JPWO2018133854A5 - - Google Patents

Description

In the formula, R ₁ to R ₁₈ are independent of each other, preferably unsubstituted or substituted linear or branched hydrocarbon residues containing 1 to 8 carbon atoms, hydrogen, hydroxyl, alkyl, alkenyl, alkynyl. , Alkylene, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl , aryloxy , arylthio , heterocycle, heterocyclic amino, halogen, alkylamino, dialkylamino, amine oxide, alkylhydroxylamino, azide, nitrate, cyano and isocyano , Alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl , heterocyclic carbonyl, alkylvinyl, allyl, carboxy, alkylthio, amide, ester, phosphonic acid ester, cycloalkylphosphonic acid ester, cycloalkylphosphonamide, sulfonic acid ester, cycloalkylsulfone Acid esters or heterocyclic sulfonic acid esters, but alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy and alkylthio are C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkylene, haloalkyl (C2-C8alkylene, haloalkyl, respectively). C1 to C8), cycloalkyl (C1 to C8), alkoxy (C1 to C8) and alkylthio (C1 to C8), for example, _R1 to R13 are arylmethyl , arylethyl , arylpropyl , _arylbutyl , hetero. Arylmethyl , heteroarylethyl , heteroarylpropyl , and heteroarylbutyl may be used, and in particular, R ₁ to R ₁₃ are phenyl, phenylmethyl, 1-methyl-2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl. , 3-Phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl or 1-benzyl- ₁ -methylethyl, where R- ₁ -R13 is fluorine, chlorine, bromine, iodine, fluoromethoxy, chloromethoxy, It may be bromomethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, aminomethoxy, aminoethoxy, aminopropyloxy, or other heteroatoms, such as O, S, P, Si and Se, R1 _- R. ₁₃ is -OR', -OC (O) R', -NR'R ", -SR', -R', -CN, -NO ₂ , -CO ₂ R', -CONR'R", -C ( O) R', -OC (O) NR'R ", -NR" C (O) R ′, -NR "CO ₂ R', -NR'-C (O) NR"R'",-NR'-SO ₂ NR"R'", -NH-C (NH ₂ ) = NH, -NR' C (NH ₂ ) = NH, -NH-C (NH ₂ ) = NR', -OP (O) (OH) ₂ , -OP (O) (OR') ₂ , -OP (O) (OR') (OR "), -OP (O) R'(OR"), -OP (O) R'R ", -OP (OH) ₂ , -OP (OR') ₂ , -OP (OR') (OR""),-OPR'R",-OPR'(OR"), -OS (O) R', -OS (O) (OR'), -OSO ₂ R', -OSO ₂ (OR'),- OSO ₂ NR'R ", -S (O) R', -S (O) (OR'), -SO ₂ R', -SO ₂ (OR'), -SO ₂ NR'R", -NR " SO ₂ R, -OSi (R') ₃ , -OSi (OR') ₃ , -Si (OR') ₃ , -Si (OR') (OR ″) (OR ′ ″), -OSi (OR ′) It may be (OR ″) (OR ′ ″), −N ₃ , −CH (Ph) ₂ , perfluoro (C1 to C4) alkoxy- or perfluoro (C1 to C4) alkyl—, and the quantity range is from 0 to aromatic. Up to the total number of valences available on the ring system; where R', R "and R'" are independently hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl , (non-substituted aryl and heteroaryl,). It is selected from the group consisting of substituted aryl )-(C1-C4) alkyl and (unsubstituted aryl ) oxy- (C1-C4) alkyl.

In certain embodiments:
-R ₁ is α- or β-hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl , aryloxy , arylthio , heterocycle, heterocyclic amino, epoxide, alkylepoxide, Alkylamino, dialkylamino, but alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy and alkylthio are C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkylene, haloalkyl (C1-C8), respectively. ), Cycloalkyl (C1 to C8), Epoxide (C1 to C8) and Alkylthio (C1 to C8).

_R2 to R18 are independently hydrogen, oxygen ₍ = O), hydroxyl, alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl , aryloxy , arylthio , heterocycle, heterocyclic amino. , Epoxides, alkyl epoxides, alkylaminos, dialkylaminos, but alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy and alkylthio are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkylene, respectively. , Haloalkyl (C1 to C8), cycloalkyl (C1 to C8), alkoxy (C1 to C8) and alkylthio (C1 to C8).

