JP2010535831A - Treatment of Duchenne muscular dystrophy - Google Patents

Abstract

が開示される。また、該化合物を含有する医薬組成物が提供される。また、該化合物及び組成物を使用して、デュシェンヌ型筋ジストロフィー、ベッカー型筋ジストロフィー及び悪液質を治療する方法が提供される。
【選択図】なしCompound of formula (1)

Is disclosed. Also provided are pharmaceutical compositions containing the compounds. Also provided are methods of treating Duchenne muscular dystrophy, Becker muscular dystrophy and cachexia using the compounds and compositions.
[Selection figure] None

Description

(Related application)
Priority is claimed herein for UK application GB0715939.5, filed August 15, 2007, entitled “TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY”. The disclosures of the above cited applications are hereby incorporated by reference in their entirety.
(Technical field)
A method of treating Duchenne muscular dystrophy is provided.

(background)
Duchenne muscular dystrophy (DMD) was first described more than 150 years ago by French neurologist Duchenne de Boulogne, and the disease was named after the universal inheritance associated with progressive deterioration of muscle function. Neuromuscular disease. DMD is characterized as an X-linked recessive genetic disorder that affects 1 in 3500 men due to mutations in the dystrophin gene. The gene is the largest in the human genome, includes 2.6 million base pairs of DNA, and contains 79 exons. Approximately 60% of dystrophin mutations are large insertions or deletions leading to downstream frameshift errors, while approximately 40% are point mutations or small frameshift rearrangements. The majority of DMD patients are deficient in dystrophin protein. Becker muscular dystrophy is a much milder form of DMD that results from a quantitative decrease or change in size of dystrophin protein. The high incidence of DMD (1 in 10,000 sperm or ovum) means that the disease will never be eliminated by genetic screening, and therefore an effective treatment is highly desirable.

  Several natural and genetically engineered DMD animal models exist and provide the main part for preclinical studies (Allamand, V. and Campbell, KP literature (animal models for muscular dystrophy: treatment Valuable tools for law development (Animal models for muscular dystrophy: valuable tools for the development of therapies)) (Hum. Mol. Genet. 9, 2459-2467 (2000))). All mouse, cat and dog models have mutations in the DMD gene, and biochemical dystrophinopathy similar to that seen in humans appears but is surprising and important with respect to their phenotype Indicates a mutation. Like humans, the dog (Golden retriever muscular dystrophy and German short-haired pointer) model has a severe phenotype; these dogs usually die of heart failure. Dogs provide the best phenocopy for human disease and are considered a high standard for preclinical studies. Unfortunately, raising these animals is expensive and difficult, and the clinical time course can vary between litters.

  The mdx mouse is the most widely used model due to availability, short gestation, time to maturity and relatively low cost (Bulfield, G., Siller, WG, Wight, PA and Moore, KJ (X chromosome-linked muscular dystrophy (mdx) in the mouse, Proc. Natl Acad. Sci. USA 81, 1189 to 1192 (1984)).

  Since the discovery of the DMD gene about 20 years ago, various degrees of success in the treatment of DMD have been achieved in preclinical animal studies, some of which have been followed up in humans. Current treatment strategies can be broadly classified into three groups: first, gene therapy efforts; second, cell therapy; and finally, pharmacological treatment. Gene-based and cell-based therapies offer the basic advantage of eliminating the need to heal secondary defects / conditions (eg contractures) separately, especially when initiated early in the course of the disease. Unfortunately, these efforts face several technical hurdles. In addition to toxicity, lack of stable expression and delivery difficulties, viral vectors, immunological responses to myoblasts and newly synthesized dystrophin have been reported.

  Pharmacological efforts to treat muscular dystrophy differ from gene-based and cell-based approaches in that they are not designed to deliver either missing genes and / or proteins. In general, pharmacological strategies use drugs / molecules in an attempt to improve the phenotype by such means as reducing inflammation, improving calcium homeostasis, and enhancing muscle progenitor cell proliferation or association. These strategies offer the advantage that the strategies can be easily delivered systemically and skillfully avoid many of the immunological and / or toxicity issues associated with vector and cell-based therapies. To do. Studies using corticosteroids and sodium cromoglycate to reduce inflammation, dantrolene to maintain calcium homeostasis, and clenbuterol to increase muscle strength have promising results, but all of these potential treatments It has not yet been shown to be effective in treating DMD.

  An alternative pharmacological approach is up-regulation therapy. Up-regulated therapy is based on increasing the expression of alternative genes that replace defective genes and is particularly advantageous when equipped with an immune response against previously absent proteins. Upregulation of eutrophin, an autosomal paralog of dystrophin, has been proposed as a potential treatment for DMD (Perkins and Davies (Neuromuscul Disord, S1: S78-S89 (2002)), Khurana and Davies (Nat Rev Drug Discov 2: 379-390 (2003)). When utrophin is overexpressed in transgenic mdx mice, utrophin is localized in the sarcolemma of muscle cells and restores dystrophin-associated protein complex (DAPC) components, thereby causing dystrophin generation Prevent and then lead to functional improvement of skeletal muscle. Delivery of utrophin by adenovirus in dogs has been shown to prevent disease states. It may be beneficial to initiate high utrophin expression immediately after birth in a mouse model, and no toxicity is observed when utrophin is ubiquitously expressed, which translates this therapy into humans It is promising. Up-regulating endogenous utrophin to a level sufficient to alleviate the pathology can be achieved by delivering small diffusible compounds.

が提供される
（式中、
R₉は、0〜4個のヘテロ原子を含有する部分的に又は完全に芳香族でありかつ1〜4個のハロゲン、C₁-C₆アルキル、OC₁-C₆アルキル又はNR₉₀(C=Q)-M-Z-R₉₃によって任意に置換されるC_5-10炭素環を表し、この中で、R₉₀は、H又はC_1-6アルキルを表し、Qは、O、S、又はNR₉₁を表し、この中でR₉₁は、H又はC_1-6アルキルを表し、Mは、ハロゲン、C_1-6アルキル、又はC_1-6アルコキシで任意に置換されるC_1-3アルキルを表し、Zは、O、S又はNR₉₂を表し、この中で、R₉₂は、H又はC_1-6アルキルを表し、及びR₉₃は、0〜4個のヘテロ原子を含有する部分的に又は完全に芳香族でありかつ1〜4個のハロゲン、C₁-C₆アルキル又はOC₁-C₆アルキルによって任意に置換されるC_5-10炭素環を表し；
A₁、A₂、A₃及びA₄のうちの3つは、CHを表し、かつA₁、A₂、A₃及びA₄のうちの1つはCR₁を表し、
この中で、R₁は、下記を表す：
ヒドロキシル、ハロゲン、カルボン酸、ピペリジン-1-イル、N-モルフォリノ、-NMe₂又は（C_1-6アルコキシ等の）アルコキシで任意に置換されるC₂-C₃アルキル、n-ブチル及びsec-ブチルから選択されたアルキル基；
ヒドロキシル、ハロゲン、CO₂(C_1-6アルキル)、又はハロゲン、カルボン酸、ピペリジン-1-イル、N-モルフォリノ、-NMe₂若しくは（C_1-6アルコキシ等の）アルコキシで置換された-O(C_1-6アルキル)若しくはC₁アルキル；
ヒドロキシル、ハロゲン、CO₂(C_1-6アルキル)、又は-O(C_1-6アルキル)；
-N-(S)-2-アミノ-3-ヒドロキシプロピオンアミド；
-N-(S)-2-(メチルアミノ)プロピオンアミド；
-N-(S)-2-アミノプロピオンアミド；
-N-2-メチルアミノアセトアミド；
-(S=O)R₂₁（式中、R₂₁はC₁-C₆アルキルを表す。）；
-SO_nR₂₂（式中、n＝0、1又は2であり、かつR₂₂は、OHで任意に置換され又はヒドロキシルで置換されたエチルで任意に置換されるCH₃、CH₂CD₃又はC_3-6アルキルを表す。）；
-SO₂NR₅₅R₂₃（式中、同一又は異別であり得るR₂₃及びR₅₅は各々、H又はC_1-6アルキルを表す。）；
-NR₅₆SO_nR₂₄（式中、n＝0、1又は2であり、かつ同一又は異別であり得るR₂₄及びR₅₆が各々、H又はC₁-C₆アルキルを表す。）；
-K-SO_n-R₂₈（式中、Kは、C₁-C₆アルキルで任意に置換されるC₁-C₃アルキルを表し、n＝0〜2であり、かつR₂₈は、1つ以上のヒドロキシ、ハロゲン、（C_1-6アルコキシ等の）アルコキシ又はアミンで任意に置換されるC₁-C₁₀アルキルを表す。）；
-CO₂R₂₆（式中、R₂₆はC_1-6アルキルを表す。）；
二置換のホスフィン酸塩（この中で、同一又は異別であり得る各置換体は、C_1-6アルキル又はC_5-10アリールを表し得る）；
1つ以上のオキソ、ヒドロキシル、ハロゲン、C₁-C₆アルキル、（C_1-6アルコキシ等の）アルコキシ又は（C_5-10アリール等の）アリール置換体によって置換されたN結合型単環式又は二環式の環；又は
NR₁₅C(=W)R₁₇（式中、
Wは、NH、S又はOを表し；
R₁₇は、C₂-アルキル、n-プロピル、又はC₄-C₁₀アルキル；1つ以上のハロゲン、ヒドロキシル、（C_1-6アルコキシ等の）アルコキシ又はアミンで置換されたC₁-C₁₀アルキル；1つ以上のC_1-6アルキル基で任意に置換されるC₁-C₄アルキル基を介してアノマー位で結合した単糖類又は二糖類単位；CH₂アリール（式中、アリールは、（5〜10員の芳香族炭化水素等の）芳香族炭化水素又は、炭素のほかに環構成成分として酸素原子、硫黄原子及び窒素原子から選択される1〜4個のヘテロ原子を含有する5〜10員の芳香族複素環を表す。）；-CH₂OCH₃、-CH₂OCH₂CH₂OCH₃、CH₂ピペリジン-1-イル又はCH₂-N-モルフォリノイルを表し；
R₁₅は、H、C_1-6アルキルを表し、又はR₁₇とともに-CH₂CH₂-、-CH₂ CH₂-、又は-CH₂CH₂CH₂-を表し；
Xは、O又はNであり；及び
Yは、O又はNである。）。 (Explanation)
Provided are compounds that upregulate endogenous utrophin in predictive screening and thus may be useful in the treatment of DMD.
In one embodiment, the compound of formula (1)

Is provided (where
R ₉ is partially or fully aromatic containing 0 to 4 heteroatoms and 1 to 4 halogens, C ₁ -C ₆ alkyl, OC ₁ -C ₆ alkyl or NR ₉₀ (C = Q) -MZR ₉₃ represents a C _5-10 carbocyclic ring optionally substituted, wherein R ₉₀ represents H or C _1-6 alkyl, and Q represents O, S, or NR ₉₁ In which R ₉₁ represents H or C _1-6 alkyl, M represents C _1-3 alkyl optionally substituted with halogen, C _1-6 alkyl, or C _1-6 alkoxy; Z represents O, S or NR ₉₂ , in which R ₉₂ represents H or C _1-6 alkyl, and R ₉₃ is partially or completely containing 0 to 4 heteroatoms. _Represents a C _5-10 carbocycle which is aromatic and optionally substituted by _{1 to} 4 halogens, C ₁ -C ₆ alkyl or OC ₁ -C ₆ alkyl;
Three of A _1, A _2, A ₃ and A ₄ represent CH, and one of A _1, A _2, A ₃ and A ₄ represent CR _1,
In this, R ₁ represents:
C ₂ -C ₃ alkyl, n-butyl and sec- optionally substituted with hydroxyl, halogen, carboxylic acid, piperidin-1-yl, N-morpholino, -NMe ₂ or alkoxy (such as C _1-6 alkoxy) An alkyl group selected from butyl;
Hydroxyl, halogen, CO ₂ (C _1-6 alkyl), or —O substituted with halogen, carboxylic acid, piperidin-1-yl, N-morpholino, —NMe ₂ or alkoxy (such as C _1-6 alkoxy) (C _1-6 alkyl) or C ₁ alkyl;
Hydroxyl, halogen, CO ₂ (C _1-6 alkyl), or —O (C _1-6 alkyl);
-N- (S) -2-amino-3-hydroxypropionamide;
-N- (S) -2- (methylamino) propionamide;
-N- (S) -2-aminopropionamide;
-N-2-methylaminoacetamide;
-(S = O) R ₂₁ (wherein R ₂₁ represents C ₁ -C ₆ alkyl);
—SO _n R ₂₂ (wherein n = 0, 1 or 2 and R ₂₂ is CH ₃ , CH ₂ CD ₃ optionally substituted with ethyl optionally substituted with OH or substituted with hydroxyl) Or represents C _3-6 alkyl);
-SO ₂ NR ₅₅ R ₂₃ (wherein, may be identical or different R ₂₃ and R ₅₅ each represent H or C _1-6 alkyl.);
-NR ₅₆ SO _n R ₂₄ (wherein, a n = 0, 1 or 2 and represents the same or different in possible R ₂₄ and R ₅₆ are each, H, or C ₁ -C ₆ alkyl.);
-K-SO _n -R _{28 wherein} K represents C ₁ -C ₃ alkyl optionally substituted with C ₁ -C ₆ alkyl, n = 0-2, and R ₂₈ is 1 Represents C ₁ -C ₁₀ alkyl optionally substituted with one or more hydroxy, halogen, alkoxy (such as C _1-6 alkoxy) or amine);
-CO ₂ R ₂₆ (wherein, R ₂₆ represents C _1-6 alkyl.);
Disubstituted phosphinates, wherein each substituent, which may be the same or different, may represent C _1-6 alkyl or C _5-10 aryl;
N-linked monocyclic substituted by one or more oxo, hydroxyl, halogen, C ₁ -C ₆ alkyl, alkoxy (such as C _1-6 alkoxy) or aryl substituents (such as C _5-10 aryl) Or a bicyclic ring; or
NR ₁₅ C (= W) R ₁₇ (where
W represents NH, S or O;
R ₁₇ is C ₂ -alkyl, n-propyl, or C ₄ -C ₁₀ alkyl; C ₁ -C ₁₀ substituted with one or more halogen, hydroxyl, alkoxy (such as C _1-6 alkoxy) or amine Alkyl; a monosaccharide or disaccharide unit bonded in the anomeric position via a C ₁ -C ₄ alkyl group optionally substituted with one or more C _1-6 alkyl groups; CH ₂ aryl, wherein aryl is 5 containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring component in addition to carbon (aromatic hydrocarbons such as 5- to 10-membered aromatic hydrocarbons) or carbon represents an aromatic heterocycle to _{10-membered); -. CH 2 OCH 3} , represents a _{-CH 2 OCH 2 CH 2 OCH 3} , CH 2 piperidin-1-yl or CH _{2-N-morpholinoethyl-yl;}
R ₁₅ represents H, C _1-6 alkyl, or together with R ₁₇ represents —CH ₂ CH ₂ —, —CH ₂ CH ₂ —, or —CH ₂ CH ₂ CH ₂ —;
X is O or N; and
Y is O or N. ).

