燥した。生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／１を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。
収量：１６５.２ｍｇ（９９％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.５２−１.６５（ｍ，４Ｈ），１.７０（ｓ，１５Ｈ），２.２９−２.４７（ｍ，１Ｈ），３.２９（ｓ，３Ｈ），３.３５−３.４３（ｍ，２Ｈ），３.９１−４.０５（ｍ，２Ｈ），４.５４（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.３３（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ），７.４８−７.５４（ｍ，２Ｈ），７.５４（ｓ，１Ｈ），７.７８−７.８４（ｍ，２Ｈ），７.８９（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５５２.０；元素分析：計算値：Ｃ₂₉Ｈ₃₇Ｎ₅Ｏ₅Ｓ＋５.１０ＨＣｌ（７３７.６６）：Ｃ，４７.２２；Ｈ，５.７５；Ｎ，９.４９；実測値：Ｃ，４７.１９；Ｈ，５.４９；Ｎ，９.４３。 Example 15
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -2-cyano -2-methylpropanamide

DIPEA (114 μL, 85.3 mg, 0.66 mmol) was added to 4-amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl]. -N-methylbenzenesulfonamide (137.0 mg, 0.30 mmol) and 2-cyano-2-methylpropanoic acid (37.3 mg, 0.33 mmol) were added to a DMF (10 mL) solution. After stirring for 20 minutes, HATU (136.9 mg, 0.36 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 2 days, quenched with water (100 mL) and extracted with EtOAc (3 × 50 mL). The collected organic phase was washed with brine solution and dried over Na ₂ SO ₄ . The product was purified by silica gel flash chromatography using hexane / EtOAc = 1/1 as eluent.
Yield: 165.2 mg (99%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.52-1.65 (m, 4H), 1.70 (s, 15H), 2.29-2. 47 (m, 1H), 3.29 (s, 3H), 3.35-3.43 (m, 2H), 3.91-4.05 (m, 2H), 4.54 (d, J = 7.42 Hz, 2H), 7.33 (d, J = 8.96 Hz, 1H), 7.48-7.54 (m, 2H), 7.54 (s, 1H), 7.78-7. 84 (m, 2H), 7.89 (d, J = 8.96 Hz, 1H); MS (ESI) (M + H) ⁺ = 552.0; Elemental analysis: calculated value: C ₂₉ H ₃₇ N ₅ O ₅ S + 5 .10 HCl (737.66): C, 47.22; H, 5.75; N, 9.49; Found: C, 47.19; H, 5.49; N, 9.43.

Ｎ−（４−｛［［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］（メチル）アミノ］スルホニル｝フェニル）−２−シアノ−２−メチルプロパンアミド（１２４ｍｇ、０.２２ｍｍｏｌ）を、触媒量のRaney−Ｎｉを含むＥｔＯＨ（２０ｍＬ）に溶解した。溶液を水素雰囲気（４０ｐｓｉ）下、Parr水素化装置を用いて、室温で終夜振盪した。溶液をCeliteを通して濾過し、溶媒を蒸発させた。収量：１２２ｍｇ（１００％）；¹ＨＮＭＲ（６００ＭＨｚ，メタノール−Ｄ₄）δ：１.４４（ｓ，６Ｈ），１.４７−１.６２（ｍ，４Ｈ），１.６６（ｓ，９Ｈ），２.２４−２.４７（ｍ，１Ｈ），３.１１（ｓ，２Ｈ），３.２６（ｓ，３Ｈ），３.３２−３.４１（ｍ，２Ｈ），３.９１−４.００（ｍ，２Ｈ），４.４９（ｄ，Ｊ＝７.６２Ｈｚ，２Ｈ），７.２５（ｄｄ，Ｊ＝８.９８，１.９５Ｈｚ，１Ｈ），７.４６−７.５２（ｍ，２Ｈ），７.５４（ｄ，Ｊ＝１.９５Ｈｚ，１Ｈ），７.７７−７.８５（ｍ，３Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５５６.０；元素分析：計算値：Ｃ₂₉Ｈ₄₁Ｎ₅Ｏ₄Ｓ＋２.９０ＴＦＡ＋０.７０Ｈ₂Ｏ（８９９.０２）：Ｃ，４６.４９；Ｈ，５.０８；Ｎ，７.７９；実測値：Ｃ，４６.４４；Ｈ，５.０３；Ｎ，７.８７。 Example 16
3-amino-N- (4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -2,2-dimethylpropanamide

N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -2-cyano -2-Methylpropanamide (124 mg, 0.22 mmol) was dissolved in EtOH (20 mL) containing a catalytic amount of Raney-Ni. The solution was shaken overnight at room temperature under a hydrogen atmosphere (40 psi) using a Parr hydrogenator. The solution was filtered through Celite and the solvent was evaporated. Yield: 122 mg (100%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.44 (s, 6H), 1.47-1.62 (m, 4H), 1.66 (s, 9H) , 2.24-2.47 (m, 1H), 3.11 (s, 2H), 3.26 (s, 3H), 3.32-3.41 (m, 2H), 3.91-4 .00 (m, 2H), 4.49 (d, J = 7.62 Hz, 2H), 7.25 (dd, J = 8.98, 1.95 Hz, 1H), 7.46-7.52 ( m, 2H), 7.54 (d, J = 1.95 Hz, 1H), 7.77-7.85 (m, 3H); MS (ESI) (M + H) ⁺ = 556.0; Elemental analysis: calculation _{value: C 29 H 41 N 5 O} 4 S + 2.90TFA + 0.70H 2 O (899.02): C, 46.49; H, 5.08; N, 7.79; Found: C, 46.44; H, 5.03; N, 7.87 .

Example 17
N ¹ - [4 - ({methyl [1- (tetrahydro -2H- pyran-4-ylmethyl) -2- (trifluoromethyl)-1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] glycinamide

４−アミノ−Ｎ−［１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−２−（トリフルオロメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（４２.０ｍｇ、０.０９ｍｍｏｌ）（製造は、以下の工程Ｂ、Ｃ、Ｄ及びＥを参照）、Ｎ−（ｔｅｒｔ−ブトキシカルボニル）グリシン（３１.４ｍｇ、０.１８ｍｍｏｌ）、ＤＩＰＥＡ（３５μＬ、２５.５ｍｇ、０.２０ｍｍｏｌ）及びＨＡＴＵ（７６.０ｍｇ、０.１８ｍｍｏｌ）のＤＭＦ（３ｍＬ）溶液を室温で２日間撹拌し、ＥｔＯＡｃ（５０ｍＬ）で希釈し、水（１０ｍＬ）、ブライン（１０ｍＬ）で洗浄し、Ｎａ₂ＳＯ₄で乾燥した。濃縮した後、残留物をＤＣＭ（３ｍＬ）に溶解し、ＴＦＡ（３ｍＬ）で処理した。溶媒を蒸発させた後、生成物を、２０〜５０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：２２.９ｍｇ（４０％）；¹ＨＮＭＲ（６００ＭＨｚ、メタノール−Ｄ₄）δ：１.３７−１.５６（ｍ，４Ｈ），２.１４−２.３７（ｍ，１Ｈ），３.２５（ｓ，３Ｈ），３.３１−３.４２（ｍ，２Ｈ），３.８８（ｓ，２Ｈ），３.９０−３.９９（ｍ，２Ｈ），４.３２（ｄ，Ｊ＝７.８１Ｈｚ，２Ｈ），７.３３（ｄ，Ｊ＝１.７６Ｈｚ，１Ｈ），７.３９（ｄｄ，Ｊ＝８.８８，２.０５Ｈｚ，１Ｈ），７.４７−７.５５（ｍ，２Ｈ），７.６７−７.８１（ｍ，３Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５２６.０；元素分析：計算値：Ｃ₂₃Ｈ₂₆Ｆ₃Ｎ₅Ｏ₄Ｓ＋１.５０ＴＦＡ＋０.４０Ｈ₂Ｏ＋０.２０ＣＨ₃ＣＮ（７１２.０１）：Ｃ，４４.５４；Ｈ，４.０９；Ｎ，１０.２３；実測値：Ｃ，４４.５０；Ｈ，４.１２；Ｎ，１０.２４。 Step ^{A: N 1 - [4 -} ({ methyl [1- (tetrahydro -2H- pyran-4-ylmethyl) -2- (trifluoromethyl)-1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] Glycinamide

4-Amino-N- [1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (42.0 mg, 0.09 mmol) (See manufacturing steps B, C, D and E below), N- (tert-butoxycarbonyl) glycine (31.4 mg, 0.18 mmol), DIPEA (35 μL, 25.5 mg, 0.20 mmol) and A solution of HATU (76.0 mg, 0.18 mmol) in DMF (3 mL) was stirred at room temperature for 2 days, diluted with EtOAc (50 mL), washed with water (10 mL), brine (10 mL), and Na ₂ SO ₄ Dried. After concentration, the residue was dissolved in DCM (3 mL) and treated with TFA (3 mL). After evaporation of the solvent, the product was purified by reverse phase HPLC using 20-50% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. Yield: 22.9 mg (40%); ¹ HNMR (600 MHz, methanol-D ₄ ) δ: 1.37-1.56 (m, 4H), 2.14-2.37 (m, 1H), 3. 25 (s, 3H), 3.31-3.42 (m, 2H), 3.88 (s, 2H), 3.90-3.99 (m, 2H), 4.32 (d, J = 7.81 Hz, 2H), 7.33 (d, J = 1.76 Hz, 1H), 7.39 (dd, J = 8.88, 2.05 Hz, 1H), 7.47-7.55 (m , 2H), 7.67-7.81 (m, 3H); MS (ESI) (M + H) ⁺ = 526.0; Elemental analysis: calculated: C ₂₃ H ₂₆ F ₃ N ₅ O ₄ S + 1.50 TFA + 0. 40H ₂ O + 0.20CH ₃ CN (712.01): C, 44.54; H, 4.09; N, 10.23; Found: C, 44.50; H, 4.12; N, 10. 24.