式中、Ｒ_１～Ｒ_１８は互いに独立して、好ましくは１～８個の炭素原子を含有する非置換又は置換の直鎖又は分岐鎖炭化水素残留物、水素、ヒドロキシル、アルキル、アルケニル、アルキニル、アルキレン、ハロアルキル、シクロアルキル 、アルコキシ、アルキルチオ、アリール、アリールオキシ、アリールチオ、ヘテロ環、ヘテロ環アミノ、ハロゲン、アルキルアミノ、ジアルキルアミノ、アミンオキシド、アルキルヒドロキシルアミノ、アジ化物、硝酸、シアノ及びイソシアノ、アルキルカルボニル、シクロアルキルカルボニル、アリールカルボニル、ヘテロ環カルボニル、アルキルビニル、アリル、カルボキシ、アルキルチオ、アミド、エステル、ホスホン酸エステル、シクロアルキルホスホン酸エステル、シクロアルキルホスホンアミド、スルホン酸エステル、シクロアルキルスルホン酸エステル又はヘテロ環スルホン酸エステルであり、但しアルキル、アルケニル、アルキニル、アルキレン、ハロアルキル、シクロアルキル、アルコキシ及びアルキルチオはそれぞれＣ１～Ｃ８アルキル、Ｃ２～Ｃ８アルケニル、Ｃ２～Ｃ８アルキニル、Ｃ２～Ｃ８アルキレン、ハロアルキル（Ｃ１～Ｃ８）、シクロアルキル（Ｃ１～Ｃ８）、アルコキシ（Ｃ１～Ｃ８）及びアルキルチオ（Ｃ１～Ｃ８）であり、例えば、Ｒ_１－Ｒ_１３はアリールメチル、アリールエチル、アリールプロピル、アリールブチル、ヘテロアリールメチル、ヘテロアリールエチル、ヘテロアリールプロピル、ヘテロアリールブチルであってもよく、特にＲ_１－Ｒ_１３はフェニル、フェニルメチル、１－メチル－２－フェニルエチル、１－フェニルプロピル、２－フェニルプロピル、３－フェニルプロピル、フェニルブチル、フェニルペンチル、フェニルへキシル又は１－ベンジル－１－メチルエチルであってもよく、Ｒ_１～Ｒ_１３はフッ素、塩素、臭素、ヨウ素、フルオロメトキシ、クロロメトキシ、ブロモメトキシ、フルオロエトキシ、クロロエトキシ、ブロモエトキシ、アミノメトキシ、アミノエトキシ、アミノプロピルオキシ、又は他のヘテロ原子であってもよく、例えばＯ、Ｓ、Ｐ、Ｓｉ及びＳｅであり、Ｒ_１－Ｒ_１３は－ＯＲ′、－ＯＣ（Ｏ）Ｒ′、－ＮＲ′Ｒ″、－ＳＲ′、－Ｒ′、－ＣＮ、－ＮＯ_２、－ＣＯ_２Ｒ′、－ＣＯＮＲ′Ｒ″、－Ｃ（Ｏ）Ｒ′、－ＯＣ（Ｏ）ＮＲ′Ｒ″、－ＮＲ″Ｃ（Ｏ）Ｒ′、－ＮＲ″ＣＯ_２Ｒ′、－ＮＲ′－Ｃ（Ｏ）ＮＲ″Ｒ′″、－ＮＲ′－ＳＯ_２ＮＲ″Ｒ′″、－ＮＨ－Ｃ（ＮＨ_２）＝ＮＨ、－ＮＲ′Ｃ（ＮＨ_２）＝ＮＨ、－ＮＨ－Ｃ（ＮＨ_２）＝ＮＲ′、－ＯＰ（Ｏ）（ＯＨ）_２、－ＯＰ（Ｏ）（ＯＲ′）_２、－ＯＰ（Ｏ）（ＯＲ′）（ＯＲ″）、－ＯＰ（Ｏ）Ｒ′（ＯＲ″）、－ＯＰ（Ｏ）Ｒ′Ｒ″、－ＯＰ（ＯＨ）_２、－ＯＰ（ＯＲ′）_２、－ＯＰ（ＯＲ′）（ＯＲ″）、－ＯＰＲ′Ｒ″、－ＯＰＲ′（ＯＲ″）、－ＯＳ（Ｏ）Ｒ′、－ＯＳ（Ｏ）（ＯＲ′）、－ＯＳＯ_２Ｒ′、－ＯＳＯ_２（ＯＲ′）、－ＯＳＯ_２ＮＲ′Ｒ″、－Ｓ（Ｏ）Ｒ′、－Ｓ（Ｏ）（ＯＲ′）、－ＳＯ_２Ｒ′、－ＳＯ_２（ＯＲ′）、－ＳＯ_２ＮＲ′Ｒ″、－ＮＲ″ＳＯ_２Ｒ、－ＯＳｉ（Ｒ′）_３、－ＯＳｉ（ＯＲ′）_３、－Ｓｉ（ＯＲ′）_３、－Ｓｉ（ＯＲ′）（ＯＲ″）（ＯＲ′″）、－ＯＳｉ（ＯＲ′）（ＯＲ″）（ＯＲ′″）、－Ｎ_３、－ＣＨ（Ｐｈ）_２、ペルフルオロ（Ｃ１～Ｃ４）アルコキシ－又はペルフルオロ（Ｃ１～Ｃ４）アルキル－であってもよく、数量範囲が０から芳香環系上の空いている原子価総数までであり；但しＲ′、Ｒ″及びＲ′″は独立して水素、（Ｃ１～Ｃ８）アルキル及びヘテロアルキル、非置換のアリール及びヘテロアリール、（非置換のアリール）－（Ｃ１～Ｃ４）アルキル及び（非置換のアリール）オキシ－（Ｃ１～Ｃ４）アルキルからなる群から選ばれ、且つ
Ｘ_１～Ｘ_８は互いに独立して酸素（Ｏ）、硫黄（Ｓ）、セレン（－Ｓｅ－）のヘテロ原子、飽和又は不飽和の、置換又は非置換の窒素（＝Ｎ－、－ＮＨ－、－ＮＲ_１４－）、及び原子価数量範囲が０から炭素環－又はヘテロ環－環系上で指示される原子の空いている原子価総数までの炭化水素残留物からなる群から選択される。
＜項２＞
Ｒ_１はα－又はβ－水素、ヒドロキシル、アルキル、アルケニル、アルキニル、アルキレン、ハロアルキル、シクロアルキル、アルコキシ、アルキルチオ、アリール、アリールオキシ、アリールチオ、ヘテロ環、ヘテロ環アミノ、エポキシド、アルキルエポキシド、アルキルアミノ、ジアルキルアミノであり、但しアルキル、アルケニル、アルキニル、アルキレン、ハロアルキル、シクロアルキル、アルコキシ及びアルキルチオはそれぞれＣ１～Ｃ８アルキル、Ｃ２～Ｃ８アルケニル、Ｃ２～Ｃ８アルキニル、Ｃ２～Ｃ８アルキレン、ハロアルキル（Ｃ１～Ｃ８）、シクロアルキル（Ｃ１～Ｃ８）、アルコキシ（Ｃ１～Ｃ８）及びアルキルチオ（Ｃ１～Ｃ８）であり；
Ｒ_２～Ｒ_１８は独立して水素、酸素（＝Ｏ）、ヒドロキシル、アルキル、アルケニル、アルキニル、アルキレン、ハロアルキル、シクロアルキル、アルコキシ、アルキルチオ、アリール、アリールオキシ、アリールチオ、ヘテロ環、ヘテロ環アミノ、エポキシド、アルキルエポキシド、アルキルアミノ、ジアルキルアミノであり、但しアルキル、アルケニル、アルキニル、アルキレン、ハロアルキル、シクロアルキル、アルコキシ及びアルキルチオはそれぞれＣ１～Ｃ８アルキル、Ｃ２～Ｃ８アルケニル、Ｃ２～Ｃ８アルキニル、Ｃ２～Ｃ８アルキレン、ハロアルキル（Ｃ１～Ｃ８）、シクロアルキル（Ｃ１～Ｃ８）、アルコキシ（Ｃ１～Ｃ８）及びアルキルチオ（Ｃ１～Ｃ８）であり；
Ｘ_１～Ｘ_８は互いに独立して酸素（Ｏ）、硫黄（Ｓ）、セレン（－Ｓｅ－）のヘテロ原子、飽和又は不飽和の、置換又は非置換の窒素（＝Ｎ－、－ＮＨ－、－ＮＲ_１４－）、及び原子価数量範囲が０から炭素環－又はヘテロ環－環系上で指示される原子の空いている原子価総数までの炭化水素残留物からなる群から選択される、＜項１＞に記載の化合物。
＜項３＞
Ｘ_１～Ｘ_８は独立して－Ｏ－、－Ｓ－、＝Ｎ－、－ＮＨ－、－ＣＨ_２－、＝ＣＨ－、－ＣＨＲ－、＝ＣＲ－、－ＣＲＲ′－又は－ＣＲ－である、＜項１＞又は＜項２＞に記載の化合物。
＜項４＞
前記化合物は以下の式Ｉの化合物である、＜項１＞に記載の化合物。