Compounds of formula I may exist in tautomeric, enantiomeric and diastereomeric forms, all of which are included within the scope of this disclosure.
Certain compounds of formula I are novel. The novel compounds of formula I are also provided with a process for preparing the compounds, compositions containing the compounds, and use of the compounds as pharmaceuticals.
Some of the compounds that fall within the scope of Formula I are known per se but are not pharmaceutically. Also provided are compounds that are known per se in the art but have not been previously described as pharmaceuticals for use as pharmaceuticals.

The present disclosure will now be described in detail with reference to the accompanying figures:
FIG. 1 shows a luciferase reporter assay (mouse H2K cells). FIG. 2 shows dose-dependent luciferase induction. FIG. 3 shows an example of anterior tibial muscle section stained using a mouse utrophin specific antibody. FIG. 4 shows that mice exposed to CPD-A (V2 and V3) showed high levels of utrophin expression compared to controls.

  All compounds of formula I can be prepared by conventional methods. Methods for preparing heteroaromatic ring systems are well known in the art. In particular, synthetic methods are described in AR Katritzk and CW Rees (Comprehensive Heterocyclic Chemistry, Vol. 1, Pergamon Press, Oxford, 1984) and Alan R. Katritzky, Charles W. Rees and EFV Scriven (Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995) (Structure, reaction, synthesis of heterocyclic compounds) And Pergamon Pr, June 1996), and The Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds). Other common sources that may be aimed at synthesizing compounds of interest include March (Advanced Organic Chemistry: Reactions, Mechanisms, and Structure), Wiley -Interscience; 5th edition (January 15, 2001)) is included. Of particular relevance are the synthesis methods discussed in WO2006 / 044503.

スキーム1
反応条件：
i．R⁹CO₂H（又はR⁹COCl）、PPA、熱；又はR⁹COCl、ジオキサン、マイクロ波、次いでNaOH
ii．R⁹COCl、ピリジン、室温
iii．TsOH、キシレン
iv．R⁹CO₂H、HATU、ピリジン、DMF
v．PPA、熱
vi．HATU、DMF、ⁱPr₂NEt、アルキルNH₂、室温
ベンゾオキサゾールIの生成は、上述に説明されるような多様な方法において実施できる。 Some general methods for synthesis are as follows.
A benzoxazole of formula I or a pharmaceutically acceptable salt thereof can be prepared from a compound of formula II.

Scheme 1
Reaction conditions:
i. R ⁹ CO ₂ H (or R ⁹ COCl), PPA, heat; or R ⁹ COCl, dioxane, microwave, then NaOH
ii. R ⁹ COCl, pyridine, room temperature
iii. TsOH, xylene
iv. R ⁹ CO ₂ H, HATU, pyridine, DMF
v. PPA, heat
vi. The formation of HATU, DMF, ⁱ Pr ₂ NEt, alkyl NH ₂ , room temperature benzoxazole I can be carried out in various ways as described above.

  For example, a compound of formula II is reacted with an acyl derivative such as an acid or acid chloride and heated at a suitable solvent and a suitable temperature in the presence of an acid catalyst such as polyphosphoric acid. This will be described above as step (i).

  The reaction can be carried out in an aprotic solvent, in one embodiment in a polar aprotic solvent such as tetrahydrofuran, at a temperature of -10 ° C to + 150 ° C. In general, the reaction can be carried out at normal pressure and at the reflux temperature of the solvent.

Alternatively, the compound of formula II can first react with an excess of acyl derivative R ⁹ COX (where X is for example Cl), whereby acylation occurs in both oxygen and nitrogen. This can occur, for example, by reaction in pyridine at room temperature (step ii). Next, ring closure to produce a compound of formula II can occur in a subsequent ring closure step in which the doubly acylated product is heated in xylene, for example in the presence of an acid catalyst such as sulfonic acid (step iii). ).

  Another illustrative example for the production of compounds of formula I is shown by steps iv and v. First, an amine is coupled with an acid using a peptide coupling reagent. The available coupling reagents are well known to those skilled in the art and include HBTU, TBTU and HATU. Amide formation in the presence of a suitable coupling reagent occurs in DMF in the presence of a nucleophilic catalyst such as pyridine, for example.

スキーム2
反応条件：
i．（i）に関する限り；スキーム1
ii．R¹⁷COCl、ピリジン（又はNEt₃、DCM）；又はR⁹CO₂H、HATU、ピリジン、DMF
iii．（i）に関する限り；スキーム1
iv．SnCl₂、EtOH、熱；又はPd/C、H₂、IMS；又はFe、NH₄Cl、IMS/水、熱
v．R⁹NCO、DCM、室温
vi．NaBH(OAc)₃、R¹⁰CHO、DCE、室温
vii．R¹⁴SO₂Cl、ピリジン、DCM、室温 When R ¹ = CO ₂ H, this acid can be coupled with the amine shown by step (vi). Suitable coupling conditions include the use of HATU in DMF in the presence of ⁱ Pr ₂ NEt, R ¹⁶ NH ₂ at room temperature.
Of particular interest are compounds in which the 6-membered ring is substituted with an amide derivative. The compound can be generated from the intermediate amine derivative III.

Scheme 2
Reaction conditions:
i. As far as (i) is concerned; Scheme 1
ii. R ¹⁷ COCl, pyridine (or NEt ₃ , DCM); or R ⁹ CO ₂ H, HATU, pyridine, DMF
iii. As far as (i) is concerned; Scheme 1
iv. SnCl ₂ , EtOH, heat; or Pd / C, H ₂ , IMS; or Fe, NH ₄ Cl, IMS / water, heat
v. R ⁹ NCO, DCM, room temperature
vi. NaBH (OAc) ₃ , R ¹⁰ CHO, DCE, room temperature
vii. R ¹⁴ SO ₂ Cl, pyridine, DCM, room temperature

Intermediate amine III can be obtained by using or as an alternative to scheme 1 step (i) (wherein R ¹ = NH ₂ ), or alternatively, steps 2 (iii) and (iv) of scheme 2. ) Can be synthesized either in the two-step process defined by. Also, a nitro substituted benzoxazole derivative V is produced from a nitro substituted phenyl derivative IV in a manner similar to that described by step 1 of Scheme 1, and then in a subsequent step nitro- Reduction of the benzoxazole derivative V yields the intermediate amine III. Those skilled in the art are well aware of suitable methods for reducing nitro groups to give amines. Selective methods for reducing NO ₂ to NH ₂ include heating in the presence of Sn / HCl or NH ₄ Cl at a temperature of 0-80 ° C. or in iron, industrial modified alcohol / water H ₂ / Pd / C in a suitable solvent such as ethanol is included.

式VIのアミド誘導体は、アミンIIIをアシル誘導体とカップリングさせることによって生成できる。このことは、例えば、ピリジンにおける又はCH₂Cl₂における適切な酸塩化物の反応によって達成できる（工程ii）。 The intermediate amine III can then be coupled or derivatized as needed (see, eg, Scheme 2a).

Amide derivatives of formula VI can be generated by coupling amine III with an acyl derivative. This can be achieved, for example, by reaction of a suitable acid chloride in pyridine or in CH ₂ Cl ₂ (step ii).

The sulfonamide derivative VII can be produced, for example, by reacting the appropriate sulfonyl chloride in CH ₂ Cl ₂ with amine III at room temperature in the presence of pyridine.
Amine derivative VIII can be generated by use of a suitable reductive amination strategy. Methods for reductive amination are well known in the art. The method includes, for example, reacting an amine with a suitable aldehyde and sodium triacetoxyborohydride in 1,2-dichloroethane.

スキーム3
反応条件：
i．R⁹COCl、ピリジン、室温
ii．Na₂S、S₈、IMS、熱
iii．Fe、NH₄Cl、IMS、熱
iv．R¹⁷COCl、ピリジン（又はNEt₃、DCM）；又はR¹⁷CO₂H、HATU、ピリジン、DMF Urea derivatives of formula IX can be produced, for example, by reacting amine III with the appropriate isocyanate in CH ₂ Cl ₂ at room temperature.
A benzothiazole of formula X or a pharmaceutically acceptable salt thereof can be prepared from a compound of formula XI.

Scheme 3
Reaction conditions:
i. R ⁹ COCl, pyridine, room temperature
ii. Na ₂ S, S ₈ , IMS, heat
iii. Fe, NH ₄ Cl, IMS, heat
iv. R ¹⁷ COCl, pyridine (or NEt ₃ , DCM); or R ¹⁷ CO ₂ H, HATU, pyridine, DMF

  A compound of formula XI can be converted to the corresponding amide, for example by reaction with a suitable acid chloride in pyridine (step (i)) or by using a suitable peptide coupling reagent. Such methods are well known to those skilled in the art, as discussed above.

スキーム4
反応条件：
i．R⁹CO₂H、PPA、熱；又はR⁹COCl、ピリジン；次いでPPA、熱
ii．SnCl₂、IMS、熱；又はPd/C、H₂、IMS
iii．R¹⁷COCl、ピリジン等（スキーム1による）
iv．R⁴NH₂、DMSO、塩基、熱
v．亜ジチオン酸ナトリウム、THF/水；（ii）も参照 The amide can then be converted to the nitrobenzothiazole of formula XII in a one-pot approach involving reaction with Na ₂ S, S ₈ at elevated temperatures in industrial modified alcohols. The nitro derivative XII can be reduced as previously discussed, and the resulting primary amine is similar to the primary amine in steps (ii), (v), (vi) and (vii) of Scheme 2. Can be operated in style.

Scheme 4
Reaction conditions:
i. R ⁹ CO ₂ H, PPA, heat; or R ⁹ COCl, pyridine; then PPA, heat
ii. SnCl ₂ , IMS, heat; or Pd / C, H ₂ , IMS
iii. R ¹⁷ COCl, pyridine, etc. (according to Scheme 1)
iv. R ⁴ NH ₂ , DMSO, base, heat
v. Sodium dithionite, THF / water; see also (ii)

  The benzimidazole of formula XII can be generated according to Scheme 4. Reaction of a diaminophenyl derivative of formula XIII with an acyl derivative such as acid or acid chloride in the presence of an acid catalyst such as polyphosphoric acid in a suitable solvent at a suitable temperature produces a benzimidazole derivative of formula XII. Is done. This will be described above as step (i). The nitro group can then be reduced and manipulated to produce other functional groups as discussed above.

スキーム5
反応条件：
i．Na₂S水和物、MeOH、NH₄Cl、水；又はNa₂S₂O₄/EtOH；又はSnCl₂、EtOH
ii．（i）に関する限り、スキーム1；又はR⁹COCl、ピリジン；次いでPPA、熱
iii．SnCl₂、EtOH、熱
iv．R¹B(OH)₂、Pd(PPh₃)₄、K₂CO₃、ジオキサン/水、マイクロ波
v．R¹⁷COCl、ピリジン、室温
vi．EtOC(S)SK、ピリジン、熱
vii．SOCl₂；又はPOCl₃
viii．R³B(OH)₂、Pd(PPh₃)₄、K₂CO₃、溶媒
ix．PPA、R²CO₂H熱 Alternatively, the benzimidazole is a dinitro compound of formula XIV (wherein X represents a leaving group, and in one embodiment a halogen such as chlorine or fluorine, for example in DMSO at elevated temperatures in the presence of a base. .) Can be produced by reacting with an amine. A subsequent selective reduction of one nitro group using sodium dithionite in THF / water can then occur to give the diamine of formula XV. The ring closure to produce the benzimidazole and manipulation of the nitro group can then proceed as described and discussed above.

Scheme 5
Reaction conditions:
i. Na ₂ S hydrate, MeOH, NH ₄ Cl, water; or Na ₂ S ₂ O ₄ / EtOH; or SnCl ₂ , EtOH
ii. As far as (i) is concerned, scheme 1; or R ⁹ COCl, pyridine; then PPA, heat
iii. SnCl _2, EtOH, heat
iv. R ¹ B (OH) ₂ , Pd (PPh ₃ ) ₄ , K ₂ CO ₃ , dioxane / water, microwave
v. R ¹⁷ COCl, pyridine, room temperature
vi. EtOC (S) SK, pyridine, heat
vii. SOCl ₂ ; or POCl ₃
viii. R ³ B (OH) ₂ , Pd (PPh ₃ ) ₄ , K ₂ CO ₃ , solvent
ix. PPA, R ² CO ₂ H fever

  Benzoxazoles of formula XVI can be prepared by methods analogous to those discussed above. For example, the method described in (ix) above includes heating the compound of formula XVII in a suitable solvent in the presence of an acid catalyst and a suitable acyl derivative, such as a carboxylic acid.

  Benzoxazoles of formula XVIII and XIX can be synthesized from the appropriate nitro compound of formula XX. Reduction of the nitro compound XX yields the corresponding aminoalcohol XXI (eg, using either Sn / HCl or other suitable methods well known to those skilled in the art). The formation of benzoxazole via reaction of aminoalcohol with the appropriate acyl derivative can then be achieved using any of the methods disclosed above.

Then, for oxazoles of formula XXIII where X = Br, the Suzuki coupling reaction can be used to yield further derivatives. Examples of suitable conditions are R ¹ B (OH) ₂ , Pd (PPh ₃ ) ₄ , K ₂ CO ₃ , dioxane / water, microwaves, in which the benzoxazole of formula XIX results . Those skilled in the art are familiar with the Suzuki coupling reaction and can easily manipulate the conditions to produce a wide variety of compounds.

For the oxazole produced by step (ii) where X = NO ₂ , the nitro group can be reduced to the corresponding amine using any of the methods well known to those skilled in the art discussed above. The amine can then be manipulated, for example, using any of the methods discussed in Scheme 2 above, to give, for example, a compound of formula XVIII.

Alternatively, a benzoxazole of formula XVIII can also be prepared from a compound of formula XX via thiocarbamate XXII and is produced by heating a compound of formula XX with EtOC (S) SK in pyridine. Compounds of formula XXII can be converted to chlorides of formula XXIII by use of well known reagents such as SOCl ₂ or POCl ₃ . For example, Suzuki coupling using the conditions described by step viii above gives the benzoxazole of formula XVIII.

In the processes described above, it may be necessary to protect functional groups present in the starting material, such as hydroxy groups or amino groups, and thus to produce one or more protecting groups to produce a compound of formula I. It may be necessary to remove.
Suitable protecting groups and methods for the removal of the protecting groups are described, for example, in T. Greene and PGM Wutts (“Protective Groups in Organic Synthesis”, John Wiley and Sons Inc., 1991). ). For example, a hydroxy group can be protected by an arylmethyl group such as phenylmethyl, diphenylmethyl or triphenylmethyl; an acyl group such as acetyl, trichloroacetyl or trifluoroacetyl; or as a tetrahydropyranyl derivative. Suitable amino protecting groups include benzyl, arylmethyl groups such as (R, S) -α-phenylethyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl. Conventional deprotection methods including hydrogenolysis, acid or base hydrolysis, or photolysis can be used. For example, arylmethyl groups can be removed by hydrogenolysis in the presence of a metal catalyst such as palladium on charcoal. Tetrahydropyranyl groups can be cleaved by hydrolysis under acidic conditions. Acyl groups can be removed by hydrolysis using a base such as sodium hydroxide or potassium carbonate, or groups such as trichloroacetyl can be removed by reduction using, for example, zinc and acetic acid.

Compounds of formula I and their salts can be isolated from their reaction mixtures using conventional techniques.
A salt of a compound of formula I may be generated by reacting the free acid, or salt thereof, or the free base, or salt or derivative thereof, with one or more equivalent suitable bases or acids. The reaction can be carried out in a salt insoluble solvent or medium, or in a salt soluble solvent such as ethanol, tetrahydrofuran or diethyl ether which can be removed in vacuo or by lyophilization. The reaction can also be a metathesis treatment or the reaction can be carried out in an ion exchange resin.

  Pharmaceutically acceptable salts of the compounds of formula I include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; group III element salts such as aluminum salts; and Ammonium salts are included. A salt with a suitable organic base, for example a salt with hydroxylamine; a lower alkylamine, for example methylamine or ethylamine; a substituted lower alkylamine, for example a salt with an alkylamine substituted with hydroxy; or monocyclic Formula nitrogen heterocycles, eg salts with piperidine or morpholine; and salts with amino acids (eg arginine, lysine etc.) or N-alkyl derivatives thereof; or amino sugars, eg N-methyl-D-glucamine or Salts with glucosamine are included. In one embodiment, non-toxic physiologically acceptable salts are provided, but other salts are also useful, for example, in isolating or purifying the product.

  Diastereoisomers can be separated using conventional techniques, for example, chromatography or fractional crystallization. The various optical isomers can be isolated by separation of racemic or other mixtures of compounds using conventional techniques such as fractional crystallization or HPLC. Alternatively, the desired optical isomer can be prepared by reaction of appropriate optically active starting materials under conditions that will not result in racemization.

Substituents that alkyl may represent include methyl, ethyl, butyl, such as sec-butyl.
Halogen may represent F, Cl, Br and I, in particular Cl.
A reference to a specific element should be construed to include all isotopes of the specific element.

In a group of compounds that may be described, A ₁ , A ₂ and A ₄ represent CH and A ₃ represents CR ₁ .
In a group of compounds, R ₉ represents 2-naphthyl.
In another group of compounds that may be described, R ₉ represents 2-naphthyl optionally substituted with halogen, or phenyl optionally substituted with halogen;
A ₁ , A ₂ and A ₄ represent CH and A ₃ represents CR ₁ in which R ₁ represents:
NR ₁₅ C (= W) R ₁₇ (where
W represents NH, S or O;
R ₁₇ is C ₂ -alkyl, n-propyl, or C ₄ -C ₁₀ alkyl; C ₁ -C ₁₀ substituted with one or more halogen, hydroxyl, alkoxy (such as C _1-6 alkoxy) or amine Alkyl; a monosaccharide or disaccharide unit bonded in the anomeric position via a C ₁ -C ₄ alkyl group optionally substituted with one or more C _1-6 alkyl groups; CH ₂ aryl, wherein aryl is 5 containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring component in addition to carbon (aromatic hydrocarbons such as 5- to 10-membered aromatic hydrocarbons) or carbon represents an aromatic heterocycle _{10-membered);. CH 2 OCH 3,} CH 2 OCH 2 CH 2 OCH 3, represents a CH ₂ piperidin-1-yl or CH _{2-N-morpholino;} and
R ₁₅ represents H, C _1-6 alkyl, or together with R ₁₇ represents —CH ₂ CH ₂ —, —CH ₂ CH ₂ —, or —CH ₂ CH ₂ CH ₂ —. ).

In a group of compounds that may be described, R ₉ is a partially or fully aromatic C _5-10 containing 0-4 heteroatoms substituted by NR ₉₀ (C = Q) -MZR ₉₃ . Represents a carbocycle, in which R ₉₀ represents H or C _1-6 alkyl, Q represents O, S, or NR ₉₁ , in which R ₉₁ is H or C _1-6 alkyl M represents C _1-3 alkyl optionally substituted with halogen, C _1-6 alkyl, or C _1-6 alkoxy, Z represents O, S or NR ₉₂ , in which R ₉₂ represents H or C _1-6 alkyl, and R ₉₃ is partially or fully aromatic containing 0 to 4 heteroatoms and 1 to 4 halogens, C ₁ —C ₆ alkyl, represents a C _5-10 carbocycle optionally substituted by OC ₁ -C ₆ alkyl.

In another group of compounds that can be described, R ₉ represents a 5-10 membered heterocyclic ring containing one or more SO _n units, where n = 0-2. And can be the same or different for each SO _n unit.
In a group of compounds that may be described, R ₁ represents an N-linked monocyclic or bicyclic ring that is a lactam.

In another group of compounds, R ₁ represents —K—SO _n —R ₂₈ , in which K represents C ₁ -C ₃ alkyl optionally substituted with C ₁ -C ₆ alkyl; n = 0 to 2 and R ₂₈ represents C ₁ -C ₁₀ alkyl optionally substituted with one or more hydroxy, halogen, alkoxy (such as C _1-6 alkoxy) or amine.
In a group of compounds, Y represents N.
In a group of compounds, X represents O.
In a group of compounds, Y represents N and X represents O.

Also comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt to a patient in need of a method for the treatment or prevention of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia The method in the patient is provided.
Also provided is the use of a compound described herein in the manufacture of a medicament for the treatment or prevention of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.

A compound of formula I for use in the treatment of DMD will generally be administered in the form of a pharmaceutical composition.
Thus, according to a further aspect, less than 80% (w / w) in one embodiment, less than 50% (w / w) in another embodiment, mixed with a pharmaceutically acceptable diluent or carrier, For example, a pharmaceutical composition is provided comprising 0.1-20% of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.

Also provided is a process for the manufacture of these pharmaceutical compositions comprising mixing the ingredients. Examples of pharmaceutical formulations that can be used, and suitable diluents or carriers are as follows:
For intravenous injection or infusion-purified water or saline;
For inhalation compositions-crude lactose;
For tablets, capsules and dragees-sugars such as microcrystalline cellulose, calcium phosphate, diatomaceous earth, lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and / or gelatin;
For suppositories-natural or hardened oils or waxes.

  If the compound is to be used, for example, in an aqueous solution for injection, it may be necessary to incorporate other excipients. In particular, chelating or sequestering agents, antioxidants, osmotic pressure adjusting agents, pH modifiers and buffers may be mentioned.

Solutions containing a compound of formula I can be evaporated if desired, for example by lyophilization or spray drying, to yield a solid composition that can be reconstituted prior to use.
When not in solution, the compound of formula I is, in one embodiment, in a form having a median population diameter of 0.01 to 10 μm. The composition may also comprise suitable preservatives, stabilizers and wetting agents, solubilizers, water soluble cellulose polymers such as hydroxypropyl methylcellulose, or water soluble glycols such as propylene glycol, sweeteners and colorants and seasonings. May be contained. Where appropriate, the compositions may be formulated in sustained release form.

The content of the compound of formula I in the pharmaceutical composition is generally about 0.01 to about 99.9% by weight, and in one embodiment about 0.1 to about 50% by weight relative to the total preparation.
The dose of the compound of formula I depends on age, weight, general health, diet, time of administration, method of administration, clearance rate, drug combination, level of disease the patient is under treatment at the time of administration, and other factors Decided in consideration.

The dose will vary depending on the target disease, condition, subject of administration, method of administration and similar items, but as a therapeutic agent for the treatment of such disease in patients suffering from Duchenne muscular dystrophy For oral administration, it is 0.01 mg to 10 g in patients suffering from the disease, in one embodiment 0.1 to 100 mg, and in certain embodiments, in a single dose or twice a day. Or administered three times.
The potential activity of compounds of formula I for use in the treatment of DMD can be demonstrated in the following predictive assays and screens.

1． Luciferase reporter assay (mouse H2K cells)
The cell line used for screening was an immortalized mdx mouse H2K that had been stably transfected with a plasmid containing an approximately 5 kb fragment of the utrophin A promoter containing the first untranslated exon linked to the luciferase reporter gene. Cell line (see FIG. 1).

Under conditions of cold and interferon-containing media, the cells survive as myoblasts. The cells are seeded in 96-well plates and cultured for 3 days in the presence of compounds. Next, the level of luciferase is determined by cell lysis and reading the light output from the expressed luciferase gene using a plate luminometer.
An example of a pharmacological dose response of a compound in the assay is shown in FIG.

2． mdx mouse
Prioritize data obtained from ADMET data, prioritize compounds with the best luciferase activity in vitro and valid ADMET data for testing in conceptual studies on mdx proof, In the study, the outcome was to identify whether any compound had the ability to increase the level of utrophin protein in dystrophin-deficient muscle when compared to control animals that received vehicle alone.

  Two animals were injected with 10 mg / kg of compound administered intraperitoneally daily for 28 days and were also administered to age-matched controls. Muscle samples were taken and processed for sectioning (to identify an increase in muscle sheath staining for utrophin) and Western blotting (to identify an overall increase in utrophin levels).

FIG. 3 shows an example of anterior tibial muscle section stained using a mouse utrophin specific antibody. Comparison with mdx muscle injected with vehicle alone shows an increase in the amount of utrophin bound to the muscle sheath.
Moreover, the muscle derived from the mouse | mouth which carried out the above-mentioned treatment was extracted, processed for Western blotting, and dye | stained with the specific antibody (refer FIG. 4). Also, the use of CPD-A administered muscle shows a significant increase in the overall level of utrophin present in both the anterior tibial muscle and the diaphragm of the leg. All mice exposed to CPD-A (V2 and V3) showed high levels of utrophin expression compared to controls.

  Second, positive upregulation data from the first 28-day study was reproduced in a 28-day study with two additional mice. A total of 3 different compounds showed the ability to increase the level of utrophin expression in mdx mice when delivered daily for 28 days by intraperitoneal administration. All the data published so far show that an increase in utrophin levels of more than 3 fold has a significant functional effect on dystrophin-deficient muscle, so this data shows that when delivered intraperitoneally Ability indicates that a significant increase in the level of utrophin found in mdx muscle occurs, thus providing confidence that this effort will ameliorate the disease.

(Maintain H2K / mdx / UtroA reporter cell line)
The H2K / mdx / UtroA reporter cell line was passaged twice a week until a culture density of 30% or less. Cells were grown at 33 ° C. in the presence of 10% CO ₂ .
The myoblasts were incubated with trypsin / EDTA in order to remove and seed the myoblasts.
Growth medium
DMEM Gibco 41966
20% FCS
1% penicillin / streptomycin
1% glutamine
Add 10mL chicken embryo extract Interferon (1276 905 Roche) fresh 10μL / 50mL medium

(Luciferase assay for 96-well plates)
Cells of the H2K / mdx / UtroA reporter cell line were seeded into 96-well plates (Falcon 353296 white opaque) at a density of about 5000 cells / well in 190 μL normal growth medium. The plates were then incubated for 24 hours at 33 ° C. in the presence of 10% CO ₂ .
Compounds were administered by adding 10 μL of diluted compound to each well to a final concentration of 10 μM. The plates were then incubated for an additional 48 hours.
Next, cells were lysed in situ (in situ) according to the manufacturer's protocol (Promega Steady-Glo Luciferase Assay System (E2520)) and then counted for 10 seconds using a plate luminometer (Victor 1420).

(Storage of compounds)
Compounds for screening were stored as 10 mM stock in 100% DMSO at −20 ° C. until needed.
(Injection of compounds into mdx mice)
Mdx was selected from breeding colonies for inspection. Mice were injected daily with either vehicle or 10 mg / kg compound using the intraperitoneal route (ip). Mice were weighed and compounds diluted in 5% DMSO, 0.1% Tween in PBS.
Mice were sacrificed by cervical dislocation at the desired time points and muscles removed for analysis.

(Analysis of muscle)
(Immunohistochemistry)
The tissue for section preparation was dissected, immersed in OCT (Bright Cryo-M-Bed), and frozen on isopentane cooled with liquid nitrogen. Unfixed 8 μM frozen sections were cut out in Bright Cryostat and stored at −80 ° C.
In preparation for staining, sections were blocked in 5% fetal calf serum in PBS for 30 minutes. The primary antibody was diluted in blocking reagent, incubated on sections for 1.5 hours in a humid chamber, and then washed 3 times for 5 minutes in PBS. The secondary antibody was diluted in a blocking reagent and incubated for 1 hour in a dark place in a humid chamber. Finally, the sections were washed 3 times in PBS for 5 minutes and the cover glass was embedded with a liquid mount. Slides were analyzed using a Leica fluorescence microscope.

Results Biological activity is assessed using a luciferase reporter assay in mouse H2K cells and classified as follows:
+ Up to 200% of control
++ 201-300% of control
+++ 301-400% of control
+++++ Over 401% of control

  Further active compounds are 2-naphthalen-2-yl-5- (pyrrolidin-1-sulfonyl) -benzoxazole, 5-methoxy-2- (naphthalen-2-yl) benzo [d] oxazole, 2- ( Naphthalen-2-yl) benzo [d] oxazol-5-ol, 5- (2- (benzyloxy) ethoxy) -2- (naphthalen-2-yl) benzo [d] oxazole, 2- (2- (naphthalene) -2-yl) benzo [d] oxazol-5-yloxy) ethanol, (2-phenyl-1H-indol-3-yl) methanol and 2- (2- (naphthalen-2-yl) benzo [d] oxazole- 5-ylsulfonyl) ethanol.

  Other active compounds include 5-methoxy-2- (naphthalen-2-yl) benzo [d] oxazole (++), 2- (naphthalen-2-yl) benzo [d] oxazol-5-ol ( ++), 5- (2- (benzyloxy) ethoxy) -2- (naphthalen-2-yl) benzo [d] oxazole (+), 2- (2- (naphthalen-2-yl) benzo [d] oxazole -5-ylsulfonyl) ethanol (++), 2- (naphthalen-2-yl) -5- (pyrrolidin-1-ylsulfonyl) benzo [d] oxazole (+), and 2- (2- (naphthalene-2 -Yl) benzo [d] oxazol-5-yloxy) ethanol (+), in which (++) and (+) have the meanings indicated for Table 1.

(Experiment)
HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD, and a Finnigan AQA mass spectrometer operating in electrospray ionization mode. The HPLC column used is Phenomenex Gemini C18 (150 x 4.6 mm). Preparative HPLC was performed on Gilson 321 where detection is performed by Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector. The preparative HPLC column used is Phenomenex Gemini C18 (150 × 10 mm) and the mobile phase is acetonitrile / water. ¹ H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR spectra were obtained as CDCl ₃ (reported in ppm) using chloroform (7.25 ppm) or DMSO-D ₆ (2.50 ppm) as standard samples. When reporting peak multiplicity, the following abbreviations are used: s (single line), d (double line), t (triple line), m (multiple line), br (widening), dd (multiple Double line double line), dt (multiple triple line double line), td (multiple double line triple line). If a coupling constant is given, report it in hertz (Hz). Column chromatography was performed either by flash chromatography (40-65 μm silica gel) or using an automated purification system (SP1 ™ Purification System from Biotage®). Reactions in the microwave were performed on an Initiator 8 ™ (Biotage). Abbreviations used are DMSO (dimethyl sulfoxide), HATU (hexafluorophosphoric acid O- (7-azabenzotriazol-1yl) -N, N, N ', N'-tetramethyluronium), HCl (chloride) Hydrogen), MgSO ₄ (magnesium sulfate), NaOH (sodium hydroxide), Na ₂ CO ₃ (sodium carbonate), NaHCO ₃ (sodium bicarbonate), STAB (sodium triacetoxyborohydride), THF (tetrahydrofuran) .

(Example 1 (Compound 1))
3- (5-Methylbenzo [d] oxazol-2-yl) pyridin-2-ol
2-Amino-4-methylphenol (123 mg, 1.0 mmol) and 2-hydroxynicotinic acid (139 mg, 1.0 mmol) were added simultaneously to polyphosphoric acid at 110 ° C. The resulting mixture was then heated to 180 ° C. for 5 hours. The solution was then poured into water. The resulting precipitate was basified with aqueous NaOH and then collected by filtration to yield 70 mg (31%) of the title compound. (LCMS RT = 5.19min, MH + 227.1)

According to the same general method, all the following compounds were prepared and purified either by trituration, recrystallization or column chromatography.

Modified method 1A:
5- (Ethylsulfonyl) -2- (naphthalen-2-ylmethyl) benzo [d] oxazole
A mixture of 2-amino-4- (ethylsulfonyl) phenol (300 mg, 1.49 mmol) and 2-naphthylacetic acid (417 mg, 2.24 mmol) was heated in polyphosphoric acid (PPA) at 125 ° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized to pH = 7 with NaOH (5M). The reaction mixture was extracted 3 times with EtOAc, the organic phases were combined, dried over sodium sulfate and concentrated in vacuo to yield a yellow oil. Purification using biotage 30% EtOAc / 70% petroleum yielded 160 mg of a yellow solid (30% yield, 97% UV purity).

5- (Ethylsulfonyl) -2- (1,2,3,4-tetrahydronaphthalen-2-yl) benzo [d] oxazole
A mixture of 2-amino-4- (ethylsulfonyl) phenol (201 mg; 2 mmol) and 1,2,3,4-tetrahydro-2-naphthoic acid (352 mg, 2 mmol) in polyphosphoric acid (PPA) at 180 ° C. Heated for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized to pH = 7 with NaOH (5M). The reaction mixture was extracted 3 times with EtOAc and the organic phases were combined, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica using 5: 1 petroleum ether / ethyl acetate. The product was then further purified by HPLC to yield the title compound as a white solid, 97% pure by UV LCMS.

Using the same general method, the following two compounds were prepared:

(Method 1A (Compound Ic))
5- (Methylsulfonyl) -2- (naphthalen-2-yl) benzo [d] oxazole
Preparation of 2-amino-4- (methylsulfonyl) phenol Boron tribromide (1M in dichloromethane, 39 mL, 39.8 mmol) to 2-methoxy-5- (methylsulfonyl) aniline (2 g, 9.94 mmol) in dichloromethane (30 mL) The resulting solution was allowed to stir at room temperature for 10 minutes and then heated at reflux for 5 hours. After 5 hours, the reaction mixture was cooled to 0 ° C. and quenched by careful addition of water. The organic layer was separated and the aqueous layer was concentrated in vacuo. The crude reaction mixture was suspended in toluene and concentrated in vacuo to give the title compound as a beige powder (4.4 g) contaminated with boron salt after 24 hours of vacuum drying.

Preparation of 5- (methylsulfonyl) -2- (naphthalen-2'-yl) benzo [d] oxazole
2-Amino-4- (methylsulfonyl) phenol (about 44% by weight, 2 g, 4.700 mmol) and 2-naphthoic acid (890 mg, 5.170 mmol) were mixed and heated to polyphosphoric acid (30 mL, heated at 110 ° C.) Added to the flask all at once. The resulting reaction mixture was heated at 120 ° C. for 16 hours and then diluted with water (200 mL). The mixture was adjusted to pH 8 with sodium potassium carbonate and the title compound was recovered by filtration as an off-white solid (1.157 g, 76%). (LCMS RT = 6.73min, MH + 324).

(Method 1Ai)
2- (4,4-Difluorocyclohexyl) -5- (ethylsulfonyl) benzo [d] oxazole
A solution of 4,4-difluorocyclohexanecarboxylic acid (0.10 g, 0.62 mmol) and oxalyl chloride (64 μL, 0.74 mmol) in DCM (2 mL) containing 1 drop of DMF was stirred at room temperature for 1 hour. The solvent is removed in vacuo, the residue is dissolved in xylene (2 mL), 2-amino-4- (ethylsulfonyl) phenol (0.13 g, 0.62 mmol) is added, and the resulting reaction mixture is refluxed at 155 ° C. for 1 hour. Heated. PTSA (59 mg, 0.31 mmol) was added and reflux continued for another 2 hours before the reaction mixture was absorbed onto silica gel. Purification by column chromatography eluting with 0/1 to 3/7 (v / v) ethyl acetate / petroleum ether yielded 117 mg (57%) of the title compound. (LCMS RT = 6.00min, MH + 330.1)

(Method 1B (Compound I))
N-methyl- (2-naphthalen-2-yl) benzo [d] oxazol-5-yl) sulfonamide
A mixture of 2-aminophenol-4-sulfomethylamide (252 mg, 1.248 mmol) and 2-naphthoyl chloride (285 mg, 1.497 mmol) in 1,4-dioxane (1.7 mL) was subjected to 200 mg under microwave activation. Heat at 15 ° C. for 15 minutes. After cooling, 1M aqueous sodium hydroxide solution was added (pH 13) and the resulting solid was collected by filtration. Vacuum drying yielded the title compound as an off-white solid (280 mg, 66%).

(E) -5- (Ethylsulfonyl) -2-styrylbenzo [d] oxazole

Modified method
5- (Ethylsulfonyl) -2- (furan-2-yl) benzo [d] oxazole 2-amino-4- (methylsulfonyl) phenol (201 mg, 1.00 mmol) in anhydrous dioxane (2 mL) was added to furan-2 chloride. -Carbonyl (98 μL, 1.00 mmol) was added at room temperature. The reaction vessel was heated in the microwave at 210 ° C. for 15 minutes. After cooling, the mixture was slowly poured into water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO ₄ and evaporated. The resulting solid was purified by column chromatography eluting with 1: 2 (v / v) ethyl acetate / hexanes to yield 40 mg (14%) of the title compound. (LCMS RT = 5.73min, MH + 277.9);

According to the same general method, all the following compounds were prepared. The acid chloride used was either a commercially available compound or synthesized from the corresponding carboxylic acid using standard conditions.

(Method 1C (Compound I))
5- (Ethylsulfonyl) -2- (naphthalen-2-ylmethyl) benzo [d] oxazole
A mixture of 2-amino-4- (ethylsulfonyl) phenol (300 mg, 1.49 mmol) and 2-naphthylacetic acid (417 mg, 2.24 mmol) was heated in polyphosphoric acid (PPA) at 125 ° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized to pH = 7 with NaOH (5M). The reaction mixture was extracted 3 times with EtOAc, the organic phases were combined, dried over sodium sulfate and concentrated in vacuo to yield a yellow oil. Purification using biotage 30% EtOAc / 70% petroleum yielded 160 mg of a yellow solid (30% yield, 97% UV purity).

5- (Ethylsulfonyl) -2- (1,2,3,4-tetrahydronaphthalen-2-yl) benzo [d] oxazole
A mixture of 2-amino-4- (ethylsulfonyl) phenol (201 mg; 2 mmol) and 1,2,3,4-tetrahydro-2-naphthoic acid (352 mg; 2 mmol) in polyphosphoric acid (PPA) at 180 ° C. for 16 hours. Heated. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized to pH = 7 with NaOH (5M). The reaction mixture was extracted 3 times with EtOAc and the organic phases were combined, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica using 5: 1 petroleum ether / ethyl acetate. The product was then further purified by HPLC to yield the title compound as a white solid, purity by UV LCMS was 97%.

Using the same general method, the following two compounds were prepared:

(Example 2)
(2- (Naphthalen-2-yl) benzo [d] oxazol-6-yl) methanol methyl 2- (naphthalen-2-yl) benzo [d] oxazole-6-carboxylate in anhydrous tetrahydrofuran (152 mg, 0.5 mmol) To the stirred suspension of was added lithium aluminum hydride (38 mg, 1.0 mmol). The resulting solution was stirred at room temperature for 16 hours. The crude mixture was then diluted with ethyl acetate and washed with 1M aqueous HCl and brine. The combined organic layers were dried over anhydrous MgSO ₄ and evaporated. The resulting product was purified by column chromatography eluting with 1: 1 (v / v) ethyl acetate / hexanes to yield 90 mg (66%) of the title compound. (LCMS RT = 6.40min, MH + 276.1)

Example 3 (Compound II)
2- (Dimethylamino) -N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide 2- (Naphthalen-2-yl) benzo [d] in dichloromethane (20 mL) at room temperature To a solution of oxazol-5-amine (390 mg, 1.50 mmol) was added 2- (dimethylamino) acetyl chloride (296 mg, 1.88 mmol) immediately after adding diisopropylethylamine (784 μL, 4.50 mmol) and a catalytic amount of DMAP. did. After 4 hours at room temperature, further diisopropylethylamine (784 μL, 4.50 mmol) and 2- (dimethylamino) acetyl chloride (237 mg, 1.50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The dichloromethane was then removed in vacuo and water was added to precipitate the solid. The resulting solid was washed with aqueous potassium carbonate to yield 430.2 mg (83%) of the title compound. (LCMS RT = 7.52min, MH + 346.2)

3,3,3-trifluoro-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) propanamide

Precursors for the following two compounds were obtained using this general method for coupling, but the product of the title compound used 3:10 (v / v) TFA / DCM at room temperature for 2 hours. Obtained after deprotection:

Using the same general method for coupling, the following compounds were obtained and did not require a deprotection step:

Example 4 (Compound II)
Similar to Method 3A, with the exception that triethylamine was used as the base instead of diisopropylamine.

(Example 5)
2-Bromo-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide
2- (Naphthalen-2-yl) benzo [d] oxazol-5-amine (1 eq, 2 g, 7.7 mmol) was added to a stirred solution of dichloromethane (40 mL) to which triethylamine (1.2 eq, 0.934 g, 9.2 mmol, 1.28 mL) and 2-bromoacetyl bromide (1.1 eq, 1.706 g, 8.4 mmol, 0.734 mL) were added. This was stirred at room temperature for 18 hours. The crude product was extracted in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. Flash column chromatography of the crude product using a gradient (1: 1 ethyl acetate / hexanes reaches 1: 0 ethyl acetate / hexanes) yielded 2.8 g (96%) of the title compound.

(Example 6)
2-morpholino-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide
2-Bromo-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide (1 eq, 0.5 g, 1.3 mmol) and potassium carbonate (1.2 eq, 0.218 g, 1.6 mmol) Was added in one portion to stirred dimethylformamide, to which morpholine (1.1 eq, 0.126 g, 1.4 mmol, 0.12 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The crude product was then extracted in dichloromethane and washed with brine. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. Flash column chromatography of the crude product using a gradient (1: 1 ethyl acetate / hexanes reaching 9: 1 ethyl acetate / hexanes) yielded 0.280 g (55%) of the title compound.

(Example 7)
N- (2-Naphthalen-2-yl) benzo [d] oxazol-5-yl) methanesulfonamide
A mixture of N- (2-naphthalen-2-yl) benzo [d] oxazol-5-amine (92 mg, 0.353 mmol), methanesulfonyl chloride (30 μL, 0.388 mmol) and pyridine (5 mL) is stirred at room temperature for 3.5 hours. did. The mixture was partitioned between ethyl acetate and water and the two layers were separated. The aqueous layer was further extracted with ethyl acetate and the combined extracts were dried (over anhydrous MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (eluting with 30% ethyl acetate in 60:40 petroleum ether) gave the title compound as a yellow solid.

(Example 8)
N- (2-Naphthalen-2-yl) benzo [d] oxazol-5-yl) propionimidoamide N- (2-Naphthalen-2-yl) benzo [d] oxazole in propiononitrile (2 mL, 28.03 mmol) To a stirred solution of 5-amine (298 mg, 1.137 mmol), trimethylsilyl trifluoromethanesulfonate (236 μL, 1.304 mmol) was added dropwise at room temperature. After stirring at room temperature for 24 hours, the mixture was partitioned between 1N aqueous sodium hydroxide and ethyl acetate and the layers were separated. The aqueous layer was further extracted with ethyl acetate and the combined extracts were dried (over anhydrous MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (30% -90% ethyl acetate in 60:40 petroleum ether, followed by gradient elution using anhydrous ethyl acetate and methanol) gave the title compound as a brown solid (73 mg, 20 g).

(Example 9)
2-Amino-4-iodophenol
A 1 M solution of BBr ₃ in DCM (40 mL, 40.15 mmol) was slowly added to anhydrous DCM (40 mL) at room temperature under an atmosphere of dry nitrogen followed by 5-iodo-2-methoxyaniline (2.50 g, 10.04 mmol). Was added. The resulting mixture was refluxed for 18 hours under nitrogen and quenched with distilled water (50 mL). The precipitated pink solid was collected by filtration and washed with water. The solid was then placed in a saturated aqueous solution of sodium bicarbonate (200 mL) and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with water until pH = 7, dried over anhydrous MgSO ₄ and evaporated to yield 1.37 g (58%) of 2 as a yellow solid.

5-Iodo-2- (naphthalen-2-yl) benzo [d] oxazole 2-amino-4-iodophenol (250 mg, 1.06 mmol) in dioxane (3 mL) and 2-naphthoyl chloride (203 mg, 1.06 mmol) Added at room temperature. The reaction vessel was heated in the microwave at 197 ° C. for 15 minutes. After cooling, the mixture was partitioned between ethyl acetate (100 mL) and water (70 mL) and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 50 mL) and the combined extracts were dried over anhydrous MgSO ₄ and evaporated in vacuo. The resulting solid was purified by column chromatography eluting using a gradient (0: 1 (v / v) ethyl acetate / hexanes to 1: 9 (v / v) ethyl acetate / hexanes). 300 mg (76%) of the title compound were produced.

The following two compounds were prepared according to the same general method.

(Example 10)
2- (Naphthalen-2-yl) benzo [d] oxazol-5-yl (phenyl) phosphinic acid ethyl tetrakis (triphenylphosphine) palladium (0) (47 mg, 0.04 mmol) and triethylamine (170 μL, 1.19 mmol) Once in a stirred solution of 5-iodo-2- (naphthalen-2-yl) benzo [d] oxazole (147 mg, 0.4 mmol) and ethyl phenylphosphinate (89 μL, 0.6 mmol) in toluene (5 mL) in the presence. And the resulting mixture was heated in a sealed tube at 100 ° C. for 3 hours in a dry nitrogen atmosphere. After cooling, the mixture was partitioned between ethyl acetate (100 mL) and water (70 mL) and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 50 mL) and the combined extracts were dried over anhydrous MgSO ₄ and evaporated in vacuo. The resulting brown oil is purified by column chromatography eluting using a gradient (0: 1 (v / v) ethyl acetate / hexanes to 8: 2 (v / v) ethyl acetate / hexanes). This yielded 109 mg (66%) of the title compound. (LCMS RT = 7.54min, MH + 414.1)

The following compounds were prepared according to the same general method.

(2- (4-Chlorophenyl) benzo [d] oxazol-5-yl (ethyl) phosphinic acid 2- (4-Chlorophenyl) benzo [d] oxazol-5-yl (ethyl) phosphinic acid in anhydrous dochloromethane (5 mL) To a stirred solution of methyl (161 mg, 0.44 mmol), trimethylsilyl bromide (120 μL, 0.88 mmol) was added dropwise at 0 ° C. The resulting solution was allowed to reach room temperature over 2 hours and stirred for 16 hours. The crude product was then diluted with dichloromethane (100 mL) and the organic layer was washed with water (50 mL) The aqueous layer was further extracted with dichloromethane (2 × 30 mL) and the combined extracts were anhydrous MgSO _4. Dried over and evaporated in vacuo, the resulting colorless solid was subjected to a gradient (1: 0 (v / v) ethyl acetate / methanol to 0: 1 (v / v) ethyl acetate / methanol). Purify by column chromatography eluting with To give the title compound 77mg (50%). (LCMS RT = 4.44min, (MH) + 320.1)

Example 11 (Compound XXXI)
N- (3- (methylsulfonyl) phenyl) naphthamide To a solution of 3-methylsulfonylaniline hydrochloride (1.12 g, 5.4 mmol) in pyridine (15 mL) was added 2-naphthoyl chloride (1.13 g, 5.9 mmol). After stirring for 4 hours, the reaction mixture was partitioned between water and EtOAc and the organic phase was dried over MgSO ₄ and concentrated in vacuo. The crude title compound was used in the next reaction without further purification.

N- (3- (methylsulfonyl) phenyl) naphthalene-2-carbothioamide
A stirred solution of N- (3- (methylsulfonyl) phenyl) naphthamide (1.67 g, 5.1 mmol) and Lawesson's reagent (1.25 g, 3.1 mmol) in toluene (36 mL) was heated to reflux for 16 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography eluting with 0/1 (v / v) to 1/0 (v / v) ethyl acetate / petroleum ether. This gave g (85%) of the title compound.

5- (Methylsulfonyl) -2- (naphthalen-2-yl) benzo [d] thiazole A solution of potassium hexacyanoferrate (III) (5.96 g, 18.1 mmol) in water (40 mL) was heated to 90 ° C. To this, a solution of N- (3- (methylsulfonyl) phenyl) naphthalene-2-carbothioamide (1.54 g, 4.5 mmol) and 3M sodium hydroxide (20 mL) in IMS (15 mL) was added dropwise over 5 minutes. And added. After stirring for 30 minutes, the reaction was cooled to room temperature, vacuum filtered and washed with water. The residue was purified by column chromatography eluting with 0/1 to 1/4 (v / v) ethyl acetate / petroleum ether to yield 137 mg (9%) of the title compound.

Example 12 (Compound XLV)
5- (2,2,2-Trideuteroethylsulfonyl) -2- (naphthalen-2-yl) benzo [d] oxazole
LHMDS (1M in THF, 1.36 mL, 1.36 mmol) was added to a solution of 5- (methylsulfonyl) -2- (naphthalen-2-yl) benzo [d] oxazole (400 mg, 1.237 mmol) in THF (30 mL). Added at −78 ° C. under ₂ . The resulting solution was allowed to stir at −78 ° C. for 1 hour before d ₃ -methyl iodide was added. The reaction mixture was allowed to warm to room temperature over 16 hours before adding saturated aqueous ammonium chloride (25 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (x3). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the title compound as an off-white solid (106 mg, 25) after column chromatography (4: 1 to 2: 1 40-60 petroleum: ethyl acetate). %). (LCMS RT = 7.00 = 6 minutes, MH + 341)

(Example 13)
(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) benzyl acetate 1,2,3,4,6-penta-O-acetyl-β in anhydrous DCM (15 mL) To a solution of -D-glucopyranose (1 g, 2.56 mmol) and benzyl glycolate (0.44 mL, 3.1 mmol) is added BF ₃ OEt ₂ (0.39 mL, 3.1 mmol) and the resulting reaction mixture is stirred at room temperature for 5 minutes. Stir for hours. The solution was neutralized with Et ₃ N and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 0/1 to 1/1 (v / v) ethyl acetate / petroleum ether to yield 1 g (78%) of the title compound.

(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) acetic acid
Degass a solution of (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylox) benzyl acetate (1 g, 2 mmol) and add Pd-C (10%, 50 mg) The solution was further degassed. After stirring under a hydrogen atmosphere for 2.5 hours, the reaction mixture was filtered over celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with 0/1 to 1/0 (v / v) ethyl acetate / petroleum ether to yield 524 mg (65%) of the title compound. (LCMS RT = 4.32 min, M 405.1).

N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-β-D-glucopyra Nosyloxy) acetamide
2- (2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) acetic acid (524 mg, 1.3 mmol) and 2- (2,3-dichlorophenyl) benzoate in DMF (6 mL) [d] A solution of oxazol-5-amine (362 mg, 1.3 mmol) was cooled to 0 ° C., HATU (593 mg, 1.56 mmol) and DIPEA (0.68 mL, 3.9 mmol) were added and the resulting reaction mixture was allowed to cool to room temperature. Warmed slowly. After stirring for 16 hours, the reaction mixture was partitioned between EtOAc (200 mL) and brine (150 mL), the aqueous phase was extracted with EtOAc (2 × 150 mL), and the combined organic phases were washed with brine (200 mL). And dried over MgSO ₄ . After removing the solvent under reduced pressure, the residue was purified by column chromatography eluting with 0/1 (v / v) to 7/3 (v / v) ethyl acetate / petroleum ether to yield 762 mg (88%) Yielded a pink solid.

N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2- (β-D glucopyranosyloxy) acetamide
N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-β-D-glucopyra A solution of nosyloxy) acetamide (0.76 g, 1.14 mmol) and ammonia (7N solution in MeOH, 14 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was triturated with hot MeOH and Et ₂ O to yield 527 mg (93%) of the title compound as a white powder. (LCMS RT = 4.98 min, MH + 500.8)

N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2- (β-D-galactopyranosyloxy) acetamide Same method for basic unit synthesis, coupling and deprotection Was used to prepare the title compound. (LCMS RT = 5.10 min, MH + 499.0).

2,3,4,6-Tetra-O-acetyl-α-D-mannopyranosyl bromide
A solution of 1,2,3,4,6-penta-O-acetyl-α-D-mannopyranose (5 g, 12.8 mmol) in 33% HBr / AcOH (60 mL) was stirred at 0 ° C. for 2 hours. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phases were washed with NaHCO ₃ (3 × 200 mL), dried over MgSO ₄ and concentrated in vacuo. The crude title compound was used in the next reaction without further purification.

(2,3,4,6-Tetra-O-acetyl-α-D-mannopyranosyloxy) benzyl acetate A solution of AgOTf (3.6 g, 14.1 mmol) in anhydrous toluene (20 mL) was added to anhydrous DCM (50 mL). ) Was added to a cooled solution (0 ° C.) of 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl bromide (12.8 mmol) and benzyl glycolate (1.82 mL, 12.8 mmol). The resulting reaction mixture was stirred for 16 h before being diluted with DCM (200 mL), washed with NaHCO ₃ (2 × 100 mL) and brine (100 mL), dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 0/1 to 1/1 (v / v) ethyl acetate / petroleum ether to yield 2.03 g (32%) of the title compound.

(2,3,4,6-tetra-O-acetyl-β-D-mannopyranosyloxy) acetic acid (2,3,4,6-tetra-O-acetyl) without column chromatography The title compound was prepared as described for -β-D-glucopyranosyloxy) acetic acid.

N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2- (2 ', 3', 4 ', 6'-tetra-O-acetyl-β-D-manno The title compound was prepared using the same general method for pyranosyloxy) acetamide coupling.

N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2- (β-D-mannopyranosyloxy) acetamide Using the same general method for deprotection, The title compound was prepared.

3'-Benzyloxypropyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside 1,2,3,4,6-penta-O-acetyl- in anhydrous DCM (25 mL) BF ₃ OEt ₂ (0.71 mL, 5.6 mmol) is added to a solution of β-D-glucopyranose (2 g, 5.1 mmol) and 3-benzyloxypropanol (0.90 mL, 5.6 mmol) and the resulting reaction mixture is stirred at room temperature. For 16 hours. The solution was neutralized with Et ₃ N and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 0/1 to 1/1 (v / v) ethyl acetate / petroleum ether to yield 2.1 g (85%) of the title compound.

3'-hydroxypropyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside
Degassed a solution of 3'-benzyloxypropyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (8.6 g, 17 mmol) and Pd-C (10%, 500 mg) Was added and the solution was degassed again. After stirring under hydrogen atmosphere for 3 hours, the reaction mixture was filtered over celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with 0/1 to 1/0 (v / v) ethyl acetate / petroleum ether to yield 4.9 g (70%) of the title compound.

3 '-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy) propanoic acid
A solution of NaCl (3 mL saturated aqueous solution), NaHCO ₃ (1.5 mL saturated aqueous solution) and NaOCl (13%, 3 mL) was added to 3′-hydroxypropyl 2,3,4,6-tetra-O-acetyl in DCM (10 mL). -β-D-galactopyranoside (0.5 g, 1.2 mmol), TEMPO (3 mg, 0.02 mmol), KBr (12 mg, 0.098 mmol), TBABr (16 mg, 0.062 mmol) and NaHCO ₃ (saturated aqueous solution 3 mL) At 0 ° C. After stirring at 0 ° C. for 30 min, the reaction mixture was neutralized with 1N HCl, extracted with DCM (3 × 10 mL), the combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 0/1 to 1/0 (v / v) ethyl acetate / petroleum ether to yield 0.45 g (88%) of the title compound.

N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -3- (β-D-galactopyranosyloxy) propanamide Uses standard methods for coupling and deprotection The title compound was prepared.

N- (2- (Naphthalen-2-yl) benzo [d] oxazol-5-yl) -2- (β-D-galactopyranosyloxy) propanamide Standard methods used for coupling and deprotection The title compound was prepared.

2- (Benzyloxy) -N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) acetamide Using standard methods for coupling, the title compound was obtained.

N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2-hydroxyacetamide
A solution of 2- (benzyloxy) -N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) acetamide (0.97 g, 2.28 mmol) was degassed and Pd-C (10% , 100 mg) was added and the solution was degassed again. After stirring for 6 hours under hydrogen atmosphere, the reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with 0/1 to 1/0 (v / v) ethyl acetate / petroleum ether. Trituration of the white solid with Et ₂ O (2 ×) yielded 380 mg (50%) of the title compound. (LCMS RT = 5.76 min, MH + 336.9)

The following compounds were prepared by the same coupling and deprotection as for N- (2- (2,3-dichlorophenyl) benzo [d] oxazol-5-yl) -2-hydroxyacetamide.

2-Hydroxy-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide Using standard methods for coupling, the title compound was obtained: required deprotection There wasn't.

(Example 14)
5- (Ethylsulfinyl) -2- (naphthalen-2-yl) benzo [d] oxazole (i) 4- (Ethylthio) phenol 4-Mercaptophenol (4.2 g, 33.3 mmol) was dissolved in acetone (35 mL). K ₂ CO ₃ (4.8 g, 35 mmol) and EtBr (3.6 mL, 49.9 mmol) were added and the mixture was stirred at room temperature for 17 hours. The mixture was filtered and the residue was washed with Et ₂ O (3 × 30 mL). The combined organics were washed with 1M NaOH (2 × 50 mL). The aqueous extracts were combined and acidified with 2M HCl. The acidic solution was extracted with Et ₂ O (2 × 50 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to yield a brown oil that crystallized on standing. The crude sulfide was purified by column chromatography (10% EtOAc / hexanes) to yield the title compound as a pale yellow oil (3.9 g, 75%) that crystallized on standing.

(Ii) 4- (Ethylthio) -2-nitrophenol
4- (Ethylthio) phenol (3.2 g, 20.5 mmol) was dissolved in AcOH (10 mL) and cooled to 0 ° C. Concentrated HNO ₃ (about 16M, 1.28 mL, 20.5 mmol) was added dropwise. Upon complete addition, the mixture was diluted with H ₂ O (20 mL) and extracted with CHCl ₃ (2 × 25 mL). The combined CHCl ₃ extracts were washed with H ₂ O (25 mL) and brine (25 mL), then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude mixture was then purified by column chromatography (25% EtOAc / hexanes) to yield the title compound as an orange oil (310 mg, 8%).

(Iii) 2-amino-4- (ethylthio) phenol
4- (Ethylthio) -2-nitrophenol (200 mg, 1.0 mmol) was dissolved in IMS / H ₂ O (5: 1, 12 mL). NH ₄ Cl (107 mg, 2.0 mmol) was added and the mixture was heated to 80 ° C. Fe powder (280 mg, 5.0 mmol) was added and the mixture was heated at this temperature for 1 h, at which time TLC analysis (50% EtOAc / hexanes) showed no starting material left. The mixture was cooled, filtered through celite and washed with MeOH until the filtrate was colorless. The filtrate was then concentrated and redissolved in EtOAc / H ₂ O. The solution was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a brown solid (100 mg, 59%).

(Iv) 5- (Ethylthio) -2- (naphthalen-2-yl) benzo [d] oxazole 2-amino-4- (ethylthio) phenol (100 mg, 0.59 mmol) was dissolved in xylene (5 mL) -Naphthoyl (113 mg, 0.59 mmol) was added. The mixture was heated to 160 ° C. for 15 minutes, at which time TLC analysis (50% EtOAc / hexanes) already showed no starting material present. pTsOH (225 mg, 1.18 mmol) was added and the mixture was heated to reflux for 2 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica. Column chromatography (gradient: 100% hexanes to 20% EtOAc / hexanes) gave the title compound as an off-white solid (130 mg, 72%).

(V) 5- (Ethylsulfinyl) -2- (naphthalen-2-yl) benzo [d] oxazole
5- (Ethylthio) -2- (naphthalen-2-yl) benzo [d] oxazole (64 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL) and cooled to -78 ° C. mCPBA (77%, 47 mg, 0.21 mmol) was added and the mixture was stirred for 1 hour, allowing the temperature to rise to -50 ° C. Na ₂ SO ₃ aqueous solution (1 mL) was added and the mixture was warmed to room temperature. The mixture was washed with 1M NaOH (3 × 5 mL) and brine (10 mL). The organic layer was dried (MgSO ₄ ), filtered and concentrated. The crude product was combined with a second batch of equivalent scale and purified by column chromatography (gradient: 50% EtOAc / hexanes to EtOAc) to yield the title compound as a white solid (40 mg, 56%). 0226-56-4

4-(ベンゾ[d]チアゾール-2-イル)チアゾール-2-アミン
2-アミノベンゼンチオール（1.00mL、9.35mmol）及び2-アミノチアゾール-4-カルボン酸（1.59g、11.21mmol）を、120℃でPPAに同時に添加し、結果として生じる混合物を210℃で18時間撹拌した。熱粗生成物を氷/水（150mL）に注ぎ、NaOHペレットでpH＝14になるまで塩基性化した。次に、水性層を酢酸エチル（3×70mL）で抽出し、組み合わせた抽出物をpH＝7になるまで鹹水で洗浄し、無水硫酸マグネシウム上で乾燥させた。結果として生じる固体を、勾配（7：3(v/v)の酢酸エチル/ヘキサンから1：0(v/v)の酢酸エチル/ヘキサンへ、次に1：0(v/v)の酢酸エチル/メタノールから98：2(v/v)の酢酸エチル/メタノールへ）を使用して溶出するカラムクロマトグラフィーによって精製すると、407mg（12％）の表題化合物を生じた。

(Example 15)
(2- (4H-1,2,4-triazol-3-ylthio) -N- (4- (benzo [d] thiazol-2-yl) thiazol-2-yl) acetamide and 2- (4H-1, General synthetic scheme for 2,4-triazol-3-ylthio) -N- (5- (benzo [d] thiazol-2-yl) pyridin-3-yl) acetamide

4- (Benzo [d] thiazol-2-yl) thiazol-2-amine
2-Aminobenzenethiol (1.00 mL, 9.35 mmol) and 2-aminothiazole-4-carboxylic acid (1.59 g, 11.21 mmol) were added simultaneously to the PPA at 120 ° C. and the resulting mixture was heated at 210 ° C. for 18 hours. Stir. The hot crude product was poured into ice / water (150 mL) and basified with NaOH pellets until pH = 14. The aqueous layer was then extracted with ethyl acetate (3 × 70 mL) and the combined extracts were washed with brine until pH = 7 and dried over anhydrous magnesium sulfate. The resulting solid was gradient (7: 3 (v / v) ethyl acetate / hexanes to 1: 0 (v / v) ethyl acetate / hexanes, then 1: 0 (v / v) ethyl acetate Purification by column chromatography eluting with / methanol to 98: 2 (v / v) ethyl acetate / methanol) yielded 407 mg (12%) of the title compound.

N-(4-(ベンゾ[d]チアゾール-2-イル)チアゾール-2-イル)-2-クロロアセトアミド
ジイソプロピルエチルアミン（1.12mL、6.43mmol）の存在下で、ジクロロメタン/テトラヒドロフラン（20mL、1：1(v/v)）における4-(ベンゾ[d]チアゾール-2-イル)チアゾール-2-アミン（250mg、1.07mmol）の撹拌した溶液に、塩化クロロアセチル（340μL、4.29mmol）を滴下して添加した。結果として生じる混合物を室温で18時間撹拌した後、粗生成物をジクロロメタン（150mL）で希釈し、有機層を鹹水（50mL）で洗浄した。水性層をジクロロメタン（2×50mL）で抽出し、組み合わせた抽出物を無水硫酸マグネシウム上で乾燥させた。結果として生じる油を、勾配（0：1(v/v)の酢酸エチル/ヘキサンから3：7(v/v)の酢酸エチル/ヘキサンへ）を使用して溶出するカラムクロマトグラフィーによって精製すると、211mg（64％）の表題化合物を生じた。

The following compounds were prepared according to the same general method.
5- (Benzo [d] thiazol-2-yl) pyridin-3-amine

N- (4- (Benzo [d] thiazol-2-yl) thiazol-2-yl) -2-chloroacetamide Dichloroethylamine (1.12 mL, 6.43 mmol) in the presence of dichloromethane / tetrahydrofuran (20 mL, 1: 1) To a stirred solution of 4- (benzo [d] thiazol-2-yl) thiazol-2-amine (250 mg, 1.07 mmol) in (v / v)) was added dropwise chloroacetyl chloride (340 μL, 4.29 mmol). Added. After the resulting mixture was stirred at room temperature for 18 hours, the crude product was diluted with dichloromethane (150 mL) and the organic layer was washed with brine (50 mL). The aqueous layer was extracted with dichloromethane (2 × 50 mL) and the combined extracts were dried over anhydrous magnesium sulfate. The resulting oil was purified by column chromatography eluting using a gradient (0: 1 (v / v) ethyl acetate / hexane to 3: 7 (v / v) ethyl acetate / hexane). Yield 211 mg (64%) of the title compound.

The following compounds were prepared according to the same general method.
N- (5- (benzo [d] thiazol-2-yl) pyridin-3-yl) -2-chloroacetamide

2- (4H-1,2,4-triazol-3-ylthio) -N- (4- (benzo [d] thiazol-2-yl) thiazol-2-yl) acetamide N- (4 in acetone (20 mL) -(Benzo [d] thiazol-2-yl) thiazol-2-yl) -2-chloroacetamide 2 (205 mg, 0.66 mmol), 1H-1,2,4-triazole-5 (4H) -thione (74 mg, A mixture of 0.73 mmol) and potassium carbonate (110 mg, 0.8 mmol) was refluxed for 2 hours. Remove the solvent in vacuo and elute the resulting solid using a gradient (0: 1 (v / v) ethyl acetate / hexanes to 1: 0 (v / v) ethyl acetate / hexanes) Purification by chromatography yielded 120 mg (48%) of the title compound.

The following compounds were prepared according to the same general method.
2- (4H-1,2,4-triazol-3-ylthio) -N- (5- (benzo [d] thiazol-2-yl) pyridin-3-yl) acetamide

(Example 16)
1- (2- (Naphthalen-2-yl) benzo [d] oxazol-5-yl) pyrrolidin-2-one
4-Chloro-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) butanamide 2- (Naphthalen-2-yl) -5-amino-benzo [] in anhydrous pyridine (7.5 mL) d] To a solution of oxazole (400 mg, 1.537 mmol), 4-bromobutyryl chloride (195 μL, 1.69 mmol) was added dropwise at 0 ° C. and the resulting reaction mixture was allowed to warm to room temperature over 16 h. It was. After this time, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous copper sulfate (x2) and then with saturated aqueous potassium carbonate (x2). The organic layer was dried over MgSO ₄ and concentrated in vacuo to give 4-chloro-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) butanamide (115 mg, 21%) as column chromatography. Occurs after graphy (2: 1 to 1: 1 40-60 petroleum: ethyl acetate). (LCMS RT = 7.42 min, MH + 365).

1- (2- (Naphthalen-2-yl) benzo [d] oxazol-5-yl) pyrrolidin-2-one 4-chloro-N- (2- (naphthalen-2-yl) benzo in anhydrous DMF under nitrogen To a solution of [d] oxazol-5-yl) butanamide (62 mg, 0.170 mmol) was added diethylamine (20 μL, 0.187 mmol) and potassium carbonate (26 mg, 0.187 mmol) and the reaction mixture was heated to 50 ° C. for 16 hours. . After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with brine (x3). The organic layer was dried over MgSO ₄ and concentrated in vacuo to give the title compound (28 mg, 50%) as a pale yellow powder after column chromatography (2: 1 to 1: 1 40-60 petroleum: ethyl acetate) It was. (LCMS RT = 7.02 min, MH + 329).

(Example 17)
2- (Benzo [b] thiophen-6-yl) -5- (ethylsulfonyl) benzo [d] oxazole 2- (Benzo [b] thiophen-6-yl)-in chloroform (15 mL) To a solution of 5- (ethylsulfonyl) benzo [d] oxazole (0.56 g, 1.5 mmol) was added m-chloroperbenzoic acid (0.65 g, 3.8 mmol). After stirring for 16 hours, sodium sulfite solution (10%) was added, shaken with the reaction mixture and fractionated. The organic phase was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography eluting with 0/1 to 4/1 (v / v) ethyl acetate / petroleum ether and then recrystallized using ethanol to yield 88 mg (15%) of the title compound. occured.

工程1：
MeOH（30mL）における2-アミノ-4-メチルフェノール（900mg、7.30mmol、1当量）及び2-ナフトアルデヒド（1.14g、7.30mmol、1当量）の溶液を50℃で30分間加熱した。真空濃縮後、DCM（40mL）に残渣を懸濁し、DDQ（2,3ジクロロ,5,6-ジシアノ-1,4-ベンゾキノン、1.74g、1.05当量、766mmol）で処理した。反応混合物を室温で10分間撹拌した後、DCMで希釈した。有機相を鹹水及びNaHCO₃水溶液で洗浄し、Na₂SO₄上で乾燥させ、真空濃縮した。この反応によって、定量可能な収量で所望の化合物が生じ、さらに精製する必要はなかった。

(Example 18)
General scheme for the synthesis of common intermediate A

Process 1:
A solution of 2-amino-4-methylphenol (900 mg, 7.30 mmol, 1 eq) and 2-naphthaldehyde (1.14 g, 7.30 mmol, 1 eq) in MeOH (30 mL) was heated at 50 ° C. for 30 min. After concentration in vacuo, the residue was suspended in DCM (40 mL) and treated with DDQ (2,3 dichloro, 5,6-dicyano-1,4-benzoquinone, 1.74 g, 1.05 eq, 766 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then diluted with DCM. The organic phase was washed with brine and aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated in vacuo. This reaction yielded the desired compound in a quantifiable yield and did not require further purification.

Process 2:
To a stirred solution of the methyl compound (1.9 g, 7.33 mmol, 1 eq) in chlorobenzene (60 mL) was added NBS (1.3 g, 7.33 mmol, 1 eq) and benzoyl peroxide (catalytic amount) in one portion at 90 ° C. The reaction mixture was heated at 90 ° C. for 1 hour and further refluxed for 4 hours. After cooling, the reaction mixture was concentrated in vacuo and suspended in EtOAc. The residue was filtered to yield 350 mg of the desired product. The organic phase was washed with brine, aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated in vacuo. The solid was triturated in EtOAc to provide 400 mg of the desired bromide compound. No further purification was attempted.

5- (morpholinomethyl) -2- (naphthalen-2-yl) benzo [d] oxazole Brominated compound A (200 mg, 0.592 mmol, 1 eq) is dissolved in anhydrous DMF (volume = 6 mL) and potassium carbonate ( 91 mg, 0.651 mmol, 1.1 eq) and morpholine (0.0057 mL, 0.651 mmol, 1.1 eq) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Water was added. The aqueous phase was extracted 3 times with EtOAc and the organic phase was washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash Jones chromatography yielded 68 mg of the desired compound in 34% yield.

5- (ethylsulfonylmethyl) -2- (naphthalen-2-yl) benzo [d] oxazole and 5- (methylsulfonylmethyl) -2- (naphthalen-2-yl) benzo [d] oxazole Step 3:
Brominated compound A (300 mg, 0.887 mmol, 1 eq) is dissolved in anhydrous THF (15 mL); a. Sodium ethanethiolate (82 mg, 0.976 mmol, 1.1 eq) or b. Sodium thiomethoxide (68 mg, 0.976 mmol, 1.1 eq) was added at room temperature. The reaction mixture was refluxed for 4 hours. After cooling, the mixture was diluted with water and extracted three times with DCM. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The bromide starting material and the desired product were co-spotted by TLC. According to LCMS (a), 59% of the desired compound was present in the crude mixture. In either case, no further purification was attempted.

Process 4:
a (or b) was dissolved in 10 mL of chloroform and 4 equivalents of MPCBA were added in one portion at 0 ° C. The reaction mixture was stirred at room temperature overnight.
a : The reaction mixture was diluted with DCM and washed twice with 1N NaOH and water. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by trituration in DCM and ether yielded the desired product in 20% yield.
b : Triturated solid, it was filtered and washed with ether to yield the desired product in 25% yield.

[3-(tert-ブチルジメチルシリルオキシ)-1-(2-(ナフタレン-2-イル)ベンゾ[d]オキサゾール-5-イルアミノ)-1-オキソプロパン-2-イルカルバミン酸((S)-(9H-フルオレン-9-イル)メチル)]、4
ジイソプロピルエチルアミン（1.59mL、9.12mmol）の存在下で、DMF（50mL）における(S)-N-Boc-O-TBDMS-セリン（1.477g、3.34mmol）の撹拌した溶液に、HATU（1.271g、3.34mmol）を室温で一度に添加し、次いで2-(ナフタレン-2-イル)ベンゾ[d]オキサゾール-5-アミン（791mg、3.04mmol）を添加し；結果として生じる混合物を室温で18時間撹拌した。酢酸エチル（200mL）と鹹水（150mL）との間で粗生成物を分画し、2つの層を分離した。水性層を酢酸エチル（2×50mL）でさらに抽出し、組み合わせた抽出物を無水硫酸マグネシウム上で乾燥させた。結果として生じる固体を、勾配（0：1(v/v)の酢酸エチル/ヘキサンから1：0(v/v)の酢酸エチル/ヘキサンへ）を使用して溶出するカラムクロマトグラフィーによって精製すると、2.05g（98％）の表題化合物を生じた。

(Example 19)

[3- (tert-Butyldimethylsilyloxy) -1- (2- (naphthalen-2-yl) benzo [d] oxazol-5-ylamino) -1-oxopropan-2-ylcarbamic acid ((S)- (9H-fluoren-9-yl) methyl)], 4
To a stirred solution of (S) -N-Boc-O-TBDMS-serine (1.477 g, 3.34 mmol) in DMF (50 mL) in the presence of diisopropylethylamine (1.59 mL, 9.12 mmol) was added HATU (1.271 g, 3.34 mmol) is added in one portion at room temperature followed by 2- (naphthalen-2-yl) benzo [d] oxazol-5-amine (791 mg, 3.04 mmol); the resulting mixture is stirred at room temperature for 18 hours did. The crude product was partitioned between ethyl acetate (200 mL) and brine (150 mL) and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 50 mL) and the combined extracts were dried over anhydrous magnesium sulfate. The resulting solid was purified by column chromatography eluting using a gradient (0: 1 (v / v) ethyl acetate / hexanes to 1: 0 (v / v) ethyl acetate / hexanes). 2.05 g (98%) of the title compound were produced.

The following compounds were prepared according to the same general method.
Methyl (1- (2- (naphthalen-2-yl) benzo [d] oxazol-5-ylamino) -1-oxopropan-2-yl) carbamic acid (S) -tert-butyl, 7

[(S) -2-amino-3- (tert-butyldimethylsilyloxy) -N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) propanamide], 5
To a stirred solution of 4 (2.08 g, 3.04 mmol) in dimethylformamide (16 mL), piperidine (4 mL, 40.5 mmol) was added dropwise at room temperature and the resulting mixture was stirred for 18 hours. The crude product was partitioned between ethyl acetate (150 mL) and brine (100 mL) and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 50 mL) and the combined extracts were dried over anhydrous magnesium sulfate. The resulting oil was purified by column chromatography eluting using a gradient (3: 7 (v / v) ethyl acetate / hexanes to 1: 0 (v / v) ethyl acetate / hexanes). 1.39 (99%) of the title compound were produced.

[(S) -2-amino-3-hydroxy-N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) propanamide], 6
To a stirred solution of 5 (1.40 g, 3.04 mmol) in THF (10 mL) was added TBAF (1M in THF, 12.16 mL, 12.16 mmol) dropwise at room temperature and the resulting mixture was stirred for 60 h. The crude product was evaporated to dryness, dissolved in ethyl acetate (200 mL) and washed with 1M NaOH in water (100 mL). The aqueous layer was further extracted with ethyl acetate (2 × 50 mL), brine (100 mL) and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 50 mL) and the combined extracts were washed with brine (2 × 50 mL) and dried over anhydrous magnesium sulfate. The resulting solid was precipitated from IMS / methanol to yield 282 mg (27%) of the title compound as a colorless solid.

[(S) -2- (methylamino) -N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) propanamide], 8
To a stirred solution of 7 (557 mg, 1.25 mmol) in DCM (10 mL) was added TFA (2 mL) dropwise at room temperature and the resulting mixture was stirred for 3 h. The reaction was quenched with saturated NaHCO ₃ (10 mL) and the aqueous layer was extracted with DCM (3 × 50 mL). The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting yellow solid is purified by column chromatography eluting using a gradient (1: 0 (v / v) ethyl acetate / methanol to 7: 3 (v / v) ethyl acetate / methanol). This yielded 310 mg (72%) of the title compound.

3- (5-Isobutylamidobenzo [d] oxazol-2-yl) quinoline 1-oxide N- (2- (quinolin-3-yl) benzo [d] oxazol-5-yl) isobutyl in anhydrous dichloromethane (15 mL) To a stirred suspension of amide (250 mg, 0.75 mmol) was added 2,2,2-trifluoroacetic anhydride (533 μL, 3.77 mmol) and hydrogen peroxide (35 wt% in H ₂ O, 550 μL in dichloromethane (15 mL). , 5.66 mmol) solution was added. The resulting solution was refluxed for 16 hours. After cooling, the crude mixture was diluted with dichloromethane and washed with aqueous NaHCO ₃ solution. The aqueous layer was extracted with dichloromethane and the organic layer was washed with water until a neutral pH was reached. The combined organic layers were dried over anhydrous MgSO ₄ and evaporated. The resulting product was purified by recrystallization from dichloromethane to yield 24 mg (9%) of the title compound. (LCMS RT = 5.15 min, (M + MeCN) +388.9).

(Example 20)
2- (Dimethylamino) -N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide hydrochloride 2- (Dimethylamino) -N- (2- ( To a stirred solution of naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide (50 mg, 0.145 mmol) is added 4M HCl in 1,4-dioxane (4 mL) and the resulting solution is 10 After being allowed to stir for minutes, it was concentrated in vacuo. The crude residue was resuspended in toluene and concentrated in vacuo again to yield the crude product as a yellow solid. This was triturated with diethyl ether and the title compound was isolated as a yellow powder (42 mg, 76%) by filtration under reduced pressure. (LCMS RT = 6.51 min, MH + 346).

2- (1H-imidazol-4-yl) -N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide hydrochloride
2- (1H-imidazol-4-yl) -N- (2- (naphthalen-2-yl) benzo [d] oxazol-5-yl) acetamide (50 mg, 0.136 mmol) was added to 1,4-dioxane (4 mL ) And the resulting mixture was heated in a CEM Disciver microwave at 150 ° C. for 10 minutes. After this time, the reaction mixture was concentrated in vacuo. The crude residue was resuspended in toluene and concentrated in vacuo again to yield the crude product as a yellow solid. This was triturated with diethyl ether and the title compound was isolated as a yellow powder (47 mg, 85%) by filtration under reduced pressure. (LCMS RT = 4.60 min).

(N-(4-(6-メチルベンゾ[d]チアゾール-2-イル)フェニル)-2-(ピリジン-2-イルオキシ)アセトアミド)
ジイソプロピルエチルアミン（510μL、2.90mmol）の存在下でDCM（30mL）における2-(ピリジン-2-イルオキシ)酢酸の撹拌した溶液に、HATU（442mg、1.16mmol）を一度に添加した後、4-(6-メチルベンゾ[d]チアゾール-2-イル)アニリン（233mg、0.97mmol）を添加し；結果として生じる混合物を室温で18時間撹拌した。生成された固体を濾過し、メタノールで洗浄し、回収し及び乾燥させると、143mg（37％）の表題化合物を生じた。

(Example 21)

(N- (4- (6-Methylbenzo [d] thiazol-2-yl) phenyl) -2- (pyridin-2-yloxy) acetamide)
To a stirred solution of 2- (pyridin-2-yloxy) acetic acid in DCM (30 mL) in the presence of diisopropylethylamine (510 μL, 2.90 mmol) was added HATU (442 mg, 1.16 mmol) in one portion, followed by 4- ( 6-Methylbenzo [d] thiazol-2-yl) aniline (233 mg, 0.97 mmol) was added; the resulting mixture was stirred at room temperature for 18 hours. The resulting solid was filtered, washed with methanol, collected and dried to yield 143 mg (37%) of the title compound.

The following compounds were prepared according to the same general method.

(Example 22)
2-((2- (Naphthalen-2-yl) benzo [d] oxazol-5-yl) methylamino) acetic acid Dissolve glycine ethyl ester hydrochloride (91 mg, 1.1 eq, 0.653 mmol) in anhydrous DMF (4 mL) 1 equivalent of triethylamine was added and the reaction mixture was stirred at room temperature for 5 minutes. In a separate flask, dissolve bromide (300 mg, 1 eq, 0.59 mmol) in anhydrous DMF (6 mL), add potassium carbonate to the mixture, then add a solution of free based glycine ethyl ester in DMF did. The reaction mixture was stirred at room temperature overnight. After 18 hours, according to TLC (50% ethyl acetate, 50% petroleum ether), some starting material is still present, 1.1 equivalents of free base glycine ethyl ester is added and the reaction mixture is stirred at 70 ° C. for 3 hours. Heated for hours. After cooling, the reaction mixture was concentrated in vacuo and diluted with DCM. The organic phase was washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by flash Jones chromatography provided a yellow solid in 42% yield.

This ester (75 mg, 0.208 mmol, 1 eq) was dissolved in a mixture of water and THF (1/1, volume = 4 mL) and 5 mL of 1M NaOH solution was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. 2N HCl solution was added to the mixture until pH = 3. The white solid was crushed and it was filtered, washed with ether and dried in a vacuum oven for 4 hours. This gave the desired product in 56% yield.

同一の一般法に従って、以下の化合物を調製した。

(Example 23)

The following compounds were prepared according to the same general method.

N- (3- (Ethylsulfonyl) phenyl) naphthalene-2-carbothioamide
To a solution of 5- (methylsulfonyl) -2- (naphthalen-2-yl) benzo [d] thiazole (0.19 g, 0.56 mmol) in anhydrous THF (7 mL) cooled to −78 ° C. was added LHMDS (1M, 0.62 mmol) was added. After stirring for 1 hour, iodomethane (0.16 g, 1.23 mmol) was added and the reaction was warmed to room temperature. After stirring for 16 hours, ammonium chloride (10 mL) was added and the reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography eluting with 0/1 to 1/4 (v / v) ethyl acetate / petroleum ether to yield 102 mg (51%) of the title compound.

(Example 24)
(S) -2-Hydroxy-N, N, N-trimethyl-4- (2- (naphthalen-2-yl) benzo [d] oxazol-5-ylamino) -4-oxobutane-1-aminium TFA salt
To a solution of L-carnitine (89 mg, 0.55 mmol) and 2- (naphthalen-2-yl) benzo [d] oxazol-5-amine (100 mg, 0.38 mmol) in DMF (2 mL), HATU (0.22 g, 0.57 mmol). ) And DiPEA (0.20 mL, 1.14 mmol) were added at 0 ° C. After stirring at ambient temperature for 16 hours, the reaction mixture was concentrated and the residue was treated with DCM / MeOH. The precipitate was filtered and purified by HPLC (H ₂ O / MeCN, 0.1% TFA) to yield 29 mg (15%) of the title compound. (LCMS RT = 4.41min, MH + = 404.2).

