JPWO2019043177A5 - - Google Patents

Description

The present invention relates to 2'-spirothiethane nucleosides, phosphates and prodrugs thereof, pharmaceutically acceptable salts and solvates thereof, and in particular to the Flaviviridae family and/or to the genus Alphavirus. and the use of such compounds as medicaments in the prevention and/or treatment of viral infections caused by the viruses to which they belong. The present invention further provides pharmaceutical compositions or combination preparations of the compounds and more preferably their use as agents for the prevention or treatment of viral infections caused by viruses belonging to the Flaviviridae family and/or to the genus Alphavirus. It relates to a composition or formulation for The invention further relates to a method for preparing this compound.

式中、
塩基は（Ｂ－１）、（Ｂ－２）、（Ｂ－３ａ）、（Ｂ－３ｂ）、（Ｂ－４）、及び（Ｂ－５）からなる群から選択され、

式中、Ｒは、水素又はＣ_１～６アルキルであり、
Ｒ^３は、水素、ハロ、メチル、ＣＨ_２Ｃｌ、ＣＨ_２Ｆ、及びＮ_３ からなる群から選択される、
並びにその一リン酸塩、二リン酸塩、三リン酸塩、及びプロドラッグ、
並びにその薬学的に許容可能な塩及び溶媒和物を提供する。
The present invention has activity against flaviviridae viruses, in particular HCV and/or dengue virus, and/or alphaviruses, in particular Chikungunya virus and/or Sindbis virus and/or Semliki Forest virus, 2'. - spirothietane nucleosides and their monophosphates, diphosphates, triphosphates and prodrugs, and pharmaceutically acceptable salts and solvates thereof.
Accordingly, one aspect of the present invention is a spirothietane nucleoside of formula (I), including all possible stereoisomers thereof :

During the ceremony,
the base is selected from the group consisting of (B-1), (B-2), (B-3a), (B-3b), (B-4), and (B-5);

wherein R is hydrogen or C _1-6 alkyl;
R3 is selected from the group consisting of hydrogen ^, halo, methyl, _CH2Cl , _{CH2F ,} and N3;
and monophosphates, diphosphates, triphosphates and prodrugs thereof,
and pharmaceutically acceptable salts and solvates thereof .

The present invention is further useful in the treatment or prevention of Flaviviridae virus infections, specifically hepatitis C and/or dengue virus infections, and/or alphavirus infections, specifically Chikungunya virus and/or Sindbis virus and /or a compound of formula (I), or a stereoisomer thereof, or a phosphate thereof (i.e. , monophosphates, diphosphates, or triphosphates) or prodrugs, or pharmaceutically acceptable salts or solvates thereof, and additional pharmaceutical agents, particularly additional antiviral agents. It relates to products containing agents.

その立体異性体であって、式中、
塩基は（Ｂ－１）、（Ｂ－２）、（Ｂ－３ａ）、（Ｂ－３ｂ）、（Ｂ－４）、及び（Ｂ－５）からなる群から選択され、

式中、Ｒは、水素又はＣ_１～６アルキルであり；
Ｒ^１は水素、

式（ａ－１）の基、式（ａ－２）の基、式（ａ－３）の基、及び式（ａ－４）の基からなる群から選択され；

式中、
Ｒ^４及びＲ^７は、それぞれ独立して水素、フェニル、ナフチル、キノリニル、イソキノリニル、及びピリジルからなる群から選択され、そのそれぞれが任意選択的に、１、２、又は３つの置換基で置換され、それぞれが独立してハロ、Ｃ_１～Ｃ_６アルキル、Ｃ_２～Ｃ_６アルケニル、Ｃ_１～Ｃ_６アルコキシ、ヒドロキシ、及びＮＲ^１６Ｒ^１６’からなる群から選択されるか、或いは、
Ｒ^４及びＲ^７は、それぞれ、任意選択的に、その窒素原子においてＣ_１～Ｃ_６アルキル又はＣ_１～Ｃ_６アルキルオキシカルボニルで置換された、且つ／又は任意の利用可能な炭素原子において、それぞれが独立してハロ、Ｃ_１～Ｃ_６アルキル、Ｃ_２～Ｃ_６アルケニル、Ｃ_１～Ｃ_６アルコキシ、ヒドロキシ、及びＮＲ^１７Ｒ^１７’からなる群から選択される１、２、若しくは３つの置換基で置換されたインドリルであり；
Ｒ^５、Ｒ^５’、Ｒ^１０、及びＲ^１０’は、それぞれ独立して、水素、Ｃ_１～Ｃ_６アルキル、ベンジル、及びフェニルからなる群から選択されるか、或いは、
Ｒ^５及びＲ^５’又はＲ^１０、及びＲ^１０’は、それらが結合している炭素原子と共にＣ_３～Ｃ_７シクロアルカンジイル、又は１個の酸素原子を含有する３～７員環の複素環を形成し；
Ｒ^６は、Ｃ_１～Ｃ_１０アルキル、Ｃ_３～Ｃ_７シクロアルキル、フェニル、及びフェニル－Ｃ_１～Ｃ_６アルキル－からなる群から選択され、フェニル又はフェニル－Ｃ_１～Ｃ_６アルキル－中のフェニル部分は、任意選択的に、それぞれ独立してヒドロキシ、Ｃ_１～Ｃ_６アルコキシ、及びＮＲ^１８Ｒ^１８’からなる群から選択される１、２、又は３つの置換基で置換され；
Ｒ^８は－ＯＲ^１９又は－ＮＲ^２０Ｒ^２０’であり；
Ｒ^９は、Ｃ_１～Ｃ_６アルキル、フェニル、及びフェニル－Ｃ_１～Ｃ_６アルキル－からなる群から選択され、フェニル又はフェニル－Ｃ_１～Ｃ_６アルキル－中のフェニル部分は、任意選択的にそれぞれ独立してハロ及びＣ_１～Ｃ_６アルキルオキシからなる群から選択される１、２、又は３つの置換基で置換され；
Ｒ^１１は、水素、Ｃ_１～Ｃ_１０アルキル、Ｃ_３～Ｃ_７シクロアルキル、フェニル、又はフェニル－Ｃ_１～Ｃ_６アルキル－からなる群から選択され、フェニル又はフェニル－Ｃ_１～Ｃ_６アルキル－中のフェニル部分は、任意選択的に、それぞれ独立してヒドロキシ、Ｃ_１～Ｃ_６アルコキシ、及びＮＲ^２３Ｒ^２３’からなる群から選択される１、２、又は３つの置換基で置換され；
Ｒ^１９は、Ｃ_１～Ｃ_６アルキル、Ｃ_３～Ｃ_７シクロアルキル、オキセタニル、（Ｃ_１～Ｃ_６アルコキシ）Ｃ_１～Ｃ_６アルキル－、－ＣＨ_２－Ｏ－（Ｃ＝Ｏ）Ｃ_１～Ｃ_６アルキル、及び－ＣＨ_２－Ｏ－（Ｃ＝Ｏ）ＯＣ_１－Ｃ_６アルキルからなる群から選択され；
Ｒ^２０は、水素、Ｃ_１～Ｃ_６アルキル、及びＣ_３～Ｃ_７シクロアルキルからなる群から選択され；且つＲ^２０’はＣ_１～Ｃ_６アルキル、Ｃ_３～Ｃ_７シクロアルキル、及び（Ｃ_１～Ｃ_６アルコキシ）Ｃ_１～Ｃ_６アルキルからなる群から選択されるか、或いは
－ＮＲ^２０Ｒ^２０’は共にアゼチジニル、ピロリジニル、又はピペリジニル環を形成し、そのそれぞれが、任意選択的に、ヒドロキシ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６アルキルオキシ、及び（Ｃ＝Ｏ）－ＯＲ^２１からなる群で置換されてもよく、Ｒ^２１は、Ｃ_１～Ｃ_１０アルキル、Ｃ_３～Ｃ_７シクロアルキル、フェニル、及びフェニル－Ｃ_１～Ｃ_６アルキル－からなる群から選択され、フェニル又はフェニル－Ｃ_１～Ｃ_６アルキル－中のフェニル部分は、任意選択的に、それぞれ独立してヒドロキシ、Ｃ_１～Ｃ_６アルコキシ、及びＮＲ^２２Ｒ^２２’からなる群から選択される１、２、又は３つの置換基で置換され；
Ｒ^２は水素、又は式（ｂ）の基であり、