式中、Ｒ_１はＨであり；Ｒ_２及びＲ_３は独立してＨ、ＯＨ、オキシビオチン、ＯＡｃ、ＯＴＢＳ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、又は＝Ｏであり、又はＲ_２及びＲ_３は独立して存在せず；Ｒ_４及びＲ_５は独立してＨ、ＯＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、＝Ｏ、オキシビオチン又はＮ_３であり；又はＲ_２／Ｒ_３及びＲ_４／Ｒ_５はこれらが接続している炭素と一緒にエポキシエタンを形成し；Ｒ_６及びＲ_７は独立してＨ、ＣＨ_２－ＯＨ、ＣＨ_２－Ｎ_３、ＣＨ_２－オキシビオチン、ＣＨ_２－ＡｃＯ、ＣＨ_２－ＯＴＢＳ、ＣＯ_２Ｍｅ、三リン酸化されたメチレン、１、２－ビスヒドロキシエタン、テトラブチルアンモニウムモノホスフェート、１－ヒドロキシプロパ－２－イン－１－イル、又はジアザシメンであり；Ｒ_８はＨ、＝Ｓ、＝Ｏ、ＮＨ－ＣＨ_３、Ｆ、Ｃｌ、Ｂｒ、Ｉ、－Ｏ－ＣＨ_３、又は重水素であり；Ｒ_９は存在せず、又はＲ_９はＨ、ＣＨ_３、Ｆ、Ｃｌ、Ｂｒ又はＩであり；Ｒ_１０はＨ、－ＣＨ_３、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＮＨ_２、ＮＨ－ＣＨ_３、ＮＨ－ＮＨ_２、＝Ｏ、ＮＨＢｎ、ビオチンアミド、ｍ－ヒドロキシアニリン、アミノシクロプロパン、アミノシクロブタン、アミノシクロペンタン、アミノシクロヘキサン、ＯＭｅ又はオクタミドであり；Ｒ_１１は存在せず、又はＲ_１１はＨ、Ｆ、Ｃｌ、Ｂｒ、又はＩであり；Ｒ_１２は存在せず、又はＲ_１２はＨ、ＮＨ_２、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＭｅ、４－ホルムアミド置換されたピラゾールであり；Ｒ_１３は存在せず又はＲ_１３はＨ、Ｏ－ＣＨ_３又はＯｍｅであり；
Ｘ_１はＯ、Ｎ又はＣであり；Ｘ_２はＮ又はＣであり；Ｘ_３はＣであり；Ｘ_４はＣ又はＮであり；Ｘ_５はＣ又はＮであり；Ｘ_６はＣ又はＮであり；Ｘ_７はＣ又はＮであり；及びＸ_８はＣ又はＮである。
＜項５＞
前記化合物は以下の式ＩＩの化合物である＜項１＞に記載の化合物。

式中、Ｒ_１はＨであり；Ｒ_２はＨ又はＯＨであり；Ｒ_３はＨ又はＯＨであり；Ｒ_４はＨ又はＯＨであり；Ｒ_５はＨ又はＯＨであり；Ｒ_６はＨ又はＯＨであり；Ｒ_７はＨ又はＯＨであり；Ｒ_８はＨであり；Ｒ_９はＨであり；Ｒ_１０はＨ、Ｆ、Ｃｌ、Ｂｒ、又はＩであり；Ｒ_１１は存在せず又はＲ_１１はＨであり；Ｒ_１２はＣＨ_３、ＮＨ_２、ＮＨ－ＣＨ_３又はＯＭｅであり；Ｒ_１３は存在せず又はＲ_１３はＨであり；Ｒ_１４はＨであり；Ｒ_１５は存在せず又はＲ_１５はＨであり；且つ
Ｘ_１はＯであり；Ｘ_２はＮであり；Ｘ_３はＣであり；Ｘ_４はＣ又はＮであり；Ｘ_５はＣであり；Ｘ_６はＮであり；Ｘ_７はＣであり；及びＸ_８はＣ又はＮである。
＜項６＞
前記化合物は以下の式ＩＩＩの化合物である＜項１＞に記載の化合物。

式中、Ｒ_１６はテトラヒドロフラン又はｔｅｒｔ－ブチルであり；Ｒ_１７はＣＨ_２－メチルベンジルであり；及びＲ_１８はＮＨ_２又はアミノベンジルであり；及び
Ｘ_２はＮであり；Ｘ_３はＣ又はＮであり；Ｘ_４はＣ又はＮであり；Ｘ_５はＣであり；Ｘ_６はＮであり；Ｘ_７はＣであり；及びＸ_８はＮである。
＜項７＞
前記化合物は以下の式Ｉの化合物である＜項１＞に記載の化合物。

式中、Ｒ_１はＨであり；Ｒ_２及びＲ_３は独立してＨ、ＯＨ、オキシビオチン、ＯＡｃ、ＯＴＢＳ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、又は＝Ｏであり、又はＲ_２及びＲ_３は独立して存在せず；Ｒ_４及びＲ_５は独立してＨ、ＯＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、＝Ｏ、又はオキシビオチンであり；又はＲ_２／Ｒ_３及びＲ_４／Ｒ_５はこれらが接続している炭素と一緒にエポキシエタンを形成し；Ｒ_６及びＲ_７は独立してＨ、ＣＨ_２－ＯＨ、ＣＨ_２－Ｎ_３、ＣＨ_２－オキシビオチン、ＣＯ_２Ｍｅ、三リン酸化されたメチレン、１、２－ビスヒドロキシエタン、テトラブチルアンモニウムモノホスフェート、１－ヒドロキシプロパ－２－イン－１－イル又はジアザシメンであり；又はＲ_４／Ｒ_５のヒドロキシル及びＲ_６／Ｒ_７のメチルヒドロキシルはこれらが接続している炭素と一緒に環状フォスフェートラクトンを形成し；Ｒ_８はＨ、＝Ｓ、＝Ｏ、ＮＨ－ＣＨ_３、Ｆ、Ｃｌ、Ｂｒ、Ｉ、－Ｏ－ＣＨ_３、又は重水素であり；Ｒ_９は存在せず、又はＲ_９はＨ、ＣＨ_３、Ｆ、Ｃｌ、Ｂｒ、又はＩであり；Ｒ_１０はＨ、－ＣＨ_３、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＮＨ_２、ＮＨ－ＮＨ_２、＝Ｏ、ＮＨＢｎ、ビオチンアミド、ｍ－ヒドロキシアニリン、アミノシクロプロパン又はオクタミドであり；Ｒ_１１は存在せず、又はＲ_１１はＨ、Ｆ、Ｃｌ、Ｂｒ又はＩであり；Ｒ_１２は存在せず、又はＲ_１２はＨ、ＮＨ_２、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＭｅ、４－ホルムアミド置換されたピラゾールであり；Ｒ_１３は存在せず又はＲ_１３はＨ、Ｏ－ＣＨ_３又はＯｍｅであり；且つ
Ｘ_１はＯ、Ｎ又はＣであり；Ｘ_２はＮ又はＣであり；Ｘ_３はＣであり；Ｘ_４はＣ又はＮであり；Ｘ_５はＣ又はＮであり；Ｘ_６はＣ又はＮであり；Ｘ_７はＣ又はＮであり；及びＸ_８はＣ又はＮである。
＜項８＞
以下の群から選択される＜項１＞に記載の化合物。