Ｎ−｛３−アミノ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝−Ｎ−メチルアセトアミド（２.７７ｇ、１０ｍｍｏｌ）のトリフルオロ酢酸（６０ｍＬ）溶液を、還流下で１８時間加熱した。溶媒を蒸発させた後、残留物をＥｔＯＡｃに溶解し、２ＮのＮａＯＨで洗浄し、Ｎａ₂ＳＯ₄で乾燥した。所望の生成物を、溶出液としてＥｔＯＡｃを用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：３.１８ｇ（９０％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝３５５.９８。 Step B: N-methyl-N- [1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-yl] acetamide

A solution of N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} -N-methylacetamide (2.77 g, 10 mmol) in trifluoroacetic acid (60 mL) was added under reflux. Heated for 18 hours. After evaporation of the solvent, the residue was dissolved in EtOAc, washed with 2N NaOH and dried over Na ₂ SO ₄ . The desired product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 3.18 g (90%); MS (ESI) (M + H) ⁺ = 355.98.

Ｎ−メチル−Ｎ−［１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−２−（トリフルオロメチル）−１Ｈ−ベンゾイミダゾール−５−イル］アセトアミド（１.７８ｇ、４.５４ｍｍｏｌ）の塩酸（３７％、４０ｍＬ）溶液を、９０℃で終夜加熱した。濃縮し、減圧下で乾燥した後、粗生成物（１.５９ｇ）をＨＣｌ塩として得、それを直接工程Ｄにおいて使用した。ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝３１４.２０。 Step C: N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-amine

Hydrochloric acid of N-methyl-N- [1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-yl] acetamide (1.78 g, 4.54 mmol) (37%, 40 mL) The solution was heated at 90 ° C. overnight. After concentration and drying under reduced pressure, the crude product (1.59 g) was obtained as the HCl salt, which was used directly in Step D. MS (ESI) (M + H) ^<+> = 314.20.

４−ニトロベンゼンスルホニルクロリド（１.２４ｇ、５.０４ｍｍｏｌ）を、Ｎ−メチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−２−（トリフルオロメチル）−１Ｈ−ベンゾイミダゾール−５−アミン・塩酸塩（１.４８ｇ、４.２３ｍｍｏｌ）、ＤＭＡＰ（０.１９ｇ、１.５７ｍｍｏｌ）及び ＤＩＰＥＡ（２.９ｍＬ、２.１９ｇ、１６.９ｍｍｏｌ）のＭｅＣＮ（６０ｍＬ）溶液に０℃で加えた。混合物を室温で終夜撹拌し、ＥｔＯＡｃ（４００ｍＬ）で希釈し、水（２×２０ｍＬ）、ＮａＨＣＯ₃（２×２０ｍＬ）、ブライン（２×２０ｍＬ）で洗浄し、Ｎａ₂ＳＯ₄で乾燥した。粗生成物をシリカゲル上で、ヘキサン／ＥｔＯＡｃ＝１／１を用いたＭＰＬＣで精製し、標題化合物を黄色の固体（１.４３ｇ、６８％）として得た。¹ＨＮＭＲ（４００ＭＨｚ，メタノール−Ｄ₄）δ：１.３９−１.５４（ｍ，４Ｈ），２.１４−２.３４（ｍ，１Ｈ），３.３２（ｓ，３Ｈ），３.３３−３.４０（ｍ，２Ｈ），３.８６−４.０１（ｍ，２Ｈ），４.３２（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.３１（ｄｄ，Ｊ＝８.８８，２.０５Ｈｚ，１Ｈ），７.４５（ｄ，Ｊ＝２.１５Ｈｚ，１Ｈ），７.７４（ｄ，Ｊ＝８.９８Ｈｚ，１Ｈ），７.７６−７.８２（ｍ，２Ｈ），８.２７−８.４２（ｍ，２Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４９９.０；元素分析：計算値：Ｃ₂₁Ｈ₂₁Ｆ₃Ｎ₄Ｏ₅Ｓ＋０.５０ＴＦＡ＋０.２０Ｈ₂Ｏ（５５９.１０）：Ｃ，４７.２６；Ｈ，３.９５；Ｎ，１０.０２；実測値：Ｃ，４７.２４；Ｈ，３.８０；Ｎ，１０.２０。 Step D: N-methyl-4-nitro-N- [1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-yl] benzenesulfonamide

4-Nitrobenzenesulfonyl chloride (1.24 g, 5.04 mmol) was converted to N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-amine. • To a solution of hydrochloride (1.48 g, 4.23 mmol), DMAP (0.19 g, 1.57 mmol) and DIPEA (2.9 mL, 2.19 g, 16.9 mmol) in MeCN (60 mL) at 0 ° C. . The mixture was stirred at room temperature overnight, diluted with EtOAc (400 mL), washed with water (2 × 20 mL), NaHCO ₃ (2 × 20 mL), brine (2 × 20 mL) and dried over Na ₂ SO ₄ . The crude product was purified on silica gel by MPLC using hexane / EtOAc = 1/1 to give the title compound as a yellow solid (1.43 g, 68%). ¹ HNMR (400 MHz, methanol-D ₄ ) δ: 1.39-1.54 (m, 4H), 2.14-2.34 (m, 1H), 3.32 (s, 3H), 3.33 −3.40 (m, 2H), 3.86−4.01 (m, 2H), 4.32 (d, J = 7.42 Hz, 2H), 7.31 (dd, J = 8.88, 2.05 Hz, 1H), 7.45 (d, J = 2.15 Hz, 1H), 7.74 (d, J = 8.98 Hz, 1H), 7.76-7.82 (m, 2H), 8.27-8.42 (m, 2H); MS (ESI) (M + H) ⁺ = 499.0; elemental analysis: calculated: C ₂₁ H ₂₁ F ₃ N ₄ O ₅ S + 0.50TFA + 0.20H ₂ O 559.10): C, 47.26; H, 3.95; N, 10.02; Found: C, 47.24; H, 3.80; N, 10.20.

Ｎ−メチル−４−ニトロ−Ｎ−［１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−２−（トリフルオロメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（１.４３ｇ、２.８７ｍｍｏｌ）を、酢酸エチル（２００ｍＬ）中、１０％Ｐｄ／Ｃ（０.５ｍｇ）を触媒に用いて、水素圧（３０〜４０ｐｓｉ）下、Parr振盪器内において、室温で１８時間水素化した。Celiteを通して濾過し、濃縮した後、白色固体（１.３２ｇ、９８％）を得た。少量の粗生成物を、２０〜７０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題化合物を対応するＴＦＡ塩として得た。¹ＨＮＭＲ（４００ＭＨｚ，メタノール−Ｄ₄）δ：１.３８−１.５５（ｍ，４Ｈ），２.１５−２.３５（ｍ，１Ｈ），３.１８（ｓ，３Ｈ），３.３３−３.４０（ｍ，２Ｈ），３.８２−４.０２（ｍ，２Ｈ），４.３２（ｄ，Ｊ＝７.６２Ｈｚ，２Ｈ），６.５８−６.６９（ｍ，２Ｈ），７.１５−７.２３（ｍ，２Ｈ），７.３５（ｄｄ，Ｊ＝８.９８，１.９５Ｈｚ，１Ｈ），７.４０（ｄ，Ｊ＝１.５６Ｈｚ，１Ｈ），７.７１（ｄ，Ｊ＝８.７９Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４６９.０；元素分析：計算値：Ｃ₂₁Ｈ₂₃Ｆ₃Ｎ₄Ｏ₃Ｓ＋０.４０ＴＦＡ（５１４.１１）：Ｃ，５０.９３；Ｈ，４.５９；Ｎ，１０.９０；実測値：Ｃ，５１.００；Ｈ，４.７２；Ｎ，１０.５４。 Step E: 4-Amino-N-methyl-N- [1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-yl] benzenesulfonamide

N-methyl-4-nitro-N- [1- (tetrahydro-2H-pyran-4-ylmethyl) -2- (trifluoromethyl) -1H-benzimidazol-5-yl] benzenesulfonamide (1.43 g, 2.87 mmol) was hydrogenated in ethyl acetate (200 mL) using 10% Pd / C (0.5 mg) as catalyst in a Parr shaker at room temperature under hydrogen pressure (30-40 psi) for 18 hours. did. After filtration through Celite and concentration, a white solid (1.32 g, 98%) was obtained. A small amount of the crude product was purified by reverse phase HPLC using 20-70% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. ¹ HNMR (400 MHz, methanol-D ₄ ) δ: 1.38-1.55 (m, 4H), 2.15-2.35 (m, 1H), 3.18 (s, 3H), 3.33 −3.40 (m, 2H), 3.82−4.02 (m, 2H), 4.32 (d, J = 7.62 Hz, 2H), 6.58-6.69 (m, 2H) 7.15-7.23 (m, 2H), 7.35 (dd, J = 8.98, 1.95 Hz, 1H), 7.40 (d, J = 1.56 Hz, 1H), 7. 71 (d, J = 8.79 Hz, 1H); MS (ESI) (M + H) ⁺ = 469.0; Elemental analysis: calculated: C ₂₁ H ₂₃ F ₃ N ₄ O ₃ S + 0.40 TFA (514.11) : C, 50.93; H, 4.59; N, 10.90; Found: C, 51.00; H, 4.72; N, 10.54.