2-アミノ-4-メトキシフェノール
IMS/H2O（180mL、2：1）における2-ニトロ-4-メトキシフェノール（6.00g、35.5mmol）及び塩化アンモニウム（9.48g、177.4mmol）の混合物を70℃に加熱した後、鉄（9.91g、177.4mmol）を添加し、結果として生じる混合物を18還流した。粗生成物を冷却し、セライトパッドで濾過した。フィルターを酢酸エチルで洗浄し、乾燥するまで濾液を蒸発させると、褐色の固体を生じ、それを酢酸エチル（250mL）と鹹水（150mL）との間で分画した。2つの層を分離し、水性層を酢酸エチル（2×50mL）でさらに抽出し、組み合わせた抽出物を無水硫酸マグネシウム上で乾燥させた。溶媒の蒸発によって褐色の固体が生じ、勾配（0：1(v/v)の酢酸エチル/ヘキサンから3：2(v/v)の酢酸エチル/ヘキサンへ）を使用して溶出するカラムクロマトグラフィーによって該固体を精製すると、3.84g（78％）の表題化合物を生じた。

(Example 25)

2-Amino-4-methoxyphenol
After heating a mixture of 2-nitro-4-methoxyphenol (6.00 g, 35.5 mmol) and ammonium chloride (9.48 g, 177.4 mmol) in IMS / H2O (180 mL, 2: 1) to 70 ° C., iron (9.91 g 177.4 mmol) was added and the resulting mixture was refluxed for 18 hours. The crude product was cooled and filtered through a celite pad. The filter was washed with ethyl acetate and the filtrate was evaporated to dryness to yield a brown solid that was partitioned between ethyl acetate (250 mL) and brine (150 mL). The two layers were separated, the aqueous layer was further extracted with ethyl acetate (2 × 50 mL), and the combined extracts were dried over anhydrous magnesium sulfate. Evaporation of the solvent yields a brown solid, eluting using a gradient (0: 1 (v / v) ethyl acetate / hexanes to 3: 2 (v / v) ethyl acetate / hexanes). The solid was purified by to yield 3.84 g (78%) of the title compound.

5-Methoxy-2- (naphthalen-2-yl) benzo [d] oxazole Prepared using the standard microwave route described previously.

2- (Naphthalen-2-yl) benzo [d] oxazol-5-ol To dry DCM (20 mL) at room temperature under dry nitrogen atmosphere, a 1 M solution of BBr ₃ in DCM (21.3 mL, 21.3 mmol), then 5-Methoxy-2- (naphthalen-2-yl) benzo [d] oxazole 2 (1.567 g, 5.33 mmol) was added slowly. The resulting mixture was refluxed under nitrogen for 18 hours and quenched with distilled water (20 mL). The crude product was then partitioned between ethyl acetate (200 mL) and water (100 mL) and the two layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 50 mL) and the combined extracts were dried over anhydrous MgSO ₄ . Evaporation of the solvent yields a yellow solid, eluting using a gradient (0: 1 (v / v) ethyl acetate / hexane to 1: 1 (v / v) ethyl acetate / hexane) The solid was purified by to yield 848 mg (57%) of the title compound.

5- (2- (Benzyloxy) ethoxy) -2- (naphthalen-2-yl) benzo [d] oxazole 2- (Naphthalen-2-yl) benzo [d] oxazole in DMF (4 mL) at room temperature To a solution of oar (0.2 g, 0.71 mmol) was added NaH (60% dispersion in oil, 34 mg, 0.86 mmol). After stirring for 0.5 hour, benzyl 2-chloroethyl ether (0.14 mL, 0.92 mmol) was added and the reaction mixture was stirred at 50 ° C. for 16 hours and quenched with distilled water (0.5 mL). The reaction mixture was partitioned between EtOAc (40 mL) and water (30 mL) and the organic phase was washed with water (2 × 30 mL) and brine (30 mL), dried over MgSO ₄ and concentrated under reduced pressure. . The residue was purified by column chromatography eluting with a gradient (0: 1 (v / v) ethyl acetate / hexanes to 3: 7 (v / v) ethyl acetate / hexanes) to yield 170 mg (61% ) Of the title compound.

(Example 26)
(2-Phenyl-1H-indol-3-yl) methanol To a solution of 2-phenylindole-3-carboxaldehyde (500 mg, 2.62 mmol, 1 eq) in anhydrous MeOH (30 mL) was added sodium borohydride (103 mg, 1.2 Equivalent, 2.71 mmol) was added in one portion at 0 ° C. The reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the aqueous phase was extracted three times with dichloromethane, dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by recrystallization in dichloromethane yielded the title compound.

(Example 27)
5- (Ethylsulfonyl) -2- (naphthalen-2-yl) benzo [d] thiazole
To a solution of 5- (methylsulfonyl) -2- (naphthalen-2-yl) benzo [d] thiazole (0.19 g, 0.56 mmol) in anhydrous THF (7 mL) cooled to −78 ° C. was added LHMDS (1M, 0.62 mmol) was added. After stirring for 1 hour, iodomethane (0.16 g, 1.23 mmol) was added and the reaction was warmed to room temperature. After stirring for 16 hours, ammonium chloride (10 mL) was added and the reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography eluting with 0/1 to 1/4 (v / v) ethyl acetate / petroleum ether to yield 102 mg (51%) of the title compound.

(Example 28)
2- (2- (Naphthalen-2-yl) benzo [d] oxazol-5-ylsulfonyl) ethanol
A solution of 2- (naphthalen-2-yl) benzo [d] oxazol-5-amine (0.15 g, 0.57 mmol) and hydrochloric acid (3 mL) was stirred at 50 ° C. for 30 minutes and then cooled to 0 ° C. A solution of sodium nitrite (0.044 g, 0.63 mmol) in water (0.5 mL) was added dropwise to the reaction and stirred for 45 minutes before adjusting the pH to pH 7 using 1M sodium hydroxide. To a solution of 2-mercaptoethanol (0.08 mL) in 1 M sodium hydroxide (1.2 mL) containing copper suspension (0.036 g, 0.58 mmol) was added the mixture dropwise and heated to 60 ° C. After stirring for 30 minutes, the reaction mixture was cooled and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude compound was purified by column chromatography eluting with 0 / 7-3 / 7 (v / v) ethyl acetate / petroleum ether to give 127 mg (69%) 2- (2- (naphthalen-2-yl) benzo [d] Oxazol-5-ylthio) ethanol was produced. To a solution of 2- (2- (naphthalen-2-yl) benzo [d] oxazol-5-ylthio) ethanol (0.13 g, 0.40 mmol) in chloroform (5 mL), add mCPBA (0.17 g, 0.99 mmol). And stirred for 16 hours. Sodium sulfite solution (10%, 5 mL) was added to the reaction mixture. The organic phase was washed with 1M sodium hydroxide, dried over MgSO4 and concentrated in vacuo. The crude compound was purified by column chromatography eluting with 0/1 to 6/4 (v / v) ethyl acetate / petroleum ether to yield 22 mg (11%) of the title compound.

Claims (14)

Compound of formula (1)

(Where
R ₉ is partially or fully aromatic containing 0 to 4 heteroatoms and 1 to 4 halogens, C ₁ -C ₆ alkyl, OC ₁ -C ₆ alkyl or NR ₉₀ ( C = Q) represents a C _5-10 carbocycle optionally substituted by -MZR ₉₃ , wherein R ₉₀ represents H or C _1-6 alkyl, and Q represents O, S, or NR ₉₁ . Wherein R ₉₁ represents H or C _1-6 alkyl, M represents C _1-3 alkyl optionally substituted with halogen, C _1-6 alkyl, or C _1-6 alkoxy, Z Represents O, S or NR ₉₂ , in which R ₉₂ represents H or C _1-6 alkyl, and R ₉₃ is partially or completely containing 0 to 4 heteroatoms. _Represents a C _5-10 carbocycle which is aromatic and optionally substituted by _{1 to} 4 halogens, C ₁ -C ₆ alkyl or OC ₁ -C ₆ alkyl;
_{Three of} A ₁ , A ₂ , A ₃ and A ₄ represent CH, and _one of A ₁ , A ₂ , A ₃ and A ₄ represents CR ₁ in which R ₁ represents:
An alkyl group selected from C ₂ -C ₃ alkyl, n-butyl and sec-butyl optionally substituted with hydroxyl, halogen, carboxylic acid, piperidin-1-yl, N-morpholino, —NMe ₂ or alkoxy;
Hydroxyl, halogen, CO ₂ (C _1-6 alkyl), or —O (C _1-6 alkyl) or C substituted with halogen, carboxylic acid, piperidin-1-yl, N-morpholino, —NMe ₂ or alkoxy ₁ alkyl hydroxyl, halogen, CO ₂ (C _1-6 alkyl), or —O (C _1-6 alkyl);
-N- (S) -2-amino-3-hydroxypropionamide;
-N- (S) -2- (methylamino) propionamide;
-N- (S) -2-aminopropionamide;
-N-2-methylaminoacetamide;
-(S = O) R ₂₁ (wherein R ₂₁ represents C ₁ -C ₆ alkyl);
—SO _n R ₂₂ (wherein n = 0, 1 or 2 and R ₂₂ is optionally substituted with OH or ethyl substituted with hydroxyl, CH ₃ , CH ₂ CD ₃ or C ₃₋ Represents ₆ alkyl);
-SO ₂ NR ₅₅ R ₂₃ (wherein, may be identical or different R ₂₃ and R ₅₅ each represent H or C _1-6 alkyl.);
-NR ₅₆ SO _n R ₂₄ (wherein, a n = 0, 1 or 2 and represents the same or different in possible R ₂₄ and R ₅₆ are each, H, or C ₁ -C ₆ alkyl.);
-K-SO _n -R _{28 wherein} K represents C ₁ -C ₃ alkyl optionally substituted with C ₁ -C ₆ alkyl, n = 0-2, and R ₂₈ is 1 Represents C ₁ -C ₁₀ alkyl optionally substituted with one or more hydroxy, halogen, alkoxy or amine.);
-CO ₂ R ₂₆ (wherein, R ₂₆ represents C _1-6 alkyl.);
Disubstituted phosphinates, wherein each substituent, which may be the same or different, may represent C _1-6 alkyl or C _5-10 aryl;
An N-linked monocyclic or bicyclic ring substituted by one or more oxo, hydroxyl, halogen, C ₁ -C ₆ alkyl, alkoxy or aryl substituents; or
NR ₁₅ C (= W) R ₁₇ (where
W represents NH, S or O;
R ₁₇ is C ₂ -alkyl, n-propyl, or C ₄ -C ₁₀ alkyl; C ₁ -C ₁₀ alkyl substituted with one or more halogen, hydroxyl, alkoxy, or amine; one or more C _1- Mono- or disaccharide units bonded in the anomeric position via a C ₁ -C ₄ alkyl group optionally substituted with ₆ alkyl groups; CH ₂ aryl, where aryl is an aromatic hydrocarbon or other than carbon to an oxygen atom as a ring-constituting component, an aromatic heterocyclic 5- to 10-membered containing 1 to 4 heteroatoms selected from a sulfur atom and a nitrogen _{atom); -. CH 2 OCH 3} , -CH 2 Represents OCH ₂ CH ₂ OCH ₃ , CH ₂ piperidin-1-yl or CH ₂ -N-morpholinoyl; and
R ₁₅ represents H, C _1-6 alkyl, or together with R ₁₇ represents —CH ₂ CH ₂ —, —CH ₂ CH ₂ —, or —CH ₂ CH ₂ CH ₂ —;
X is O or N; and
Y is O or N. ). A _1, A ₂ and A ₄ represent CH, and A ₃ represents CR _1, compound of claim 1. The compound according to claim 1 or 2, wherein R ₉ represents 2-naphthyl. R ₉ represents 2-naphthyl optionally substituted with halogen, or phenyl optionally substituted with halogen;
A compound according to claim ₁ , wherein A ₁ , A ₂ and A ₄ represent CH and A ₃ represents CR _{1 wherein} R ₁ represents
NR ₁₅ C (= W) R ₁₇ (where
W represents NH, S or O;
R ₁₇ is C ₂ -alkyl, n-propyl, or C ₄ -C ₁₀ alkyl; C ₁ -C ₁₀ alkyl substituted with one or more halogen, hydroxyl, alkoxy or amine; one or more C _1- Mono- or disaccharide units bonded in the anomeric position via a C ₁ -C ₄ alkyl group optionally substituted with ₆ alkyl groups; CH ₂ aryl (wherein aryl is an aromatic hydrocarbon or carbon atom A 5- to 10-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring component.); CH ₂ OCH ₃ , CH ₂ Represents OCH ₂ CH ₂ OCH ₃ , CH ₂ piperidin-1-yl or CH ₂ -N-morpholino; and
R ₁₅ represents H, C _1-6 alkyl, or together with R ₁₇ represents —CH ₂ CH ₂ —, —CH ₂ CH ₂ —, or —CH ₂ CH ₂ CH ₂ —. ). R ₉ represents a 5- to 10-membered heterocyclic ring containing one or more SO _n units, where n = 0 to 2 and is the same or different for each SO _n unit The compound of claim 1 obtained. The compound according to claim 1, wherein R ₁ represents an N-linked monocyclic or bicyclic ring which is a lactam. R ₁ represents —K—SO _n —R ₂₈ , in which K represents C ₁ -C ₃ alkyl optionally substituted with C ₁ -C ₆ alkyl; n = 0-2 And R ₂₈ represents C ₁ -C ₁₀ alkyl optionally substituted with one or more halogen, alkoxy or amine. R ₉ represents a partially or fully aromatic C _5-10 carbocycle containing 0-4 heteroatoms substituted by NR ₉₀ (C = Q) -MZR ₉₃ , in which , R ₉₀ represents H or C _1-6 alkyl, Q represents O, S, or NR ₉₁ , in which R ₉₁ represents H or C _1-6 alkyl, M represents halogen, C _1-6 alkyl, or C _1-3 alkyl optionally substituted with C _1-6 alkoxy, Z represents O, S or NR ₉₂ , in which R ₉₂ is H or C _{1 -6} alkyl, and R ₉₃ is partially or fully aromatic containing 0 to 4 heteroatoms and 1 to 4 halogens, C ₁ -C ₆ alkyl, OC _1- It represents a C _5-10 carbon ring optionally substituted by C ₆ alkyl, the compound of claim 1 wherein.   2. A compound according to claim 1, wherein Y represents N.   2. A compound according to claim 1, wherein X represents O.   2. A compound according to claim 1, wherein Y represents N and X represents O. Compounds selected from the table below:

.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.   A method for the treatment or prevention of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia, comprising administering the compound according to any one of claims 1 to 12.

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