＜項９＞
以下の群から選択される＜項１＞に記載の化合物。

＜項１０＞
以下の群から選択される＜項１＞に記載の化合物。

＜項１１＞
＜項１＞～＜項１０＞のいずれか一項に定義される式Ｉ、ＩＩ又はＩＩＩのヌクレオシド類似化合物又はその薬学的に受容可能な塩及びペントスタチンを含有する組成物。
＜項１２＞
コルジセピン及びペントスタチンからなるか、又は以下の化合物の一つ及びペントスタチンからなる、＜項１＞に記載の組成物。

＜項１３＞
以下の式のプロドラッグ。

＜項１４＞
以下の群から選択される＜項１３＞に記載のプロドラッグ。

＜項１５＞
以下の式の修飾化合物。

＜項１６＞
以下の群から選択される＜項１３＞に記載の修飾化合物。

＜項１７＞
＜項１＞～＜項１０＞のいずれか一項に定義される式Ｉ、式ＩＩ又は式ＩＩＩのヌクレオシド類似化合物又はその薬学的に受容可能な塩の治療有効量を被験者に投与することを含む、概日リズム調節方法、好ましくは概日リズム位相シフト方法。
＜項１８＞
前記化合物はＰｅｒ２－Ｌｕｃピーク時に投与されるがトラフ時に投与されない、＜項１７＞に記載の方法。
＜項１９＞
＜項１１＞又は＜項１２＞に定義される組成物及びペントスタチンの治療有効量を被験者に投与することを含む、概日リズム調節方法、好ましくは概日リズム位相シフト方法。
＜項２０＞
前記組成物はＰｅｒ２－Ｌｕｃピーク時に投与されるがトラフ時に投与されない、＜項１９＞に記載の方法。
＜項２１＞
＜項１３＞又は＜項１４＞に定義されるプロドラッグの治療有効量を被験者に投与することを含む、概日リズム調節方法、好ましくは概日リズム位相シフト方法。
＜項２２＞
＜項１５＞又は＜項１６＞に定義される修飾化合物の治療有効量を被験者に投与することを含む、概日リズム調節方法、好ましくは概日リズム位相方法。
＜項２３＞
＜項１＞～＜項１０＞のいずれか一項に定義される化合物、又はその薬学的に受容可能な塩の概日リズム調節用薬物、好ましくは概日リズム位相シフト用薬物の製造における使用。
＜項２４＞
＜項１１＞又は＜項１２＞に定義される組成物の概日リズム調節用薬物、好ましくは概日リズム位相シフト用薬物の製造における使用。
＜項２５＞
＜項１３＞又は＜項１４＞に定義されるプロドラッグの概日リズム調節用薬物、好ましくは概日リズム位相シフト用薬物の製造における使用。
＜項２６＞
＜項１５＞又は＜項１６＞に定義される修飾化合物の概日リズム調節用薬物、好ましくは概日リズム位相シフト用薬物の製造における使用。
＜項２７＞
前記薬物は時差、シフトワーク、年齢による睡眠障害、又は概日リズム時計に関連する睡眠障害の治療に使用可能である、＜項２３＞～＜項２６＞のいずれか一項に記載の使用。
＜項２８＞
腸内投与、静脈内投与、経口投与又は舌下投与用に調製可能である、請求項１～１０のいずれか一項に記載の化合物又は＜項１１＞又は＜項１２＞に記載の組成物。
＜項２９＞
前記薬物はカフェイン、メラトニン、ゾルピデム、エスゾピクロン、ザレプロン又はトリアゾラムからなる群より選択される薬剤と組み合わせ可能である、＜項２３＞～＜項２６＞のいずれか一項に記載の使用。
＜項３０＞
前記被験者は時差、シフトワーク、年齢による睡眠障害又は概日体内時計に関連する睡眠障害を患う人又はこれらを患うリスクのある人である、＜項１７＞～＜項２６＞のいずれか一項に記載の方法。
＜項３１＞
ＣＤＫ９調節による前記時計位相シフトにおける＜項１＞～＜項１０＞のいずれか一項に記載の化合物の使用。
＜項３２＞
ＲＵＶＢＬヘリカーゼの、コルジセピンが仲介するＰｅｒ２－ｄＬｕｃ誘導及び時計位相シフトの仲介における使用、及びＲＵＶＢＬヘリカーゼのコルジセピンのダイレクトターゲットとしての使用であって、但しＲＵＶＢＬヘリカーゼは＜項１＞～＜項１０＞のいずれか一項に記載の化合物のターゲットである。
＜項３３＞
ＲＵＶＢＬヘリカーゼはＲＵＶＢＬ１ヘリカーゼ又はＲＵＶＢＬ２ヘリカーゼである、＜項３２＞に記載の使用。 References 1. Mohamed A. Sarah C.I. Gilles G. ; Etc., Nucleos. Nucleot. Nucl. , 2007, 26 (8-9), pp. 1125-1128 2. Valdes J. Cedillo R. Alicia H. C. ; Etc., Bioorg. Med. Chem. Let. , 2002, 12 (16), pp. 2221-2224 3. Rajput V. K. Mukhopadhyay B. Tetrahedron Lett. , 2006, 47 (33), 5939-5941 4. Aubin Y. Audran G. Monti H. ; Etc., Bioorg. Med. Chem. 2008, 16 (1), 374-381 pages 5. Fonvielle M. Chemama M. et al. Lecerf M. et al. ; Etc., Angew. Chem. Int. Edit. , 2010, 49 (30), pp. 5115-5119 6. Szuekova L. Spical L. Dolezal K. ; Etc., Bioorg. Med. Chem. , 2009, 17 (5), 1938-1947. Page 7. Bookser B. C. Raffale N. et al. B. , J. Org. Chem. , 2007, 72 (1), pp. 173-179 8. Lin T. S. Cheng J. C. Ishiro K. ; Etc., J. Med. Chem. , 1985, 28 (9), pp. 1194-1198 9. Claire C. Salim K. Carla A. H. P. ; Etc., Bioconjugate Chem. , 2010, 21 (6), 1062-1069 pp. 10. C. Hoffmann, H.M. -G. Genieser, M. et al. Veron and B. Jastorff, Bioorganic & Medical Chemistry Letters, Vol. 6, No. 21, 2571-2574, 1996
11. Lourido, Sebastian; Zhang, Chao; Lopez, Michael S. Tang, Keliang; Barks, Jennifer; Wang, Qilling; Wildman, Scott A. Shokat, Kevan M. Sibley, L. et al. David. Journal of Medicinal Chemistry, 2013, vol. 56, # 7, pp. 3068-3077 12. WO201214996A
13. Robins, Morris J.M. Wilson, John, S.A. Madej, Danuta; Low, Nicholas H. et al. Hanske, Fritz; Wnuk, Stanislaw F. -Journal of Organic Chemistry, 1995, vol. 60, # 24, 7902-7908 pp. 14. Ikehara; Maruyama; Miki Tetrahedron, 1978, vol. 34, # 8, pp. 1133-1138 15. Masaharu Yoshikawa, Tetsuya Kato and Tadao Takenishi, Bulletin of The Chemical Society of Japan, VOL. 4 2 3505-3508 (1969)
16. Ray, Adrian S. Yang, Zhenjun; Chu, Chung K. et al. Anderson, Karen S. et al. -International Agents and Chemotherapy, 2002, vol. 46, # 3, pp. 887-891 17. Glaudemans, C.I. P. J. Fletcher, Jr. , H. G. J. Org. Chem. , 1963, 28, 3004-3006
18. Mikhailopulo, Igor A; Pricota, Tamara I; Sivets, Grigori G; Altona, Cornelis-The Journal of organic chemistry, 2003, vol. 68, # 15, pp. 5897-5908 19. Robins; Neschadimenko; Ro; Yuan; Borchardt; Wnuk-Journal of Organic Chemistry, 1998, vol. 63, # 4, pp. 1205-1211 20. Beck, D. W. Etc., J Neuropathol & Experimental Neurol 1984 43 (3) 219-224
21. Cheng, P. et al. Etc., Genes & Development 2005 19 (2) 234-241
22. Dentin, R. et al. Etc., Nature 2007 449 (7160) 366-369
23. Gorynia, S.M. Etc., Journal of Structural Biology 2011 176 (3) 279-291.
24. Hirota, T.I. Etc., PLOS Biology 2010 8 (12) e100559
25. Hirota, T.I. Etc., Science 2012 337 (6098) 1094-1097
26. Hu, Z. Evidence-Based Complex and Alternative Med 2013 2013 2013
27. Huang, Z. -L. Etc., Nat Neurosci 2005 8 (7) 858-859
28. Huges, M. et al. E. Etc., PLos Genet 2009 5 (4) e10000442
29. Huges, M. et al. E. Etc., Journal of biological rhythms 2010 25 (5) 372-380
30. Koike, N.M. Etc., Science 2012 338 (6105) 349-354
31. Liu, A. C. Etc., Cell 2007 129 (3) 605-616
32.9 NIBS16-071-1WO
33. Matias, P. et al. M. Etc., Frontiers in Molecular Biosciences 2015 2 (17)
34. Pardridge, W.M. M. NeuroRX 2005 2 (1) 3-14
35. Pardridge, W.M. M. Etc., J Pharmacol and Expert Therapeutics 1994 268 (1) 14-18
36. Pizarro, A.M. Etc., Nucleic Acids Research 2012
37. Rosenbaum, J. Mol. Etc., Science signing 2013 6 (266) mr1
38. Sato, T.M. K. Etc., Nat Genet 2006 38 (3) 312-319
39. Shi, G.M. Etc., PNAS, USA 2013 110 (12) 4750-4755
40. Takahashi, J. Mol. S. Etc., Nat Rev Genet 2008 9 (10) 746-775
41. Takahashi, J. Mol. S. Etc., Science 2008 322 (5903) 909-912
42. Woo, P.M. W. K. Etc., Journal of Heterocyclic Chemistry 1974 11 (4) 641-643
43. Yamaguchi, Y.M. Etc. Science 2013 342 (6154) 85-90
44. Yoo, S.M. -H. Etc., PNAS, USA 2004 101 (15) 5339-5346
45. Zhang, E.I. E. And S. A. KayNat Rev Mol Cell Biol 2010 11 (11) 746-776
46. Zhang, E.I. E. Etc. Cell 2009 139 (1) 199-210
47. Zhang, R.M. Etc. PNAS, USA 2014 111 (45) 16219-16224
48. Zhao, Z. Etc. Cell 2015 163 (5) 1064-1078
<Additional Notes>
<Item 1>
Compounds of the following formulas I, II and III.