Example 18
N ^1- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (ethyl) amino] sulfonyl} phenyl) glycinamide

４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−エチルベンゼンスルホンアミド（８５.１ｍｇ、０.１５ｍｍｏｌ）（製造は、以下の工程Ｂ、Ｃ、Ｄ、Ｅ、Ｆ及びＧを参照）、Ｎ−（ｔｅｒｔ−ブトキシカルボニル）グリシン（５２.６ｍｇ、０.３ｍｍｏｌ）、ＤＩＰＥＡ（５７μＬ、４２.７ｍｇ、０.３３ｍｍｏｌ）及びＨＡＴＵ（１２５.５ｍｇ、０.３０ｍｍｏｌ）のＤＭＦ溶液（５ｍＬ）を、室温でウィークエンド中撹拌し、ＥｔＯＡｃ（５０ｍＬ）で希釈し、水（１０ｍＬ）、ブライン（１０ｍＬ）で洗浄し、Ｎａ₂ＳＯ₄で乾燥した。濃縮後、粗生成物を、シリカゲル上で、ＥｔＯＡｃを用いたＭＰＬＣにより精製し、白色固体（１０３.３ｇ）を得、それを４ＮのＨＣｌのジオキサン溶液で処理した。溶媒を蒸発させた後、生成物を、１０〜５０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：８７.３ｍｇ（９１％）；¹ＨＮＭＲ（４００ＭＨｚ，メタノール−Ｄ₄）δ：１.０７（ｔ，Ｊ＝７.０３Ｈｚ，３Ｈ），１.５１−１.６２（ｍ，４Ｈ），１.６８（ｓ，９Ｈ），２.２６−２.４９（ｍ，１Ｈ），３.３２−３.４１（ｍ，２Ｈ），３.７２（ｑ，Ｊ＝７.２９Ｈｚ，２Ｈ），３.９０（ｓ，２Ｈ），３.９２−３.９９（ｍ，２Ｈ），４.５２（ｄ，Ｊ＝７.６２Ｈｚ，２Ｈ），７.２２（ｄｄ，Ｊ＝８.９８，１.９５Ｈｚ，１Ｈ），７.５３−７.６１（ｍ，３Ｈ），７.７３−７.８１（ｍ，２Ｈ），７.８８（ｄ，Ｊ＝８.７９Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５２８.０；元素分析：計算値：Ｃ₂₇Ｈ₃₇Ｎ₅Ｏ₄Ｓ＋２.６０ＴＦＡ＋４.００Ｈ₂Ｏ＋０.８０ＣＨ₃ＣＮ（９２９.０６）：Ｃ，４３.７０；Ｈ，５.４２；Ｎ，８.７４；実測値：Ｃ，４３.６６；Ｈ，５.４６；Ｎ，８.７８。 Step A: N ^1- (4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (ethyl) amino] sulfonyl} phenyl) Glycinamide

4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-ethylbenzenesulfonamide (85.1 mg, 0.15 mmol) (See steps B, C, D, E, F and G below), N- (tert-butoxycarbonyl) glycine (52.6 mg, 0.3 mmol), DIPEA (57 μL, 42.7 mg, 0.33 mmol) and HATU (125.5 mg, 0.30 mmol) in DMF (5 mL) were stirred during the weekend at room temperature, diluted with EtOAc (50 mL), washed with water (10 mL), brine (10 mL). , Dried over Na ₂ SO ₄ . After concentration, the crude product was purified on silica gel by MPLC using EtOAc to give a white solid (103.3 g) which was treated with 4N HCl in dioxane. After evaporation of the solvent, the product was purified by reverse phase HPLC using _{10~50% CH 3 CN / H 2} O, then freeze dried to give the title compound as the corresponding TFA salt. Yield: 87.3 mg (91%); ¹ HNMR (400 MHz, methanol-D ₄ ) δ: 1.07 (t, J = 7.03 Hz, 3H), 1.51-1.62 (m, 4H), 1.68 (s, 9H), 2.26-2.49 (m, 1H), 3.32-3.41 (m, 2H), 3.72 (q, J = 7.29 Hz, 2H), 3.90 (s, 2H), 3.92-3.99 (m, 2H), 4.52 (d, J = 7.62 Hz, 2H), 7.22 (dd, J = 8.98, 1 .95 Hz, 1H), 7.53-7.61 (m, 3H), 7.73-7.81 (m, 2H), 7.88 (d, J = 8.79 Hz, 1H); MS (ESI ) (M + H) ⁺ = 528.0; Elemental analysis: Calculated: C ₂₇ H ₃₇ N ₅ O ₄ S + 2.60TFA + 4.00H ₂ O + 0.80CH ₃ CN (929.06): C, 43.70; .42; N, 8. 4; Found: C, 43.66; H, 5.46; N, 8.78.

水素化ナトリウム（１.２０ｇ、３０ｍｍｏｌ）を、Ｎ−（４−フルオロ−３−ニトロフェニル）アセトアミド（３.９６ｇ、２０ｍｍｏｌ）（製造は、実施例１の工程Ｂを参照）のＴＨＦ（１００ｍＬ）溶液に０℃で加えた。撹拌を２０分間続けた後、ヨードメタン（９.３２ｇ、６０ｍｍｏｌ）を加えた。反応混合物を室温で終夜撹拌し、飽和のＮａＨＣＯ₃（３０ｍＬ）でクエンチし、ＥｔＯＡｃ（３×１００ｍＬ）で抽出した。集めた有機相を飽和のＮａＣｌ（２×３０ｍＬ）で洗浄した。濾過し、濃縮した後、残留物を、シリカゲル上で、ヘキサン／ＥｔＯＡｃ＝１／１を用いたＭＰＬＣのより精製し、標題化合物を黄色の固体（２.３６ｇ、５２％）として得た。¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.１４（ｔ，Ｊ＝６.９３ Ｈｚ，３Ｈ），１.８８（ｓ，３Ｈ），３.７７（ｑ，Ｊ＝７.０Ｈｚ，２Ｈ），７.３４−７.４３（ｍ，１Ｈ），７.４８（ｓ，１Ｈ），７.８７−７.９８（ｍ，１Ｈ）。 Step B: N-ethyl-N- (4-fluoro-3-nitrophenyl) acetamide

Sodium hydride (1.20 g, 30 mmol) was added to THF (100 mL) of N- (4-fluoro-3-nitrophenyl) acetamide (3.96 g, 20 mmol) (see step B of Example 1 for preparation). To the solution was added at 0 ° C. Stirring was continued for 20 minutes before iodomethane (9.32 g, 60 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with saturated NaHCO ₃ (30 mL) and extracted with EtOAc (3 × 100 mL). The collected organic phase was washed with saturated NaCl (2 × 30 mL). After filtration and concentration, the residue was purified by MPLC on silica gel using hexane / EtOAc = 1/1 to give the title compound as a yellow solid (2.36 g, 52%). ¹ HNMR (400 MHz, chloroform-D) δ: 1.14 (t, J = 6.93 Hz, 3H), 1.88 (s, 3H), 3.77 (q, J = 7.0 Hz, 2H) , 7.34-7.43 (m, 1H), 7.48 (s, 1H), 7.87-7.98 (m, 1H).

４−アミノメチルテトラヒドロピラン（１.３２ｇ、１１.４ｍｍｏｌ）を、ＥｔＯＨ（７０ｍＬ）中のＮ−エチル−Ｎ−（４−フルオロ−３−ニトロフェニル）アセトアミド（２.３６ｇ、１０.４ｍｍｏｌ）及び炭酸ナトリウム（２.４３ｇ、２２.９ｍｍｏｌ）の混合物に室温で加えた。反応混合物を６０℃で２日間（for a wewo）加熱した。エタノールを蒸発させた後、残留物を水（５０ｍＬ）で希釈し、ＥｔＯＡｃ（３×１００ｍＬ）で抽出した。集めた有機相を飽和のＮａＣｌ（２×５０ｍＬ）で洗浄し、Ｎａ₂ＳＯ₄で乾燥した。濾過し、濃縮した後、残留物を、シリカゲル上で、ヘキサン／ＥｔＯＡｃ＝１／１を用いたＭＰＬＣにより精製し、標題化合物を橙赤色の固体（２.８３ｇ、８５％）として得た。¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.１１（ｔ，Ｊ＝７.１３Ｈｚ，３Ｈ），１.３８−１.５２（ｍ，２Ｈ），１.７８（ｍ，２Ｈ），１.８６（ｓ，３Ｈ），１.９２−２.０４（ｍ，１Ｈ），３.２０−３.２９（ｍ，２Ｈ），３.３９−３.４９（ｍ，２Ｈ），３.７１（ｑ，Ｊ＝７.０９Ｈｚ，２Ｈ），４.００−４.０８（ｍ，２Ｈ），６.９１（ｄ，Ｊ＝８.９８ Ｈｚ，１Ｈ），７.２４（ｄ，Ｊ＝２.５４Ｈｚ，１Ｈ），８.０１（ｄ，Ｊ＝２.５４Ｈｚ，１Ｈ），８.２２（ｔ，Ｊ＝４.９８Ｈｚ，１Ｈ）。 Step C: N-ethyl-N- {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide

4-Aminomethyltetrahydropyran (1.32 g, 11.4 mmol) was added to N-ethyl-N- (4-fluoro-3-nitrophenyl) acetamide (2.36 g, 10.4 mmol) in EtOH (70 mL) and To a mixture of sodium carbonate (2.43 g, 22.9 mmol) was added at room temperature. The reaction mixture was heated at 60 ° C. for 2 days. After evaporating the ethanol, the residue was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The collected organic phases were washed with saturated NaCl (2 × 50 mL) and dried over Na ₂ SO ₄ . After filtration and concentration, the residue was purified on silica gel by MPLC using hexane / EtOAc = 1/1 to give the title compound as an orange solid (2.83 g, 85%). ¹ HNMR (400 MHz, chloroform-D) δ: 1.11 (t, J = 7.13 Hz, 3H), 1.38-1.52 (m, 2H), 1.78 (m, 2H), 1. 86 (s, 3H), 1.92-2.04 (m, 1H), 3.20-3.29 (m, 2H), 3.39-3.49 (m, 2H), 3.71 ( q, J = 7.09 Hz, 2H), 4.00-4.08 (m, 2H), 6.91 (d, J = 8.98 Hz, 1H), 7.24 (d, J = 2. 54 Hz, 1 H), 8.01 (d, J = 2.54 Hz, 1 H), 8.22 (t, J = 4.98 Hz, 1 H).

