JP2006504803A - Pyrazole derivative - Google Patents

Abstract

または薬学的に許容できるその塩、溶媒和物、もしくは誘導体、ならびにこれらの調製方法、これらの調製方法で使用する中間体、これらを含有する組成物、およびこのピラゾール誘導体の使用に関する。本発明の化合物は、酵素の逆転写酵素に結合し、そのモジュレーター、特に阻害剤となる。本発明の化合物は、それ自体、逆転写酵素の阻害によって影響を受ける障害を含む様々な障害の治療に有用である。問題の障害には、後天性免疫不全症候群（ＡＩＤＳ）などの、ヒト免疫不全ウイルス（ＨＩＶ）および遺伝的に関係のあるレトロウイルスによって引き起こされるものが含まれる。The present invention provides a pyrazole derivative of formula (I) wherein R ¹ -R ⁴ are as defined herein:

Or a pharmaceutically acceptable salt, solvate or derivative thereof, and methods for their preparation, intermediates used in these methods of preparation, compositions containing them, and use of the pyrazole derivatives. The compounds of the present invention bind to the enzyme reverse transcriptase and become modulators, particularly inhibitors. The compounds of the present invention are themselves useful for the treatment of various disorders, including those affected by reverse transcriptase inhibition. Disorders in question include those caused by human immunodeficiency virus (HIV) and genetically related retroviruses, such as acquired immunodeficiency syndrome (AIDS).

Description

  The present invention relates to pyrazole derivatives, their use as pharmaceuticals, compositions containing them, processes for their preparation and intermediates used in such processes.

  Reverse transcriptase is involved in the infectious life cycle of human immunodeficiency virus (HIV). Compounds that interfere with the function of this enzyme have shown utility in the treatment of conditions caused by HIV and genetically related retroviruses, such as acquired immune deficiency syndrome (AIDS). Since this virus can mutate and become resistant to the effects of known modulators, there is a continuing need for new and better modulators, particularly inhibitors, of HIV reverse transcriptase.

  The N (hydroxyethyl) pyrazole derivatives of US Pat. No. 3,303,200 are said to have antiviral activity. N-phenylpyrazoles (J. Med. Chem., 2000, 43, 1034), C and S-linked arylpyrazoles (WO 02/04424), and the aryl bonds of O and S are adjacent to the nitrogen atom Several pyrazoles have been disclosed as reverse transcriptase inhibitors, including O- and S-linked arylpyrazoles (WO 02/30907).

  According to the invention, the compound of formula (I)

または薬学的に許容できるその塩、溶媒和物もしくは誘導体
［式中、
Ｒ^１は、（ｉ）１〜４個の窒素へテロ原子、または（ｉｉ）１もしくは２個の窒素へテロ原子および１個の酸素もしくは１個の硫黄へテロ原子、または（ｉｉｉ）１もしくは２個の酸素もしくは硫黄へテロ原子を含む、５員または６員の芳香族複素環基であり、前記複素環基は、ハロ、オキソ、−ＣＮ、−ＣＯＲ^５、−ＣＯＮＲ^５Ｒ^５、−ＳＯ_２ＮＲ^５Ｒ^５、−ＮＲ^５ＳＯ_２Ｒ^５、−ＯＲ^５、ＯＲ^１１、−ＮＲ^５Ｒ^５、−（Ｃ_１〜Ｃ_６アルキレン）−ＮＲ^５Ｒ^５、Ｒ^７、またはＲ^１１で置換されていてもよく、
Ｒ^２は、Ｈ、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_６アルケニル、Ｃ_３〜Ｃ_６アルキニル、Ｃ_３〜Ｃ_７シクロアルキル、Ｃ_３〜Ｃ_７シクロアルケニル、フェニル、ベンジル、Ｒ^８、またはＲ^９であり、前記のＣ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_７シクロアルキル、フェニル、およびベンジルは、ハロ、−ＯＲ^５、−ＯＲ^１０、−ＣＮ、−ＣＯ_２Ｒ^７、−ＯＣＯＮＲ^５Ｒ^５、−ＣＯＮＲ^５Ｒ^５、−Ｃ（＝ＮＲ^５）ＮＲ^５ＯＲ^５、−ＣＯＮＲ^５ＮＲ^５Ｒ^５、−ＮＲ^６Ｒ^６、−ＮＲ^５Ｒ^１０、−ＮＲ^５ＣＯＲ^５、−ＮＲ^５ＣＯＲ^８、−ＮＲ^５ＣＯＲ^１０、−ＮＲ^５ＣＯ_２Ｒ^５、−ＮＲ^５ＣＯＮＲ^５Ｒ^５、−ＳＯ_２ＮＲ^５Ｒ^５、−ＮＲ^５ＳＯ_２Ｒ^５、−ＮＲ^５ＳＯ_２ＮＲ^５Ｒ^５、Ｒ^８、またはＲ^９で置換されていてもよく、
Ｒ^３は、Ｈ、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_７シクロアルキル、フェニル、ベンジル、ハロ、−ＣＮ、−ＯＲ^７、−ＣＯ_２Ｒ^５、−ＣＯＮＲ^５Ｒ^５、Ｒ^８、またはＲ^９であり、前記のＣ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_７シクロアルキル、フェニル、およびベンジルは、ハロ、−ＣＮ、−ＯＲ^５、−ＣＯ_２Ｒ^５、−ＣＯＮＲ^５Ｒ^５、−ＯＣＯＮＲ^５Ｒ^５、−ＮＲ^５ＣＯ_２Ｒ^５、−ＮＲ^６Ｒ^６、−ＮＲ^５ＣＯＲ^５、−ＳＯ_２ＮＲ^５Ｒ^５、−ＮＲ^５ＣＯＮＲ^５Ｒ^５、−ＮＲ^５ＳＯ_２Ｒ^５、Ｒ^８、またはＲ^９で置換されていてもよく、
Ｒ^４は、フェニル、ナフチル、またはピリジルであり、それぞれ、Ｒ^８、ハロ、−ＣＮ、Ｃ_１〜Ｃ_６アルキル、Ｃ_１〜Ｃ_６ハロアルキル、Ｃ_３〜Ｃ_７シクロアルキル、Ｃ_１〜Ｃ_６アルコキシ、−ＣＯＮＲ^５Ｒ^５、ＯＲ^１１、Ｓｏ_ｘＲ^６、Ｏ−（Ｃ_１〜Ｃ_６アルキレン）−ＣＯＮＲ^５Ｒ^５、Ｏ−（Ｃ_１〜Ｃ_６アルキレン）−ＮＲ^５Ｒ^５、またはＯ−（Ｃ_１〜Ｃ_６アルキレン）−ＯＲ^６で置換されていてもよく、
各Ｒ^５は、それぞれ独立に、Ｈ、Ｃ_１〜Ｃ_６アルキルまたはＣ_３〜Ｃ_７シクロアルキルのいずれかであり、あるいは、２個のＲ^５基が同じ窒素原子に結合しているとき、これらの２個の基は、これらの結合相手である窒素原子と一緒になって、アゼチジニル、ピロリジニル、ピペリジニル、ホモピペリジニル、ピペラジニル、ホモピペラジニル、またはモルホリニルを表し、前記のアゼチジニル、ピロリジニル、ピペリジニル、ホモピペリジニル、ピペラジニル、ホモピペラジニル、およびモルホリニルは、Ｃ_１〜Ｃ_６アルキルまたはＣ_３〜Ｃ_７シクロアルキルで置換されていてもよく、
各Ｒ^６は、それぞれ独立に、Ｈ、Ｃ_１〜Ｃ_６アルキル、またはＣ_３〜Ｃ_７シクロアルキルのいずれかであり、
Ｒ^７は、Ｃ_１〜Ｃ_６アルキルまたはＣ_３〜Ｃ_７シクロアルキルであり、
Ｒ^８は、（ｉ）１〜４個の窒素へテロ原子、または（ｉｉ）１もしくは２個の窒素へテロ原子および１個の酸素もしくは１個の硫黄ヘテロ原子、または（ｉｉｉ）１もしくは２個の酸素もしくは硫黄ヘテロ原子を含む、５員もしくは６員の芳香族複素環基であり、前記複素環基は、ハロ、オキソ、−ＣＮ、−ＣＯＲ^５、−ＣＯＮＲ^５Ｒ^５、−ＳＯ_２ＮＲ^５Ｒ^５、−ＮＲ^５ＳＯ_２Ｒ^５、−ＯＲ^５、−ＮＲ^５Ｒ^５、−（Ｃ_１〜Ｃ_６アルキレン）−ＮＲ^５Ｒ^５、Ｃ_１〜Ｃ_６アルキル、フルオロ（Ｃ_１〜Ｃ_６）アルキル、またはＣ_３〜Ｃ_７シクロアルキルで置換されていてもよく、
Ｒ^９は、（ｉ）１もしくは２個の窒素へテロ原子、または（ｉｉ）１個の窒素へテロ原子および１個の酸素もしくは１個の硫黄へテロ原子、または（ｉｉｉ）１個の酸素もしく硫黄へテロ原子を含む、飽和または部分的に不飽和の４〜７員複素環であり、前記複素環基は、オキソ、Ｃ_１〜Ｃ_６アルキル、Ｃ_３〜Ｃ_７シクロアルキル、−ＳＯ_２Ｒ^５、−ＣＯＮＲ^５Ｒ^５、−ＣＯＯＲ^５、−ＣＯ−（Ｃ_１〜Ｃ_６アルキレン）−ＯＲ^５、または−ＣＯＲ^５で置換されていてもよく、またヘテロ原子に隣接していない炭素原子が、ハロ、−ＯＲ^５、−ＮＲ^５Ｒ^５、−ＮＲ^５ＣＯＲ^５、−ＮＲ^５ＣＯＯＲ^５、−ＮＲ^５ＣＯＮＲ^５Ｒ^５、−ＮＲ^５ＳＯ_２Ｒ^５、または−ＣＮで置換されていてもよく、
Ｒ^１０は、Ｒ^８、Ｒ^９、−ＯＲ^５、−ＣＯＮＲ^５Ｒ^５、−ＮＲ^５ＣＯＲ^５、または−ＮＲ^５Ｒ^５で置換されているＣ_１〜Ｃ_６アルキルであり、
Ｒ^１１は、ハロ、−ＣＮ、−ＣＯＲ^５、−ＣＯＮＲ^５Ｒ^５、−ＳＯ_２ＮＲ^５Ｒ^５、−ＮＲ^５ＳＯ_２Ｒ^５、−ＯＲ^５、−ＮＲ^５Ｒ^５、−（Ｃ_１〜Ｃ_６アルキレン）−ＮＲ^５Ｒ^５、Ｃ_１〜Ｃ_６アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、またはＣ_３〜Ｃ_７シクロアルキルで置換されていてもよいフェニルであり、
ｘは、０、１、または２である］が提供される。