In the formula, R ₁ to R ₁₈ are independent of each other, preferably unsubstituted or substituted linear or branched hydrocarbon residues containing 1 to 8 carbon atoms, hydrogen, hydroxyl, alkyl, alkenyl, alkynyl. , Alkylene, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl , aryloxy , arylthio , heterocycle, heterocyclic amino, halogen, alkylamino, dialkylamino, amine oxide, alkylhydroxylamino, azide, nitrate, cyano and isocyano , Alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl , heterocyclic carbonyl, alkylvinyl, allyl, carboxy, alkylthio, amide, ester, phosphonic acid ester, cycloalkylphosphonic acid ester, cycloalkylphosphonamide, sulfonic acid ester, cycloalkylsulfone Aryl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy and alkylthio are C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkylene, respectively. Haloalkyl (C1 to C8), cycloalkyl (C1 to C8), alkoxy (C1 to C8) and alkylthio (C1 to C8), for example, _R1-1 to R13 are arylmethyl , arylethyl , arylpropyl , _arylbutyl . , Heteroarylmethyl , Heteroarylethyl , Heteroarylpropyl , Heteroarylbutyl , _in particular R1 _- R13 is phenyl, phenylmethyl, 1-methyl-2-phenylethyl, 1-phenylpropyl, 2- It may be phenylpropyl, 3-phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl or 1-benzyl- ₁ -methylethyl, with _R1 to R13 being fluorine, chlorine, bromine, iodine, fluoromethoxy, chloro. It may be methoxy, bromomethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, aminomethoxy, aminoethoxy, aminopropyloxy, or other heteroatoms, such as O, S, P, Si and Se, R ₁ -R ₁₃ is -OR', -OC (O) R', -NR'R ", -SR', -R', -CN, -NO ₂ , -CO ₂ R', -CONR'R",- C (O) R', -OC (O) NR'R ", -NR" C (O) R', -NR "CO ₂ R', -NR'-C (O) NR"R'",-NR'-SO ₂ NR"R'", -NH-C (NH ₂ ) = NH , -NR'C (NH ₂ ) = NH, -NH-C (NH ₂ ) = NR', -OP (O) (OH) ₂ , -OP (O) (OR') ₂ , -OP (O) (OR') (OR "), -OP (O) R'(OR"), -OP (O) R'R ", -OP (OH) ₂ , -OP (OR') ₂ , -OP (OR" ′) (OR ″), -OPR'R ″, -OPR ′ (OR ″), -OS (O) R ′, -OS (O) (OR ′), -OSO ₂ R ′, -OSO ₂ (OR) ′), -OSO ₂ NR'R ", -S (O) R', -S (O) (OR'), -SO ₂ R', -SO ₂ (OR'), -SO ₂ NR'R" , -NR "SO ₂ R, -OSi (R') ₃ , -OSi (OR') ₃ , -Si (OR') ₃ , -Si (OR') (OR") (OR'"), -OSi (OR ′) (OR ″) (OR ′ ″), −N ₃ , −CH (Ph) ₂ , perfluoro (C1-C4) alkoxy-or perfluoro (C1-C4) alkyl-may be in quantity range. Is from 0 to the total number of vacant valences on the aromatic ring system; where R', R ″ and R ′ ″ are independently hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl , It is selected from the group consisting of (unsubstituted aryl )-(C1-C4) alkyl and (unsubstituted aryl ) oxy- (C1-C4) alkyl, and X ₁ to X ₈ are independent of each other and oxygen (O). , Sulfur (S), heteroatoms of selenium (-Se-), saturated or unsaturated, substituted or unsubstituted nitrogen (= N-, -NH-, -NR _14- ), and valence quantity range 0 Selected from the group consisting of hydrocarbon residues up to the total number of vacant valences of the atoms indicated on the carbon ring-or heterocyclic-ring system.
<Item 2>
R ₁ is α- or β-hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl , aryloxy , arylthio , heterocycle, heterocyclic amino, epoxide, alkylepoxide, alkyl. Amino and dialkylamino, except that alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy and alkylthio are C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkylene, haloalkyl (C1- C8), cycloalkyl (C1-C8), alkoxy (C1-C8) and alkylthio (C1-C8);
_R2 to R18 are independently hydrogen, oxygen ₍ = O), hydroxyl, alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl , aryloxy , arylthio , heterocycle, heterocyclic amino. , Epoxide, alkyl epoxide, alkylamino, dialkylamino, except that alkyl, alkenyl, alkynyl, alkylene, haloalkyl, cycloalkyl, alkoxy and alkylthio are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C2- C8 alkylene, haloalkyl (C1-C8), cycloalkyl (C1-C8), alkoxy (C1-C8) and alkylthio (C1-C8);
X ₁ to X ₈ are independent atoms of oxygen (O), sulfur (S), selenium (-Se-), saturated or unsaturated, substituted or unsubstituted nitrogen (= N-, -NH-). , -NR _14- ), and selected from the group consisting of hydrocarbon residues having a valence quantity range from 0 to the total number of vacant valences of the atoms indicated on the carbocycle-or heterocycle-ring system. , <Item 1>.
<Item 3>
X ₁ to X ₈ are independently -O-, -S-, = N-, -NH-, -CH _2- , = CH-, -CHR-, = CR-, -CRR'-or -CR- Item 5. The compound according to <Item 1> or <Item 2>.
<Item 4>
Item 5. The compound according to <Item 1>, wherein the compound is a compound of the following formula I.