式中、
Ｒ^１２は、Ｃ_１～Ｃ_６アルキル、フェニル、及びフェニル－Ｃ_１～Ｃ_６アルキル－からなる群から選択され、フェニル又はフェニル－Ｃ_１～Ｃ_６アルキル－中のフェニル部分は、任意選択的にそれぞれ独立してハロ及びＣ_１～Ｃ_６アルキルオキシからなる群から選択される１、２、又は３つの置換基で置換されるか；或いは
Ｒ^１及びＲ^２は結合して、式（ｃ－１）又は（ｃ－２）の二価ラジカルを形成し、

式中、
Ｒ^１３及びＲ^１３’は、それぞれ独立して水素、Ｃ_１～Ｃ_６アルキル、ベンジル、及びフェニルからなる群から選択されるか；或いは
Ｒ^１３及びＲ^１３’は、それらが結合している炭素原子と共に、Ｃ_３～Ｃ_７シクロアルカンジイル、又は１個の酸素原子を含有する３～７員環の複素環を形成し；
Ｒ^１４は、Ｃ_１～Ｃ_１０アルキル、Ｃ_３～Ｃ_７シクロアルキル、フェニル、及びフェニル－Ｃ_１～Ｃ_６アルキル－からなる群から選択され、フェニル又はフェニル－Ｃ_１～Ｃ_６アルキル－中のフェニル部分は、任意選択的に、それぞれ独立してヒドロキシ、Ｃ_１～Ｃ_６アルコキシ、及びＮＲ^２４Ｒ^２４’からなる群から選択される１、２、又は３つの置換基で置換され；
Ｒ^１５は－ＯＲ^２５又は－ＮＲ^２６Ｒ^２６’であり、式中、
Ｒ^２５は、水素；Ｃ_１～Ｃ_６アルキル；それぞれ独立して、フェニル、ナフチル、Ｃ_３～Ｃ_７シクロアルキル、ヒドロキシル、及びＣ_１～Ｃ_６アルキルオキシからなる群から選択される１、２、又は３つの置換基で置換されたＣ_１～Ｃ_３アルキル；Ｃ_３～Ｃ_７シクロアルキル；（Ｃ_１～Ｃ_６アルコキシ）Ｃ_１～Ｃ_６アルキル－；－ＣＨ_２－Ｏ－（Ｃ＝Ｏ）Ｃ_１～Ｃ_６アルキル；－ＣＨ_２－Ｏ－（Ｃ＝Ｏ）ＯＣ_１～Ｃ_６アルキル－；１個の酸素原子を含有する３～７員環の複素環；並びにＡｒからなる群から選択され；
Ａｒは、フェニル、ナフチル、キノリニル、イソキノリニル、及びピリジルからなる群から選択され、そのそれぞれが任意選択的に、１、２、又は３つの置換基で置換され、それぞれが独立してハロ、Ｃ_１～Ｃ_６アルキル、Ｃ_２～Ｃ_６アルケニル、Ｃ_１～Ｃ_６アルコキシ、ヒドロキシ、及びＮＲ^２７Ｒ^２７’からなる群から選択されるか；或いは、
Ａｒは、任意選択的に、その窒素原子においてＣ_１～Ｃ_６アルキル又はＣ_１～Ｃ_６アルキルオキシカルボニルで置換された、且つ／又は任意の利用可能な炭素原子において、それぞれが独立してハロ、Ｃ_１～Ｃ_６アルキル、Ｃ_２～Ｃ_６アルケニル、Ｃ_１～Ｃ_６アルコキシ、ヒドロキシ、及びＮＲ^２８Ｒ^２８’からなる群から選択される１、２、若しくは３つの置換基で置換されたインドリルであり；
Ｒ^２６は、水素、Ｃ_１～Ｃ_６アルキル、及びＣ_３～Ｃ_７シクロアルキルからなる群から選択され；且つＲ^２６’はＣ_１～Ｃ_６アルキル、Ｃ_３～Ｃ_７シクロアルキル、及び（Ｃ_１～Ｃ_６アルコキシ）Ｃ_１～Ｃ_６アルキルからなる群から選択されるか、或いは
－ＮＲ^２６Ｒ^２６’は共にアゼチジニル、ピロリジニル、又はピペリジニル環を形成し、そのそれぞれが、任意選択的に、ヒドロキシ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６アルキルオキシ、及び（Ｃ＝Ｏ）－ＯＲ^２７からなる群で置換されてもよく、Ｒ^２７は、Ｃ_１～Ｃ_１０アルキル、Ｃ_３～Ｃ_７シクロアルキル、フェニル、及びフェニル－Ｃ_１～Ｃ_６アルキル－からなる群から選択され、フェニル又はフェニル－Ｃ_１～Ｃ_６アルキル－中のフェニル部分は、任意選択的に、それぞれ独立してヒドロキシ、Ｃ_１～Ｃ_６アルコキシ、及びＮＲ^２９Ｒ^２９’からなる群から選択される１、２、又は３つの置換基で置換され；
Ｒ^１６、Ｒ^１６’、Ｒ^１７、Ｒ^１７’、Ｒ^１８、Ｒ^１８’、Ｒ^２２、Ｒ^２２’、Ｒ^２３、Ｒ^２３’、Ｒ^２４、Ｒ^２４’、Ｒ^２７、Ｒ^２７’、Ｒ^２８、Ｒ^２８’、Ｒ^２９、及びＲ^２９’はそれぞれ水素及びＣ_１～Ｃ_６アルキルから選択され；
Ｒ^３は、水素、ハロ、メチル、ＣＨ_２Ｃｌ、ＣＨ_２Ｆ、及びＮ_３からなる群から選択される、化合物と、その立体異性体と；
その薬学的に許容可能な塩及び溶媒和物と、を提供する。
In certain embodiments, the present invention provides compounds of formula (I) having formula (I'):