Ｎ−エチル−Ｎ−｛３−ニトロ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝アセトアミド（２.８３ｇ、８.７９ｍｍｏｌ）を、酢酸エチル（２００ｍＬ）中、１０％Ｐｄ／Ｃ（０.２ｇ）を触媒に用いて、水素圧（３０〜４０ｐｓｉ）下、Parr振盪器内において、室温で１６時間水素化した。Celiteを通して濾過し、濃縮した後、淡黄色の固体（２.４５ｇ、９５％）を得、それを精製せずに直接次の工程で用いた。ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝２９２.３。 Step D: N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} -N-ethylacetamide

N-ethyl-N- {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide (2.83 g, 8.79 mmol) in 10% ethyl acetate (200 mL) Pd / C (0.2 g) was used as a catalyst and hydrogenated for 16 hours at room temperature in a Parr shaker under hydrogen pressure (30-40 psi). After filtration through Celite and concentration, a pale yellow solid (2.45 g, 95%) was obtained, which was used directly in the next step without purification. MS (ESI) (M + H) ^<+> = 292.3.

ＤＣＭ（６０ｍＬ）、次いでＤＣＥ（３０ｍＬ）中、Ｎ−｛３−アミノ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝−Ｎ−エチルアセトアミド（８０３.１ｍｇ、２.７５ｍｍｏｌ）、ＤＭＡＰ（６７１.９ｍｇ、５.５０ｍｍｏｌ）及びトリメチルアセチルクロリド（３８０.９ｍｇ、３.１６ｍｍｏｌ）を用いて、実施例７における工程Ｅの手順に従った。粗生成物を、シリカゲル上で、ＥｔＯＡｃ／ＭｅＯＨ＝２０／１を用いたＭＰＬＣにより精製した。収量：６９４.１ｍｇ（７１％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.１２（ｔ，Ｊ＝７.１３Ｈｚ，３Ｈ），１.５１−１.５７（ｍ，４Ｈ），１.５８（ｓ，９Ｈ），１.８３（ｓ，３Ｈ），２.２１−２.４０（ｍ，１Ｈ），３.２６−３.４３（ｍ，２Ｈ），３.７８（ｑ，Ｊ＝７.２３Ｈｚ，２Ｈ），３.９４−４.０７（ｍ，２Ｈ），４.２２（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.０２（ｄｄ，Ｊ＝８.５９，１.９５Ｈｚ，１Ｈ），７.３４（ｄ，Ｊ＝８.５９Ｈｚ，１Ｈ），７.５４（ｄ，Ｊ＝０.９８Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝３５８.０７。 Step E: N- [2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-ethylacetamide

N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} -N-ethylacetamide (803.1 mg, 2.75 mmol) in DCM (60 mL) and then in DCE (30 mL). ), DMAP (671.9 mg, 5.50 mmol) and trimethylacetyl chloride (380.9 mg, 3.16 mmol), followed the procedure of Step E in Example 7. The crude product was purified by MPLC on silica gel using EtOAc / MeOH = 20/1. Yield: 694.1 mg (71%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.12 (t, J = 7.13 Hz, 3H), 1.51-1.57 (m, 4H), 1 .58 (s, 9H), 1.83 (s, 3H), 2.21-2.40 (m, 1H), 3.26-3.43 (m, 2H), 3.78 (q, J = 7.23 Hz, 2H), 3.94-4.07 (m, 2H), 4.22 (d, J = 7.42 Hz, 2H), 7.02 (dd, J = 8.59, 1. 95 Hz, 1H), 7.34 (d, J = 8.59 Hz, 1H), 7.54 (d, J = 0.98 Hz, 1H); MS (ESI) (M + H) ⁺ = 358.07.

Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−エチルアセトアミド （６４８.３ｍｇ、２.０６ｍｍｏｌ）を、ＥｔＯＨ／２ＮのＨＣｌ＝３／２（１５ｍＬ）に溶解し、次いで、マイクロ波装置（Personal Chemistry Smith Synthesizer製）内で、１２０℃で３時間加熱した。濃縮し、減圧下で乾燥した後、標題の生成物を灰白色の固体（７５４.７１ｍｇ、１００％）として得た。ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝３１６.３。 Step F: 2-tert-butyl-N-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine

N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-ethylacetamide (648.3 mg, 2.06 mmol) was added to EtOH / It was dissolved in 2N HCl = 3/2 (15 mL), and then heated at 120 ° C. for 3 hours in a microwave apparatus (Personal Chemistry Smith Synthesizer). After concentration and drying under reduced pressure, the title product was obtained as an off-white solid (754.71 mg, 100%). MS (ESI) (M + H) ^<+> = 316.3.

４−ニトロベンゼンスルホニルクロリド（４４５.９ｍｇ、２.０１ｍｍｏｌ）を、２−ｔｅｒｔ−ブチル−Ｎ−エチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−アミン・塩酸塩（３５４.１ｍｇ、１.０１ｍｍｏｌ）及びＤＭＡＰ（４９１.７ｍｇ、４.０３ｍｍｏｌ）のＭｅＣＮ（２０ｍＬ）溶液に加えた。反応混合物を室温で終夜撹拌し、ＥｔＯＡｃ（１００ｍＬ）で希釈し、ＮａＨＣＯ₃（１０ｍＬ）、ブライン（１０ｍＬ）で洗浄し、Ｎａ₂ＳＯ₄で乾燥した。粗生成物を、シリカゲル上で、ヘキサン／ＥｔＯＡｃ＝１／１を用いたＭＰＬＣにより精製し、標題の化合物を黄色の固体（３９９.６ｍｇ、８０％）として得た。ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝５０１.０。 Step G: N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-ethyl-4-nitrobenzenesulfonamide

4-Nitrobenzenesulfonyl chloride (445.9 mg, 2.01 mmol) was added to 2-tert-butyl-N-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine hydrochloride. Salt (354.1 mg, 1.01 mmol) and DMAP (491.7 mg, 4.03 mmol) were added to a solution of MeCN (20 mL). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (100 mL), washed with NaHCO ₃ (10 mL), brine (10 mL), and dried over Na ₂ SO ₄ . The crude product was purified on silica gel by MPLC using hexane / EtOAc = 1/1 to give the title compound as a yellow solid (399.6 mg, 80%). MS (ESI) (M + H) ^<+> = 501.0.

Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−エチル−４−ニトロベンゼンスルホンアミド（３９９.６ｍｇ、０.７９８ｍｍｏｌ）を、酢酸エチル（５０ｍＬ）中、１０％Ｐｄ／Ｃ（１００ｍｇ）を触媒に用いて、水素圧（３０〜４０ｐｓｉ）下、Parr振盪器内において、室温で６時間水素化した。Celiteを通して濾過し、濃縮した後、白色の固体（４５７.９ｍｇ、１００％）を得た。粗生成物の少量を２０〜５０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。¹ＨＮＭＲ（４００ＭＨｚ，メタノール−Ｄ₄）δ：１.０４（ｔ，Ｊ＝７.１３Ｈｚ，３Ｈ），１.４９−１.６５（ｍ，４Ｈ），１.６８（ｓ，９Ｈ），２.２５−２.５５（ｍ，１Ｈ）３.３２−３.４３（ｍ，２Ｈ），３.６６（ｑ，Ｊ＝７.０３Ｈｚ，２Ｈ），３.８８−４.０４（ｍ，２Ｈ），４.５３（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），６.５０−６.６９（ｍ，２Ｈ），７.１９−７.２６（ｍ，２Ｈ），７.２８（ｄｄ，Ｊ＝８.９８，１.９５Ｈｚ，１Ｈ），７.５０（ｄ，Ｊ＝１.７６Ｈｚ，１Ｈ），７.９０（ｄ，Ｊ＝８.９８ Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４７１.０；元素分析：計算値：Ｃ₂₅Ｈ₃₄Ｎ₄Ｏ₃Ｓ＋１.８０ＴＦＡ＋０.３０ Ｈ₂Ｏ（６８１.２９）：Ｃ，５０.４２；Ｈ，５.３９；Ｎ，８.２２；実測値：Ｃ，５０.３８；Ｈ，５.２１；Ｎ，８.４４。 Step H: 4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-ethylbenzenesulfonamide

N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-ethyl-4-nitrobenzenesulfonamide (399.6 mg, 0.798 mmol) ) Was hydrogenated in ethyl acetate (50 mL) using 10% Pd / C (100 mg) as catalyst in a Parr shaker under hydrogen pressure (30-40 psi) for 6 hours. After filtration through Celite and concentration, a white solid (457.9 mg, 100%) was obtained. A small portion of the crude product was purified by reverse phase HPLC using 20-50% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. ¹ HNMR (400 MHz, methanol-D ₄ ) δ: 1.04 (t, J = 7.13 Hz, 3H), 1.49-1.65 (m, 4H), 1.68 (s, 9H), 2 .25-2.55 (m, 1H) 3.32-3.43 (m, 2H), 3.66 (q, J = 7.03 Hz, 2H), 3.88-4.04 (m, 2H) ), 4.53 (d, J = 7.42 Hz, 2H), 6.50-6.69 (m, 2H), 7.19-7.26 (m, 2H), 7.28 (dd, J = 8.98, 1.95 Hz, 1H), 7.50 (d, J = 1.76 Hz, 1H), 7.90 (d, J = 8.98 Hz, 1H); MS (ESI) (M + H) ⁺ = 471.0; elemental analysis: _{calculated: C 25 H 34 N 4 O} 3 S + 1.80TFA + 0.30 H 2 O (681.29): C, 50.42; H, 5.39; N, 8. 22; measured values: C, 50.38; H, .21; N, 8.44.