In the formula, R ₁ is H; R ₂ and R ₃ are independently H, OH, oxybiotin, OAc, OTBS, F, Cl, Br, I, or = O, or R ₂ and R ₃ Do not exist independently; _R4 and R5 are independently H, OH, F, Cl, Br, I _, = O _{, oxybiotin} or N3; or _R2 / R3 and _R4 / R ₅ forms an epoxy ethane together with the carbon to which they are connected; R ₆ and R ₇ independently H, CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CH _2- AcO, CH ₂ -OTBS, CO ₂ Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, 1-hydroxyprop-2-in-1-yl, or diazasimene; R ₈ is H, = S, = O, NH-CH ₃ , F, Cl, Br, I, -O-CH ₃ , or dehydrogen; R ₉ is absent or R ₉ is H, CH. ₃ , F, Cl, Br or I; R ₁₀ is H, -CH ₃ , F, Cl, Br, I, NH ₂ , NH-CH ₃ , NH-NH ₂ , = O, NHBn, biotinamide, m-hydroxyaniline, aminocyclopropane, aminocyclobutane, aminocyclopentane, aminocyclohexane, OME or octamid; R ₁₁ is absent, or R ₁₁ is H, F, Cl, Br, or I; R ₁₂ is absent, or R ₁₂ is H, NH ₂ , F, Cl, Br, I, OMe, 4-formamide substituted pyrazole; R ₁₃ is absent or R ₁₃ is H, O-CH. ₃ or Ome;
X ₁ is O, N or C; X ₂ is N or C; X ₃ is C; X ₄ is C or N; X ₅ is C or N; X ₆ is C or N; X ₇ is C or N; and X ₈ is C or N.
<Item 5>
The compound according to <Item 1>, wherein the compound is a compound of the following formula II.

In the formula, R ₁ is H; R ₂ is H or OH; R ₃ is H or OH; R ₄ is H or OH; R ₅ is H or OH; R ₆ is H. Or OH; R ₇ is H or OH; R ₈ is H; R ₉ is H; R ₁₀ is H, F, Cl, Br, or I; R ₁₁ is absent Or R ₁₁ is H; R ₁₂ is CH ₃ , NH ₂ , NH-CH ₃ or OMe; R ₁₃ is absent or R ₁₃ is H; R ₁₄ is H; R ₁₅ is Not present or R ₁₅ is H; and X ₁ is O; X ₂ is N; X ₃ is C; X ₄ is C or N; X ₅ is C; X ₆ is N; X ₇ is C; and X ₈ is C or N.
<Item 6>
The compound according to <Item 1>, wherein the compound is a compound of the following formula III.

In the formula, R ₁₆ is tetrahydrofuran or tert-butyl; R ₁₇ is CH ₂ -methylbenzyl; and R ₁₈ is NH ₂ or aminobenzyl; and X ₂ is N; X ₃ is C or N; X ₄ is C or N; X ₅ is C; X ₆ is N; X ₇ is C; and X ₈ is N.
<Item 7>
The compound according to <Item 1>, wherein the compound is a compound of the following formula I.