A stereoisomer thereof, wherein
the base is selected from the group consisting of (B-1), (B-2), (B-3a), (B-3b), (B-4), and (B-5);

wherein R is hydrogen or C _1-6 alkyl;
R ¹ is hydrogen,

selected from the group consisting of a group of formula (a-1), a group of formula (a-2), a group of formula (a-3), and a group of formula (a-4);

During the ceremony,
^R4 and ^R7 are each independently selected from the group consisting of hydrogen, phenyl, naphthyl, quinolinyl, isoquinolinyl, and pyridyl, each of which is optionally substituted with 1, 2, or 3 substituents; , each independently selected from the group consisting of halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, hydroxy, and NR ¹⁶ R ^16′ ; or
each of R ⁴ and R ⁷ is optionally substituted at its nitrogen atom with C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyloxycarbonyl and/or at any available carbon atom, 1, 2, or 3 each independently selected from the group consisting of halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, hydroxy, and NR ¹⁷ R ^17′ is indolyl substituted with a substituent;
R ⁵ , R ^5′ , R ¹⁰ and R ^10′ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, benzyl and phenyl; or
R ⁵ and R ^5′ or R ¹⁰ and R ^10′ are C ₃ -C ₇ cycloalkanediyl together with the carbon atom to which they are attached, or a 3- to 7-membered heterocyclic ring containing one oxygen atom. forming a ring;
R ⁶ is selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, in phenyl or phenyl-C ₁ -C ₆ alkyl- is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ¹⁸ R ^18′ ;
R ⁸ is -OR ¹⁹ or -NR ²⁰ R ^20' ;
R ⁹ is selected from the group consisting of C ₁ -C ₆ alkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein the phenyl moiety in phenyl or phenyl-C ₁ -C ₆ alkyl- is optionally each independently substituted with 1, 2, or 3 substituents selected from the group consisting of halo and C ₁ -C ₆ alkyloxy;
R ¹¹ is selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, or phenyl-C ₁ -C ₆ alkyl-, phenyl or phenyl-C ₁ -C ₆ alkyl; the phenyl moieties in — are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ²³ R ^23′ ;
R ¹⁹ is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, oxetanyl, (C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl-, —CH ₂ —O—(C═O)C _{1 -C6} alkyl, and _{-CH2 -} O-(C=O)OC1 _- C6 alkyl;
R ²⁰ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₇ cycloalkyl; and R ^20′ is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and ( C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl, or —NR ²⁰ R ^20′ together form an azetidinyl, pyrrolidinyl, or piperidinyl ring, each of which is optionally , hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, and (C═O)—OR ²¹ wherein R ²¹ is C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein the phenyl moieties in phenyl or phenyl-C ₁ -C ₆ alkyl- are each optionally independently is substituted with 1, 2, or 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ²² R ^22′ ;
R ² is hydrogen or a group of formula (b),

During the ceremony,
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein the phenyl moiety in phenyl or phenyl-C ₁ -C ₆ alkyl- is optionally are each independently substituted with 1, 2, or 3 substituents selected from the group consisting of halo and C ₁ -C ₆ alkyloxy; or R ¹ and R ² are joined to form the formula (c -1) or (c-2) to form a divalent radical,

During the ceremony,
R ¹³ and R ^13′ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, benzyl, and phenyl; or R ¹³ and R ^13′ are the carbon to which they are attached; together with the atoms form a C3-C7 cycloalkanediyl or a _3- to ₇ -membered heterocyclic ring containing one oxygen atom;
R ¹⁴ is selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, in phenyl or phenyl-C ₁ -C ₆ alkyl- is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ²⁴ R ^24′ ;
R ¹⁵ is —OR ²⁵ or —NR ²⁶ R ^26′ , wherein
R ²⁵ is hydrogen; C ₁ -C ₆ alkyl; 1,2 each independently selected from the group consisting of phenyl, naphthyl, C ₃ -C ₇ cycloalkyl, hydroxyl, and C ₁ -C ₆ alkyloxy; , or C ₁ -C ₃ alkyl substituted with three substituents; C ₃ -C ₇ cycloalkyl; (C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl-; -CH ₂ -O-(C= the group consisting of O) C ₁ -C ₆ alkyl; —CH ₂ —O—(C=O)OC ₁ -C ₆ alkyl-; a 3- to 7-membered heterocyclic ring containing one oxygen atom; selected from;
Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, and pyridyl, each of which is optionally substituted with 1, 2, or 3 substituents, each independently halo, C _{1 -C6} alkyl, _{C2 -} C6 alkenyl, C1 _- ^C6 alkoxy, hydroxy, and _NR27R27 ^' ; or
Ar is optionally substituted at its nitrogen atom with C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyloxycarbonyl and/or at any available carbon atom each independently halo , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, hydroxy, and NR ²⁸ R ^28′ substituted with 1, 2, or 3 substituents is indolyl;
R ²⁶ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₇ cycloalkyl; and R ^26′ is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and ( C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl, or —NR ²⁶ R ^26′ together form an azetidinyl, pyrrolidinyl, or piperidinyl ring, each of which is optionally , hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, and (C═O)—OR ²⁷ , wherein R ²⁷ is C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein the phenyl moieties in phenyl or phenyl-C ₁ -C ₆ alkyl- are each optionally independently is substituted with 1, 2, or 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ²⁹ R ^29′ ;
^R16 , R16 ^' , ^R17 , R17 ^' , R18, R18 ^' , ^R22 , R22 ^' , ^R23 , R23 ^' , ^R24 , R24 ^' , ^R27 , ^{R27 '} , R ²⁸ , R ^28′ , R ²⁹ , and R ^29′ are each selected from hydrogen and C ₁ -C ₆ alkyl;
compounds and stereoisomers thereof ^, wherein R3 is selected from the group consisting of hydrogen, halo, methyl, _CH2Cl , _{CH2F ,} and N3;
and pharmaceutically acceptable salts and solvates thereof.

式中、
Ｒ^１５は－ＯＲ^２５であり、式中、Ｒ^２５は、水素、Ｃ_１～Ｃ_６アルキル、フェニル、Ｃ_３～Ｃ_７シクロアルキル、並びにそれぞれ独立して、フェニル、ナフチル、Ｃ_３～Ｃ_７シクロアルキル、ヒドロキシル、及びＣ_１～Ｃ_６アルキルオキシからなる群から選択される１、２、又は３つの置換基で置換されたＣ_１～Ｃ_３アルキルからなる群から選択される。別の実施形態では、Ｒ^２５はＣ_１～Ｃ_６アルキル、又はフェニル、Ｃ _１ ～Ｃ _２ アルキルオキシ、又はＣ _３ ～Ｃ _７ シクロアルキルで置換したＣ_１～Ｃ_２アルキルである。更なる実施形態では、Ｒ^２５はＣ_３～Ｃ_７シクロアルキル、より具体的にはシクロペンチルである。更なる実施形態では、Ｒ^２５はＣ_２～Ｃ_４アルキル、より具体的にはｉ－プロピルである。
A subgroup of compounds of formula (I) are compounds of formula (I′) as defined herein, wherein R ¹ and R ² are joined to form a divalent radical of (c-2), or is a subgroup of the compounds of (I'),

During the ceremony,
R ¹⁵ is —OR ²⁵ , wherein R ²⁵ is hydrogen, C ₁ -C ₆ alkyl, phenyl, C ₃ -C ₇ cycloalkyl, and each independently phenyl, naphthyl, C ₃ -C ₇ is selected from the group consisting of C ₁ -C ₃ alkyl substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, hydroxyl, and C ₁ -C ₆ alkyloxy; In another embodiment, R ²⁵ is C ₁ -C ₆ alkyl, or C ₁ -C ₂ alkyl substituted with phenyl , C ₁ -C ₂ alkyloxy, or C 3 _-C 7 _cycloalkyl . In a further embodiment, R ²⁵ is C ₃ -C ₇ cycloalkyl, more particularly cyclopentyl. In a further embodiment, R ²⁵ is C ₂ -C ₄ alkyl, more particularly i-propyl.

The following aspects may be included.
[1] a compound of formula (I)

or its stereoisomer
(wherein the base is selected from the group consisting of (B-1), (B-2), (B-3a), (B-3b), (B-4), and (B-5),

wherein R is hydrogen or C _{1 to 6} is an alkyl,
R. ³ is hydrogen, halo, methyl, CH ₂ Cl, CH ₂ F, and N ₃ selected from the group consisting of
or a monophosphate, diphosphate, triphosphate, or prodrug thereof;
Or a pharmaceutically acceptable salt or solvate thereof.
[2] having the formula (I′),

During the ceremony,
R. ¹ is hydrogen,

, a group of formula (a-1), a group of formula (a-2), a group of formula (a-3), and a group of formula (a-4);

During the ceremony,
R. ⁴ and R ⁷ are each independently selected from the group consisting of hydrogen, phenyl, naphthyl, quinolinyl, isoquinolinyl, and pyridyl, each of which is optionally each independently halo, C ₁ ～C ₆ alkyl, C ₂ ～C ₆ alkenyl, C ₁ ～C ₆ alkoxy, hydroxy, and NR ¹⁶ R. ^16' substituted with 1, 2, or 3 substituents selected from the group consisting of; or
R. ⁴ and R ⁷ each independently, optionally at its nitrogen atom, C ₁ ～C ₆ alkyl or C ₁ ～C ₆ at alkyloxycarbonyl and/or at any available carbon atom each independently halo, C ₁ ～C ₆ alkyl, C ₂ ～C ₆ alkenyl, C ₁ ～C ₆ alkoxy, hydroxy, and NR ¹⁷ R. ^17' indolyl substituted with 1, 2, or 3 substituents selected from the group consisting of;
R. ⁵ , R ^5' , R ¹⁰ and R ^10' are each independently hydrogen, C ₁ ～C ₆ is selected from the group consisting of alkyl, benzyl, and phenyl; or
R. ⁵ and R ^5' , or R ¹⁰ and R ^10' together with the carbon atom to which they are attached, C ₃ ～C ₇ forming a cycloalkanediyl or a 3- to 7-membered heterocyclic ring containing one oxygen atom;
R. ⁶ is C ₁ ～C ₁₀ alkyl, C ₃ ～C ₇ cycloalkyl, phenyl, and phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-, wherein phenyl or phenyl-C ₁ ～C ₆ The phenyl moieties in alkyl- are optionally each independently hydroxy, C ₁ ～C ₆ alkoxy, and NR ¹⁸ R. ^18' substituted with 1, 2, or 3 substituents selected from the group consisting of;
R. ⁸ Ha-OR ¹⁹ or -NR ²⁰ R. ^20' is;
R. ⁹ is C ₁ ～C ₆ alkyl, phenyl, and phenyl-C-C ₆ is selected from the group consisting of alkyl-, wherein phenyl or phenyl-C ₁ ～C ₆ The phenyl moieties in alkyl- are optionally each independently halo, and C ₁ ～C ₆ substituted with 1, 2, or 3 substituents selected from the group consisting of alkyloxy;
R. ¹¹ is hydrogen, C ₁ ～C ₁₀ alkyl, C ₃ ～C ₇ cycloalkyl, phenyl, or phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-, wherein phenyl or phenyl-C ₁ ～C ₆ The phenyl moieties in alkyl- are optionally each independently hydroxy, C ₁ ～C ₆ alkoxy, and NR ²³ R. ^23' substituted with 1, 2, or 3 substituents selected from the group consisting of;
R. ¹⁹ is C ₁ ～C ₆ alkyl, C ₃ ～C ₇ cycloalkyl, oxetanyl, (C ₁ ～C ₆ alkoxy) C ₁ ～C ₆ Alkyl-, -CH ₂ -O-(C=O)C ₁ ～C ₆ alkyl, and —CH ₂ -O-(C=O)OC ₁ ～C ₆ selected from the group consisting of alkyl;
R. ²⁰ is hydrogen, C ₁ ～C ₆ alkyl, and C ₃ ～C ₇ is selected from the group consisting of cycloalkyl; ^20' is C ₁ ～C ₆ alkyl, C ₃ ～C ₇ cycloalkyl, and (C ₁ ～C ₆ alkoxy) C ₁ ～C ₆ is selected from the group consisting of alkyl-; or
-NR ²⁰ R. ^20' together form an azetidinyl, pyrrolidinyl, or piperidinyl ring, each of which is optionally hydroxy, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ alkyloxy, and (C═O)—OR ²¹ may be substituted with the group consisting of R ²¹ is C ₁ ～C ₁₀ alkyl, C ₃ ～C ₇ cycloalkyl, phenyl, and phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-, wherein phenyl or phenyl-C ₁ ～C ₆ The phenyl moieties in alkyl- are optionally each independently hydroxy, C ₁ ～C ₆ alkoxy, and NR ²² R. ^22' substituted with 1, 2, or 3 substituents selected from the group consisting of;
R. ² is hydrogen or a group of formula (b),

During the ceremony,
R. ¹² is C ₁ ～C ₆ alkyl, phenyl, and phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-,
In the formula, phenyl or phenyl-C ₁ ～C ₆ The phenyl moieties in alkyl- are optionally each independently halo, and C ₁ ～C ₆ substituted with 1, 2, or 3 substituents selected from the group consisting of alkyloxy; or
R. ¹ and R ² combines to form a divalent radical of formula (c-1) or (c-2),

During the ceremony,
R. ¹³ and R ^13' are each independently hydrogen, C ₁ ～C ₆ is selected from the group consisting of alkyl, benzyl, and phenyl; or
R. ¹³ and R ^13' together with the carbon atom to which they are attached, C ₃ ～C ₇ forming a cycloalkanediyl or a 3- to 7-membered heterocyclic ring containing one oxygen atom;
R. ¹⁴ is C ₁ ～C ₁₀ alkyl, C ₃ ～C ₇ cycloalkyl, phenyl, and phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-, wherein phenyl or phenyl-C ₁ ～C ₆ The phenyl moieties in alkyl- are optionally each independently hydroxy, C ₁ ～C ₆ alkoxy, and NR ²⁴ R. ^24' substituted with 1, 2, or 3 substituents selected from the group consisting of;
R. ¹⁵ Ha-OR ²⁵ or -NR ²⁶ R. ^26' is;
R. ²⁵ is hydrogen; ₁ ～C ₆ alkyl; each independently phenyl, naphthyl, C ₃ ～C ₇ cycloalkyl, hydroxyl, and C ₁ ～C ₆ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyloxy ₁ ～C ₃ Alkyl; ₃ ～C ₇ cycloalkyl; (C ₁ ～C ₆ alkoxy) C ₁ ～C ₆ alkyl-; -CH ₂ -O-(C=O)C ₁ ～C ₆ alkyl; -CH ₂ -O-(C=O)OC ₁ ～C ₆ alkyl; a 3- to 7-membered heterocyclic ring containing one oxygen atom, and selected from the group consisting of Ar;
Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, and pyridyl, each of which is optionally each independently halo, C ₁ ～C ₆ alkyl, C ₂ ～C ₆ alkenyl, C ₁ ～C ₆ alkoxy, hydroxy, and NR ²⁷ R. ^27' substituted with 1, 2, or 3 substituents selected from the group consisting of; or
Ar optionally has, at its nitrogen atom, C ₁ ～C ₆ alkyl or C ₁ ～C ₆ at alkyloxycarbonyl and/or at any available carbon atom each independently halo, C ₁ ～C ₆ alkyl, C ₂ ～C ₆ alkenyl, C ₁ ～C ₆ alkoxy, hydroxy, and NR ²⁸ R. ^28' indolyl substituted with 1, 2, or 3 substituents selected from the group consisting of;
R. ²⁶ is hydrogen, C ₁ ～C ₆ alkyl, and C ₃ ～C ₇ is selected from the group consisting of cycloalkyl; ^26' is C ₁ ～C ₆ alkyl, C ₃ ～C ₇ cycloalkyl, and (C ₁ ～C ₆ alkoxy) C ₁ ～C ₆ is selected from the group consisting of alkyl-; or
-NR ²⁶ R. ^26' together form an azetidinyl, pyrrolidinyl, or piperidinyl ring, each of which is optionally hydroxy, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ alkyloxy, and (C═O)—OR ²⁷ may be substituted with the group consisting of R ²⁷ is C ₁ ～C ₁₀ alkyl, C ₃ ～C ₇ cycloalkyl, phenyl, and phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-, wherein phenyl or phenyl-C ₁ ～C ₆ The phenyl moieties in alkyl- are optionally each independently hydroxy, C ₁ ～C ₆ alkoxy, and NR ²⁹ R. ^29' substituted with 1, 2, or 3 substituents selected from the group consisting of;
R. ¹⁶ , R ^16' , R ¹⁷ , R ^17' , R ¹⁸ , R ^18' , R ²² , R ^22' , R ²³ , R ^23' , R ²⁴ , R ^24' , R ²⁷ , R ^27' , R ²⁸ , R ^28' , R ²⁹ , and R ^29' are each independently hydrogen and C ₁ ～C ₆ selected from alkyl;
R. ³ is hydrogen, halo, methyl, CH ₂ Cl, CH ₂ F, and N ₃ The compound according to [1] above, which is selected from the group consisting of
[3] R. ¹ is hydrogen,

, a group of formula (a-1), a group of formula (a-2), and a group of formula (a-3), wherein
R. ⁴ and R ⁷ are each independently phenyl or naphthyl, each of which is optionally each independently halo, C ₁ ～C ₆ alkyl, C ₂ ～C ₆ alkenyl, C ₁ ～C ₆ alkoxy, hydroxy, and NR ¹⁶ R. ^16' substituted with 1, 2, or 3 substituents selected from the group consisting of R ¹⁶ and R ^16' are each independently hydrogen, and C ₁ ～C ₆ is selected from alkyl; or R ⁴ and R ⁷ are each independently indolyl;
R. ⁵ and R ^5' are each independently hydrogen, C ₁ ～C ₆ is selected from the group consisting of alkyl, benzyl, and phenyl; or R ⁵ and R ^5' are C together with the carbon atom to which they are attached ₃ ～C ₇ forming a cycloalkanediyl;
R. ⁶ is C ₁ ～C ₁₀ alkyl, C ₃ ～C ₇ cycloalkyl, and phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-;
R. ⁸ Ha-OR ¹⁹ or -NR ²⁰ R. ^20' is; ¹⁹ is C ₁ ～C ₆ alkyl or C ₃ ～C ₇ is cycloalkyl;
R. ²⁰ is hydrogen and R ^20' is C ₁ ～C ₆ alkyl or C ₃ ～C ₇ is cycloalkyl;
R. ⁹ is C ₁ ～C ₆ is alkyl;
R. ² is hydrogen or a group of formula (b), where R ¹² is C ₁ ～C ₆ is alkyl; or
R. ¹ and R ² combines to form a divalent radical of formula (c-1) or (c-2), wherein
R. ¹³ and R ^13' are each independently hydrogen, C ₁ ～C ₆ is selected from the group consisting of alkyl, benzyl, and phenyl; or R ¹³ and R ^13' are C together with the carbon atom to which they are attached ₃ ～C ₇ forming a cycloalkanediyl;
R. ¹⁴ is C ₁ ～C ₁₀ alkyl, C ₃ ～C ₇ cycloalkyl, and phenyl-C ₁ ～C ₆ is selected from the group consisting of alkyl-;
R. ¹⁵ Ha-OR ²⁵ or -NR ²⁶ R. ^26' where R ²⁵ is C ₁ ～C ₆ Alkyl; Phenyl; C ₃ ～C ₇ cycloalkyl; and each independently phenyl, naphthyl, C ₃ ～C ₇ cycloalkyl, hydroxyl, and C ₁ ～C ₆ C substituted with 1, 2, or 3 substituents selected from the group consisting of alkyloxy ₁ ～C ₃ is selected from the group consisting of alkyl; ²⁶ is hydrogen; R ^26' is C ₁ ～C ₆ alkyl or C ₃ ～C ₇ The compound according to [2] above, which is cycloalkyl.
[4] R ¹ teeth,
hydrogen,

, and the group consisting of the group of formula (a-1)
or R ¹ and R ² is combined to form a divalent radical of formula (c-2), the compound according to the above [2] or [3].
[5] R. ⁴ is phenyl, halophenyl, di-C ₁ ～C ₄ alkylphenyl or naphthyl;
R. ⁵ and R ^5' are each independently hydrogen, C ₁ ～C ₆ is alkyl, benzyl, or phenyl;
R. ⁶ is C ₁ ～C ₆ is alkyl;
R. ¹⁵ Ha-OR ²⁵ and where R ²⁵ is C ₁ ～C ₆ C substituted with alkyl or phenyl ₁ ～C ₂ alkyl, C ₁ ～C ₂ alkyloxy, or C ₃ ～C ₇ The compound according to any one of [2] to [4] above, which is cycloalkyl.
[6] the base is (B-1), (B-2), or (B-3a); ³ are hydrogen, halo, and N ₃ The compound according to any one of [1] to [5] above, which is selected from the group consisting of
[7] A pharmaceutical composition comprising a therapeutically effective amount, particularly an antiviral effective amount, of a compound of formula (I) as defined in any one of [1] to [6] above, and a pharmaceutically acceptable carrier. thing.
[8] A pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount, particularly an antiviral effective amount, of a compound of formula (I) as defined in any one of [1] to [6] above. A process for preparing the pharmaceutical composition according to [7] above, characterized in that
[9] A compound as defined in any one of [1] to [6] above, or a pharmaceutical composition as defined in [7] above, for use as a medicament.
[10] The compound according to any one of [1] to [6] above, or the above [ 7].
[11] A compound according to any one of [1] to [6] above, or a pharmaceutical composition as defined in [7] above, for use as an inhibitor of HCV and/or dengue virus.
[12] The compound according to any one of [1] to [6] above, or in [7] above, for use as an inhibitor of Chikungunya virus and/or Sindbis virus and/or Semliki Forest virus A pharmaceutical composition as defined.
[13] Flaviviridae, comprising administering an anti-flaviviridae and/or anti-alphavirus effective amount of a compound of formula (I) as defined in any one of [1] to [6] above and/or methods of treating warm-blooded animals, particularly humans, infected with alphaviruses or at risk of infection with Flaviviridae and/or alphaviruses.
[14] Any of the above [1] to [6] as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of flaviviridae virus infection and/or the treatment or prevention of alphavirus infection. A product comprising a compound of formula (I) as defined in any one of paragraphs and an additional pharmaceutical agent, in particular an additional antiviral agent.

Claims (19)

Compounds of Formula (I)

or its stereoisomer
( wherein the base is selected from the group consisting of (B-1), (B-2), (B-3a), (B-3b), (B-4), and (B-5),

wherein R is hydrogen or C _1-6 alkyl;
R3 is selected from the group consisting of hydrogen ^, halo, methyl, _CH2Cl , _{CH2F ,} and N3)
or a monophosphate, diphosphate, or triphosphate thereof, or a pharmaceutically acceptable salt or solvate thereof . having the formula (I′),

During the ceremony,
R ¹ is hydrogen;

, a group of formula (a-1), a group of formula (a-2), a group of formula (a-3), and a group of formula (a-4);

During the ceremony,
R ⁴ and R ⁷ are each independently selected from the group consisting of hydrogen, phenyl, naphthyl, quinolinyl, isoquinolinyl, and pyridyl, each of which is optionally each independently halo, C ₁ -C substituted with 1, 2, or 3 substituents selected from the group consisting of C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, hydroxy, and NR ¹⁶ R ^16′ ; ⁴ and R ⁷ are each independently optionally at the nitrogen atom, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyloxycarbonyl, and/or at any available carbon atom, 1, 2, or 3 each independently selected from the group consisting of halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, hydroxy, and NR ¹⁷ R ^17′ is indolyl substituted with a substituent;
R ⁵ , R ^5′ , R ¹⁰ and R ^10′ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, benzyl and phenyl, or R ⁵ and R ^5′ , or R ¹⁰ and R ^10′ together with the carbon atom to which they are attached form a C ₃ -C ₇ cycloalkanediyl or a 3- to 7-membered heterocyclic ring containing one oxygen atom;
R ⁶ is selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein phenyl or phenyl-C ₁ -C The phenyl moieties in 6alkyl- are optionally each independently ₁ , 2, or 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ¹⁸ R ^18′ is replaced by;
R ⁸ is -OR ¹⁹ or -NR ²⁰ R ^20' ;
R ⁹ is selected from the group consisting of C ₁ -C ₆ alkyl, phenyl, and phenyl-C-C ₆ alkyl-, wherein the phenyl or phenyl moiety in phenyl-C ₁ -C ₆ alkyl- is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo and C ₁ -C ₆ alkyloxy;
R ¹¹ is selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, or phenyl-C ₁ -C ₆ alkyl-, wherein phenyl or phenyl-C ₁ The phenyl moieties in ~ _C6alkyl- are optionally each independently ₁ , 2, or 3 selected from the group consisting of hydroxy, C1- _C6alkoxy , and ^{NR23R23 '} substituted with a substituent of;
R ¹⁹ is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, oxetanyl, (C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl-, —CH ₂ —O—(C═O)C _{1 -C6} alkyl, and _{-CH2 -} O-(C=O)OC1 _- C6 alkyl;
R ²⁰ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₇ cycloalkyl; R ^20′ is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and ( or _{—NR 20} R ₂₀ ^′ together ^form an _azetidinyl , pyrrolidinyl, or piperidinyl ring, each of which is optionally may be substituted with the group consisting of hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, and (C═O)—OR ²¹ , wherein R ²¹ is C ₁ -C ₁₀ alkyl, is selected from the group consisting of C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein the phenyl moiety in phenyl or phenyl-C ₁ -C ₆ alkyl- is optional each independently substituted with 1, 2, or 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ²² R ^22′ ;
R ² is hydrogen or a group of formula (b),

During the ceremony,
R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-;
wherein the phenyl or phenyl moieties in the phenyl-C ₁ -C ₆ alkyl- are optionally each independently selected from the group consisting of halo and C ₁ -C ₆ alkyloxy 1, 2 or substituted with three substituents; or R ¹ and R ² combine to form a divalent radical of formula (c-1) or (c-2),

During the ceremony,
R ¹³ and R ^13′ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, benzyl, and phenyl; or R ¹³ and R ^13′ are the carbon to which they are attached; together with the atoms form a C3-C7 cycloalkanediyl or a _3- to ₇ -membered heterocyclic ring containing one oxygen atom;
R ¹⁴ is selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein phenyl or phenyl-C ₁ -C The phenyl moieties in 6alkyl- are optionally each independently ₁ , 2, or 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ²⁴ R ^24′ is replaced by;
R ¹⁵ is —OR ²⁵ or —NR ²⁶ R ^26′ ;
R ²⁵ is hydrogen; C ₁ -C ₆ alkyl; 1, 2, each independently selected from the group consisting of phenyl, naphthyl, C ₃ -C ₇ cycloalkyl, hydroxyl, and C ₁ -C ₆ alkyloxy; or C ₁ -C ₃ alkyl substituted with 3 substituents; C ₃ -C ₇ cycloalkyl; (C ₁ -C ₆ alkoxy)C ₁ -C ₆ alkyl-; -CH ₂ -O-(C= O) C ₁ -C ₆ alkyl; —CH ₂ —O—(C═O)OC ₁ -C ₆ alkyl; a 3- to 7-membered heterocyclic ring containing one oxygen atom, and from the group consisting of Ar selected;
Ar is selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, and pyridyl, each of which is optionally each independently halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted with 1, 2, or 3 substituents selected from the group consisting of C ₁ -C ₆ alkoxy, hydroxy, and NR ^{27 ″} R ^27′ ; or
Ar is optionally C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyloxycarbonyl at its nitrogen atom and/or at any available carbon atom each independently halo, C ₁ indolyl substituted with ₁ , 2, or 3 substituents selected from the group consisting of _-C6 alkyl, _{C2 -} C6 alkenyl, C1 _- C6 alkoxy, hydroxy, and ^{NR28R28 '} ; can be;
R ²⁶ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and C ₃ -C ₇ cycloalkyl; R ^26′ is C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, and ( or ^{—NR 26} _{R 26} ^′ together form _an azetidinyl, pyrrolidinyl, or piperidinyl ring, _each of which is optionally may be substituted with the group consisting of hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, and (C═O)—OR ²⁷ , wherein R ²⁷ is C ₁ -C ₁₀ alkyl, is selected from the group consisting of C ₃ -C ₇ cycloalkyl, phenyl, and phenyl-C ₁ -C ₆ alkyl-, wherein the phenyl moiety in phenyl or phenyl-C ₁ -C ₆ alkyl- is optional each independently substituted with 1, 2, or 3 substituents selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, and NR ²⁹ R ^29′ ;
^R16 , R16 ^' , ^R17 , R17 ^' , R18, R18 ^' , ^R22 , R22 ^' , ^R23 , R23 ^' , ^R24 , ^{R24 '} , R27 ^'' , R27 ^' , R ²⁸ , R ^28′ , R ²⁹ , and R ^29′ are each independently selected from hydrogen and C ₁ -C ₆ alkyl;
_2. The compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable compound thereof ^, wherein R3 is selected from the group consisting of hydrogen, halo, methyl, _CH2Cl , _CH2F , and N3. salts or solvates . R ¹ is hydrogen;

, a group of formula (a-1), a group of formula (a-2), and a group of formula (a-3), wherein R ⁴ and R ⁷ are each independently phenyl or naphthyl each of which is optionally each independently from halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, hydroxy, and NR ¹⁶ R ^16′ substituted with 1, 2, or 3 substituents selected from the group of wherein R ¹⁶ and R ^16′ are each independently selected from hydrogen and C ₁ -C ₆ alkyl; or R ⁴ and R ⁷ are each independently indolyl;
R ⁵ and R ^5′ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, benzyl, and phenyl; or R ⁵ and R ^5′ are the carbon to which they are attached; together with the atoms to form a C ₃ -C ₇ cycloalkanediyl;
R ⁶ is selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, and phenyl-C ₁ -C ₆ alkyl-;
R ⁸ is —OR ¹⁹ or —NR ²⁰ R ^20′ ; wherein R ¹⁹ is C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl;
R ²⁰ is hydrogen and R ^20′ is C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl;
R ⁹ is C ₁ -C ₆ alkyl;
R ² is hydrogen or a group of formula (b), wherein R ¹² is C ₁ -C ₆ alkyl; or
R ¹ and R ² combine to form a divalent radical of formula (c-1) or (c-2), wherein
R ¹³ and R ^13′ are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, benzyl, and phenyl; or R ¹³ and R ^13′ are the carbon to which they are attached; together with the atoms to form a C ₃ -C ₇ cycloalkanediyl;
R ¹⁴ is selected from the group consisting of C ₁ -C ₁₀ alkyl, C ₃ -C ₇ cycloalkyl, and phenyl-C ₁ -C ₆ alkyl-;
R ¹⁵ is —OR ²⁵ or —NR ²⁶ R ^26′ , wherein R ²⁵ is C ₁ -C ₆ alkyl; phenyl; C ₃ -C ₇ cycloalkyl; selected from the group consisting of C ₁ -C ₃ alkyl substituted with 1, 2, or 3 substituents selected from the group consisting of ₃ -C ₇ cycloalkyl, hydroxyl, and C ₁ -C ₆ alkyloxy; R ²⁶ is hydrogen; R ^26′ is C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl , or a stereoisomer thereof, or a pharmaceutically acceptable salts or solvates . ^R1 is
hydrogen,

, and groups of formula (a-1), or R ¹ and R ² combine to form a divalent radical of formula (c-2). or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof . R ⁴ is phenyl, halophenyl, di-C ₁ -C ₄ alkylphenyl, or naphthyl;
R ⁵ and R ^5′ are each independently hydrogen, C ₁ -C ₆ alkyl, benzyl, or phenyl;
R ⁶ is C ₁ -C ₆ alkyl;
R ¹⁵ is —OR ²⁵ , wherein R ²⁵ is C ₁ -C ₆ alkyl or C ₁ -C ₂ alkyl substituted with phenyl , C ₁ -C ₂ alkyloxy, or C 3 _-C 7 _cycloalkyl ; A compound according to any one of claims 2 to 4 , or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, which is 6. Any of claims 1-5, wherein the base is (B-1), (B- ₂ ), or (B ^- 3a) and R3 is selected from the group consisting of hydrogen, halo, and N3 A compound according to claim 1 , or a stereoisomer thereof, or a monophosphate, diphosphate, or triphosphate thereof, or a pharmaceutically acceptable salt or solvate thereof . the following:

or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof. A therapeutically effective amount of a compound according to any one of claims 1 to 7 , or a stereoisomer thereof, or a monophosphate, diphosphate, or triphosphate thereof, or a pharmaceutically acceptable A pharmaceutical composition comprising a possible salt or solvate and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier comprises a therapeutically effective amount of a compound according to any one of claims 1 to 7 , or a stereoisomer thereof, or a monophosphate, diphosphate, or triphosphate thereof. Process for preparing the pharmaceutical composition according to claim 8 , characterized in that it is intimately mixed with an acid salt, or a pharmaceutically acceptable salt or solvate thereof . 9. A pharmaceutical composition according to claim 8 for use as a medicament. 9. The pharmaceutical composition according to claim 8 , for use in treating or preventing flaviviridae virus infection and/or treating or preventing alphavirus infection. 9. A pharmaceutical composition according to claim 8 for use as an inhibitor of HCV and/or dengue virus. 9. A pharmaceutical composition according to claim 8 for use as an inhibitor of Chikungunya virus and/or Sindbis virus and/or Semliki Forest virus. A pharmaceutical composition for use in a method of treating a warm-blooded animal infected with, or at risk of becoming infected with, Flaviviridae and/or alphaviruses, comprising:
The pharmaceutical composition comprises a compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a monophosphate, diphosphate, or triphosphate thereof, or a pharmaceutically including acceptable salts or solvates,
The method comprises an anti-flaviviridae and/or anti-alphavirus effective amount of the compound, or a stereoisomer thereof, or a monophosphate, diphosphate, or triphosphate thereof, or a pharmaceutically A pharmaceutical composition comprising administering an acceptable salt or solvate . 8. A combination preparation according to any one of claims 1 to 7 for simultaneous, separate or sequential use in the treatment or prophylaxis of Flaviviridae virus infections and/or in the treatment or prophylaxis of alphavirus infections. or a stereoisomer thereof, or a monophosphate, diphosphate, or triphosphate thereof, or a pharmaceutically acceptable salt or solvate thereof , and an additional pharmaceutical agent. 9. The pharmaceutical composition of claim 8, wherein said therapeutically effective amount is an antiviral effective amount. 10. The process of claim 9, wherein said therapeutically effective amount is an antiviral effective amount. 15. The pharmaceutical composition according to claim 14, wherein said warm-blooded animal is human. 16. The product of Claim 15, wherein said additional pharmaceutical agent is an additional antiviral agent.