Example 19
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) acetamide

２−ｔｅｒｔ−ブチル−Ｎ−メチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−アミン（製造は、以下の工程Ｂ〜Ｆを参照）（２００ｍｇ、０.６６３ｍｍｏｌ）及びＤＭＡＰ（１６ｍｇ、０.１３２ｍｍｏｌ）をＤＣＭ（１０ｍＬ）に溶解した。Ｎ−アセチルスルファニリルクロリド（１８６ｍｇ、０.７９６ｍｍｏｌ）を加え、溶液を室温で４８時間撹拌した。溶液を飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。生成物を、１０〜７０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、次いで凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：３５３ｍｇ（８７％）；¹ＨＮＭＲ（４００ＭＨｚ，メタノール−Ｄ₄）δ：１.５１−１.５７（ｍ，２Ｈ），１.５６−１.６５（ｍ，２Ｈ），１.６８（ｓ，９Ｈ），２.１４（ｓ，３Ｈ），２.３２−２.４１（ｍ，１Ｈ），３.２５（ｓ，３Ｈ），３.３５（ｔｄ，Ｊ＝１１.４７，２.６４Ｈｚ，２Ｈ），３.９３（ｄ，Ｊ＝２.９３ Ｈｚ，１Ｈ），３.９６（ｄ，Ｊ＝３.７１Ｈｚ，１Ｈ），４.５２（ｄ，Ｊ＝７.６２Ｈｚ，２Ｈ），７.３２（ｄｄ，Ｊ＝８.９８，２.１５Ｈｚ，１Ｈ），７.４５（ｄ，Ｊ＝８.９８ Ｈｚ，２Ｈ），７.５４（ｄ，Ｊ＝１.５６Ｈｚ，１Ｈ），７.７１（ｄ，Ｊ＝８.９８ Ｈｚ，２Ｈ），７.８８（ｄ，Ｊ＝８.９８Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝４９９.０；元素分析：計算値：Ｃ₂₆Ｈ₃₄Ｎ₄Ｏ₄Ｓ＋１.５ＴＦＡ ＋０.１Ｈ₂Ｏ：Ｃ，５１.８７；Ｈ，５.３６；Ｎ，８.３４；実測値：Ｃ，５１.９１；Ｈ，５.２８；Ｎ，８.２６。 Step A: N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) acetamide

2-tert-Butyl-N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine (for preparation, see steps BF below) (200 mg, 0. 663 mmol) and DMAP (16 mg, 0.132 mmol) were dissolved in DCM (10 mL). N-acetylsulfanyl chloride (186 mg, 0.796 mmol) was added and the solution was stirred at room temperature for 48 hours. The solution was washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The product was purified by reverse phase HPLC using 10-70% CH ₃ CN / H ₂ O and then lyophilized to give the title compound as the corresponding TFA salt. ^{Yield: 353mg (87%); 1} HNMR (400MHz, methanol _{-D 4) δ: 1.51-1.57 (m} , 2H), 1.56-1.65 (m, 2H), 1.68 ( s, 9H), 2.14 (s, 3H), 2.32-2.41 (m, 1H), 3.25 (s, 3H), 3.35 (td, J = 11.47, 2. 64 Hz, 2H), 3.93 (d, J = 2.93 Hz, 1H), 3.96 (d, J = 3.71 Hz, 1H), 4.52 (d, J = 7.62 Hz, 2H) 7.32 (dd, J = 8.98, 2.15 Hz, 1H), 7.45 (d, J = 8.98 Hz, 2H), 7.54 (d, J = 1.56 Hz, 1H) , 7.71 (d, J = 8.98 Hz, 2H), 7.88 (d, J = 8.98 Hz, 1H); MS (ESI) (M + H) ⁺ = 499.0; Elemental analysis: calculated value : C ₂₆ H ₃₄ N ₄ O ₄ S + 1 _{.5TFA + 0.1H 2 O: C,} 51.87; H, 5.36; N, 8.34; Found: C, 51.91; H, 5.28 ; N, 8.26.

クロロギ酸メチル（１３.２ｍＬ、１７０.２ｍｍｏｌ）を、４−フルオロ−３−ニトロアニリン（２４.１５ｇ、１５４.７ｍｍｏｌ）及びＤＩＰＥＡ（３５ｍＬ、２０１ｍｍｏｌ）の冷（０℃）ジクロロメタン（２００ｍＬ）溶液に加えた。反応混合物を室温で終夜撹拌した。溶液をジクロロメタン（２００ｍＬ）で希釈し、２ＭのＨＣｌ、ブラインで洗浄し、ＭｇＳＯ₄で乾燥した。溶媒を濃縮し、生成物を更に精製せずに次の工程で用いた。収量：３５.５ｇ（９９％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：３.８１（ｓ，３Ｈ），７.０２（ｓ，１Ｈ），７.２３（ｍ，１Ｈ），７.７２（ｄ，Ｊ＝８.５９Ｈｚ，１Ｈ），８.１７（ｄｄ，Ｊ＝６.３５，２.６４Ｈｚ，１Ｈ）。 Step B: Methyl (4-fluoro-3-nitrophenyl) carbamate

Methyl chloroformate (13.2 mL, 170.2 mmol) was added to a cold (0 ° C.) dichloromethane (200 mL) solution of 4-fluoro-3-nitroaniline (24.15 g, 154.7 mmol) and DIPEA (35 mL, 201 mmol). added. The reaction mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane (200 mL), washed with 2M HCl, brine and dried over MgSO ₄ . The solvent was concentrated and the product was used in the next step without further purification. Yield: 35.5 g (99%); ¹ HNMR (400 MHz, chloroform-D) δ: 3.81 (s, 3H), 7.02 (s, 1H), 7.23 (m, 1H), 7. 72 (d, J = 8.59 Hz, 1H), 8.17 (dd, J = 6.35, 2.64 Hz, 1H).

（４−フルオロ−３−ニトロフェニル）カルバミン酸メチル（２.０ｇ、９.３２ｍｍｏｌ）及び４−アミノメチルテトラヒドロピラン（１.２８ｇ、１１.２ｍｍｏｌ）を、ＴＥＡ（２.０ｍＬ、１４.０ｍｍｏｌ）を含むＥｔＯＨ（５０ｍＬ）中、７５℃で４８時間撹拌した。溶媒を蒸発させた。残留物をＥｔＯＡｃに溶解し、５％ＫＨＳＯ₄水溶液、飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。粗生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／１を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：２.５３ｇ（８８％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４２（ｍ，２Ｈ），１.７３（ｄ，Ｊ＝１.７６Ｈｚ，１Ｈ），１.７６（ｄ，Ｊ＝１.９５Ｈｚ，１Ｈ），１.８８−２.０１（ｍ，１Ｈ），３.２２（ｄｄ，Ｊ＝６.７４，５.５７Ｈｚ，２Ｈ），３.４２（ｔｄ，Ｊ＝１１.８６，２.０５Ｈｚ，２Ｈ），３.７８（ｓ，３Ｈ），４.０１（ｄ，Ｊ＝４.３０Ｈｚ，１Ｈ），４.０４（ｄ，Ｊ＝３.５１Ｈｚ，１Ｈ），６.４８（ｂｒ.ｓ，１Ｈ），６.８５（ｄ，Ｊ＝９.３７Ｈｚ，１Ｈ），７.６５（ｂｒ.ｓ，１Ｈ），８.０３−８.０９（ｍ，２Ｈ）。 Step C: Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} carbamate

Methyl (4-fluoro-3-nitrophenyl) carbamate (2.0 g, 9.32 mmol) and 4-aminomethyltetrahydropyran (1.28 g, 12.2 mmol) were added to TEA (2.0 mL, 14.0 mmol). In EtOH (50 mL) and stirred at 75 ° C. for 48 hours. The solvent was evaporated. The residue was dissolved in EtOAc, washed with 5% aqueous KHSO ₄ solution, saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The crude product was purified by silica gel flash chromatography using hexane / EtOAc = 1/1 as eluent. Yield: 2.53 g (88%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.42 (m, 2H), 1.73 (d, J = 1.76 Hz, 1H), 1.76 (d , J = 1.95 Hz, 1H), 1.88-2.01 (m, 1H), 3.22 (dd, J = 6.74, 5.57 Hz, 2H), 3.42 (td, J = 11.86, 2.05 Hz, 2H), 3.78 (s, 3H), 4.01 (d, J = 4.30 Hz, 1H), 4.04 (d, J = 3.51 Hz, 1H), 6.48 (br.s, 1H), 6.85 (d, J = 9.37 Hz, 1H), 7.65 (br.s, 1H), 8.03-8.09 (m, 2H).

｛３−ニトロ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝カルバミン酸メチル（２.５３ｇ、８.１８ｍｍｏｌ）を、触媒量の１０％Ｐｄ／Ｃを含むＥｔＯＡｃ（５０ｍＬ）に溶解した。溶液を水素雰囲気（４０ｐｓｉ）下、Parrの水素化装置を用いて、室温で終夜振盪した。溶液をCeliteを通して濾過し、溶媒を蒸発させた。収量：２.２９ｇ（９９％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４０（ｍ，２Ｈ），１.７０−１.７４（ｍ，１Ｈ），１.７４−１.７７（ｍ，１Ｈ），１.８１−１.９２（ｍ，１Ｈ），２.９９（ｄ，Ｊ＝６.６４Ｈｚ，２Ｈ），３.３４（ｂｒ.ｓ，２Ｈ），３.４１（ｄｔ，Ｊ＝１１.８１，２.１５Ｈｚ，２Ｈ），３.７４（ｓ，３Ｈ），３.９９（ｄ，Ｊ＝３.５１Ｈｚ，１Ｈ），４.０２（ｄ，Ｊ＝３.５１Ｈｚ，１Ｈ），６.３８（ｂｒ.ｓ，１Ｈ），６.５５−６.６０（ｍ，１Ｈ），６.６２−６.６８（ｍ，１Ｈ），６.９５（ｂｒ.ｓ，１Ｈ）。 Step D: Methyl {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} carbamate

Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} carbamate (2.53 g, 8.18 mmol) was added to a catalytic amount of 10% Pd / C in EtOAc (50 mL). ). The solution was shaken overnight at room temperature using a Parr hydrogenator under a hydrogen atmosphere (40 psi). The solution was filtered through Celite and the solvent was evaporated. Yield: 2.29 g (99%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.40 (m, 2H), 1.70-1.74 (m, 1H), 1.74-1.77 (M, 1H), 1.81-1.92 (m, 1H), 2.99 (d, J = 6.64 Hz, 2H), 3.34 (br.s, 2H), 3.41 (dt , J = 11.81, 2.15 Hz, 2H), 3.74 (s, 3H), 3.99 (d, J = 3.51 Hz, 1H), 4.02 (d, J = 3.51 Hz, 1H), 6.38 (br.s, 1H), 6.55-6.60 (m, 1H), 6.62-6.68 (m, 1H), 6.95 (br.s, 1H) .

｛３−アミノ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝カルバミン酸メチル（２.２９ｇ、８.２０ｍｍｏｌ）及びＤＭＡＰ（０.２０ｇ、１.６４ｍｍｏｌ）をＤＣＭ（７５ｍＬ）に溶解した。トリメチルアセチルクロリド（１.１０ｍＬ、９.０２ｍｍｏｌ）を滴下しながら加え、溶液を室温で２時間撹拌した。溶液をＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。残留物をＡｃＯＨ（２５ｍＬ）に溶解し、マイクロ波装置（Personal Chemistry製）を用いて、１２５℃で１時間加熱した。溶媒を蒸発させた。残留物をＥｔＯＡｃに溶解し、ＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。粗生成物を、溶離液としてヘキサン／アセトン＝４／３を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：１.８１ｇ（６４％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δｐｐｍ：１.４８−１.５４（ｍ，４Ｈ）１.５６（ｓ，９Ｈ）２.２３−２.３５（ｍ，１Ｈ）３.２７−３.３５（ｍ，２Ｈ）３.７８（ｓ，３Ｈ）３.９６（ｔ，Ｊ＝２.９３Ｈｚ，１Ｈ）３.９９（ｔ，Ｊ＝３.０３Ｈｚ，１Ｈ）４.１８（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ）６.６３（ｂｒ.ｓ，１Ｈ）７.２４−７.２８（ｍ，１Ｈ）７.４１（ｂｒ.ｓ，１Ｈ）７.６１（ｄ，Ｊ＝１.９５Ｈｚ，１Ｈ）。 Step E: [2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] methyl carbamate

Methyl {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} carbamate (2.29 g, 8.20 mmol) and DMAP (0.20 g, 1.64 mmol) were added to DCM (75 mL). ). Trimethylacetyl chloride (1.10 mL, 9.02 mmol) was added dropwise and the solution was stirred at room temperature for 2 hours. The solution was washed with aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The residue was dissolved in AcOH (25 mL) and heated at 125 ° C. for 1 hour using a microwave apparatus (Personal Chemistry). The solvent was evaporated. The residue was dissolved in EtOAc, washed with aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The crude product was purified by silica gel flash chromatography using hexane / acetone = 4/3 as eluent. Yield: 1.81 g (64%); ¹ HNMR (400 MHz, chloroform-D) δ ppm: 1.48-1.54 (m, 4H) 1.56 (s, 9H) 2.23-2.35 (m , 1H) 3.27-3.35 (m, 2H) 3.78 (s, 3H) 3.96 (t, J = 2.93 Hz, 1H) 3.99 (t, J = 3.03 Hz, 1H 4.18 (d, J = 7.42 Hz, 2H) 6.63 (br.s, 1H) 7.24-7.28 (m, 1H) 7.41 (br.s, 1H) 7.61 (D, J = 1.95 Hz, 1H).

［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］カルバミン酸メチル（１.８０ｇ、５.２１ｍｍｏｌ）を、ＴＨＦ（７５ｍＬ）に０℃で溶解した。１ＭのＨＣｌ／エーテル（７.３ｍＬ、７.２９ｍｍｏｌ）を滴下しながら加え、溶液を０℃で１５分間撹拌した。ＬｉＡｌＨ₄（９８８ｍｇ、２６.１ｍｍｏｌ）をゆっくり加え、溶液を室温で終夜撹拌した。反応を、０℃において、ＭｅＯＨ（５ｍＬ）、その後水（１０ｍＬ）を加えてクエンチし、そして、溶液を室温で３０分間撹拌した。無水Ｎａ₂ＳＯ₄（１０ｇ）を加え、溶液を室温で更に３０分間撹拌した。溶液を濾過し、溶媒を蒸発させた。残留物をＥｔＯＡｃに溶解し、ＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。溶媒を蒸発させた。収量：１.５４ｇ（９８％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.４９−１.５３（ｍ，４Ｈ），１.５３−１.５７（ｍ，９Ｈ），２.２２−２.３２（ｍ，１Ｈ），２.８７（ｓ，３Ｈ），３.２６−３.３５（ｍ，２Ｈ），３.９５（ｔ，Ｊ＝３.０３Ｈｚ，１Ｈ），３.９７−４.００（ｍ，１Ｈ），４.１３（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），６.６１（ｄｄ，Ｊ＝８.５９，２.１５Ｈｚ，１Ｈ），６.９９（ｄ，Ｊ＝１.９５Ｈｚ，１Ｈ），７.１１（ｄ，Ｊ＝８.５９Ｈｚ，１Ｈ）。 Step F: 2-tert-butyl-N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine

Methyl [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] carbamate (1.80 g, 5.21 mmol) was added to THF (75 mL) in 0. Dissolved at ° C. 1M HCl / ether (7.3 mL, 7.29 mmol) was added dropwise and the solution was stirred at 0 ° C. for 15 min. LiAlH ₄ (988 mg, 26.1 mmol) was added slowly and the solution was stirred at room temperature overnight. The reaction was quenched at 0 ° C. by the addition of MeOH (5 mL) followed by water (10 mL) and the solution was stirred at room temperature for 30 minutes. Anhydrous Na ₂ SO ₄ (10 g) was added and the solution was stirred at room temperature for an additional 30 minutes. The solution was filtered and the solvent was evaporated. The residue was dissolved in EtOAc, washed with aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The solvent was evaporated. Yield: 1.54 g (98%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.59-1.53 (m, 4H), 1.53-1.57 (m, 9H), 2.22 -2.32 (m, 1H), 2.87 (s, 3H), 3.26-3.35 (m, 2H), 3.95 (t, J = 3.03 Hz, 1H), 3.97 -4.00 (m, 1H), 4.13 (d, J = 7.42 Hz, 2H), 6.61 (dd, J = 8.59, 2.15 Hz, 1H), 6.99 (d, J = 1.95 Hz, 1H), 7.11 (d, J = 8.59 Hz, 1H).

Example 20
N- (4-{[[2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl) -2-piperidine -1-ylacetamide

４−アミノ−Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチルベンゼンスルホンアミド（製造は、以下の工程Ｂ〜Ｃを参照）（８０ｍｇ、０.０１７５ｍｍｏｌ）及びブロモアセチルクロリド（０.０３６ｍＬ、０.０４３８ｍｍｏｌ）を、触媒量のＤＭＡＰを含むＤＣＥ（３ｍＬ）中で、室温で３時間撹拌した。ピペリジン（０.０８６ｍＬ、０.０８７５ｍｍｏｌ）を加え、溶液をマイクロ波装置（Personal Chemistr製）を用いて、１２５℃で１５分間加熱した。溶液を飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。生成物を、１０〜７０％ＣＨ₃ＣＮ／Ｈ₂Ｏを用いた逆相ＨＰＬＣにより精製し、そして凍結乾燥して、標題の化合物を対応するＴＦＡ塩として得た。収量：７６ｍｇ（６２％）；¹ＨＮＭＲ（６００ＭＨｚ，ＣＤ₃ＯＤ）δ：１.４０−１.４５（ｍ，３Ｈ），１.４４−１.５２（ｍ，２Ｈ），１.５７（ｓ，９Ｈ），１.７−１.８０（ｍ，３Ｈ），１.８０−１.８７（ｍ，２Ｈ），２.２１−２.２８（ｍ，１Ｈ），２.９８（ｔ，Ｊ＝１１.０１Ｈｚ，２Ｈ），３.１５（ｓ，３Ｈ），３.２４（ｔ，Ｊ＝１１.３９Ｈｚ，２Ｈ），３.５０（ｍ，２Ｈ），３.８３（ｄ，Ｊ＝３.８４Ｈｚ，１Ｈ），３.８５（ｄ，Ｊ＝３.３３ Ｈｚ，１Ｈ），４.０１（ｓ，２Ｈ），４.４１（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.１８（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ），７.４０（ｄ，Ｊ＝８.７０Ｈｚ，２Ｈ），７.４９（ｓ，１Ｈ），７.６５（ｄ，Ｊ＝８.７０ Ｈｚ，２Ｈ），７.７６（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝ ５８２.０。 Step A: N- (4-{[[2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] (methyl) amino] sulfonyl} phenyl)- 2-piperidin-1-ylacetamide

4-amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide (See BC) (80 mg, 0.0175 mmol) and bromoacetyl chloride (0.036 mL, 0.0438 mmol) were stirred in DCE (3 mL) containing a catalytic amount of DMAP at room temperature for 3 hours. Piperidine (0.086 mL, 0.0875 mmol) was added and the solution was heated at 125 ° C. for 15 minutes using a microwave apparatus (Personal Chemistr). The solution was washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The product was purified by reverse phase HPLC using 10-70% CH ₃ CN / H ₂ O and lyophilized to give the title compound as the corresponding TFA salt. Yield: 76 mg (62%); ¹ H NMR (600 MHz, CD ₃ OD) δ: 1.40-1.45 (m, 3H), 1.44-1.52 (m, 2H), 1.57 (s 9H), 1.7-1.80 (m, 3H), 1.80-1.87 (m, 2H), 2.21-2.28 (m, 1H), 2.98 (t, J = 11.01 Hz, 2H), 3.15 (s, 3H), 3.24 (t, J = 11.39 Hz, 2H), 3.50 (m, 2H), 3.83 (d, J = 3) .84 Hz, 1H), 3.85 (d, J = 3.33 Hz, 1H), 4.01 (s, 2H), 4.41 (d, J = 7.42 Hz, 2H), 7.18 ( d, J = 8.96 Hz, 1H), 7.40 (d, J = 8.70 Hz, 2H), 7.49 (s, 1H), 7.65 (d, J = 8.70 Hz, 2H) , 7.76 (d, J = 8.96 Hz, 1H); MS (ES I) (M + H) ⁺ = 582.0.

２−ｔｅｒｔ−ブチル−Ｎ−メチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−アミン（６０ｍｇ、０.１９９ｍｍｏｌ）及びｐ−ニトロフェニルスルホニルクロリド（５７ｍｇ、０.２５９ｍｍｏｌ）を、触媒量のＤＭＡＰを含むＤＣＭ（３ｍＬ）中において、室温で終夜撹拌した。溶液を飽和のＮａＨＣＯ₃水溶液、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。粗生成物を、溶離液としてヘキサン／ＥｔＯＡｃ＝１／１を用いたシリカゲルフラッシュクロマトグラフィーにより精製した。収量：８９ｍｇ（９２％）；¹ＨＮＭＲ（４００ＭＨｚ，クロロホルム−Ｄ）δ：１.５０−１.６０（ｍ，１３Ｈ），２.２４−２.３５（ｍ，１Ｈ），３.２７（ｓ，３Ｈ），３.３０−３.３８（ｍ，２Ｈ），３.９９（ｔ，Ｊ＝２.８３Ｈｚ，１Ｈ），４.０２（ｔ，Ｊ＝２.９３Ｈｚ，１Ｈ），４.２０（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.１９−７.２３（ｍ，２Ｈ），７.２８−７.３５（ｍ，１Ｈ），７.７７（ｄ，Ｊ＝８.７９Ｈｚ，２Ｈ），８.３０（ｄ，Ｊ＝８.９８ Ｈｚ，２Ｈ）。 Step B: N- [2-tert-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methyl-4-nitrobenzenesulfonamide

2-tert-Butyl-N-methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine (60 mg, 0.199 mmol) and p-nitrophenylsulfonyl chloride (57 mg, 0 .259 mmol) was stirred in DCM (3 mL) containing a catalytic amount of DMAP at room temperature overnight. The solution was washed with saturated aqueous NaHCO ₃ solution, brine and dried over anhydrous MgSO ₄ . The crude product was purified by silica gel flash chromatography using hexane / EtOAc = 1/1 as eluent. Yield: 89 mg (92%); ¹ HNMR (400 MHz, chloroform-D) δ: 1.50-1.60 (m, 13H), 2.24-2.35 (m, 1H), 3.27 (s , 3H), 3.30-3.38 (m, 2H), 3.99 (t, J = 2.83 Hz, 1H), 4.02 (t, J = 2.93 Hz, 1H), 4.20 (D, J = 7.42 Hz, 2H), 7.19-7.23 (m, 2H), 7.28-7.35 (m, 1H), 7.77 (d, J = 8.79 Hz, 2H), 8.30 (d, J = 8.98 Hz, 2H).

Ｎ−［２−ｔｅｒｔ−ブチル−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−Ｎ−メチル−４−ニトロベンゼンスルホンアミド（８５ｍｇ、０.１７５ｍｍｏｌ）を、触媒量の１０％Ｐｄ／Ｃを含む、ＥｔＯＨ／ＥｔＯＡｃ＝１／１（２０ｍＬ）中に溶解した。溶液を、Parr水素化装置を用いて、水素雰囲気（４０ｐｓｉ）下、室温で１２時間振盪した。溶液をCeliteを通して濾過し、溶媒を蒸発させた。収量：８０ｍｇ（９９％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４５７.６。 Step C: 4-Amino-N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methylbenzenesulfonamide

N- [2-tert-butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -N-methyl-4-nitrobenzenesulfonamide (85 mg, 0.175 mmol). Dissolved in EtOH / EtOAc = 1/1 (20 mL), containing a catalytic amount of 10% Pd / C. The solution was shaken for 12 hours at room temperature under a hydrogen atmosphere (40 psi) using a Parr hydrogenator. The solution was filtered through Celite and the solvent was evaporated. Yield: 80 mg (99%); MS (ESI) (M + H) ⁺ = 457.6.

Example 20
N- [4-({[2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] -2 , 2-Dimethylpropanamide

２，２−ジメチルプロパノイルクロリド（３０μＬ、０.２４ｍｍｏｌ）を、４−アミノ−Ｎ−［２−（１，１−ジフルオロエチル）−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］ベンゼンスルホンアミド（１００ｍｇ、０.２２ｍｍｏｌ）（製造は以下の工程Ｂ〜Ｅを参照）及びＥｔ₃Ｎ（３７μＬ、０.２６ｍｍｏｌ）のＤＣＥ（１２ｍＬ）溶液に加えた。反応混合物を終夜撹拌し、溶媒を濃縮した。生成物を、１０〜９０％ＭｅＣＮ／水勾配を用いた逆相ＨＰＬＣにより精製し、標題の化合物のＴＦＡ塩を白色固体として得た。収量：１０５ｍｇ（８８％）；¹ＨＮＭＲ（６００ＭＨｚ，ＣＤ₃ＯＤ）δ：１.２５（ｓ，９Ｈ），１.３５−１.４８（ｍ，５Ｈ），２.１９（ｔ，Ｊ＝１９.２０Ｈｚ，３Ｈ），２.２３−２.２９（ｍ，１Ｈ），３.８９（ｄｄ，Ｊ＝１０.８８，３.２０Ｈｚ，２Ｈ），４.２８（ｄ，Ｊ＝７.６８Ｈｚ，２Ｈ），７.１８（ｄｄ，Ｊ＝８.８３，１.９２Ｈｚ，１Ｈ），７.４１（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.５５（ｄ，Ｊ＝８.９６Ｈｚ，１Ｈ），７.５９−７.７０（ｍ，４Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ＝５３５.０；元素分析：計算値：Ｃ₂₆Ｈ₃₂Ｆ₂Ｎ₄Ｏ₄Ｓ＋０.２ＴＦＡ＋０.８Ｈ₂Ｏ＋０.１ＭｅＣＮ：Ｃ，５５.４７；Ｈ，５.９７；Ｎ，９.９７；実測値：Ｃ，５５.４２；Ｈ，６.０２；Ｎ，９.９０。 Step A: N- [4-({[2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl ] -2,2-Dimethylpropanamide

2,2-Dimethylpropanoyl chloride (30 μL, 0.24 mmol) was added to 4-amino-N- [2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H. - benzimidazol-5-yl] benzenesulfonamide (100mg, 0.22mmol) (preparation following steps refer to B to E) were added to the DCE (12 mL) solution of and Et ₃ N (37μL, 0.26mmol) . The reaction mixture was stirred overnight and the solvent was concentrated. The product was purified by reverse phase HPLC using a 10-90% MeCN / water gradient to give the TFA salt of the title compound as a white solid. Yield: 105 mg (88%); ¹ HNMR (600 MHz, CD ₃ OD) δ: 1.25 (s, 9H), 1.35-1.48 (m, 5H), 2.19 (t, J = 19 .20Hz, 3H), 2.23-2.29 (m, 1H), 3.89 (dd, J = 10.88, 3.20Hz, 2H), 4.28 (d, J = 7.68Hz, 2H), 7.18 (dd, J = 8.83, 1.92 Hz, 1H), 7.41 (d, J = 1.79 Hz, 1H), 7.55 (d, J = 8.96 Hz, 1H) ), 7.59-7.70 (m, 4H); MS (ESI) (M + H) ⁺ = 535.0; Elemental analysis: calculated: C ₂₆ H ₃₂ F ₂ N ₄ O ₄ S + 0.2TFA + 0.8H ₂ O + 0.1 MeCN: C, 55.47; H, 5.97; N, 9.97; Found: C, 55.42; H, 6.02; N, 9.90.

ＨＡＴＵ（１.５８ｇ、４.１７ｍｍｏｌ）及びＮ−｛３−アミノ−４−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］フェニル｝アセトアミド（１.００ｇ、３.７ｍｍｏｌ）を、２，２−ジフルオロプロパン酸（０.４３ｇ、３.９８ｍｍｏｌ）及びＤＩＰＥＡ（０.８０ｍＬ、４.５５ｍｍｏｌ）のＤＭＦ（１００ｍＬ）溶液に、周囲温度で加えた。反応混合物を終夜撹拌し、溶媒を濃縮させた。中間体を８０℃で３時間、氷酢酸（１００ｍＬ）中で加熱し、溶媒を濃縮した。粗生成物をＤＣＭ（３００ｍＬ）に回収し、飽和のＮａＨＣＯ₃溶液（３×１００ｍＬ）、ブラインで洗浄し、無水ＭｇＳＯ₄で乾燥した。溶媒を濃縮し、生成物を、ＤＣＭ中ＭｅＯＨ（５％）、アセトン（１０％）を有する溶離液を用いた順相ＭＰＬＣで精製し、標題の化合物を白色固体として得た。収量：１.０７ｇ（８３％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝ ３３８.２。 Step B: N- [2- (1,1-Difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] acetamide

HATU (1.58 g, 4.17 mmol) and N- {3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} acetamide (1.00 g, 3.7 mmol), To a solution of 2-difluoropropanoic acid (0.43 g, 3.98 mmol) and DIPEA (0.80 mL, 4.55 mmol) in DMF (100 mL) was added at ambient temperature. The reaction mixture was stirred overnight and the solvent was concentrated. The intermediate was heated in glacial acetic acid (100 mL) at 80 ° C. for 3 h and the solvent was concentrated. The crude product was collected in DCM (300 mL), washed with saturated NaHCO ₃ solution (3 × 100 mL), brine and dried over anhydrous MgSO ₄ . The solvent was concentrated and the product was purified by normal phase MPLC using eluent with MeOH in DCM (5%), acetone (10%) to give the title compound as a white solid. Yield: 1.07 g (83%); MS (ESI) (M + H) ⁺ = 338.2.

Ｎ−［２−（１，１−ジフルオロエチル）−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］アセトアミド （１０７０ｍｇ、３.１７ｍｍｏｌ）、６ＭのＮａＯＨ水溶液（５ｍＬ）及びＭｅＯＨ（５ｍＬ）の混合物を、７０℃で２４時間加熱した。反応混合物を水（２００ｍＬ）で希釈し、生成物をＥｔＯＡｃ（４×１００ｍＬ）で抽出した。集めた有機層を無水Ｎａ₂ＳＯ₄で乾燥し、溶媒を濃縮して、標題の化合物を白色固体として得た。収量：９００ｍｇ（９６％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝２９６.２。 Step C: 2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine

N- [2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] acetamide (1070 mg, 3.17 mmol), 6M aqueous NaOH A mixture of (5 mL) and MeOH (5 mL) was heated at 70 ° C. for 24 hours. The reaction mixture was diluted with water (200 mL) and the product was extracted with EtOAc (4 × 100 mL). The collected organic layers were dried over anhydrous Na ₂ SO ₄ and the solvent was concentrated to give the title compound as a white solid. Yield: 900 mg (96%); MS (ESI) (M + H) ⁺ = 296.2.

４−ニトロベンゼンスルホニルクロリド（５６２ｍｇ、２.５３ｍｍｏｌ）を、２−（１，１−ジフルオロエチル）−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−アミン（５００ｍｇ、１.６９ｍｍｏｌ）及びＤＭＡＰ（４１３ｍｇ、３.３８ｍｍｏｌ）のＤＣＥ（４０ｍＬ）溶液に０℃で加えた。反応混合物を周囲温度まで温め、そして１時間撹拌した。溶媒を濃縮し、生成物を、２０〜９０％ＥｔＯＡｃ／ヘプタンを用いたシリカゲル上でのＭＰＬＣにより精製し、標題の化合物を白色固体として得た。収量：３７８ｍｇ（４７％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４８１.３。 Step D: N- [2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -4-nitrobenzenesulfonamide

4-Nitrobenzenesulfonyl chloride (562 mg, 2.53 mmol) was added to 2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-amine (500 mg, 1.69 mmol) and DMAP (413 mg, 3.38 mmol) in DCE (40 mL) at 0 ° C. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The solvent was concentrated and the product was purified by MPLC on silica gel using 20-90% EtOAc / heptane to give the title compound as a white solid. Yield: 378 mg (47%); MS (ESI) (M + H) ⁺ = 481.3.

Ｎ−［２−（１，１−ジフルオロエチル）−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−イル］−４−ニトロベンゼンスルホンアミド（３７８ｍｇ、０.７８ｍｍｏｌ）、Ｐｄ／Ｃ１０％（触媒量）及びＥｔＯＡｃ（５０ｍＬ）の混合物を、Parr（登録商標）水素化装置内で、水素圧（４０ｐｓｉ）下で終夜振盪した。反応混合物を、Celiteパッドを通して濾過し、溶媒を濃縮し、標題の化合物を白色固体として得た。収量：３６５ｍｇ（９９％）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４５１.３。 Step E: 4-Amino-N- [2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] benzenesulfonamide

N- [2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] -4-nitrobenzenesulfonamide (378 mg, 0.78 mmol) , Pd / C 10% (catalytic amount) and EtOAc (50 mL) were shaken overnight in a Parr® hydrogenator under hydrogen pressure (40 psi). The reaction mixture was filtered through a Celite pad and the solvent was concentrated to give the title compound as a white solid. Yield: 365 mg (99%); MS (ESI) (M + H) ⁺ = 451.3.

３−メチルブタン酸（２９ｍｇ、０.２４ｍｍｏｌ）を用いて、実施例２０の工程Ａに従い、標題化合物のＴＦＡ塩を白色固体として得た。収量：１１０ｍｇ（９２％）；¹ＨＮＭＲ（６００ＭＨｚ，ＣＤ₃ＯＤ）δ：０.９６（ｄ，Ｊ＝６.４０Ｈｚ，６Ｈ），１.３６−１.４９（ｍ，４Ｈ），２.０６−２.１６（ｍ，２Ｈ），２.１７−２.２３（ｍ，４Ｈ），２.２３−２.２８（ｍ，１Ｈ），３.２６−３.３５（ｍ，２Ｈ），３.８４−３.９３（ｍ，２Ｈ），４.２８（ｄ，Ｊ＝７.４２Ｈｚ，２Ｈ），７.１９（ｄｄ，Ｊ＝８.８３，１.９２Ｈｚ，１Ｈ），７.４２（ｄ，Ｊ＝１.７９Ｈｚ，１Ｈ），７.５６（ｄ，Ｊ＝８.７１Ｈｚ，１Ｈ），７.６３（ｓ，４Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝ ５３５.０；元素分析：計算値：Ｃ₂₆Ｈ₃₂Ｎ₄Ｏ₄Ｓ＋０.９ＴＦＡ＋０.７Ｈ₂Ｏ：Ｃ，５１.３８；Ｈ，５.３２；Ｎ，８.６２；実測値：Ｃ，５１.４４；Ｈ，５.３４；Ｎ，８.５３。 Example 21
N- [4-({[2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] -3 -Methylbutanamide

The TFA salt of the title compound was obtained as a white solid according to Step 20 of Example 20 using 3-methylbutanoic acid (29 mg, 0.24 mmol). Yield: 110 mg (92%); ¹ HNMR (600 MHz, CD ₃ OD) δ: 0.96 (d, J = 6.40 Hz, 6H), 1.36-1.49 (m, 4H), 2.06 -2.16 (m, 2H), 2.17-2.23 (m, 4H), 2.23-2.28 (m, 1H), 3.26-3.35 (m, 2H), 3 .84-3.93 (m, 2H), 4.28 (d, J = 7.42 Hz, 2H), 7.19 (dd, J = 8.83, 1.92 Hz, 1H), 7.42 ( d, J = 1.79 Hz, 1H), 7.56 (d, J = 8.71 Hz, 1H), 7.63 (s, 4H); MS (ESI) (M + H) ⁺ = 535.0; Elemental analysis: _{Calculated: C 26 H 32 N 4 O} 4 S + 0.9TFA + 0.7H 2 O: C, 51.38; H, 5.32; N, 8.62; Found: C, 51 .44; H, 5.34; N, 8.53.

４−（アセチルアミノ）ベンゼンスルホニルクロリド（６６ｍｇ、０.２８ｍｍｏｌ）を、２−（１，１−ジフルオロエチル）−１−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−１Ｈ−ベンゾイミダゾール−５−アミン（７０ｍｇ、０.２３ｍｍｏｌ）及びＤＭＡＰ（５８ｍｇ、０.４７ｍｍｏｌ）のＭｅＣＮ溶液に、７０℃で加えた。反応混合物を１時間撹拌し、そして、溶媒を濃縮した。生成物を、１０〜９０％ＭｅＣＮ／水の勾配を用いた逆相分取型ＨＰＬＣにより精製し、標題化合物のＴＦＡ塩を白色固体として得た。収量：４３ｍｇ（３０％）；¹ＨＮＭＲ（６００ＭＨｚ，ＣＤ₃ＯＤ）δ：１.３５−１.４８（ｍ，５Ｈ），２.０６−２.１３（ｍ，３Ｈ），２.１９（ｔ，Ｊ＝１９.４６Ｈｚ，３Ｈ），３.９０（ｄ，Ｊ＝９.４７Ｈｚ，２Ｈ），４.２８（ｄ，Ｊ＝７.６８Ｈｚ，２Ｈ），７.１８（ｄ，Ｊ＝６.４０Ｈｚ，１Ｈ），７.４１（ｓ，１Ｈ），７.５５（ｄ，Ｊ＝７.４２Ｈｚ，１Ｈ），７.５９−７.６７（ｍ，６Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺＝４９３.０。 [Example 22]
N- [4-({[2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazol-5-yl] amino} sulfonyl) phenyl] acetamide

4- (Acetylamino) benzenesulfonyl chloride (66 mg, 0.28 mmol) was dissolved in 2- (1,1-difluoroethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-benzimidazole-5 To a solution of amine (70 mg, 0.23 mmol) and DMAP (58 mg, 0.47 mmol) in MeCN was added at 70 ° C. The reaction mixture was stirred for 1 hour and the solvent was concentrated. The product was purified by reverse phase preparative HPLC using a 10-90% MeCN / water gradient to give the TFA salt of the title compound as a white solid. Yield: 43 mg (30%); ¹ HNMR (600 MHz, CD ₃ OD) δ: 1.35-1.48 (m, 5H), 2.06-2.13 (m, 3H), 2.19 (t , J = 19.46 Hz, 3H), 3.90 (d, J = 9.47 Hz, 2H), 4.28 (d, J = 7.68 Hz, 2H), 7.18 (d, J = 6. 40 Hz, 1H), 7.41 (s, 1H), 7.55 (d, J = 7.42 Hz, 1H), 7.59-7.67 (m, 6H); MS (ESI) (M + H) ⁺ = 493.0.

Claims (14)

Formula I:

(Where
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl)
Or a pharmaceutically acceptable salt, diastereomer, enantiomer, or a mixture thereof. The compound of claim 1, wherein:
R ¹ is selected from methyl, ethyl, propyl, isopropyl, t-butyl, 2,2-dimethyl-1-propyl, cyclopropyl and cyclobutyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl;
Compound. The compound of claim 1, wherein:
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are methyl;
Compound. The compound of claim 1, wherein:
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl;
R ² is selected from —H and methyl;
R ³ is methyl; and R ⁴ and R ⁵ are fluoro;
Compound. Less than:

And a pharmaceutically acceptable salt thereof. Formula I:

(Where
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally amino, cyano, halogen and C _2-5 heterocycloalkyl Substituted by one or more groups selected from:
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl)
Or a pharmaceutically acceptable salt, diastereomer, enantiomer, or a mixture thereof.   7. A compound according to any one of claims 1 to 6 for use as a medicament.   Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for treating pain.   Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for treating anxiety disorders.   Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for treating cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, gastrointestinal disorders and cardiovascular disorders.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.   A method of treating pain in a warm-blooded animal comprising administering to the animal in need thereof a therapeutically effective amount of a compound according to any one of claims 1-6. Formula I:

A process for the preparation of a compound of formula II wherein a compound of formula II is reacted with a compound of formula III

A method involving that.
Where
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl. Formula I:

Wherein the compound of formula IV:

The method comprising causing the compound to react with the ^{R 1 -C (= O) -X} .
Where
X is selected from -Cl, -Br and -I;
R ¹ is selected from C _1-6 alkyl and C _3-6 cycloalkyl optionally substituted by amino, cyano, halogen and C _2-5 heterocycloalkyl;
R ² is selected from —H and methyl; and R ³ , R ⁴ and R ⁵ are independently selected from fluoro and methyl.