In the formula, R ₁ is H; R ₂ and R ₃ are independently H, OH, oxybiotin, OAc, OTBS, F, Cl, Br, I, or = O, or R ₂ and R ₃ Do not exist independently; R ₄ and R ₅ are independently H, OH, F, Cl, Br, I, = O, or oxybiotin; or R ₂ / R ₃ and R ₄ / R ₅ Form epoxy ethane together with the carbon to which they are connected; R ₆ and R ₇ independently H, CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CO ₂ Me, 3 Phosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, 1-hydroxyprop-2-in-1-yl or diazasimene; or R ₄ / R ₅ hydroxyl and R ₆ / R. The methyl hydroxyl of ₇ forms a cyclic phosphate lactone with the carbon to which they are connected; R ₈ is H, = S, = O, NH-CH ₃ , F, Cl, Br, I, -O- CH ₃ or dehydrogen; R ₉ is absent, or R ₉ is H, CH ₃ , F, Cl, Br, or I; R ₁₀ is H, -CH ₃ , F, Cl, Br. , I, NH ₂ , NH-NH ₂ , = O, NHBn, biotinamide, m-hydroxyaniline, aminocyclopropane or octamid; R ₁₁ is absent or R ₁₁ is H, F, Cl, Br Or I; R ₁₂ is absent, or R ₁₂ is H, NH ₂ , F, Cl, Br, I, OMe, 4-formamide substituted pyrazole; R ₁₃ is absent or R ₁₃ Is H, O-CH ₃ or Ome; and X ₁ is O, N or C; X ₂ is N or C; X ₃ is C; X ₄ is C or N; X ₅ is C or N; X ₆ is C or N; X ₇ is C or N; and X ₈ is C or N.
<Item 8>
Item 2. The compound according to <Item 1> selected from the following groups.

<Item 9>
Item 2. The compound according to <Item 1> selected from the following groups.

<Item 10>
Item 2. The compound according to <Item 1> selected from the following groups.

<Item 11>
A composition containing a nucleoside analog of formula I, II or III defined in any one of <Item 1> to <Item 10> or a pharmaceutically acceptable salt thereof and pentostatin.
<Item 12>
Item 3. The composition according to <Item 1>, which comprises cordycepin and pentostatin, or consists of one of the following compounds and pentostatin.

<Item 13>
Prodrug of the following formula.

<Item 14>
Item 6. The prodrug according to <Item 13> selected from the following groups.

<Item 15>
The modified compound of the following formula.

<Item 16>
Item 2. The modified compound according to <Item 13>, which is selected from the following group.

<Item 17>
Administering to a subject a therapeutically effective amount of a nucleoside-like compound of formula I, formula II or formula III or a circadianly acceptable salt thereof as defined in any one of <Item 1> to <Item 10>. Including, circadian rhythm adjustment method, preferably circadian rhythm phase shift method.
<Item 18>
Item 17. The method according to Item 17, wherein the compound is administered at the peak of Per2-Luc but not at the time of trough.
<Item 19>
A circadian rhythm adjusting method, preferably a circadian rhythm phase shift method, comprising administering to the subject a therapeutically effective amount of the composition and pentostatin defined in <Item 11> or <Item 12>.
<Item 20>
Item 19. The method according to Item 19, wherein the composition is administered at the peak of Per2-Luc but not at the time of trough.
<Item 21>
A circadian rhythm adjusting method, preferably a circadian rhythm phase shift method, comprising administering to a subject a therapeutically effective amount of a prodrug as defined in <Item 13> or <Item 14>.
<Item 22>
A circadian rhythm adjusting method, preferably a circadian rhythm phase method, comprising administering to the subject a therapeutically effective amount of the modified compound as defined in <Item 15> or <Item 16>.
<Item 23>
Use in the manufacture of a circadian rhythm-regulating drug, preferably a circadian rhythm phase-shifting drug, of a compound defined in any one of <Item 1> to <Item 10>, or a pharmaceutically acceptable salt thereof. ..
<Item 24>
Use in the manufacture of a circadian rhythm regulating drug, preferably a circadian rhythm phase shift drug, of the composition defined in <Item 11> or <Item 12>.
<Item 25>
Use of a prodrug as defined in <Item 13> or <Item 14> in the manufacture of a circadian rhythm adjusting drug, preferably a circadian rhythm phase shift drug.
<Item 26>
Use of the modified compound defined in <Item 15> or <Item 16> in the production of a drug for adjusting circadian rhythm, preferably a drug for circadian rhythm phase shift.
<Item 27>
Item 6. The use according to any one of <Item 23> to <Item 26>, wherein the drug can be used for the treatment of sleep disorders related to time difference, shift work, age-related sleep disorders, or circadian rhythm clocks.
<Item 28>
The compound according to any one of claims 1 to 10 or the composition according to <Item 11> or <Item 12>, which can be prepared for intestinal administration, intravenous administration, oral administration or sublingual administration. ..
<Item 29>
Item 6. The use according to any one of <Item 23> to <Item 26>, wherein the drug can be combined with a drug selected from the group consisting of caffeine, melatonin, zolpidem, eszopiclone, zaleplon or triazolam.
<Item 30>
The subject is a person who suffers from a sleep disorder related to time difference, shift work, age-related sleep disorder or circadian clock, or a person who is at risk of suffering from these, any one of <Item 17> to <Item 26>. The method described in.
<Item 31>
Use of the compound according to any one of <Item 1> to <Item 10> in the clock phase shift by adjusting CDK9.
<Item 32>
The use of RUVBL helicase in the mediation of cordycepin-mediated Per2-dLuc induction and clock phase shift, and the use of RUVBL helicase as a direct target of cordycepin, where the RUVBL helicase is described in <Item 1> to <Item 10>. It is the target of the compound according to any one of the above.
<Item 33>
Item 32. The use according to <Item 32>, wherein the RUVBL helicase is an RUVBL1 helicase or an RUVBL2 helicase.

Claims (23)

A composition comprising a compound of formula I-1, I-2, I-3 or I-4 or a pharmaceutically acceptable salt thereof, and pentostatin.