Or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein
R ¹ is (i) 1 to 4 nitrogen heteroatoms, or (ii) 1 or 2 nitrogen heteroatoms and 1 oxygen or 1 sulfur heteroatom, or (iii) 1 or containing two oxygen or sulfur heteroatoms, or an aromatic heterocyclic group having 5-membered or 6-membered, the heterocyclic group, halo, oxo, ^-CN, -COR 5, -CONR ⁵ R ^5, - _{^{SO 2 NR 5 R 5, -NR}} 5 SO 2 R 5, -OR 5, oR 11, -NR 5 R 5, - at _(C 1 -C ₆ ^alkylene) -NR ^{5 R 5,} R ⁷ or ^{R 11,} May be replaced,
R ² is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl, phenyl, benzyl, R ⁸ , Or R ⁹ and the aforementioned C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and benzyl are halo, —OR ⁵ , —OR ¹⁰ , —CN, —CO ₂ R ⁷ , —OCONR ^{5 R 5, -CONR 5 R 5} , -C (= NR 5) NR 5 OR 5, -CONR 5 NR 5 R 5, -NR 6 R 6, -NR 5 R 10, -NR 5 COR 5, -NR ⁵ COR ⁸ , —NR ⁵ COR ¹⁰ , —NR ⁵ CO ₂ R ⁵ , —NR ⁵ CONR ⁵ R ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , —NR ⁵ SO ₂ NR ⁵ R ⁵ , R ⁸ Or optionally substituted with R ⁹ ,
R ³ is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, benzyl, halo, —CN, —OR ⁷ , —CO ₂ R ⁵ , —CONR ⁵ R ⁵ , R ⁸ , or R ⁹ and the aforementioned C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and benzyl are halo, —CN, —OR ⁵ , —CO ₂ R ⁵ , —CONR ⁵ R ⁵ , — OCONR ⁵ R ⁵ , —NR ⁵ CO ₂ R ⁵ , —NR ⁶ R ⁶ , —NR ⁵ COR ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ CONR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , R ⁸ or R ⁹ may be substituted,
R ⁴ is phenyl, naphthyl, or pyridyl and is R ⁸ , halo, —CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C _{6, respectively.} ^{alkoxy, -CONR 5 R 5, oR 11} , So x R 6, O- (C 1 ~C 6 _{^{alkylene) -CONR 5 R 5, O- (}} C 1 ~C 6 alkylene) ^-NR 5 ^{R 5} or O, - _(C 1 ~C ₆ alkylene) may be substituted with -OR ^6,
Each R ⁵ is independently H, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl, or when two R ⁵ groups are attached to the same nitrogen atom, These two groups, together with their binding nitrogen atom, represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, or morpholinyl and are azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl , homopiperazinyl, and morpholinyl _may be optionally substituted with C 1 -C ₆ alkyl or _C 3 -C ₇ cycloalkyl,
Each R ⁶ is independently either H, C ₁ -C ₆ alkyl, or C ₃ -C ₇ cycloalkyl;
R ⁷ is C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
R ⁸ is (i) 1 to 4 nitrogen heteroatoms, or (ii) 1 or 2 nitrogen heteroatoms and 1 oxygen or 1 sulfur heteroatom, or (iii) 1 or 2 including pieces of oxygen or sulfur heteroatoms, a 5-membered or 6-membered aromatic heterocyclic group, the heterocyclic group, halo, ^{oxo, -CN, -COR 5, -CONR 5} R 5, -SO 2 _{^{NR 5 R 5, -NR 5 SO}} 2 R 5, -OR 5, -NR 5 R 5, - (C 1 ~C 6 _{^{alkylene) -NR 5 R 5, C 1}} ~C 6 alkyl, fluoro _(C 1 ~ C ₆₎ alkyl, or _C 3 -C ₇ cycloalkyl being optionally substituted with,
R ⁹ is (i) 1 or 2 nitrogen heteroatoms, or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulfur heteroatom, or (iii) 1 oxygen Moshiku to sulfur containing hetero atoms, a 4-7 membered heterocyclic ring saturated or partially unsaturated, said heterocyclic group, _oxo, C 1 -C _{6 alkyl,} C 3 -C ₇ cycloalkyl, - ^May be substituted with SO ₂ R ⁵ , —CONR ⁵ R ⁵ , —COOR ⁵ , —CO— (C ₁ -C ₆ alkylene) -OR ⁵ , or —COR ⁵ and is not adjacent to a heteroatom. carbon atoms, ^{halo, -OR 5, -NR 5 R 5} , -NR 5 COR 5, -NR 5 COOR 5, -NR 5 CONR 5 R 5, substituted by -NR ⁵ _SO 2 ^R 5 or -CN, You may,
R ¹⁰ is C ₁ -C ₆ alkyl substituted with R ⁸ , R ⁹ , —OR ⁵ , —CONR ⁵ R ⁵ , —NR ⁵ COR ⁵ , or —NR ⁵ R ⁵ ;
R ¹¹ is halo, —CN, —COR ⁵ , —CONR ⁵ R ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , —OR ⁵ , —NR ⁵ R ⁵ , — (C ₁ to C ₆ alkylene) -NR ⁵ R ⁵ , C ₁ -C ₆ alkyl, halo (C ₁ -C ₆ ) alkyl, or phenyl optionally substituted with C ₃ -C ₇ cycloalkyl,
x is 0, 1, or 2.] is provided.

In the above definition, halo means fluoro, chloro, bromo, or iodo. Unless stated otherwise, alkyl, alkenyl, alkynyl, alkylene, and alkoxy groups containing the requisite number of carbon atoms may be branched or unbranched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. Examples of alkenyl include ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methylpropen-1-yl, or 2-methylpropen-3-yl is included. Examples of alkynyl include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyne-1- File. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, and 1,3-propylene. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When R ¹ and R ² are taken together, they form a 5- or 6-membered ring with the nitrogen and carbon atoms of the pyrazole ring to which they are attached. If the heterocyclic group R ⁸ or R ⁹ is bonded to an oxygen, sulfur, or nitrogen heteroatom, the heterocyclic group R ⁸ or R ⁹ must be bonded via a carbon atom on the ring. Further, when the heterocyclic group R ⁹ is bonded to an oxygen, sulfur, or nitrogen heteroatom, the heterocyclic group R ⁹ must be bonded via a cyclic carbon atom that is not adjacent to the cyclic heteroatom. Don't be.

  Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

  Suitable acid addition salts are those generated from acids that form non-toxic salts, examples of which are hydrochloride, hydrobromide, hydroiodide, chloride, bromide, iodide , Sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate, camsylate, D And L-lactate, D and L-tartrate, esylate, mesylate, malonate, orotate, glucoseptate, methyl sulfate, stearate, glucuronate, 2-naphthylate, Tosylate, hibenzate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate, and pamoate .

  Suitable base salts are those generated from bases that form non-toxic salts, examples of which are sodium, potassium, aluminum, calcium, magnesium, zinc, choline, diolamine, allamine, arginine, glycine , Tromethamine, benzathine, lysine, meglumine, and diethylamine.

  For a review of suitable salts, see Berge et al. Pharm. Sci. 66, 1-19, 1977, and Bigley et al., “Encyclopedia of Pharmaceutical Technology”, Marcel Decker Inc, New York, 1996, 13, 453-497.

  Pharmaceutically acceptable solvates of the compounds of formula (I) include the hydrates thereof.

  The compound of formula (I) may be pharmaceutically acceptable derivatives thereof by modifying any of the functional groups in the compound. Examples of such derivatives are Drugs of Today, Vol. 19, No. 9, 1983, 499-538; Topics in Chemistry, Chapter 31, 306-316; Bundgaard, “Design of Prodrugs”, Elsevier, 1985, Chapter 1 (documents in these disclosures are incorporated herein by reference), esters, carbonates, hemiesters, phosphates, nitro Esters, sulfates, sulfoxides, amides, sulfonamides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals, and ketals are included.

  The present invention includes all isomers of the compounds of formula (I), including all geometrical, tautomeric, and optically isomeric forms, as well as their respective mixtures (eg, racemic mixtures), and pharmaceutically acceptable Including salts, solvates or derivatives thereof.

  Separation of diastereoisomers can be achieved by conventional techniques, such as subjecting a stereoisomer mixture of compounds to fractional crystallization, chromatography, or high performance liquid chromatography (HPLC). Individual enantiomers of a compound can be prepared from the optically pure corresponding intermediate, or prepared by resolution, such as subjecting the corresponding racemate to HPLC using an appropriate chiral carrier, or A salt of a diastereoisomer formed by appropriately reacting a corresponding racemic compound with an appropriate optically active acid or base can be prepared by fractional crystallization.

  Compounds of formula (I), and pharmaceutically acceptable salts, solvates or derivatives thereof have the ability to crystallize into one or more forms, i.e. a property known as polymorphism. All such polymorphic forms ("polymorphs") may be included within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature or pressure, or both, and can also be attributed to varying crystallization processes. Polymorphs can be distinguished by various physical properties, and the x-ray diffraction pattern, solubility behavior, and melting point of a compound are usually used to distinguish polymorphs.

  Compounds of formula (I), pharmaceutically acceptable salts, solvates and derivatives thereof, isomers thereof, and polymorphs thereof are hereinafter referred to as compounds of the invention.

  Preferred compounds of the invention are compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.

Preferably, R ¹ comprises (i) 1 to 2 nitrogen heteroatoms, or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulfur heteroatom, 5 or 6-membered aromatic heterocyclic group, the heterocyclic group, halo, ^{oxo, -CN, -OR 5, -OR 11} , -NR 5 R 5, - (C 1 ~C 6 alkylene) -NR ⁵ R ⁵ , R ⁷ , or R ¹¹ may be substituted.

Preferably, R ¹ is a 5- or 6-membered aromatic heterocycle comprising (i) 1 to 2 nitrogen heteroatoms, or (ii) 1 nitrogen heteroatome and 1 sulfur heteroatom. A heterocyclic group, and the heterocyclic group may be substituted with —OR ¹¹ , —NR ⁵ R ⁵ , R ⁷ , or R ¹¹ .

Preferably, R ¹ is a (5) 6 or 6 membered aromatic heterocyclic group containing (i) 1 to 2 nitrogen heteroatoms, or (ii) 1 nitrogen heteroatom and 1 sulfur heteroatom. There, the heterocyclic _group, C 1 -C ₆ alkyl, phenyl, _phenoxy, C 1 -C ₆ alkoxy phenoxy, or ^-NR 5 ^{R 5} may be substituted with.

Preferably, R ¹ is pyridinyl, pyrimidinyl, pyrazinyl, or thiazolyl, each of C ₁ -C ₂ alkyl, phenyl, C ₁ -C ₂ alkoxyphenoxy, —N (CH ₃ ) ₂ , —N (CH _2). CH ₃ ) ₂ , or N (CH ₃ ) (CH ₂ CH ₃ ) may be substituted.

Preferably, R ² is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, phenyl, benzyl, or R ⁹ , wherein said phenyl, benzyl, or C ₁ -C ₆ alkyl is halo, _{^{-OR 5, -OR 10, -CN,}} -CO 2 R 7, -OCONR 5 R 5, -CONR 5 R 5, -C (= NR 5) NR 5 OR 5, -CONR 5 NR 5 R 5, - ^{NR 6 R 6, -NR 5 R} 10, -NR 5 COR 5, -NR 5 COR 8, -NR 5 COR 10, -NR 5 CO 2 R 5, -NR 5 CONR 5 R 5, -SO 2 NR 5 R ⁵ , —NR ⁵ SO ₂ R ⁵ , R ⁸ , or R ⁹ may be substituted.

Preferably, R ² is C ₁ -C ₆ alkyl, phenyl, or benzyl, and said C ₁ -C ₆ alkyl may be substituted with halo, —OR ⁵ , —OR ¹⁰ , or —CN. .

Preferably, R ² is C ₁ -C ₃ alkyl or benzyl, and said C ₁ -C ₃ alkyl may be substituted by —CN.

Preferably, R ³ is H, C ₁ -C ₆ alkyl, or C ₃ -C ₇ cycloalkyl, wherein said C ₁ -C ₆ alkyl is halo, —CN, —OR ⁵ , —CO ₂ R ⁵ , -CONR ⁵ R ⁵ , -OCONR ⁵ R ⁵ , -NR ⁵ CO ₂ R ⁵ , -NR ⁶ R ⁶ , -NR ⁵ COR ⁵ , -SO ₂ NR ⁵ R ⁵ , -NR ⁵ CONR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , R ⁸ , or R ⁹ may be substituted.

Preferably R ³ is H or C ₁ -C ₆ alkyl.

Preferably R ³ is H or C ₁ -C ₄ alkyl.

Preferably R ³ is methyl or ethyl.

Preferably, R ⁴ may be substituted with R ⁸ , halo, —CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₆ alkoxy. Good phenyl.

Preferably, R ⁴ is phenyl substituted with R ⁸ , halo, —CN, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

Preferably R ⁴ is phenyl substituted with —CN.

Preferably R ⁴ is 3,5-dicyanophenyl.

Preferably, R ⁸ is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, halo, —CN, —COR ⁵ , —CONR ⁵ R ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ SO _{2, respectively.} ^{R 5, -OR 5, -NR 5} R 5, - (C 1 ~C 6 _{^{alkylene) -NR 5 R 5, C 1}} ~C 6 alkyl, fluoro _(C 1 ~C ₆₎ alkyl or _C 3 -C, _It may be substituted with ₇ cycloalkyl.

Preferably, R ⁸ is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, respectively, halo, —CN ^{, -COR 5, -CONR 5 R 5} , -SO 2 NR 5 R 5, -NR 5 SO 2 R 5, -OR 5, -NR 5 R 5, - (C 1 ~C 6 alkylene) ^-NR 5 R ^5, _C 1 -C ₆ alkyl, fluoro _(C 1 ~C ₆₎ alkyl, or _C 3 -C ₇ cycloalkyl with may be substituted.

Preferably, R ⁸ is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, respectively, —OR ⁵ , It may be substituted with —NR ⁵ R ⁵ or C ₁ -C ₆ alkyl.

Preferably, R ⁸ is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, respectively, —OH, — It may be substituted with NH ₂ or methyl.

Preferably, R ⁹ is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl, piperazinyl, or diazepinyl, respectively, oxo, C ₁ -C ₆ alkyl, C ₃ -C _{7 ^{cycloalkyl, -SO 2 R 5, -CONR 5}} R 5, -COOR 5, -CO- (C 1 ~C 6 alkylene) -OR ^5, or may be substituted with -COR ^5, also A carbon atom that is not adjacent to the heteroatom is halo, —OR ⁵ , —NR ⁵ R ⁵ , —NR ⁵ COR ⁵ , —NR ⁵ COOR ⁵ , —NR ⁵ CONR ⁵ R ⁵ , —NR ⁵ SO ₂ R ^5. Or may be substituted with -CN.

Preferably, R ⁹ is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl, or morpholinyl, oxo, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, —SO ₂ R ⁵ , —CONR ⁵ R, respectively. ⁵ , —COOR ⁵ , —CO— (C ₁ -C ₆ alkylene) -OR ⁵ , or —COR ⁵ , and a carbon atom not adjacent to a heteroatom is halo, —OR ⁵ , —NR ⁵ R ⁵ , —NR ⁵ COR ⁵ , —NR ⁵ COOR ⁵ , —NR ⁵ CONR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , or —CN may be substituted.

Preferably, R ⁹ is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl, or morpholinyl, each of C ₁ -C ₆ alkyl, —SO ₂ R ⁵ , —CONR ⁵ R ⁵ , —COOR ⁵ , —CO— ( C ₁ -C ₆ alkylene) —OR ⁵ , or —COR ⁵ may be substituted, and a carbon atom that is not adjacent to a heteroatom may be substituted with —OR ⁵ or —NR ⁵ COR ^5. .

Preferably, R ⁹ is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl, or morpholinyl, and is —CH ₃ , —SO ₂ CH ₃ , —CONH ₂ , —COOCH ₃ , —COCH ₂ OCH ₃ , or —COCH, respectively. _The carbon atom which is not adjacent to the hetero atom may be substituted with —OCH ₃ or —NHCOCH ₃ .

Preferably, R ¹⁰ is C ₁ -C ₄ alkyl substituted with R ⁸ , R ⁹ , —OR ⁵ , —CONR ⁵ R ⁵ , —NR ⁵ COR ⁵ , or —NR ⁵ R ⁵ .

Preferably, R ¹⁰ is C ₁ -C ₄ alkyl substituted with R ⁹ , —OR ⁵ , —NR ⁵ COR ⁵ , or —NR ⁵ R ⁵ .

Preferably, R ¹⁰ is C ₁ -C ₂ alkyl substituted with tetrahydrofuranyl, —OCH ₃ , —NHCOCH ₃ , or —NH ₂ .

Preferably, R ¹¹ is halo, —CN, —COR ⁵ , —CONR ⁵ R ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , —OR ⁵ , —NR ⁵ R ⁵ , — ( C ₁ -C ₆ alkylene) -NR ⁵ R ⁵ , C ₁ -C ₆ alkyl, halo (C ₁ -C ₆ ) alkyl, or phenyl substituted with C ₃ -C ₇ cycloalkyl.

Preferably, R ¹¹ is phenyl substituted with halo, —CN, —CONR ⁵ R ⁵ , —SO ₂ NR ⁵ R ⁵ , or —OR ⁵ .

Preferably R ¹¹ is phenyl substituted with —OR ⁵ .

Preferably R ¹¹ is phenyl substituted with C ₁ -C ₂ alkoxy.

  Preferred compounds according to the invention include all preferred combinations of the individual substituents indicated above.

Preferred compounds of the invention are:
5- [3-ethyl-1-methyl-5- (pyridin-2-yloxy) -1H-pyrazol-4-yloxy] -isophthalonitrile, ie the compound of Example 6, and pharmaceutically acceptable salts thereof, Solvate or derivative.

  The compounds of the present invention may have advantages over the prior art in terms of several useful properties such as potency, duration of action, pharmacokinetics, activity spectrum, side effect profile, solubility, chemical stability, etc. .

  The compounds of the present invention may be prepared by any method known in the art for preparing compounds of similar structure. The compounds of this invention can be prepared by the procedures described in the methods below, by the detailed methods described in the Examples, or by methods analogous to either. The invention also includes any one or more of these methods for preparing the compounds of the invention, as well as any novel intermediates used therein.

In the following methods, R ¹ , R ² , R ³ , and R ⁴ are as defined previously for compounds of formula (I), unless otherwise stated, and R ^a is a lower alkyl group (eg, Alkyl group such as methyl).

  Compounds of formula (I) can be prepared according to Scheme 1.

  According to Scheme 1, a compound of formula (I) can be prepared by reacting a compound of formula (V) with an alcohol of formula (IV) under normal conditions. This reaction is carried out in the presence of a catalyst such as a transition metal catalyst, preferably a palladium catalyst (eg, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride) in a polar aprotic solvent (eg, N, N-dimethylformamide), in the presence of a solvent such as N-dimethylformamide, at an elevated temperature from ambient temperature, such as around 50 ° C., in an inert atmosphere, such as carbon monoxide, and under elevated pressure, such as around 345 kPa. .

  A compound of formula (V) can be prepared from a compound of formula (III) by derivatizing its hydroxy group to a leaving group (Lg). Lg is conveniently a reactive ester group such as a sulfonic acid ester group (eg, trifluoromethanesulfonic acid ester). This reaction involves the presence of a derivatizing agent such as a sulfonic acid amide (eg phenyltriflamide), a base such as a trialkylamine base (eg triethylamine), a solvent such as a halogenated alkane (eg dichloromethane). It is convenient to carry out at a temperature higher than ambient temperature, such as below and ambient temperature.

  A compound of formula (III) can be prepared by reacting a compound of formula (VII) with a hydrazine of formula (VI) or a salt or hydrate thereof. This reaction may be carried out in a solvent such as a protic solvent (eg, acetic acid) at ambient to elevated temperatures, such as ambient temperature, optionally an acid (eg, acetic acid), or a tertiary amine (eg, triethylamine), etc. It is convenient to carry out in the presence of

  A compound of formula (VII) can be prepared by reacting a compound of formula (IX) with an alcohol of formula (VIII). This reaction can be accomplished with a solvent such as a polar solvent (eg, acetone), a base such as an inorganic base, preferably a metal carbonate (eg, potassium carbonate or cesium carbonate), optionally sodium iodide or tetrabutylammonium iodide. Conveniently, it is carried out from ambient to elevated temperatures, such as in the presence of a nuclear catalyst and at elevated temperatures (eg under reflux conditions).

  Chloroketoesters of formula (IX) are commercially available, known in the literature, or can be prepared by conventional methods (eg, chlorination of the corresponding ketoester using, for example, sulfonyl chloride).

  According to Scheme 1, compounds of formula (I) can also be prepared by reacting an alcohol of formula (III) with a compound of formula (II) under normal conditions. This reaction may be carried out using a base such as an inorganic base, preferably a metal carbonate (eg potassium carbonate), optionally a solvent such as a polar aprotic solvent (eg N, N-dimethylacetamide), optionally copper (I). Conveniently, it is carried out in the presence of a catalyst, such as a catalyst, and from ambient to elevated temperatures, such as elevated temperatures (eg reflux conditions).

  Alternatively, a compound of formula (I) can also be prepared from a compound of formula (III) by reaction with an alcohol of formula (IV) under dehydrating conditions, as provided by the Mitsunobu reaction. This reaction is conveniently carried out in the presence of a solvent such as diethyl azodicarboxylate, triphenylphosphine, ether (eg tetrahydrofuran) and at low to ambient temperatures, such as 0 ° C.

The compound of formula (I) wherein R ³ is halo is a compound of formula (X) under normal conditions

から調製することができる。無機酸塩化物（たとえば、ＰＯＣｌ_３）などの無機酸ハロゲン化物、場合によって極性の非プロトン溶媒（たとえば、Ｎ，Ｎ−ジメチルホルムアミド）などの溶媒の存在下、かつ周囲温度などの、低い温度から周囲温度で反応を実施すると好都合である。

Can be prepared from Inorganic acid halides such as inorganic acid chlorides (eg POCl ₃ ), optionally in the presence of solvents such as polar aprotic solvents (eg N, N-dimethylformamide) and from low temperatures such as ambient temperature It is convenient to carry out the reaction at ambient temperature.

  Compounds of formula (X) can be prepared using the routes described above mutatis mutandis.

  One skilled in the art will recognize that compounds of formula (I) can often be converted to other compounds of formula (I), for example, by functional group transformations including, for example, the following interconversions.

Compounds of formula (I) wherein R ² is optionally substituted C ₁ -C ₆ alkyl are prepared from compounds of formula (I) where R ² is H by reaction with an alkylating agent. be able to. Suitable alkylating agents include bromoacetonitrile, ethyl 4-chloroacetoacetate, methyl bromoacetate, and chloroethylamine hydrochloride. Alkylation can be accomplished using an appropriate solvent such as an alcohol (eg ethanol) or a polar aprotic solvent (eg N, N-dimethylformamide), a metal hydride (eg sodium hydride) or a metal alkoxide (eg sodium ethoxy). Conveniently, it is carried out at ambient to elevated temperatures, such as in the presence of a base such as d) and under reflux conditions.

Compounds of formula (I) in which R ² or R ³ contains a hydroxy group can be prepared from the corresponding compounds of formula (I) in which R ² or R ³ contains an ester group by reduction. This reduction is conveniently performed with a metal hydride agent such as lithium aluminum hydride in a solvent such as ether (e.g. diethyl ether) at a low temperature such as -78C to 0C.

Compounds of formula (I) in which R ² or R ³ is substituted with a heterocycle of formula R ⁸ and R ⁹ can be prepared by standard heterocycle formation reactions well known to those skilled in the art (eg , "Advanced Organic Chemistry", 3rd edition, Gerry March, or "Comprehensive Heterocyclic Chemistry", AR Katritzky, C. W. Rees, Vol. ).

Compounds of formula (I) wherein R ³ is —CO ₂ H can be prepared by hydrolysis of the corresponding compound of formula (I) wherein R ³ is —CO ₂ R ⁵ . This reaction is performed in the presence of a solvent such as an alcohol (eg, aqueous ethanol) or ether (eg, 1,4-dioxane aqueous solution) and a base such as a metal hydroxide (eg, sodium hydroxide). This is convenient. One skilled in the art can convert such acids to primary amides by reacting with ammonia and a suitable coupling agent such as carbodiimide, eg, dicyclohexylcarbodiimide, and such primary amides can then be salified. It will be appreciated that dehydration with a suitable dehydrating agent such as phosphoryl can be converted to the nitrile.

Compounds of formula (I) wherein R ³ is C ₁ -C ₆ alkyl can be obtained by halogenation using a suitable halogenating agent, C ₁ -C, wherein R ³ is substituted with halo (such as bromo) Can be converted to compounds of formula (I) which are ₆ alkyls. This reaction is conveniently carried out in the presence of a solvent such as a haloalkane (eg dichloromethane) and at ambient temperature. Suitable halogenating agents include halogen (eg bromine) or N-halosuccinimide (eg N-bromosuccinimide).

Compounds of formula (I) containing —OH, —NH—, or —NH ₂ groups are each represented by —OP ¹ , —NP ¹ —, or —NHP ¹ groups, wherein group P ¹ is a suitable protecting group. Can be prepared by deprotection of the corresponding compounds including: Examples of suitable protecting groups will be apparent to those skilled in the art. For example, Theodora W. Green and Peter G. M.M. See Wuts' “Protecting groups in Organic Synthesis” (2nd edition), 1991, John Wiley and Sons. Compounds containing such —OP ¹ , —NP ¹ —, or —NHP ¹ groups can be prepared using the routes described above, mutatis mutandis.

  Compounds of formula (II), (IV), and (VI) and (VIII) are either commercially available, known in the literature, or well known to those skilled in the art, such as those described in the preparation examples below. Easily prepared by conventional methods.

  Compounds of formula (III), (V), or (X) are important intermediates and are another aspect of the present invention.

  The compounds of the invention can be administered alone, but generally are mixed with a suitable pharmaceutical excipient, diluent or carrier selected in accordance with the intended route of administration and standard pharmaceutical practice. Will be administered.

  For example, the compounds of the present invention may contain flavoring or coloring agents, tablets, capsules, multiparticulates for immediate release, delayed release, modified release, sustained release, pulsed release, or controlled release applications (Multi-particulates), gels, films, ovules, elixirs, solutions, or suspensions can be administered orally, buccal, or sublingually. The compounds of the present invention can also be administered as a rapidly dispersing or rapidly dissolving dosage form, or in the form of a high energy dispersion or as coated particles. Appropriate formulations of the compounds of the invention may be in coated or uncoated form, as appropriate.

  Such solid pharmaceutical compositions, such as tablets, are supplemented with microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, glycine, starch (preferably corn, potato or tapioca starch). Disintegrants such as form, sodium starch glycolate, croscarmellose sodium, certain complex silicates, and polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia The granulating binder may be contained. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included.

General Examples Tablet formulations should normally contain from 0.01 mg to 500 mg of active compound, and tablet fill weights may range from 50 mg to 1000 mg. The formulation example of a 10 mg tablet is illustrated below.

Ingredient% w / w
Compounds of the invention 10.000 ^*
Lactose 64.125
Starch 21.375
Croscarmellose sodium 3.000
Magnesium stearate 1.500
^* Amount adjusted according to drug activity

  Tablets are made by standard methods, such as direct compression or wet or dry granulation. The tablet core may be coated with a suitable topcoat.

  Similar types of solid compositions may be used in gelatin or HPMC capsules as fillers. Preferred fillers in this regard include lactose, starch, cellulose, lactose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the compounds of the invention may be combined with various sweetening, flavoring, coloring or coloring agents, emulsifiers and / or suspending agents, water, ethanol, propylene glycol and glycerin. Can be combined with diluents such as, as well as mixtures thereof.

  The compounds of the invention are administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraureterally, intrasternally, intracranial, intramuscularly, or subcutaneously. It can also be administered by infusion or needleless injection techniques. For such parenteral administration, the compounds of the invention are most often used in the form of a sterile aqueous solution, which is a salt or glucose sufficient to render other substances, eg, the solution, isotonic with blood. May be contained. The aqueous solution should be appropriately buffered if necessary (preferably at pH 3-9). Suitable parenteral formulations are readily formulated under aseptic conditions by standard pharmaceutical techniques well known to those skilled in the art.

  For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention is usually from 0.01 to 30 mg / kg, preferably from 0.01 to 5 mg / kg (in one or more doses). kg.

  That is, a tablet or capsule of a compound of the invention may optionally contain from 1 to 500 mg of active compound for administration in one or more at a time. In any event, the physician will determine the actual dosage that will best suit any individual patient, and that dosage will vary depending on the age, weight, and response of the particular patient. The above dosage is an example of an average case. Of course, in individual cases, higher or lower dosage ranges may be justified and such dosages are within the scope of the present invention. One skilled in the art will appreciate that for the treatment of certain conditions, the compounds of the invention may be taken as a single dose, as needed or desired.

  The compounds of the invention can also be administered intranasally or by inhalation and can be sprayed, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane (HFA). 134A [TM]), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [TM]), carbon dioxide, or other suitable gas, or Conveniently delivered from a pressurized container, pump, spray, atomizer or nebulizer in the form of a dry powder inhaler or aerosol spray without use. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Pressurized containers, pumps, sprays, atomizers, or nebulizers may contain solutions or suspensions of the active compound, for example using a mixture of ethanol and propellant as a solvent, and lubricants such as triolein It may further contain acid sorbitan. Capsules and cartridges (eg, made of gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

  Alternatively, the compounds of the invention can be administered in the form of suppositories or pessaries, or topically applied in the form of a gel, hydrogel, lotion, solution, cream, ointment, or powder. The compounds of the invention may be administered dermally or transdermally using, for example, a skin patch. It may also be administered by the pulmonary or rectal route.

  The compounds of the present invention may be administered by the eye route. For eye use, the compound may be in the form of a fine suspension in isotonic sterile saline, pH adjusted, or preferably as a solution of isotonic sterile saline, pH adjusted. Can be formulated in combination with a preservative such as benzylalkonium chloride. Alternatively, it may be formulated in an ointment such as petrolatum.

  For topical application to the skin, the compounds of the present invention can be one or more of, for example, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene hybrid, emulsifying wax, and water. And can be formulated as a suitable ointment containing the active compound suspended or dissolved in a mixture. Or, for example, suspended in a mixture of one or more of mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, stearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. It may be formulated as a suitable turbid or dissolved lotion or cream.

  The compounds of the present invention may be used in combination with cyclodextrins. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Once the drug-cyclodextrin complex is formed, the solubility, dissolution rate, bioavailability, and / or stability of the drug molecule may be altered. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. In addition to direct complexation with the drug, cyclodextrins may be used as auxiliary additives, such as carriers, diluents, or solubilizers. α, β, and γ cyclodextrins are most commonly used and suitable examples are described in WO91 / 11172, WO94 / 02518, and WO98 / 55148.

  As used herein, all references to treatment are intended to include curative, symptomatic, and prophylactic treatment.

  Oral administration is preferred.

  Included within the scope of the present invention are embodiments comprising the co-administration of a compound of the present invention and one or more additional therapeutic agents, as well as containing one or more additional therapeutic agents with the compounds of the present invention. Composition. Such combination therapy is particularly useful for the prevention and / or treatment of infection with HIV and related retroviruses that can rapidly evolve into strains that are resistant to any single agent therapy. Alternatively, additional therapeutic agents may be desirable for the treatment of diseases and conditions that occur as a result of or associated with the disease being treated with the compounds of the present invention. For example, treatment of HIV or similar retroviral infections may be desirable for additional treatment of opportunistic infections, neoplasms, and other conditions that occur as a result of the immunocompromised state of the patient being treated.

Preferred combinations of the invention include a compound of the invention and one or more of the following:
(A) reverse transcriptase inhibitors such as abacavir, adefovir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine,
(B) non-nucleoside reverse transcriptase inhibitors such as capavirine, delavirdine, efavirenz, nevirapine,
(C) HIV protease inhibitors such as indinivir, nelfinavir, ritonavir, saquinavir,
(D) CCR5 antagonists such as TAK-779 and UK-427,857,
(E) a CXCR4 antagonist such as AMD-3100,
(F) integrase inhibitors such as L-870, 810 and S-1360,
(G) a viral fusion inhibitor such as T-20,
(H) Trizivir, KNI-272, Amprenavir, GW-33908, FTC, PMPA, MKC-442, MSC-204, MSH-372, DMP450, PNU-140690, ABT-378, KNI-764, DPC-083 , Investigational drugs such as TMC-120, TMC-125,
Concurrent or sequential treatment with (i) an antifungal agent such as fluconazole, itraconazole, voriconazole or (j) an antibacterial agent such as azithromycin is included.

  The activity of the compounds of the present invention as a reverse transcriptase inhibitor can be measured using the following assay.

[Inhibition of HIV-1 reverse transcriptase]
Using purified recombinant HIV-1 reverse transcriptase (RT, enzyme no. 2.7.7.49) obtained by expression in E. coli, a 96 well plate assay system was established and Poly (rA) -oligo (DT) Reverse Transscriptase [3H] -SPA enzyme assay system (Amersham NK9020) or [3H] -Flash plate enzyme assay system (NEN-SMP103) is used according to the manufacturer's recommendations to assay large numbers of samples . The compound is dissolved in 100% DMSO and diluted with an appropriate buffer to give a final DMSO concentration of 5%. Inhibitory activity is expressed as a percentage of inhibition relative to the DMSO control. The concentration at which the compound inhibits reverse transcriptase by 50% is indicated as the IC ₅₀ of the compound.

The compounds of Examples 1 and 6 had IC ₅₀ values of 5400 nmol and 391 nmol, respectively, when tested according to the above procedure.

Therefore, the present invention
(I) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof,
(Ii) a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof;
(Iii) a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier together with a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof,
(Iv) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof for use as a medicament;
(V) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof for use as an inhibitor or modulator of reverse transcriptase;
(Vi) a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of infection with HIV or genetically related retroviruses or the resulting acquired immune deficiency syndrome (AIDS) A salt, solvate or composition,
(Vii) use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or composition thereof for the manufacture of a medicament having inhibitory activity of reverse transcriptase inhibition or modulating activity;
(Viii) a compound of formula (I) or pharmaceutically for the manufacture of a medicament for the treatment of infection with HIV or genetically related retroviruses or the consequent acquired immune deficiency syndrome (AIDS) The use of an acceptable salt, solvate or composition thereof,
(Ix) a method for the treatment of infection with HIV or genetically related retroviruses or the consequent acquired immune deficiency syndrome (AIDS) comprising a compound of formula (I) or a pharmaceutically acceptable Methods comprising administering a therapeutically effective amount of a salt, solvate, or composition, as well as (xi) certain novel intermediates disclosed herein are provided.

  The following examples illustrate the preparation of compounds of formula (I). The synthesis of certain intermediates used therein is described in the preparation section following the examples.

¹ H nuclear magnetic resonance (NMR) spectra were consistent with the intended structure in all cases. The characteristic chemical shift (δ) is a customary abbreviation that indicates the main peak, eg s, ie singlet, d, ie doublet, t, ie triplet, q, ie quadruple, m, ie Using a multiple line, br, that is, broad, it is shown in parts per million on the low magnetic field side from tetramethylsilane. The following abbreviations are: HRMS: high resolution mass spectrometry, hplc: high performance liquid chromatography, nOe: nuclear overhauser effect, m. p. : Melting point, CDCl ₃ : Deuterated chloroform, D ₆ -DMSO: Deuterium dimethyl sulfoxide, CD ₃ OD: Deuterium methanol. When thin layer chromatography (TLC) is used, it refers to silica gel TLC using silica gel 60F ₂₅₄ plates, where R _f is the distance traveled by the compound divided by the distance traveled by the solvent facing the TLC plate. It is.

Example 1
5- [3-Ethyl-1-methyl-5- (pyridin-2-yloxy) -1H-pyrazol-4-yloxy] -isophthalonitrile

調製例５のピラゾール（１０ｍｇ、０．３７ミリモル）と２−クロロピリジン（５５ｍｇ、０．４９ミリモル）とを混合し、１．５時間１４５℃に加熱した。混合物を室温に冷却し、酢酸エチル（１０ｍｌ）と水（１０ｍｌ）とに分配した。水溶液を酢酸エチル（２×１０ｍｌ）で抽出した。有機溶液を合わせて減圧下で蒸発させ、残渣をメタノール含有ジクロロメタン（１：９９）を使用するシリカゲルのクロマトグラフィーによって精製して、標題化合物を黄色の固体（３０ｍｇ）として得た。
^１Ｈ ＮＭＲ（４００ ＭＨｚ，ＣＤ_３ＯＤ）：δ １．１８（ｍ，３Ｈ），２．４９（ｍ，２Ｈ），３．６０（ｓ，３Ｈ），７．００（ｍ，１Ｈ），７．１５（ｍ，１Ｈ），７．６（ｓ，２Ｈ），７．７２（ｍ，１Ｈ），７．８０（ｍ，１Ｈ），８．１２（ｍ，１Ｈ）．
ＬＲＭＳ（ＡＰＣＩ）：ｍ／ｚ［Ｍ＋Ｈ］^＋ ３４６

The pyrazole of Preparation Example 5 (10 mg, 0.37 mmol) and 2-chloropyridine (55 mg, 0.49 mmol) were mixed and heated to 145 ° C. for 1.5 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous solution was extracted with ethyl acetate (2 × 10 ml). The organic solutions were combined and evaporated under reduced pressure and the residue was purified by chromatography on silica gel using dichloromethane (1:99) in methanol to give the title compound as a yellow solid (30 mg).
¹ H NMR (400 MHz, CD ₃ OD): δ 1.18 (m, 3H), 2.49 (m, 2H), 3.60 (s, 3H), 7.00 (m, 1H), 7 .15 (m, 1H), 7.6 (s, 2H), 7.72 (m, 1H), 7.80 (m, 1H), 8.12 (m, 1H).
LRMS (APCI): m / z [M + H] ⁺ 346

(Examples 2 to 10)
The following general formula

の表１の各化合物は、対応するピラゾールおよびハロゲン化アリールを使用して、実施例
１と類似の方法によって調製した。

Each of the compounds in Table 1 was prepared by a method analogous to Example 1 using the corresponding pyrazole and aryl halide.

(Example 2)
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.10 (m, 3H), 2.40 (m, 2H), 3.6 (s, 3H), 7.38 (m, 1H), 7.8 (s, 2H), 8.05 (s, 1H), 8.62 (m, 2H).
LRMS (APCI): m / z [M + H] ⁺ 347

(Example 3)
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.26 (m, 6H), 2.48 (m, 2H), 2.64 (m, 2H), 3.70 (s, 3H), 7. 50 (m, 3H), 8.38 (m, 2H)
LRMS (APCI): m / z [M + H] ⁺ 375.

Example 4
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (m, 3H), 2.48 (m, 2H), 3.75 (s, 3H), 7.50 (m, 8H), 8. 70 (m, 2H).
LRMS (APCI): m / z [M + H] ⁺ 423

(Example 5)
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (m, 3H), 2.49 (m, 2H), 3.15 (m, 6H), 3.70 (s, 3H), 6. 23 (m, 1H), 7.45 (m, 2H), 8.00 (m, 2H).
LRMS (APCI): m / z [M + H] ⁺ 390

(Example 6)
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (m, 3H), 2.48 (m, 2H), 3.82 (s, 3H), 3.85 (s, 3H), 6. 95 (m, 4H), 7.42 (s, 2H), 7.52 (s, 1H), 8.20 (s, 2H).
LRMS (APCI): m / z [M + H] ⁺ 469

(Example 7)
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (m, 3H), 2.48 (m, 2H), 3.70 (s, 3H), 7.42 (s, 2H), 7. 50 (s, 1H), 8.00 (s, 1H), 8.38 (s, 1H), 8.42 (s, 1H).
LRMS (APCI): m / z [M + H] ⁺ 347

(Example 8)
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (m, 3H), 2.48 (m, 2H), 3.80 (s, 3H), 6.80 (m, 1H), 7. 10 (m, 1H), 7.42 (s, 2H), 7.50 (s, 1H).
LRMS (APCI): m / z [M + H] ⁺ 352

Example 9
¹ H NMR (400 MHz, DMSO 0-d ₆ ): δ 1.10 (m, 3H), 2.47 (m, 2H), 3.0 (m, 2H), 4.20 (m, 2H), 7.38 (m, 1H), 7.5 (s, 2H), 8.05 (s, 1H), 8.60 (m, 2H).
LRMS (APCI): m / z [M + H] ⁺ 386

(Example 10)
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (m, 3H), 2.54 (m, 2H), 5.2 (s, 2H), 7.00 (m, 1H), 7. 15-7.25 (m, 5H), 7.5 (s, 3H), 8.4 (m, 2H).
LRMS (APCI): m / z [M + H] ⁺ 423

(Example 11)
5- [3-Ethyl-1- (2-hydroxy-ethyl) -5- (pyridin-2-yloxy) -1H-pyrazol-4-yloxy] -isophthalonitrile

調製例１０のシリルエーテル（３２ｍｇ、０．０７ミリモル）のテトラヒドロフラン（３ｍｌ）溶液にフッ化テトラブチルアンモニウム（テトラヒドロフラン中１Ｍ、７２μｌ、０．０７ミリモル）を加え、混合物を１．５時間攪拌した。追加の量のフッ化テトラブチルアンモニウム（テトラヒドロフラン中１Ｍ、３３μｌ、０．０３ミリモル）を加え、混合物をさらに４５分間攪拌した。ブラインおよびジクロロメタンを加え、層を分離した。有機層を硫酸マグネシウムで乾燥させ、減圧下で蒸発させた。残渣をメタノール含有ジクロロメタン（２：９８〜３．５：９６．５の勾配）を使用するシリカゲルのクロマトグラフィーによって精製して、標題化合物を黄色の油（２１ｍｇ）として得た。
^１Ｈ ＮＭＲ（４００ ＭＨｚ，ＣＤＣｌ_３）：δ １．１８（ｍ，３Ｈ），２．４９（ｍ，２Ｈ），４．０７（ｍ，４Ｈ），６．９０（ｍ，１Ｈ），７．１０（ｍ，１Ｈ），７．４５（ｍ，３Ｈ），７．６０（ｍ，１Ｈ），８．１０（ｍ，１Ｈ）．
ＬＲＭＳ（ＡＰＣＩ）：ｍ／ｚ［Ｍ＋Ｈ］^＋ ３７６．

To a solution of the silyl ether of Preparation Example 10 (32 mg, 0.07 mmol) in tetrahydrofuran (3 ml) was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 72 μl, 0.07 mmol) and the mixture was stirred for 1.5 hours. An additional amount of tetrabutylammonium fluoride (1M in tetrahydrofuran, 33 μl, 0.03 mmol) was added and the mixture was stirred for an additional 45 minutes. Brine and dichloromethane were added and the layers were separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol-containing dichloromethane (2:98 to 3.5: 96.5 gradient) to give the title compound as a yellow oil (21 mg).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.18 (m, 3H), 2.49 (m, 2H), 4.07 (m, 4H), 6.90 (m, 1H), 7. 10 (m, 1H), 7.45 (m, 3H), 7.60 (m, 1H), 8.10 (m, 1H).
LRMS (APCI): m / z [M + H] ⁺ 376.

(Preparation Example 1)
1,3-dibromo-5-methoxybenzene

３，５−ジブロモフルオロベンゼン（５．００ｇ、１９．０ミリモル、Ａｌｄｒｉｃｈ）をＮ，Ｎ−ジメチルホルムアミド（９５ｍｌ）に溶かした攪拌溶液に、窒素雰囲気中にて０℃でナトリウムメトキシド（メタノール中４．５Ｍ溶液、８．８０ｍｌ、４１．０ミリモル）を滴下した。反応液を室温に温め、１時間攪拌し、次いで減圧下で蒸発させた。残渣をジエチルエーテルに溶解させ、水（３×３００ｍｌ）およびブライン（３００ｍｌ）で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、減圧下で濃縮して、標題化合物を白色の固体（５．１３ｇ）として得た。
^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ ３．７９（ｓ，３Ｈ），７．００（ｓ，２Ｈ），７．２６（ｓ，１Ｈ）．
ＬＲＭＳ：ｍ／ｚ ＴＳ＋ ２６６［Ｍ＋Ｈ］ ^＋

To a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol, Aldrich) in N, N-dimethylformamide (95 ml) was added sodium methoxide (in methanol) at 0 ° C. in a nitrogen atmosphere. 4.5M solution, 8.80 ml, 41.0 mmol) was added dropwise. The reaction was warmed to room temperature, stirred for 1 hour and then evaporated under reduced pressure. The residue was dissolved in diethyl ether, washed with water (3 × 300 ml) and brine (300 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (5.13 g) Got as.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, 1H).
LRMS: m / z TS + 266 [M + H] ⁺

(Preparation Example 2)
3,5-dicyanomethoxybenzene

調製例１の臭化物（３８．０ｇ、１４３ミリモル）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（９．３ｇ、１６．８ミリモル）、およびシアン化亜鉛（２０．０ｇ、１７２ミリモル）をＮ，Ｎ−ジメチルホルムアミド（３００ｍｌ）に溶かした攪拌溶液に、窒素雰囲気中にて室温でトリス（ジベンジリデンアセトン）ジパラジウム（０）（６．５３ｇ、７．１５ミリモル）を一度に加えた。反応液を１００℃で１４時間加熱し、室温に冷却した。水（１５００ｍｌ）を加え、混合物を酢酸エチル（３×５００ｍｌ）での抽出にかけた。有機物を合わせて濾過し、濾液を水（５００ｍｌ）で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、減圧下で濃縮した。得られる固体をトルエン（１０００ｍｌ）で摩砕して、標題化合物（１８．０ｇ）を黄褐色の固体として得た。
^１Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）：δ＝３．８３（３Ｈ，ｓ），７．３１（２Ｈ，ｓ），７．４８（１Ｈ，ｓ）．

The bromide of Preparation 1 (38.0 g, 143 mmol), 1,1′-bis (diphenylphosphino) ferrocene (9.3 g, 16.8 mmol), and zinc cyanide (20.0 g, 172 mmol). To a stirred solution dissolved in N, N-dimethylformamide (300 ml), tris (dibenzylideneacetone) dipalladium (0) (6.53 g, 7.15 mmol) was added in one portion at room temperature in a nitrogen atmosphere. The reaction was heated at 100 ° C. for 14 hours and cooled to room temperature. Water (1500 ml) was added and the mixture was extracted with ethyl acetate (3 × 500 ml). The organics were combined and filtered, and the filtrate was washed with water (500 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene (1000 ml) to give the title compound (18.0 g) as a tan solid.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 3.83 (3H, s), 7.31 (2H, s), 7.48 (1H, s).

(Preparation Example 3)
3,5-dicyanohydroxybenzene

三塩化アルミニウム（３２．４ｇ、２４３ミリモル）をジクロロメタン（２５０ｍｌ）に懸濁させた攪拌懸濁液に、窒素雰囲気中にて０℃で調製例２のエーテル（９．６０ｇ、６０．７ミリモル）を少量ずつ加えた。懸濁液を４５℃で６日間攪拌し、次いで室温に冷却し、氷上に注いだ（４５０ｍｌ）。濃塩酸（４５０ｍｌ）を滴下し、得られた懸濁液を室温で１０分間攪拌した。生成した固体を濾過によって単離し、水で洗浄し、五酸化リンで乾燥させて、標題化合物を黄褐色の固体（７．８３ｇ）として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ ７．３６（ｍ，２Ｈ），７．５６（ｍ，１Ｈ）．

To a stirred suspension of aluminum trichloride (32.4 g, 243 mmol) in dichloromethane (250 ml) was added the ether of Preparation 2 (9.60 g, 60.7 mmol) at 0 ° C. in a nitrogen atmosphere. Was added in small portions. The suspension was stirred at 45 ° C. for 6 days, then cooled to room temperature and poured onto ice (450 ml). Concentrated hydrochloric acid (450 ml) was added dropwise and the resulting suspension was stirred at room temperature for 10 minutes. The resulting solid was isolated by filtration, washed with water and dried over phosphorous pentoxide to give the title compound as a tan solid (7.83 g).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.36 (m, 2H), 7.56 (m, 1H).

(Preparation Example 4)
2- (3,5-Dicyano-phenoxy) -3-oxo-pentanoic acid methyl ester

２−クロロ−３−オキソ−ペンタン酸メチルエステル（２０ｇ、１２１．５ミリモル）のアセトン（１００ｍｌ）溶液を、窒素雰囲気中で、アセトン（４００ｍｌ）中の調製例３のフェノール（１７．５ｇ、１２１．５ミリモル）および炭酸セシウム（４３．５ｇ、１３３．６ミリモル）に加えた。混合物を室温で１５分間攪拌し、次いで２．５時間加熱還流した。水を加え、溶媒を減圧下で蒸発させた。残りの水溶液をジクロロメタン（３×３００ｍｌ）での抽出にかけ、有機層を合わせて硫酸マグネシウムで乾燥させ、減圧下で蒸発させた。残りの橙色の油を予めシリカゲルに吸着させ、次いで酢酸エチル含有ペンタン（２０：８０〜８０：２０の勾配）を使用するシリカゲルのクロマトグラフィーによって精製して、標題化合物を黄色の固体（２７ｇ）として得た。
Ｍ．ｐ．９３−９５℃
実測値；Ｃ，６１．５７；Ｈ，４．５４；Ｎ，１０．０６；Ｃ_１４Ｈ_１２Ｎ_２Ｏ_４計算値Ｃ，６１．７６；Ｈ，４．４４；Ｎ，１０．２９％．

A solution of 2-chloro-3-oxo-pentanoic acid methyl ester (20 g, 121.5 mmol) in acetone (100 ml) was stirred in a nitrogen atmosphere with the phenol of Preparation 3 (17.5 g, 121 ml) in acetone (400 ml). .5 mmol) and cesium carbonate (43.5 g, 133.6 mmol). The mixture was stirred at room temperature for 15 minutes and then heated to reflux for 2.5 hours. Water was added and the solvent was evaporated under reduced pressure. The remaining aqueous solution was extracted with dichloromethane (3 × 300 ml) and the organic layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The remaining orange oil was pre-adsorbed onto silica gel and then purified by chromatography on silica gel using pentane containing ethyl acetate (20:80 to 80:20 gradient) to afford the title compound as a yellow solid (27 g) Obtained.
M.M. p. 93-95 ° C
Found; C, 61.57; H, 4.54 ; N, 10.06; C 14 H 12 N 2 O 4 Calculated C, 61.76; H, 4.44; N, 10.29%.

(Preparation Example 5)
5- (3-Ethyl-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yloxy) -isophthalonitrile

調製例４のエステル（４ｇ、１４．７ミリモル）を酢酸（５０ｍｌ）に溶解させ、メチルヒドラジン（０．８７ｍｌ、１６．２ミリモル）を加えた。混合物を窒素雰囲気中にて室温で３時間攪拌し、溶媒を減圧下で蒸発させた。残渣をジエチルエーテルで摩砕して、標題化合物をピンク色の固体（２．７５ｇ）として得た。
Ｍ．ｐ．２３５−ｄｅｃ
ＬＲＭＳ：ｍ／ｚ ＥＳ＋ ２６９［Ｍ＋Ｈ］ ^＋

The ester of Preparation 4 (4 g, 14.7 mmol) was dissolved in acetic acid (50 ml) and methylhydrazine (0.87 ml, 16.2 mmol) was added. The mixture was stirred at room temperature for 3 hours in a nitrogen atmosphere and the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether to give the title compound as a pink solid (2.75 g).
M.M. p. 235-dec
LRMS: m / z ES + 269 [M + H] ⁺

(Preparation Example 6)
5- [1- (2-Cyano-ethyl) -3-ethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yloxy] -isophthalonitrile

標題化合物は、調製例４のエステルと３−ヒドラジノ−プロピオニトリルとから、調製例５に記載のものと類似の手順に従って５７％の収率で得た。
Ｍ．ｐ．２０３．５−２０４．５℃
ＡＰＣＩ ＭＳ ｍ／ｚ ３０８［Ｍ＋Ｈ］^＋

The title compound was obtained in 57% yield from the ester of Preparation 4 and 3-hydrazino-propionitrile according to a procedure similar to that described in Preparation 5.
M.M. p. 203.5-204.5 ° C
APCI MS m / z 308 [M + H] ⁺

(Preparation Example 7)
5- [3-Ethyl-1- (2-hydroxy-ethyl) -5-oxo-4,5-dihydro-1H-pyrazol-4-yloxy] -isophthalonitrile

標題化合物は、調製例４のエステルと２−ヒドラジノ−エタノールとから、調製例５に記載のものと類似の手順に従って７３％の収率で得た。
Ｍ．ｐ．２０３．５−２０４．５℃
ＡＰＣＩ ＭＳ ｍ／ｚ ２９７［Ｍ−Ｈ］⁻

The title compound was obtained in 73% yield from the ester of Preparation 4 and 2-hydrazino-ethanol following a procedure similar to that described in Preparation 5.
M.M. p. 203.5-204.5 ° C
APCI MS m / z 297 [M−H] ⁻

(Preparation Example 8)
5- (1-Benzyl-3-ethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yloxy) -isophthalonitrile

標題化合物は、調製例４のエステルとベンジルヒドラジンとから、調製例５に記載のものと類似の手順に従って５２％の収率で得た。
ＡＰＣＩ ＭＳ ｍ／ｚ ３４５［Ｍ＋Ｈ］^＋

The title compound was obtained in 52% yield from the ester of Preparation 4 and benzylhydrazine according to a procedure similar to that described in Preparation 5.
APCI MS m / z 345 [M + H] ⁺

(Preparation Example 9)
5- {1- [2- (t-Butyl-dimethyl-silanyloxy) -ethyl] -3-ethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yloxy} -isophthalonitrile

Ｎ，Ｎ−ジメチルホルムアミド（２０ｍｌ）およびトリエチルアミン（５．６ｍｌ、４０．３ミリモル）中の調製例７のアルコール（４．０ｇ、１３．４ミリモル）の溶液に、塩化ｔ−ブチル−ジメチル−シリル（２．４ｇ、１６．１ミリモル）を加えた。混合物を窒素雰囲気中にて室温で３時間撹拌し、次いで酢酸エチルと水とに分配した。有機層をブライン（２×１００ｍｌ）で洗浄し、硫酸マグネシウムで乾燥させ、減圧下で蒸発させた。残渣をジクロロメタンを溶離液として使用するシリカゲルのクロマトグラフィーによって精製して、標題化合物（３．６ｇ）を得た。
Ｍ．ｐ．２０３．５−２０４．５℃
ＡＰＣＩ ＭＳ ｍ／ｚ ４１３［Ｍ＋Ｈ］^＋

To a solution of the alcohol of Preparation 7 (4.0 g, 13.4 mmol) in N, N-dimethylformamide (20 ml) and triethylamine (5.6 ml, 40.3 mmol) was added t-butyl-dimethyl-silyl chloride. (2.4 g, 16.1 mmol) was added. The mixture was stirred at room temperature for 3 hours in a nitrogen atmosphere and then partitioned between ethyl acetate and water. The organic layer was washed with brine (2 × 100 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane as eluent to give the title compound (3.6 g).
M.M. p. 203.5-204.5 ° C
APCI MS m / z 413 [M + H] ⁺

(Preparation Example 10)
5- [1- [2- (t-Butyl-dimethyl-silanyloxy) -ethyl] -3-ethyl-5- (pyridin-2-yloxy) -1H-pyrazol-4-yloxy] -isophthalonitrile

調製例９のピラゾール（１５０ｍｇ、０．３６ミリモル）と２−クロロピリジン（５４ｍｇ、０．４７ミリモル）の混合物を２時間１５０℃に加熱し、次いで酢酸エチルと水とに分配した。有機層を減圧下で蒸発にかけ、残渣をメタノール含有ジクロロメタンを溶離液として使用する（２：９８）シリカゲルのクロマトグラフィーによって精製して、標題化合物（３２ｍｇ）を得た。
ＬＣＭＳ：ｍ／ｚ ＥＳ^＋ ５１２［Ｍ＋Ｎａ］^＋

A mixture of the pyrazole (150 mg, 0.36 mmol) of Preparation 9 and 2-chloropyridine (54 mg, 0.47 mmol) was heated to 150 ° C. for 2 hours and then partitioned between ethyl acetate and water. The organic layer was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using methanol-containing dichloromethane as the eluent (2:98) to give the title compound (32 mg).
LCMS: m / z ES ⁺ 512 [M + Na] ⁺

Claims (11)

Compound of formula (I)

Or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein
R ¹ is (i) 1 to 4 nitrogen heteroatoms, or (ii) 1 or 2 nitrogen heteroatoms and 1 oxygen or 1 sulfur heteroatom, or (iii) 1 or containing two oxygen or sulfur heteroatoms, or an aromatic heterocyclic group having 5-membered or 6-membered, the heterocyclic group, halo, oxo, ^-CN, -COR 5, -CONR ⁵ R ^5, - _{^{SO 2 NR 5 R 5, -NR}} 5 SO 2 R 5, -OR 5, oR 11, -NR 5 R 5, - at _(C 1 -C ₆ ^alkylene) -NR ^{5 R 5,} R ⁷ or ^{R 11,} May be replaced,
R ² is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl, phenyl, benzyl, R ⁸ , Or R ⁹ and the aforementioned C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and benzyl are halo, —OR ⁵ , —OR ¹⁰ , —CN, —CO ₂ R ⁷ , —OCONR ^{5 R 5, -CONR 5 R 5} , -C (= NR 5) NR 5 OR 5, -CONR 5 NR 5 R 5, -NR 6 R 6, -NR 5 R 10, -NR 5 COR 5, -NR ⁵ COR ⁸ , —NR ⁵ COR ¹⁰ , —NR ⁵ CO ₂ R ⁵ , —NR ⁵ CONR ⁵ R ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , —NR ⁵ SO ₂ NR ⁵ R ⁵ , R ⁸ Or optionally substituted with R ⁹ ,
R ³ is H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, benzyl, halo, —CN, —OR ⁷ , —CO ₂ R ⁵ , —CONR ⁵ R ⁵ , R ⁸ , or R ⁹ and the aforementioned C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, and benzyl are halo, —CN, —OR ⁵ , —CO ₂ R ⁵ , —CONR ⁵ R ⁵ , — OCONR ⁵ R ⁵ , —NR ⁵ CO ₂ R ⁵ , —NR ⁶ R ⁶ , —NR ⁵ COR ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ CONR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , R ⁸ or R ⁹ may be substituted,
R ⁴ is phenyl, naphthyl, or pyridyl and is R ⁸ , halo, —CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C _{6, respectively.} ^{alkoxy, -CONR 5 R 5, oR 11} , So x R 6, O- (C 1 ~C 6 _{^{alkylene) -CONR 5 R 5, O- (}} C 1 ~C 6 alkylene) ^-NR 5 ^{R 5} or O, - _(C 1 ~C ₆ alkylene) may be substituted with -OR ^6,
Each R ⁵ is independently H, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl, or when two R ⁵ groups are attached to the same nitrogen atom, These two groups, together with their binding nitrogen atom, represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, or morpholinyl and are azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl , homopiperazinyl, and morpholinyl _may be optionally substituted with C 1 -C ₆ alkyl or _C 3 -C ₇ cycloalkyl,
Each R ⁶ is independently either H, C ₁ -C ₆ alkyl, or C ₃ -C ₇ cycloalkyl;
R ⁷ is C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl,
R ⁸ is (i) 1 to 4 nitrogen heteroatoms, or (ii) 1 or 2 nitrogen heteroatoms and 1 oxygen or 1 sulfur heteroatom, or (iii) 1 or containing two oxygen or sulfur heteroatoms, a 5-membered or 6-membered aromatic heterocyclic group, the heterocyclic group, halo, oxo, ^-CN, -COR 5, -CONR ⁵ R ^5, -SO _{^{2 NR 5 R 5, -NR 5}} SO 2 R 5, -OR 5, -NR 5 R 5, - (C 1 ~C 6 _{^{alkylene) -NR 5 R 5, C 1}} ~C 6 alkyl, fluoro _{(C 1} -C ₆₎ alkyl, or _C 3 -C ₇ cycloalkyl being optionally substituted with,
R ⁹ is (i) 1 or 2 nitrogen heteroatoms, or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulfur heteroatom, or (iii) 1 oxygen or containing sulfur heteroatoms, a 4-7 membered heterocyclic ring saturated or partially unsaturated, said heterocyclic group, _oxo, C 1 -C _{6 alkyl,} C 3 -C ₇ cycloalkyl, -SO Carbon that may be substituted with ₂ R ⁵ , —CONR ⁵ R ⁵ , —COOR ⁵ , —CO— (C ₁ -C ₆ alkylene) -OR ⁵ , or —COR ⁵ , and not adjacent to a heteroatom The atom is substituted with halo, —OR ⁵ , —NR ⁵ R ⁵ , —NR ⁵ COR ⁵ , —NR ⁵ COOR ⁵ , —NR ⁵ CONR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , or —CN. You can,
R ¹⁰ is C ₁ -C ₆ alkyl substituted with R ⁸ , R ⁹ , —OR ⁵ , —CONR ⁵ R ⁵ , —NR ⁵ COR ⁵ , or —NR ⁵ R ⁵ ;
R ¹¹ is halo, —CN, —COR ⁵ , —CONR ⁵ R ⁵ , —SO ₂ NR ⁵ R ⁵ , —NR ⁵ SO ₂ R ⁵ , —OR ⁵ , —NR ⁵ R ⁵ , — (C ₁ to C ₆ alkylene) -NR ⁵ R ⁵ , C ₁ -C ₆ alkyl, halo (C ₁ -C ₆ ) alkyl, or phenyl optionally substituted with C ₃ -C ₇ cycloalkyl,
x is 0, 1, or 2.]   A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.   3. A pharmaceutical composition according to claim 2 comprising one or more additional therapeutic agents.   4. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, or a pharmaceutical composition according to claim 2 or 3 for use as a medicament.   4. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, or a pharmaceutical composition according to claim 2 or 3 for use as an inhibitor or modulator of reverse transcriptase.   A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of infection with HIV or a genetically related retrovirus, or the resulting acquired immunodeficiency syndrome (AIDS), A solvate or derivative, or a pharmaceutical composition according to claim 2 or 3.   A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, or a pharmaceutically acceptable salt, solvate or derivative thereof, for the manufacture of a medicament having a reverse transcriptase inhibitory or modulating activity. Use of a pharmaceutical composition.   A compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating infection with HIV or a genetically related retrovirus, or the resulting acquired immune deficiency syndrome (AIDS) Use of a salt, solvate or derivative, or a pharmaceutical composition according to claim 2 or 3.   A method for the treatment of infection with HIV or genetically related retroviruses or the consequent acquired immune deficiency syndrome (AIDS), comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable 4. A method comprising administering a salt, solvate or derivative thereof, or a pharmaceutical composition according to claim 2 or 3. A process for the preparation of a compound of formula (I) or a salt, solvate or pharmaceutically acceptable derivative thereof,
(A) Compound of formula (V)

Reaction under normal conditions with an alcohol of the formula (IV), ie R ¹ —OH (IV),
(B) Alcohol of formula (III)

Reaction under normal conditions with a compound of formula (II), ie Lg-R ¹ (II),
(C) a reaction of a compound of formula (III) with an alcohol of formula (IV) under dehydrating conditions;
(D) For the preparation of compounds of formula (I) wherein R ³ is halo, see compounds of formula (X)

Halogenation under normal conditions of
(E) interconversion of a compound of formula (I) to another compound of formula (I), or (F) deprotection of a protected derivative of the compound of formula (I), further comprising processes (A) to A method wherein a compound of formula (I) prepared by any one process of (F) may be converted to a pharmaceutically acceptable salt, solvate or derivative thereof.   A compound of formula (III), (IV), or (X).