(In the formula, R ₁ is H;
R ₂ and R ₃ are independently H, OH, oxybiotin, OAc, OTBS, F, Cl, Br, or I;
R ₄ and R ₅ are independently H, OH, F, Cl, Br, I, oxybiotin or N ₃ ; or R ₂ / R ₃ and R ₄ / R ₅ are the carbons to which they are connected. Forming epoxy ethane together;
R ₆ and R ₇ are independently H, CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CH ₂ -AcO, CH ₂ -OTBS, CO ₂ Me, triphosphorylated methylene, 1 , 2-Bishydroxyethane, tetrabutylammonium monophosphate, or 1-hydroxyprop-2-in-1-yl;
R8 is H, NH _- CH ₃ , F, Cl, Br, I, -O-CH ₃ , or deuterium;
R ₉ is H, NH-CH ₃ , F, Cl, Br, I, -O-CH ₃ , or deuterium;
R ₁₀ is H, dehydrogen, -CH ₃ , F, Cl, Br, I, NH ₂ , NH-CH ₃ , NH-NH ₂ , NHBn, biotinamide, -NR "C (O) R', m- Hydroxyaniline, aminocyclopropane, aminocyclobutane, aminocyclopentane, aminocyclohexane, OME or octamid, where R'and R "are independently hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl. And heteroaryl, selected from the group consisting of (unsubstituted aryl)-(C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl;
R ₁₂ is H, deuterium, NH ₂ , F, Cl, Br, I, OME, or 4-formamide substituted pyrazole;
X ₁ is O, -NR _14- , or -CRR'-where R ₁₄ , R, and R'are independently H, alkyl, aryl, heteroaryl, -C (O) alkyl, -C. (O) Aryl, -SO ₂ alkyl, or -SO ₂ aryl. ) At _least one of R2 _, R3 _, R4 _, R5, _R6 and _R7 is not H, and at _least one of R2 _, R3 _, R4 _, R5, _R6 and _R7 The composition according to claim 1, which is not deuterium. 1 according to claim 1, wherein R ₂ is H and R ₃ is OH, oxybiotin, OAc, or OTBS; or R ₃ is H and R ₂ is OH, oxybiotin, OAc, or OTBS. Composition. R ₄ is H, R ₅ is OH, F, Cl, Br, I, oxybiotin, or N ₃ ; or R ₅ is H and R ₄ is OH, F, Cl, Br, I, The composition according to claim ₁ , which is oxybiotin or N3. R ₆ is H, R ₇ is CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CH ₂ -AcO, CH ₂ -OTBS, CO ₂ Me, triphosphorylated methylene 1, 2-Bishydroxyethane, tetrabutylammonium monophosphate, or 1-hydroxyprop-2-in-1-yl; or R ₇ is H, R ₆ is CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CH ₂ -AcO, CH ₂ -OTBS, CO ₂ Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, or 1-hydroxyprop-2-in. The composition according to claim 1, which is -1-yl. A composition containing a nucleoside analog selected from the following compounds or a pharmaceutically acceptable salt thereof, and pentostatin.

The composition according to claim 6, wherein the composition comprises cordycepin and pentostatin, or the composition comprises one of the following compounds and pentostatin.

The composition according to any one of claims 1 to 7, which can be prepared for intestinal administration, intravenous administration, oral administration or sublingual administration. Compounds selected from the following.

The compound according to claim 9, which can be prepared for intestinal administration, intravenous administration, oral administration or sublingual administration. Use of the composition defined in any one of claims 1 to 8 in the manufacture of a drug for circadian rhythm adjustment, circadian rhythm phase shift, or for increasing amplitude of circadian rhythm vibration. Production of a drug for adjusting circadian rhythm, shifting circadian rhythm phase, or increasing amplitude of circadian rhythm vibration of the compound defined in claim 9 or 10 or a pharmaceutically acceptable salt thereof. Use in. The use according to claim 11 or 12, wherein the drug is used for the treatment of sleep disorders associated with time lag, shift work, age-related sleep disorders, or circadian rhythm clocks. The use according to claim 11 or 12, wherein the drug can be combined with a drug selected from the group consisting of caffeine, melatonin, zolpidem, eszopiclone, zaleplon and triazolam. Compounds of formula I-1, I-2, I-3 or I-4 or pharmaceutically scholarly thereof in the manufacture of drugs for CDK9 regulation, circadian rhythm phase shift, or circadian rhythm vibration amplitude increase. Use of acceptable salt.

(In the formula, R ₁ is H;
R ₂ and R ₃ are independently H, OH, oxybiotin, OAc, OTBS, F, Cl, Br, or I;
R ₄ and R ₅ are independently H, OH, F, Cl, Br, I, oxybiotin or N ₃ ; or R ₂ / R ₃ and R ₄ / R ₅ are the carbons to which they are connected. Forming epoxy ethane together;
R ₆ and R ₇ are independently H, CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CH ₂ -AcO, CH ₂ -OTBS, CO ₂ Me, triphosphorylated methylene, 1 , 2-Bishydroxyethane, tetrabutylammonium monophosphate, or 1-hydroxyprop-2-in-1-yl;
R8 is H, NH _- CH ₃ , F, Cl, Br, I, -O-CH ₃ , or deuterium;
R ₉ is H, NH-CH ₃ , F, Cl, Br, I, -O-CH ₃ , or deuterium;
R ₁₀ is H, dehydrogen, -CH ₃ , F, Cl, Br, I, NH ₂ , NH-CH ₃ , NH-NH ₂ , NHBn, biotinamide, -NR "C (O) R', m- Hydroxyaniline, aminocyclopropane, aminocyclobutane, aminocyclopentane, aminocyclohexane, OME or octamid, where R'and R "are independently hydrogen, (C1-C8) alkyl and heteroalkyl, unsubstituted aryl. And heteroaryl, selected from the group consisting of (unsubstituted aryl)-(C1-C4) alkyl and (unsubstituted aryl) oxy- (C1-C4) alkyl;
R ₁₂ is H, deuterium, NH ₂ , F, Cl, Br, I, OME, or 4-formamide substituted pyrazole;
X ₁ is O, -NR ₁₄ -or -CRR'-where R ₁₄ , R, and R'are independently H, alkyl, aryl, heteroaryl, -C (O) alkyl, -C ( O) Aryl, -SO ₂ alkyl, or -SO ₂ aryl. ) At _least one of R2 _, R3 _, R4 _, R5, _R6 and _R7 is not H, and at _least one of R2 _, R3 _, R4 _, R5, _R6 and _R7 The use according to claim 15, which is not deuterium. _{25 . _ _} Use of. R ₄ is H and R ₅ is OH, F, Cl, Br, I, oxybiotin, or N ₃ ; or R ₅ is H and R ₄ is OH, F, Cl, Br, I, The use according to claim 15, which is _oxybiotin , or N3. R ₆ is H, R ₇ is CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CH ₂ -AcO, CH ₂ -OTBS, CO ₂ Me, triphosphorylated methylene 1, 2-Bishydroxyethane, tetrabutylammonium monophosphate, or 1-hydroxyprop-2-in-1-yl; or R ₇ is H, R ₆ is CH ₂ -OH, CH ₂ -N ₃ , CH ₂ -oxybiotin, CH ₂ -AcO, CH ₂ -OTBS, CO ₂ Me, triphosphorylated methylene, 1,2-bishydroxyethane, tetrabutylammonium monophosphate, or 1-hydroxyprop-2-in. The use according to claim 15, which is -1-yl. The use according to any one of claims 15 to 19, wherein the drug is used for the treatment of time difference, shift work, age-related sleep disorders, or sleep disorders associated with a circadian rhythm clock. The use according to any one of claims 15 to 20, wherein the drug can be combined with a drug selected from the group consisting of caffeine, melatonin, zolpidem, eszopiclone, zaleplon and triazolam. Use of a compound selected from the following, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for circadian rhythm phase shift or for increasing amplitude of circadian rhythm vibration.

22. The use of claim 22, wherein the compound is selected from: