JP2004515449A - Small molecule modulator of 6G protein-coupled receptor - Google Patents

Abstract

Disclosed herein are small molecule modulators of the 6G protein-coupled receptor, methods of making such compounds, and methods of using such compounds.

Description

【００６７】
好ましくは、ＩＣ_５０決定のために、極大における投与反応範囲が対照の８０〜１２０パーセントの範囲内にあり（「％対照」）、そして極小で対照の２０〜−２０パーセントにあることであるが、しかし、このようなパラメーターは熟練者の選択事項であり、熟練者の特定の要求に依存するものである。
【００６８】
実施例５
方向づけしたライブラリーのスクリーニング
上記の結果に基づいて、ＡＲＥ１１２化合物の構造活性分析は、一連のＡＲＥ１１２ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，３−ジチアゾール−３−イリデン）の誘導体、ならびにＡＲＥ１１１ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）の誘導体が、同様のＧＰＲ６反アゴニスト活性および選択性を有するであろうことを示唆する。Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，３−ジチアゾール−３−イリデン）およびＮ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）の誘導体の方向づけしたライブラリーを合成した（下記の実施例８および９参照）。ＩＣ_５０値は、下記のアッセイを用い、アッセイの数（括弧内）の平均値±標準偏差を計算して決定した。これらも上記のプロトコールを用いて評価し、そして結果を表Ｂに纏めた。
【００６９】
【表２】

【００７０】
【表３】

【００７１】
実施例６
生体内分析
１．２４時間絶食動物の飼料／水摂取および体重
生体内機能性アッセイからのＡＲＥ１１２のプロフィールは、この化合物が選択的ＧＰＲ６反アゴニスト性を示すことを示唆した。ＧＰＲ６反アゴニストの生体内アセスメントは、ラットの絶食の後の食餌摂取に対するＡＲＥ１１２の効果を測定することにより行った。絶食は、正常より高い摂食挙動を誘発するために使用した（例えば対照／ビヒクル処理動物は摂食亢進症であった）。
【００７２】
動物（雄のスプラグ−ドーリー（Ｓｐｒａｇｕｅ−Ｄａｗｌｅｙ）ラットを以下の試験に使用した）を２４時間絶食し、次いで腹膜内（ＩＰ）に０、６．７５、１３．５、２７および５４ｍｇ／ｋｇの化合物ＡＲＥ１１２を注射した。３０分後に、ラットに標準ラット飼料ペレットを与え、その後、注射後６．５時間の間、観察した。
【００７３】
データは、化合物ＡＲＥ１１２を用いてＩＰ処理した動物は、低下した食餌摂取、水摂取および体重増加を示すことを明らかにした。図５Ａでは、注射の１．５時間後に、ビヒクル処理動物は食餌約６グラムを摂取し、一方ＡＲＥ１１２処理動物（５４ｍｇ／ｋｇ）は食餌３グラムを摂取した。時間が経過すると、データは、ビヒクル処理体は実質的により多い食餌を摂取し（注射後６．５時間で１４ｇ以下）、一方ＡＲＥ１１２処理動物、特に５４ｍｇ／ｋｇのＡＲＥ１１２処理の動物は、４ｇを摂取したことを示す（図５Ａ参照）。２７および５４ｍｇ／ｋｇの投与においてはそれぞれ４および５倍の水摂取低下もこのデータで明らかになり、これは摂取した食餌量の低下量と平行しているように思われることがデータによっても証明された（図５Ｂ参照）。ビヒクル処理ラットは、２０ｇの体重増加を示し、一方ＡＲＥ１１２処理ラットでは下記が明らかになった。１３．５ｍｇ／ｋｇ処理は１１ｇ体重増加、２７および５４ｍｇ／ｋｇ処理は体重増加なし（図５Ｃ参照）。
２．非絶食動物における基礎食餌／水摂取および体重
動物をその最も活動的な期間（ダークサイクル）でも観察し、そして基礎食餌摂取および水の両方を測定した。この試験においては、動物は絶食せず、その代わりに正常な活動を観察した。
【００７４】
ダークサイクルの開始の３０分前（すなわち午後６時３０分）に動物へ０、６．７５、１３．５、２７および５４ｍｇ／ｋｇの化合物ＡＲＥ１１２をＩＰ投与し、次いで標準ラット食餌ペレットを与え（すなわち化合物投与の３０分後）そして投与後１５．５時間観察した。図６Ａに示したデータは、ＡＲＥ１１２を投与した動物が、ビヒクル投与動物ほどは摂取しなかったことを明らかにしている。例えば、ビヒクル投与動物は４時間の間に食餌９ｇを摂取したが、１３．５ｍｇ／ｋｇおよび５４ｍｇ／ｋｇの投与量で処理した動物は同じ期間内に半分以下を摂取した（それぞれ食餌４および２ｍｇ／ｋｇ）。絶食ラットと同様に、非絶食ラットも水摂取および体重増加の低下を示した（図６Ｂおよび６Ｃ参照）。
【００７５】
ＡＲＥ１１２の長期効果（６０日間）も試験した。動物（処理ｎ＝４、対照ｎ＝５）を毎日一回、腹膜内にＡＲＥ１１２を用いて２２日間処理し、そして６０日間評価した。１〜３日目において、１３．５ｍｇ／ｋｇで処理した動物は、最初体重が低下し、そして４日目から３１日目の間に動物は次第に体重が増加したが、ビヒクル処理動物よりは低かった。３１日目から６０日目までは、データは、処理動物とビヒクル動物との間に体重の著しい相違があるという意見を支持している。データは、ＡＲＥ１１２の毎日反復する投与（１３．５ｍｇ／ｋｇ）が、非絶食ラットにおいて長期の体重低下を誘発するという結論を支持する。図１１参照。
３．絶食動物に対するＡＲＥ１１２の脳室内（ＩＣＶ）投与
ａ外科手術
側脳室上を目標とするＩＣＶカニューレを用いて動物を準備した。この外科手術のために、イソフランの連続吸入を用いて動物を全身麻酔状態とし、頭部定位装置内に固定した。外科手術は、臨床感染を防止するために、専用室内で、滅菌器具、手術用手袋および無菌操作を用いて行った。手術場所は、シェーブし、ブタジン溶液およびアルコールを用いて消毒した。尾または手足を挟んで動物の反応を試験して、麻酔のレベルに関して動物を連続的に監視した。２３ゲージステンレス鋼管（長さ７ｍｍ）で作られたカニューレを座標：ブレグマからＡ／Ｐ−０．６ｍｍ、ブレグマからＭ／Ｌ＋／−２．０ｍｍ、頭骨面下からＤ／Ｖ３．２ｍｍを用いて脳室の上１ｍｍの点まで下げた。ステンレス鋼ネジ３本と歯科用セメントを用いてガイドを頭骨に固定した。座標は、パキシノスとワトソンの定位地図（Ｐａｘｉｎｏｓ， Ｇ． ａｎｄ Ｗａｔｓｏｎ， Ｃ． Ｔｈｅ Ｒａｔ Ｂｒａｉｎ， Ｎｅｗ Ｙｏｒｋ， Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ， １９８２）などの定位脳地図に基づいた。カニューレ埋め込みの後、３０ゲージのステンレス鋼ダミースタイレットをカニューレに挿入した。外科手術の最後に、熱源（回復ケージの半分に向いた加熱ランプ）を体温維持のために使用し、一方で動物を麻酔から回復させた。外科手術の後少なくとも一週間回復させた後に化合物のＩＣＶ注射を行った。
ｂ．ＡＲＥ１１２の投与
化合物投与の前２４時間、動物を絶食させた。
【００７６】
ＩＣＶ注射のために、ダミースタイレットを埋め込んだカニューレから取り出し、そして４５％シクロデキストリン溶液中のＡＲＥ１１２懸濁液を含む３０ゲージのステンレス鋼注射カニューレを、埋め込んだカニューレの下部先端（ｖｅｎｔｒａｌ ｔｉｐ） を１．５ｍｍ越える深さに挿入した。他の（挿入されない）注射カニューレの末端を化合物懸濁液を含むＰＥ１０管の６０ｃｍに取り付け、これに管の自由端で２５μｌハミルトン注射器に取り付けた。次いで、ＡＲＥ１１２懸濁液（０、２５、５０、１００ｎｍｏｌを含む）の１０μｌを、ハミルトン注射器のプランジャーへの軽くどちらかといえば機械的な圧力により供給した。注入した体積は、１０μｌハミルトン注射器を用いて事前に校正したＰＥ管上の印により確認した。注射が終了すると、注射カニューレの引き取りの際に埋め込んだカニューレの上部先端（ｄｏｒｓａｌ ｔｉｐ）から観察されたあらゆる液体を記録し、ダミースタイレットを埋め込んだカニューレ内に挿入した。
【００７７】
データは、すべての投与量のＡＲＥ１１２投与の２時間後に、動物は実質的に、より少ない食餌を摂取したことを明らかにした（約６倍少ない食餌を摂取した）。３時間後に、ビヒクルラットは食餌約２．５ｇを摂取したが、ＡＲＥ１１２処理ラットは約１．０ｇまたはこれ以下を摂取した。図７Ａ参照。試験動物（２５および５０ｎｍｏｌ）は、ビヒクルと同程度の水量、すなわち約１７ｇを飲んだ。さらに高い投与量（例えば１００ｎｍｏｌ）では、半分以下を摂取した（図７Ｃ参照）。データは、ＡＲＥ１１２の１００ｎｍｏｌの投与のＩＰ投与を用いて作製したデータと一致して、ＩＣＶ処理動物は、約１２ｇの増加であったビヒクル処理動物と比較評価すると、体重増加が本質的にさらに少なかった（例えば５ｇ）。図７Ｃ参照。
４．運動機能に対するＡＲＥ１１２の効果
運動機能に対するＡＲＥ１１２の効果も試験した。運動機能は、自動化した歩行活動ケージを用いて評価した。運動活動の自動記録を可能とする光電池で周囲を囲った標準げっ歯類ケージ内に動物を入れた。動物は刺激的な強制がなくそしてケージ内を自由に動き廻ることができた。
【００７８】
雄スプラーグ−ドーレイ・ラット（投与量あたりにｎ＝４〜９）を歩行活動ケージ内に入れる前にＡＲＥ１１２（ＩＰ）を投与した。データを図８に示す。データに基づいて、ＡＲＥ１１２注射の直後の１．５時間は、歩行活動ケージに動物を収容した場合に、ＡＲＥ１１２は歩行活動に影響しないことが結論できる。ＡＲＥ１１２は投与の１６時間後に歩行活動を低下させるとの結論をデータが支持するので（図８参照）、従って、ＡＲＥ１１２はいくらか鎮静作用を有し（例えば動物は弛緩したように見え、そして不安そうな挙動はほとんど示さない）、この鎮静作用は、穏和でそして食餌摂取の減少により、またそれ自体ではあり得ないことが分かる。
【００７９】
この穏和な鎮静作用の別の証拠として、動物をその驚愕反射を決定するために測定した。このアッセイにおいて、試験前４．５時間は絶食していないラットにＡＲＥ１１２を経口投与した。動物に１２ｄｂの前パルス、次いで１２０ｄｂのパルスを与え、続いて動物が跳躍する高さを測定した。図１２は、投与ラット（すなわち、６．７５、１３．５および５４ｍｇ／ｋｇ）の平均驚愕幅を示す。ビヒクルおよび６．７５ｍｇ／ｋｇの低投与量処理ラットと比較して、１３．５および５４ｍｇ／ｋｇの処理ラットは、パルスに反応してそれ程高くは跳躍しなかった。このデータは、ＡＲＥ１１２の高投与量で、動物は穏和な鎮静活性を示すことをさらに示唆する。
５．経口有効性：ＡＲＥ１１２
作製した生体内データに基づいて、化合物ＡＲＥ１１２の経口生物学的使用能を決定した。化合物を強制経口投与により、６．７５〜５４ｍｇ／ｋｇの範囲の投与量を与えた。図９Ａおよび９Ｂに示したデータは、ＡＲＥ１１２の経口投与も絶食と非絶食ラットとの両者で食餌摂取を低下させるという結論を支持する。ＡＲＥ１１２の効果は、投与量に依存しそしてＩＰ投与後に観察された効果と同程度である。図９Ａでは、化合物の経口投与の２４時間前からラットを絶食させた。このアッセイでは、ビヒクル処理ラットは、２．５時間で食餌約６ｇを摂取し、一方注射を受けたラット、特にＡＲＥ１１２の２５および５４ｍｇ／ｋｇを投与されたラットは、それぞれ約６および４ｇを摂取した。時間が経過すると、ビヒクル処理ラットはさらに大量を、投与の８時間後で約１４ｇを摂取し、一方処理ラット（２７および５４ｍｇ／ｋｇ）はそれぞれ約８ｇおよび６ｇを摂取した（図９Ａ参照）。
【００８０】
二回目のアッセイで、ラットに強制経口摂取でＡＲＥ１１２を用いて処理したが絶食はしなかった。データは、食餌摂取量のさらに大きい低下を明らかにし、例えば化合物の投与１８時間後で、ビヒクルラットは食餌約１５ｇを摂取し、一方注射ラット（すべての投与量で）は、５ｇまたはこれ以下を摂取した。化合物ＡＲＥ１１２で処理すると食餌摂取が約３倍減少する（図９Ｂ参照）。これらのデータは、ＡＲＥ１１２が経口活性であることとの結論を支持する。
６．その他の化合物の評価
数種の他のＧＰＲ６反アゴニストも、経口投与を用いて、２４時間絶食条件下で評価した。以下に表記した類似体は、５４ｍｇ／ｋｇと等価である２００μｍｏｌ／ｋｇで試験した。さらにＡＲＥ１１４は１００μｍｏｌ／ｋｇ（２７ｍｇ／ｋｇ）でも評価した。データを下記の表Ｃに纏めた。
【００８１】
【表４】

【００８２】
同じ条件下で試験した第二のアッセイでは、数種の他の類似体を１００μｍｏｌ／ｋｇで評価した。データを下記の表Ｄに纏めた。
【００８３】
【表５】

【００８４】
図１０において、化合物の経口投与の２４時間前からラットを絶食させた。このアッセイにおいて、類似体ＡＲＥ１３０、ＡＲＥ１３５、ＡＲＥ１３６およびＡＲＥ１４０は、１００μｍｏｌ／ｋｇを投与した。特に３種の類似体、ＡＲＥ１３０、ＡＲＥ１３６およびＡＲＥ１４０は、投与後８時間の期間で食餌の遅い摂取（例えば２時間あたりに約１〜１．５ｇ）を明らかにし、一方ビヒクルラットは２時間あたりに約２〜２．５ｇを摂取した。ビヒクルラットと同様に、開環構造である類似体ＡＲＥ１３５は、投与後８時間の間に、ラットが２時間あたりに約２．５ｇを増加しながら摂取することを明らかにした（図１０Ａ参照）。さらに、ビヒクルラットおよび類似体ＡＲＥ１３５を投与されたラットの体重は、約１９．５ｇ増加した。反対に、閉環構造は、下記のような体重増加の低下を明らかにした。ＡＲＥ１１２−６ｇ、ＡＲＥ１３０−９ｇ、ＡＲＥ１３６−１１ｇおよびＡＲＥ１４０−１４ｇ。図１０Ｃ参照。
【００８５】
処理ラット、特にはＡＲＥ１３０おびＡＲＥ１３６は、ビヒクル動物と比較してさらに少ない量の水を飲み、すなわちそれぞれ約１０ｇおよび４ｇである。一方、類似体ＡＲＥ１３５およびＡＲＥ１４０は、同程度の量を飲んだ（すなわち約１９ｇ）。図１０Ｂ参照。これらのデータは、閉環構造、好ましくはＡＲＥ１１２、ＡＲＥ１３０、ＡＲＥ１３６およびＡＲＥ１４０、さらに好ましくはＡＲＥ１１２およびＡＲＥ１３０、そして最も好ましくはＡＲＥ１１２が第６Ｇタンパク質共役型受容体に特異性であるであることを示唆する。
【００８６】
下記の表Ｅは、ＡＲＥ１１２の類似体に対する数個のＩＣ_５０を表示している。ＩＣ_５０値は、実施例４Ａで開示したＧＴＰアッセイを用いて導出した。類似体ＡＲＥ１３０、ＡＲＥ１３６およびＡＲＥ１４０の低濃度では、ＧＰＲ６は活性化されており、従ってＧＴＰのＧＤＰへの変換を刺激する。このデータは、閉環構造がＧＰＲ６に対する選択反アゴニストであるという示唆を支持する。
【００８７】
【表６】

【００８８】
実施例７
ＧＰＲ６反アゴニスト
本明細書内で提供する特許開示および情報に基づいて、当該業界の通常の熟練者は、ＧＰＲ６の反アゴニスト、アゴニストおよび部分アゴニストである候補化合物を直接同定する能力があると信じられる。さらに好ましくは、これらは、このような直接同定の前にこれらの特性（例えばＧＰＲ６への選択性）を証明されていない小分子化合物である。アゴニストに対して、スクリーニングにおける目的は、測定された信号を増加させる小分子を見いだすことである。
【００８９】
以下で我々は、我々の最も好ましい小分子ＧＰＲ６反アゴニストを開示する。本明細書で開示された化合物の種々の立体異性体があることが認められている。本発明は、ラセミ化合物、個々の鏡像異性体、およびこれらの混合物も含むことを意図している。
１．開鎖アリール系列
ＧＰＲ６インバースアゴニストの第一の系列として、以下のように構造的に表される「開鎖アリール（ｏｐｅｎ ｃｈａｉｎ ａｒｙｌ）」が開示される（注：Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１の１種もしくはそれ以上の選択が非対称もしくはジアステレオマーの分子をもたらす場合には、ラセミ混合物、ジアステレオマーの混合物、ならびに分離された（＋）および（−）の鏡像異性体もしくはジアステレオマーのそれぞれは、開示される系列の範囲内、および後に続く請求の範囲の範囲内にある）：
【００９０】
【化２７】

【００９１】
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６でありかつｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニル、シクロアルキル、アルキルシクロアルキル、シクロアルキルアルキル、アリールおよびＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、前記アリールのいずれかの位置で４個までの置換基により場合によっては置換されてよく、各前記位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が１個のアリール環を含有し、前記アリール環が前記アリール環上の２個の隣接する位置で置換される場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；または、
Ｒ^１３およびＲ^１４は、飽和もしくは不飽和のいずれかであってよく、かつＯ、ＮおよびＳから選択される４個までのヘテロ原子を含有してよい５、６もしくは７員の環構造の一部を形成してよく、また、前記環構造は、いずれかの位置で：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよいか；または
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される。
【００９２】
優先的に記される以下の条件がそれにより当てはまることができ、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が全部Ｈである場合には、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４の最低１個がＨ以外であり；また、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が全部Ｈである場合には、Ｒ^３はＣｌ、ＣＨ_３もしくはＯＣＨ_３でなく；また、Ｒ^１、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が全部Ｈである場合には、Ｒ^２、Ｒ^３およびＲ^４がＯＣＨ_３でない。
【００９３】
「アリール部分」は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる。
【００９４】
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる。本明細を通じて、「アルキルアリール」という用語は、それに結合されたアリール部分を有するアルキル部分（例えばベンジル基）を意味することを意図している。
【００９５】
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【００９６】
以下のように構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される：
【００９７】
【化２８】

【００９８】
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつ、ｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニル、シクロアルキル、アルキルシクロアルキル、シクロアルキルアルキル、アリールおよびＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、前記アリールのいずれかの位置で４個までの置換基により場合によっては置換されてよく、各前記位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が１個のアリール環を含有し、前記アリール環が前記アリール環上の２個の隣接する位置で置換される場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；または、
Ｒ^１３およびＲ^１４は、飽和もしくは不飽和のいずれかであってよく、かつＯ、ＮおよびＳから選択される４個までのヘテロ原子を含有してよい５、６もしくは７員の環構造の一部を形成してよく、そして、前記環構造は、いずれかの位置で：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよいか；または
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される前記１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される。
２．閉鎖アリール系列
ＧＰＲ６インバースアゴニストの第二の系列は、以下のように構造的に表される「閉鎖アリール（ｃｌｏｓｅｄ ｃｈａｉｎ ａｒｙｌ）」である：
【００９９】
【化２９】

【０１００】
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつ、ｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニル、シクロアルキル、アルキルシクロアルキル、シクロアルキルアルキル、アリールおよびＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される前記１個のアリール環を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、
Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成してよく、各こうした構造はＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される前記１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される；
優先的に記される以下の条件がこれにより当てはまることができ、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が全部Ｈである場合には、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４の最低１個がＨ以外であり；そして、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が全部Ｈである場合には、Ｒ^３がＣｌ、ＣＨ_３もしくはＯＣＨ_３でなく；そして、Ｒ^１、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１が全部Ｈである場合には、Ｒ^２、Ｒ^３およびＲ^４はＯＣＨ_３でない。
【０１０１】
「アリール部分」は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる。
【０１０２】
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる。
【０１０３】
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【０１０４】
以下のように構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される：
【０１０５】
【化３０】

【０１０６】
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつ、ｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニル、シクロアルキル、アルキルシクロアルキル、シクロアルキルアルキル、アリールおよびＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される前記１個のアリール基を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、
Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成してよく、各こうした構造はＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される前記１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される；
３．開鎖の６員ヘテロアリール系列
ＧＰＲ６インバースアゴニストの第三の系列は、以下のように構造的に表される「開鎖の６員ヘテロアリール」である：
【０１０７】
【化３１】

【０１０８】
式中、Ｖ、Ｗ、Ｘ、ＹおよびＺの最低１個がＮから選択され、かつ、ＮでないＶ、Ｗ、Ｘ、ＹおよびＺのそれぞれがＣＲ^１、ＣＲ^２、ＣＲ^３、ＣＲ^４およびＣＲ^５から独立に選択されるが、但し、Ｖ、Ｗ、Ｘ、ＹおよびＺの最低２個がＮ以外であり；
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつ、ｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニル、シクロアルキル、アルキルシクロアルキル、シクロアルキルアルキル、アリールおよびＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される前記１個のアリール環を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、
Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成し、各こうした構造はＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される；
アリール部分は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる；
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる。
【０１０９】
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【０１１０】
前述の開鎖の６員ヘテロアリール系列により構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される。
４．閉鎖の６員ヘテロアリール系列
ＧＰＲ６インバースアゴニストの第四の系列は、以下のように構造的に表される「閉鎖の６員ヘテロアリール」である：
【０１１１】
【化３２】

【０１１２】
式中、Ｖ、Ｗ、Ｘ、ＹおよびＺの最低１個がＮから選択され、かつ、ＮでないＶ、Ｗ、Ｘ、ＹおよびＺのそれぞれがＣＲ^１、ＣＲ^２、ＣＲ^３、ＣＲ^４およびＣＲ^５から独立に選択されるが、但し、Ｖ、Ｗ、Ｘ、ＹおよびＺの最低２個がＮ以外であり；
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつ、ｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニル、シクロアルキル、アルキルシクロアルキル、シクロアルキルアルキル、アリールおよびＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される前記１個のアリール環を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、
Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成し、各こうした構造はＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される前記１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される；
アリール部分は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる；
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる；
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【０１１３】
前述の閉鎖の６員ヘテロアリール系列により構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される。
５．開鎖の５員ヘテロアリール（下位系列ａ）
ＧＰＲ６インバースアゴニストの第五の系列は、以下のように構造的に表される「開鎖の５員ヘテロアリール」である：
【０１１４】
【化３３】

【０１１５】
式中、ＺはＮＲ^４、ＯおよびＳから選択され；
Ｗ、ＸもしくはＹはＮ、ＣＲ^１、ＣＲ^２およびＣＲ^３から独立に選択されるが、但し、ＺがＯでありかつＹがＮである場合には、ＷがＣＲ^１でありかつＸがＣＲ^２であり；
Ｒ^１、Ｒ^２およびＲ^３は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^４はＨ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、ＣＯＲ^５、ＣＳＲ^５およびＳＯ_２Ｒ^５から選択され；
Ｒ^５、Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつ、ｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニルもしくはシクロアルキル、もしくはアルキルシクロアルキル、シクロアルキルアルキル、もしくはアリールおよびＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される１個のアリール環を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成し、各こうした構造はＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される前記１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される。
【０１１６】
アリール部分は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる；
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる。
【０１１７】
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【０１１８】
前述の開鎖の５員ヘテロアリール系列により構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される。
６．閉鎖の５員ヘテロアリール（下位系列ａ）
ＧＰＲ６インバースアゴニストの第六の系列として、以下のように構造的に表される「閉鎖の５員ヘテロアリール下位系列ａ」が開示される：
【０１１９】
【化３４】

【０１２０】
式中、ＺはＮＲ^４、ＯおよびＳから選択され；
Ｗ、ＸもしくはＹはＮ、ＣＲ^１、ＣＲ^２およびＣＲ^３から独立に選択されるが、但し、ＺがＯでありかつＹがＮである場合には、ＷがＣＲ^１でありかつＸがＣＲ^２であり；
Ｒ^１、Ｒ^２およびＲ^３は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^４はＨ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、ＣＯＲ^５、ＣＳＲ^５およびＳＯ_２Ｒ^５から選択され；
Ｒ^５、Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈ、（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であるか、もしくはｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニルもしくはシクロアルキル、もしくはアルキルシクロアルキル、もしくはシクロアルキルアルキル、またはアリールもしくはＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される１個のアリール環を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成し、各こうした構造はＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される前記１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される。
【０１２１】
アリール部分は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる；
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる。
【０１２２】
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【０１２３】
前述の閉鎖の５員ヘテロアリール系列により構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される。
７．開鎖の５員ヘテロアリール（下位系列ｂ）
ＧＰＲ６インバースアゴニストの第七の系列として、以下のように構造的に表される「開鎖の５員ヘテロアリール下位系列ｂ」が開示される：
【０１２４】
【化３５】

【０１２５】
式中、ＹはＮＲ^４、ＯもしくはＳから選択され；
Ｗ、ＸもしくはＺはＮまたはＣＲ^１、ＣＲ^２もしくはＣＲ^３からそれぞれ独立に選択されるが、但し、ＹがＯでありかつＺがＮである場合には、ＷがＣＲ^１でありかつＸがＣＲ^２であり；
Ｒ^１、Ｒ^２およびＲ^３は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^４はＨ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、ＣＯＲ^５、ＣＳＲ^５およびＳＯ_２Ｒ^５であり；
Ｒ^５、Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつ、ｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニルもしくはシクロアルキル、もしくはアルキルシクロアルキル、もしくはシクロアルキルアルキル、またはアリールもしくはＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される１個のアリール環を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成し、各こうした構造がＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される。
【０１２６】
アリール部分は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる；
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる。
【０１２７】
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【０１２８】
前述の開鎖の５員ヘテロアリール系列により構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される。
８．閉鎖の５員ヘテロアリール（下位系列ｂ）
ＧＰＲ６インバースアゴニストの第八の系列として、以下のように構造的に表される「閉鎖の５員ヘテロアリール下位系列ｂ」が開示される：
【０１２９】
【化３６】

【０１３０】
式中、ＹはＮＲ^４、ＯもしくはＳから選択され；
Ｗ、ＸもしくはＺはＮまたはＣＲ^１、ＣＲ^２もしくはＣＲ^３からそれぞれ独立に選択されるが、但し、ＹがＯでありかつＺがＮである場合には、ＷがＣＲ^１でありかつＸがＣＲ^２であり；
Ｒ^１、Ｒ^２およびＲ^３は、以下：
Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、Ｒ^１２、ＣＦ_３、ＣＦ_２Ｒ^１２、ＣＦ_２ＣＦ_２、ＣＣｌ_３、ＣＣｌ_２Ｒ^１２、ＣＣｌ_２ＣＣｌ_２Ｒ^１２、ＮＲ^１３Ｒ^１４、ＮＲ^１５ＣＯＲ^１２、ＮＲ^１５ＳＯ_２Ｒ^１２、ＯＲ^１２、ＯＣＦ_３、ＯＣＦ_２Ｒ^１２、ＯＣＦ_２ＣＦ_２Ｒ^１２、ＯＣＯＲ^１２、ＯＳＯ_２Ｒ^１２、ＯＰＯ（ＯＲ^１２）_２、ＳＲ^１２、ＳＣＦ_３、ＳＣＦ_２Ｒ^１２、ＳＣＦ_２ＣＦ_２Ｒ^１２、ＳＣＯＲ^１２、ＳＯ_３Ｒ^１２、ＳＯ_２ＮＲ^１３Ｒ^１４、ＰＯ（ＯＲ^１２）_３、ＰＯ（ＯＲ^１２）_２Ｒ^１２、ＮＯ_２、ＣＮ、ＣＮＲ^１５（ＮＲ^１３Ｒ^１４）、ＣＮＲ^１５（ＳＲ^１２）、ＣＯＯＲ^１２、ＣＯＳＲ^１２、ＣＯＮＲ^１３Ｒ^１４からそれぞれ独立に選択され、かつ、
ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５のいずれかの２個の隣接する位置が、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；
Ｒ^４はＨ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、ＣＯＲ^５、ＣＳＲ^５およびＳＯ_２Ｒ^５から選択され；
Ｒ^５、Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^６およびＲ^７は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され
Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリールおよびアルキルアリールからそれぞれ独立に選択され；
Ｒ^１２は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキル、Ｃ_２−８のアルケニル、アリール、アルキルアリール、（ＣＨ_２）_ｎＮＲ^１３Ｒ^１４、（ＣＨ_２）_ｍＳＯ_３Ｈおよび（ＣＨ_２）_ｍＣＯ_２Ｈ（ここで、ｎは２から６であり、かつｍは１から６である）から選択され；
Ｒ^１３およびＲ^１４は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_２−８アルケニルもしくはシクロアルキル、もしくはアルキルシクロアルキル、もしくはシクロアルキルアルキル、またはアリールもしくはＣＨ_２アリールからそれぞれ独立に選択され、ここで、各前記アリール基もしくは前記ＣＨ_２アリール基の前記アリール部分は、いずれかの位置で：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択される４個までの置換基により場合によっては置換されてよく、かつ、
ここで、Ｒ^１３および／もしくはＲ^１４が、アリール環上の２個の隣接する位置で置換される前記１個のアリール環を含有する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯもしくはＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができるか；あるいは、
Ｒ^１３およびＲ^１４は、５、６もしくは７員の飽和の環構造または５、６もしくは７員の不飽和の環構造の一部を形成し、各こうした構造はＯ、ＮおよびＳから選択される４個までのヘテロ原子を場合によっては含有し、かつ、ここで、各前記環構造はいずれかの位置で４個までの置換基により場合によっては置換されてよく、各位置は：
Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＣＦ_３、ＣＣｌ_３、ＣＨ_３、Ｃ_２Ｈ_５、Ｃ_３Ｈ_７、Ｃ_４Ｈ_９、ＮＨ_２、ＮＨＣＨ_３、Ｎ（ＣＨ_３）_２、ＮＨＣ_２Ｈ_５、Ｎ（Ｃ_２Ｈ_５）_２、ＮＨＣ_３Ｈ_７、Ｎ（Ｃ_３Ｈ_７）_２、ＮＨＣ_４Ｈ_９、Ｎ（Ｃ_４Ｈ_９）_２、ＮＨＣＯＨ、ＮＨＣＯＣＨ_３、ＮＨＣＯＣ_２Ｈ_５、ＮＨＣＯＣ_３Ｈ_７、ＮＨＣＯＣ_４Ｈ_９、ＮＨＳＯ_２ＣＨ_３、ＮＨＳＯ_２Ｃ_２Ｈ_５、ＮＨＳＯ_２Ｃ_３Ｈ_７、ＮＨＳＯ_２Ｃ_４Ｈ_９、ＯＨ、ＯＣＨ_３、ＯＣ_２Ｈ_５、ＯＣ_３Ｈ_７、ＯＣ_４Ｈ_７、ＯＣ_４Ｈ_９、ＯＣ_５Ｈ_９、ＯＣ_５Ｈ_１１、ＯＣ_６Ｈ_１１、ＯＣ_６Ｈ_１３、ＯＣＦ_３、ＯＣＯＣＨ_３、ＯＣＯＣ_２Ｈ_５、ＯＣＯＣ_３Ｈ_７、ＯＣＯＣ_４Ｈ_９、ＯＳＯ_２ＣＨ_３、ＯＳＯ_２Ｃ_２Ｈ_５、ＯＳＯ_２Ｃ_３Ｈ_７、ＯＳＯ_２Ｃ_４Ｈ_９、ＳＨ、ＳＣＨ_３、ＳＣ_２Ｈ_５、ＳＣ_３Ｈ_７、ＳＣ_４Ｈ_７、ＳＣ_４Ｈ_９、ＳＣ_５Ｈ_９、ＳＣ_５Ｈ_１１、ＳＣ_６Ｈ_１１、ＳＣ_６Ｈ_１３、ＳＣＦ_３、ＳＣＯＣＨ_３、ＳＣＯＣ_２Ｈ_５、ＳＣＯＣ_３Ｈ_７、ＳＣＯＣ_４Ｈ_９、ＳＯ_３ＣＨ_３、ＳＯ_３Ｃ_２Ｈ_５、ＳＯ_３Ｃ_３Ｈ_７、ＳＯ_３Ｃ_４Ｈ_９、ＳＯ_２ＮＨ_２、ＳＯ_２ＮＨＣＨ_３、ＳＯ_２Ｎ（ＣＨ_３）_２、ＳＯ_２ＮＨＣ_２Ｈ_５、ＳＯ_２Ｎ（Ｃ_２Ｈ_５）_２、ＳＯ_２ＮＨＣ_３Ｈ_７、ＳＯ_２Ｎ（Ｃ_３Ｈ_７）_２、ＳＯ_２ＮＨＣ_４Ｈ_９、ＳＯ_２Ｎ（Ｃ_４Ｈ_９）_２、ＮＯ_２、ＣＮ、ＣＯＯＣＨ_３、ＣＯＯＣ_２Ｈ_５、ＣＯＯＣ_３Ｈ_７、ＣＯＯＣ_４Ｈ_９、ＣＯＳＣＨ_３、ＣＯＳＣ_２Ｈ_５、ＣＯＳＣ_３Ｈ_７、ＣＯＳＣ_４Ｈ_９、ＣＯＮＨ_２、ＣＯＮＨＣＨ_３、ＣＯＮ（ＣＨ_３）_２、ＣＯＮＨＣ_２Ｈ_５、ＣＯＮ（Ｃ_２Ｈ_５）_２、ＣＯＮＨＣ_３Ｈ_７、ＣＯＮ（Ｃ_３Ｈ_７）_２、ＣＯＮＨＣ_４Ｈ_９、ＣＯＮ（Ｃ_４Ｈ_９）_２から独立に選択され、かつ、
ここで、Ｒ^１３およびＲ^１４がアリール環上の２個の隣接する位置で置換される１個のアリール環を形成する場合には、前記２個の隣接する位置は、ＣＨＣＨＣＨＣＨ、ＣＨ_２ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨＣＨＣＨ_２、ＣＨ_２ＣＨ_２ＣＨ_２、ＣＨ_２ＣＨ_２、ＳＣＨ_２Ｓ、ＳＣＨ_２ＣＨ_２Ｓ、ＯＣＨ_２ＯおよびＯＣＨ_２ＣＨ_２Ｏから選択される鎖により結合されて二環構造を形成することができ；そして
Ｒ^１５は、Ｈ、Ｃ_１−８の直鎖アルキル、分枝状アルキル、Ｃ_３−８シクロアルキル、Ｃ_４−９のアルキルシクロアルキルもしくはシクロアルキルアルキルおよびＣ_２−８アルケニルから選択される。
【０１３１】
アリール部分は、５もしくは６員の芳香族複素環（Ｎ、ＯもしくはＳから独立に選択される４個までのヘテロ原子を含有する）または６員の芳香族非複素環または多環であることができる；
適するＣ_１−８アルキル基の例は、限定されるものでないがメチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチルおよびｔ−ブチルを挙げることができる。
【０１３２】
５もしくは６員環部分の例は、限定されるものでないがフェニル、フラニル、チエニル、イミダゾリル、ピリジル、ピロリル、オキサゾリル、イソキサゾリル、トリアゾリル、ピラゾリル、テトラゾリル、チアゾリルおよびイソチアゾリルを挙げることができる。多環部分の例は、限定されるものでないがナフチル、ベンゾチアゾリル、ベンゾフラニル、ベンズイミダゾリル、キノリル、イソキノリル、インドリル、キノキサリニル、キナゾリニルおよびベンゾチエニルを挙げることができる。
【０１３３】
前述の閉鎖の５員ヘテロアリール下位系列により構造的に表される小分子とＧＰＲ６受容体を接触させることによる前記受容体の調節方法がさらに開示される。
【０１３４】
実施例８Ａ
合成のアプローチ
本発明で開示される化合物は多様な合成操作に従って容易に製造することができ、その全部は当業者に馴染みがあるであろう。下に示される一般的合成において、標識された置換基「Ｒ」は、下に開示される化合物の定義で示されると同一の同定を有する。
【０１３５】
【化３７】

【０１３６】
下に開示されるアプローチにおいて、「プロトコルＡ」は式（ＩＩＩ）までの合成アプローチであり、また、「プロトコルＢ」は式（Ｖ）までの合成アプローチである。これらのアプローチのそれぞれにおいて、プロトコルＡにより製造される化合物は、その後、順に、プロトコルＢにより製造される化合物の出発原料として使用されることが示される。
【０１３７】
式（ＩＩＩ）および（Ｖ）の化合物、またはその溶媒和物もしくは生理学的に機能的な誘導体を、製薬学的組成物中の有効成分、とりわけＧＰＲ６インバースアゴニストとして使用することができる。本明細書で明らかにされるデータは、ＧＰＲ６インバースアゴニストが、限定されるものでないがヒトを挙げることができる哺乳動物における臨床的肥満もしくは体重過剰の障害の治療もしくは予防に使用すべきであるという結論を支持する。式（ＩＩＩ）および（Ｖ）の化合物は、経口、舌下、非経口、直腸、局所の投与もしくは経皮貼付剤により投与してよい。経皮貼付剤は、薬物の最小限の分解を伴う有効な様式で薬物を吸収のため提示することにより、制御された速度で薬物を分注する。典型的には、経皮貼付剤は、不浸透性の裏打ち層、単一の圧力感受性の接着剤および放出裏当てを伴う除去可能な保護層を含んで成る。当業者は、当業者の必要に基づき、所望の効能のある経皮貼付剤を製造するのに適切な技術を理解しかつ真価を認めるであろう。
【０１３８】
中性の形態の式（ＩＩＩ）および（Ｖ）の化合物に加えて、該化合物の受容体特異性を変えないイオン化可能な置換基の適切な付加により、該化合物の生理学的に許容できる塩を形成させかつ治療薬として使用することもまたできる。所望の生物学的効果を達成するために多様な量の式（ＩＩＩ）および（Ｖ）の化合物が必要とされることができる。該量は、特定の化合物、それについて意図される使用、投与手段および治療される個体の状態（これらの投薬パラメータの全部は医薬技術の当業者の水準内にある）のような因子に依存することができる。典型的な用量は、哺乳動物の体重１キログラムあたり０．００１ないし２００ｍｇの範囲にあると期待してよい。単位用量は１から２００ｍｇまでの式（ＩＩＩ）もしくは（Ｖ）の化合物を含有してよく、また、個別にもしくは複合物で１日に１回もしくはそれ以上投与してよい。式（ＩＩＩ）および（Ｖ）の化合物の塩もしくは溶媒和物の場合には、用量は陽イオン（塩について）もしくは溶媒和されない化合物に基づく。
【０１３９】
限定されるものでないが、最低１種の担体もしくは賦形剤（例えば製薬学的担体もしくは賦形剤）と組み合わせられた有効成分としての式（ＩＩＩ）および（Ｖ）の最低１種の化合物ならびに／またはそれらの許容できる塩もしくは溶媒和物（例えば製薬学的に許容できる塩もしくは溶媒和物）を含んで成る製薬学的組成物を挙げることができる組成物。製薬学的組成物は、ＧＰＲ６インバースアゴニストが指示される臨床状態の治療で使用してよい。式（ＩＩＩ）および（Ｖ）の最低１種の化合物を、単位投与剤形で固体もしくは液体のいずれかの形態の担体と組み合わせてよい。製薬学的担体は組成物中の他の成分と適合性でなくてはならず、また、個々の受領者により耐えられなければならない。所望される場合、およびこうした成分が組成物中の他の成分と適合性である場合は、本発明の製薬学的組成物に他の生理学的有効成分を組み込んでよい。製剤は、いずれかの適する方法により、典型的には、必要とされる比率で液体もしくは微細に分割された固体の担体または双方と有効成分（１種もしくは複数）を均一に混合すること、そしてその後、必要な場合は生じる混合物を所望の形状に形成することにより製造してよい。
【０１４０】
結合剤、増量剤、許容できる湿潤剤、錠剤化滑沢剤および崩壊剤のような慣習的賦形剤を、経口投与のための錠剤およびカプセル剤で使用してよい。経口投与のための液体製剤は、溶液、乳剤、水性もしくは油性の懸濁剤およびシロップ剤の形態であってよい。あるいは、経口製剤は、使用前に水もしくは別の適する液体ベヒクルを用いて再構成することができる乾燥粉末の形態であってよい。懸濁化剤もしくは乳化剤、（可食性油を包含する）非水性ベヒクル、保存剤、ならびに着香料および着色剤のような付加的添加物を液体製剤に添加してよい。非経口の投薬形態は、本発明の化合物を適する液体ベヒクルに溶解すること、および該溶液を充填する前に濾過滅菌すること、そして適切なバイアルもしくはアンプルを封止することにより製造してよい。これらは、投薬形態を製造するための当該技術分野で公知の多くの適切な方法の数例にすぎない。
【０１４１】
ＧＰＲ６インバースアゴニストを製薬学的組成物中で有効成分として利用する場合、これらはヒトでのみならず、しかし他の非ヒト哺乳動物での使用も同様に意図していることが示される。実際、動物の健康管理の領域における最近の進歩は、飼い慣らされた（ｄｏｍｅｓｔｉｃ）動物（例えばネコおよびイヌ）における肥満の治療のためのＧＰＲ６インバースアゴニスト、ならびに疾患もしくは障害が明白でない他の飼い慣らされた動物（例えば、ウシ、ニワトリ、サカナなどのような食用（ｆｏｏｄ−ｏｒｉｅｎｔｅｄ）動物）におけるＧＰＲ６アゴニストの使用が考慮されることを命令している。当業者は、こうした設定におけるこうした化合物の利用性を理解していると容易に信じられる。
【０１４２】
以下は、化合物ＡＲＥ１１２のものと類似のＧＰＲ６インバースアゴニスト活性および選択性を表すことが決定された化合物の構造の表示である。
【０１４３】
【化３８】

【０１４４】
【化３９】

【０１４５】
【化４０】

【０１４６】
【化４１】

【０１４７】
【化４２】

【０１４８】
実施例８Ｂ
化合物ＡＲＥ１１１〜ＡＲＥ１５６の製造
質量スペクトルは、コンビスクリーン（ＣｏｍｂｉＳｃｒｅｅｎ） Ｃ１８逆相カラム（５０ｍｍ ｘ ４．６ｍｍ内径）を用いるシマズデュアルポンプ（Ｓｈｉｍａｚｕ ｄｕａｌ ｐｕｍｐ） （ＬＣ８ポンプ２基）ＨＰＬＣに連結したＰＥ Ｓｃｉｅｘ ＡＰＩ １５０ ＥＸ質量分析計に記録した。勾配溶離は、５分間で、０．０５％ＴＦＡを含む９５％水／０．３５％ＴＦＡを含む５％アセトニトリルから１００％アセトニトリルまで、流量３．５ｍｌ／分であった。ＨＰＬＣから溶離した試料は、特に断らない限り、通常、シマズＳＰＤ−１０ＡＶＰ検出器を用いて２２０ｎｍで測定した。すべての試薬は、市販供給先から購入した。
調製法１
ＡＲＥ１１１ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−チオフェン−２−カルボキシアミドおよび
ＡＲＥ１１２ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−チオフェン−２−カルボキシアミド
の調製および分析
下記の化合物のそれぞれの生成のために、下記の合成プロトコールを使用した。
プロトコールＡ：
乾燥アセトン（８０ｍｌ）中のチオシアン酸カリウム（２．１４ｇ、２２ミリモル）の新たに調製した溶液に、チオフェン−２−カルボニル クロリド（２．９３ｇ、２０ミリモル）を室温で滴下して加えた。次いで反応混合物を還流しながら１５分間加熱すると、チオフェン−２−カルボニル イソチオシアナートがその場で黄色の懸濁液として得られる。加熱を止め、そして２−イミダゾリジンチオン（２．０４ｇ、２０ミリモル）を加えた。次いで混合物を還流しながらさらに４時間加熱し、次いで放冷し、次いで室温で一晩攪拌した（１５時間）。水５０ｍｌを加え、そして混合物をさらに室温で数分間攪拌した。得られた沈殿物を濾過して集め、そして水、水／メタノール（１：１）およびメタノールで洗浄すると、化合物ＡＲＥ１１１（２．８６５ｇ、収率＝５３％）が得られた。
【０１４９】
質量スペクトル：ｍ／ｚ（％）：２７２．０（Ｍ＋Ｈ，１００）、Ｃ_９Ｈ_９Ｎ_３ＯＳ_３＝２７０．９８として計算
ＨＰＬＣ保持時間：２．９７分
プロトコールＢ：
エタノール（３０ｍｌ）中のＡＲＥ１１１（２ｇ、７．３７ミリモル）懸濁液に、濃塩酸（０．７５ｍｌ）および３０％過酸化水素（２ｍｌ）を加えた。反応混合物を還流しながら油浴内で２時間加熱すると黄色の懸濁液が白色に変化する。得られた沈殿物を濾過して集め、そしてエタノールで洗浄すると、塩酸塩が得られ、これを次いでエタノール（２０ｍｌ）中に懸濁し、そして２８〜３０％水酸化アンモニウム（１ｍｌ）を用いて処理すると、遊離の塩基が生成する。反応混合物を室温で２０分間攪拌し、次いで得られた沈殿物を濾過して集め、エタノールで洗浄しそして乾燥すると、化合物ＡＲＥ１１２（１．３０４ｇ、収率＝６６％）が黄色がかった固体として得られる。
【０１５０】
ＭＳ（ＥＳ＋）：ｍ／ｚ（％）：２７０（Ｍ＋Ｈ，１００）
質量スペクトル：ｍ／ｚ（％）：２７０．０（Ｍ＋Ｈ，１００）、Ｃ_９Ｈ_７Ｎ_３ＯＳ_３＝２６９．９８として計算
ＨＰＬＣ保持時間：２．３６分
調製法２
ＡＲＥ１１３ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−ベンズアミドおよび
ＡＲＥ１１４ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−ベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに塩化ベンゾイルを用いて、上記プロトコールＡの手順に従うと、ＡＲＥ１１３が黄色がかった固体として生成する。
【０１５１】
質量スペクトル：ｍ／ｚ（％）：２６６．０（Ｍ＋Ｈ，１００）、Ｃ_１１Ｈ_１１Ｎ_３ＯＳ_２＝２６５．０２として計算
ＨＰＬＣ保持時間：３．２９分
ＡＲＥ１１１の代わりにＡＲＥ１１３を用いて上記プロトコールＢの手順に従うと、ＡＲＥ１１４が白色固体として生成する。
【０１５２】
質量スペクトル：ｍ／ｚ（％）：２６３．８（Ｍ＋Ｈ，６１）、Ｃ_１１Ｈ_９Ｎ_３ＯＳ_２＝２６３．０２として計算
ＨＰＬＣ保持時間：２．５３分
調製法３
ＡＲＥ１１５ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−４−トリフルオロメチルベンズアミドおよび
ＡＲＥ１１６ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−４−トリフルオロメチルベンズアミド、
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに４−（トリフルオロメチル）ベンゾイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１１５が黄色がかった固体として生成する。
【０１５３】
質量スペクトル：ｍ／ｚ（％）：１７３．０（１００）、３３４．２（Ｍ＋Ｈ，８３）、Ｃ_１２Ｈ_１０Ｆ_３Ｎ_３ＯＳ_２＝３３３．０１として計算
ＨＰＬＣ保持時間：３．６９分
ＡＲＥ１１１の代わりにＡＲＥ１１５を用いてプロトコールＢに従うと、ＡＲＥ１１６が白色固体として生成する。
【０１５４】
質量スペクトル：ｍ／ｚ（％）：３３２．０（Ｍ＋Ｈ，１００）、Ｃ_１２Ｈ_１２Ｆ_３Ｎ_３ＯＳ_２＝３３１．０１として計算
ＨＰＬＣ保持時間：３．２８分
調製法４
ＡＲＥ１１７ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−４−ｔ−ブチルベンズアミドおよび
ＡＲＥ１１８ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−４−ｔ−ブチルベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに４−ｔ−ブチルベンゾイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１１７が黄色がかった固体として生成する。
【０１５５】
質量スペクトル：ｍ／ｚ（％）：１６１．０（１００）、３２２．０（Ｍ＋Ｈ，５３）、Ｃ_１５Ｈ_１９Ｎ_３ＯＳ_２＝３２１．４５として計算
ＨＰＬＣ保持時間：３．９７分
ＡＲＥ１１１の代わりにＡＲＥ１１７を用いてプロトコールＢに従うと、ＡＲＥ１１８が白色固体として生成する。
【０１５６】
質量スペクトル：ｍ／ｚ（％）：３２０．０（Ｍ＋Ｈ，１００）、Ｃ_１５Ｈ_１７Ｎ_３ＯＳ_２＝３１９．４５として計算
ＨＰＬＣ保持時間：３．７２分
調製法５
ＡＲＥ１１９ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−４−クロロベンズアミドおよび
ＡＲＥ１２０ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−４−クロロベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに４−クロロベンゾイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１１９が黄色がかった固体として生成する。
【０１５７】
質量スペクトル：ｍ／ｚ（％）：１３９．０（１００）、３００．０（Ｍ＋Ｈ，５６）、Ｃ_１１Ｈ_１０ＣｌＮ_３ＯＳ_２＝２９８．９８として計算
ＨＰＬＣ保持時間：３．５２分
ＡＲＥ１１１の代わりにＡＲＥ１１９を用いてプロトコールＢに従うと、ＡＲＥ１２０が白色固体として生成する。
【０１５８】
質量スペクトル：ｍ／ｚ（％）：１３９．０（１００）、２９８．０（Ｍ＋Ｈ，７２）、Ｃ_１１Ｈ_８ＣｌＮ_３ＯＳ_２＝２９６．９８として計算
ＨＰＬＣ保持時間：３．０１分
調製法６
ＡＲＥ１２１ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−４−メトキシベンズアミドおよび
ＡＲＥ１２２ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−４−メトキシベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに４−メトキシベンゾイル
クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１２１が黄色がかった固体として生成する。
【０１５９】
質量スペクトル：ｍ／ｚ（％）：１３５．０（１００）、２９６．２（Ｍ＋Ｈ，３９）、Ｃ_１２Ｈ_１３Ｎ_３Ｏ_２Ｓ_２＝２９５．０３として計算
ＨＰＬＣ保持時間：３．３７分
ＡＲＥ１１１の代わりにＡＲＥ１２１を用いてプロトコールＢに従うと、ＡＲＥ１２２が白色固体として生成する。
【０１６０】
質量スペクトル：ｍ／ｚ（％）：２９４．０（Ｍ＋Ｈ，１００）、Ｃ_１２Ｈ_１１Ｎ_３Ｏ_２Ｓ_２＝２９３．０３として計算
ＨＰＬＣ保持時間：２．８９分
調製法７
ＡＲＥ１２３ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−３−メトキシベンズアミドおよび
ＡＲＥ１２４ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−３−メトキシベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに３−メトキシベンゾイル
クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１２３が黄色がかった固体として生成する。
【０１６１】
質量スペクトル：ｍ／ｚ（％）：１３５．２（１００）、２９６．２（Ｍ＋Ｈ，５３）、Ｃ_１２Ｈ_１３Ｎ_３Ｏ_２Ｓ_２＝２９５．０３として計算
ＨＰＬＣ保持時間：３．２０分
ＡＲＥ１１１の代わりにＡＲＥ１２３を用いてプロトコールＢに従うと、ＡＲＥ１２４が白色固体として生成する。
【０１６２】
質量スペクトル：ｍ／ｚ（％）：２９４．０（Ｍ＋Ｈ，１００）、Ｃ_１２Ｈ_１１Ｎ_３Ｏ_２Ｓ_２＝２９３．０３として計算
ＨＰＬＣ保持時間：２．９４分
調製法８
ＡＲＥ１２５ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−３−メチルベンズアミドおよび
ＡＲＥ１２６ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−３−メチルベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに３−メチルベンゾイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１２５が黄色がかった固体として生成する。
【０１６３】
質量スペクトル：ｍ／ｚ（％）：１１９．４（１００）、２８０．０（Ｍ＋Ｈ，４７）、Ｃ_１２Ｈ_１３Ｎ_３ＯＳ_２＝２７９．０３として計算
ＨＰＬＣ保持時間：３．５９分
ＡＲＥ１１１の代わりにＡＲＥ１２５を用いてプロトコールＢに従うと、ＡＲＥ１２６が白色固体として生成する。
【０１６４】
質量スペクトル：ｍ／ｚ（％）：２７８．０（Ｍ＋Ｈ，１００）、Ｃ_１２Ｈ_１１Ｎ_３ＯＳ_２＝２７７．０３として計算
ＨＰＬＣ保持時間：３．１１分
調製法９
ＡＲＥ１２７ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−４−フルオロベンズアミドおよび
ＡＲＥ１２８ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−４−フルオロベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに４−フルオロベンゾイル
クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１２７が黄色がかった固体として生成する。
【０１６５】
質量スペクトル：ｍ／ｚ（％）：１２３．２（１００）、２８４．２（Ｍ＋Ｈ，７５）、Ｃ_１１Ｈ_１０ＦＮ_３ＯＳ_２＝２８３．０１として計算
ＡＲＥ１１１の代わりにＡＲＥ１２７を用いてプロトコールＢに従うと、ＡＲＥ１２８が白色固体として生成する。
【０１６６】
質量スペクトル：ｍ／ｚ（％）：１２３．２（１００）、２８２．２（Ｍ＋Ｈ，９０）、Ｃ_１１Ｈ_８ＦＮ_３ＯＳ_２＝２８１．０１として計算
ＨＰＬＣ保持時間：２．６８分
調製法１０
ＡＲＥ１２９ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−３−フルオロベンズアミドおよび
ＡＲＥ１３０ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−３−フルオロベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに３−フルオロベンゾイル
クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１２９が黄色がかった固体として生成する。
【０１６７】
質量スペクトル：ｍ／ｚ（％）：１２３．２（１００）、２８４．３（Ｍ＋Ｈ，６１）、Ｃ_１１Ｈ_１０ＦＮ_３ＯＳ_２＝２８３．０１として計算
ＨＰＬＣ保持時間：３．２４分
ＡＲＥ１１１の代わりにＡＲＥ１２９を用いてプロトコールＢに従うと、ＡＲＥ１３０が白色固体として生成する。
【０１６８】
質量スペクトル：ｍ／ｚ（％）：２８２．２（Ｍ＋Ｈ，１００）、Ｃ_１１Ｈ_８ＦＮ_３ＯＳ_２＝２８１．０１として計算
ＨＰＬＣ保持時間：２．９７分
調製法１１
ＡＲＥ１３１ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−２−フルオロベンズアミドおよび
ＡＲＥ１３２ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−２−フルオロベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに２−フルオロベンゾイル
クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１３１が黄色がかった固体として生成する。
【０１６９】
質量スペクトル：ｍ／ｚ（％）：１２３．２（１００）、２８４．０（Ｍ＋Ｈ，６７）、Ｃ_１１Ｈ_１０ＦＮ_３ＯＳ_２＝２８３．０１として計算
ＨＰＬＣ保持時間：３．０７分
ＡＲＥ１１１の代わりにＡＲＥ１３１を用いてプロトコールＢに従うと、ＡＲＥ１３２が白色固体として生成する。
【０１７０】
質量スペクトル：ｍ／ｚ（％）：２８２．２（Ｍ＋Ｈ，１００）、Ｃ_１１Ｈ_８ＦＮ_３ＯＳ_２＝２８１．０１として計算
ＨＰＬＣ保持時間：２．７２分
調製法１２
ＡＲＥ１３３ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−２，４−ジフルオロベンズアミドおよび
ＡＲＥ１３４ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−２，４−ジフルオロベンズアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに２，４−ジフルオロベンゾイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１３３が黄色固体として生成する。
【０１７１】
質量スペクトル：ｍ／ｚ（％）：１４１．０（１００）、３０２．２（Ｍ＋Ｈ，３９）、Ｃ_１１Ｈ_９Ｆ_２Ｎ_３ＯＳ_２＝３０１．０１として計算
ＨＰＬＣ保持時間：３．２３分
ＡＲＥ１１１の代わりにＡＲＥ１３３を用いてプロトコールＢに従うと、ＡＲＥ１３４が白色固体として生成する。
【０１７２】
質量スペクトル：ｍ／ｚ（％）：３００．０（Ｍ＋Ｈ，１００）、Ｃ_１１Ｈ_７Ｆ_２Ｎ_３ＯＳ_２＝２９９．００として計算
ＨＰＬＣ保持時間：２．８６分
調製法１３
ＡＲＥ１３５ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−ナフチル−２−カルボキシアミドおよび
ＡＲＥ１３６ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−ナフチル−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに２−ナフトイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１３５が黄色がかった固体として生成する。
【０１７３】
質量スペクトル：ｍ／ｚ（％）：１５５．０（１００）、３１６．０（Ｍ＋Ｈ，５６）、Ｃ_１５Ｈ_１３Ｎ_３ＯＳ_２＝３１５．４０として計算
ＨＰＬＣ保持時間：３．８８分
ＡＲＥ１１１の代わりにＡＲＥ１３５を用いてプロトコールＢに従うと、ＡＲＥ１３６が白色固体として生成する。
【０１７４】
質量スペクトル：ｍ／ｚ（％）：３１４．０（Ｍ＋Ｈ，１００）、Ｃ_１５Ｈ_１１Ｎ_３ＯＳ_２＝３１３．４０として計算
ＨＰＬＣ保持時間：３．４１分
調製法１４
ＡＲＥ１３７ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−ナフチル−１−カルボキシアミドおよび
ＡＲＥ１３８ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−ナフチル−１−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりに１−ナフトイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１３７が黄色固体として生成する。
【０１７５】
質量スペクトル：ｍ／ｚ（％）：１５５．０（１００）、３１６．０（Ｍ＋Ｈ，３９）、Ｃ_１５Ｈ_１３Ｎ_３ＯＳ_２＝３１５．４０として計算
ＨＰＬＣ保持時間：３．８０分
ＡＲＥ１１１の代わりにＡＲＥ１３７を用いてプロトコールＢに従うと、ＡＲＥ１３８が白色固体として生成する。
【０１７６】
質量スペクトル：ｍ／ｚ（％）：３１４．０（Ｍ＋Ｈ，１００）、Ｃ_１５Ｈ_１１Ｎ_３ＯＳ_２＝３１３．０５として計算
ＨＰＬＣ保持時間：３．３８分
調製法１５
ＡＲＥ１３９ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−ベンゾチオフェン−２−カルボキシアミドおよび
ＡＲＥ１４０ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−ベンゾチオフェン−２−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりにベンゾ〔ｂ〕チオフェン−２−カルボニル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１３９が黄色がかった固体として生成する。
【０１７７】
質量スペクトル：ｍ／ｚ（％）：１６０．８（１００）、３２１．８（Ｍ＋Ｈ，５１）、Ｃ_１３Ｈ_１１Ｎ_３ＯＳ_３＝３２０．９９として計算
ＨＰＬＣ保持時間：３．９２分
ＡＲＥ１１１の代わりにＡＲＥ１３９を用いてプロトコールＢに従うと、ＡＲＥ１４０が白色固体として生成する。
【０１７８】
質量スペクトル：ｍ／ｚ（％）：３２０．０（Ｍ＋Ｈ，１００）、Ｃ_１３Ｈ_９Ｎ_３ＯＳ_３＝３１８．９９として計算
ＨＰＬＣ保持時間：３．４７分
調製法１６
ＡＲＥ１４３ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−フラン−２−カルボキシアミドおよび
ＡＲＥ１４４ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−フラン−２−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わり２−フロイル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１４３が黄色がかった固体として生成する。
【０１７９】
質量スペクトル：ｍ／ｚ（％）：２５６．０（Ｍ＋Ｈ，１００）、Ｃ_９Ｈ_９Ｎ_３Ｏ_２Ｓ_２＝２５５．００として計算
ＨＰＬＣ保持時間：２．８６分
ＡＲＥ１１１の代わりにＡＲＥ１４３を用いてプロトコールＢに従うと、ＡＲＥ１４４が白色固体として生成する。
【０１８０】
質量スペクトル：ｍ／ｚ（％）：２５４．２（Ｍ＋Ｈ，１００）、Ｃ_９Ｈ_９Ｎ_３Ｏ_２Ｓ_２＝２５３．００として計算
ＨＰＬＣ保持時間：２．１３分
調製法１７
ＡＲＥ１４８ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−２，５−ジメチルイソオキサゾール−４−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わり２，５−ジメチルイソオキサゾール−４−カルボニル クロリドを用いて、プロトコールＡに従うと、化合物Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−２，５−ジメチルイソオキサゾール−４−カルボキシアミドが黄色がかった固体として生成する。
【０１８１】
ＡＲＥ１１１の代わりに上記化合物を用いてプロトコールＢに従うと、ＡＲＥ１４８が白色固体として生成する。
【０１８２】
質量スペクトル：ｍ／ｚ（％）：２８３．０（Ｍ＋Ｈ，１００）、Ｃ_１０Ｈ_１０Ｎ_４Ｏ_２Ｓ_２＝２８２．０２として計算
ＨＰＬＣ保持時間：２．５３分
調製法１８
ＡＲＥ１４９ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−イソオキサゾール−３−カルボキシアミドおよび
ＡＲＥ１５０ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−イソオキサゾール−３−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりイソオキサゾール−３−カルボニル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１４９が黄色がかった固体として生成する。
【０１８３】
質量スペクトル：ｍ／ｚ（％）：２５７．０（Ｍ＋Ｈ，１００）、Ｃ_８Ｈ_８Ｎ_４Ｏ_２Ｓ_２＝２５５．９９として計算
ＨＰＬＣ保持時間：２．７６分
ＡＲＥ１１１の代わりにＡＲＥ１４９を用いてプロトコールＢに従うと、ＡＲＥ１５０が白色固体として生成する。
【０１８４】
質量スペクトル：ｍ／ｚ（％）：２５５．２（Ｍ＋Ｈ，１００）、Ｃ_８Ｈ_６Ｎ_４Ｏ_２Ｓ_２＝２５３．９９として計算
ＨＰＬＣ保持時間：２．０９分
調製法１９
ＡＲＥ１５１ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−２−（４−クロロフェニル）−３−（トリフルオロメチル）ピラゾール−４−カルボキシアミドおよび
ＡＲＥ１５２ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−２−（４−クロロフェニル）−３−（トリフルオロメチル）ピラゾール−４−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わり２−（４−クロロフェニル）−３−（トリフルオロメチル）ピラゾール−４−カルボニル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１５１が黄色がかった固体として生成する。
【０１８５】
質量スペクトル：ｍ／ｚ（％）：２７３．０（１００）、４３４．０（Ｍ＋Ｈ，７６）、Ｃ_１５Ｈ_１１ＣｌＦ_３Ｎ_４Ｏ_２Ｓ_２＝４３２．９９として計算
ＨＰＬＣ保持時間：４．２５分
ＡＲＥ１１１の代わりにＡＲＥ１５１を用いてプロトコールＢに従うと、ＡＲＥ１５２が白色固体として生成する。
【０１８６】
質量スペクトル：ｍ／ｚ（％）：４３１．８（Ｍ＋Ｈ，１００）、Ｃ_１５Ｈ_９ ＣｌＦ_３ Ｎ_５ ＯＳ_２ ＝４３１．８として計算
ＨＰＬＣ保持時間：３．７７分
調製法２０
ＡＲＥ１５３ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−２−（４−クロロフェニル）−３−（トリフルオロメチル）ピラゾール−４−カルボキシアミドの調製および分析
チオフェン−２−カルボニル クロリドの代わり２−メチル−５−フェニルイソオキサゾール−４−カルボニル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１５３が黄色がかった固体として生成する。
【０１８７】
質量スペクトル：ｍ／ｚ（％）：３４４．８（Ｍ＋Ｈ，１００）、Ｃ_１５Ｈ_１２Ｎ_４Ｏ_２Ｓ_２＝３４４．４２として計算
ＨＰＬＣ保持時間：４．５７分
調製法２１
ＡＲＥ１５４ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−ピリジン−２−メチルチオ−３−カルボキシアミドの調製および分析
チオフェン−２−カルボニル クロリドの代わりピリジン−２−メチルチオ−３−カルボニル クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１５４が黄色がかった固体として生成する。
【０１８８】
質量スペクトル：ｍ／ｚ（％）：１５２．２（１００）、３１３．２（Ｍ＋Ｈ，１００）、Ｃ_１１Ｈ_１２Ｎ_４ＯＳ_３＝３１２．０２として計算
ＨＰＬＣ保持時間：３．３１分
調製法２２
ＡＲＥ１５５ Ｎ−（２−チオキソ−イミダゾリジン−１−カルボチオイル）−ピリジン−３−カルボキシアミドおよび
ＡＲＥ１５６ Ｎ−（５，６−ジヒドロ−３Ｈ−イミダゾ〔２，１−ｃ〕−１，２，４−ジチアゾール−３−イリデン）−ピリジン−３−カルボキシアミド
の調製および分析
チオフェン−２−カルボニル クロリドの代わりピリジン−３−カルボニル
クロリドを用いて、プロトコールＡに従うと、ＡＲＥ１５５が黄色がかった固体として生成する。
【０１８９】
質量スペクトル：ｍ／ｚ（％）：１６５．０（１００）、２６７．０（Ｍ＋Ｈ，５０）、Ｃ_１０Ｈ_１０Ｎ_４ＯＳ_２＝２６６．０３として計算
ＨＰＬＣ保持時間：２．２９分
ＡＲＥ１１１の代わりにＡＲＥ１５５を用いてプロトコールＢに従うと、ＡＲＥ１５６が白色固体として生成する。
【０１９０】
質量スペクトル：ｍ／ｚ（％）：２６５．０（Ｍ＋Ｈ，１００）、Ｃ_１０Ｈ_８Ｎ_４ＯＳ_２＝２６４．０１して計算
ＨＰＬＣ保持時間：１．８７分
本発明の種々の態様は、種々の構成性活性受容体、発現系、種々のアッセイ、および種々の化合物から成る。当該業界の専門家は、どの受容体がどの発現系およびアッセイ方法と一緒に使用すべきかを理解するであろう。すべては本発明の教示の範囲内であると考える。さらに、当該業界の専門家は、本明細書中に記載した説明のための実施例への各種の変化、追加、置換、および変形が、本発明の精神から外れることなく可能であり、従って、本発明の範囲内にあると考えられることを認めるであろう。実際に、以上に開示したアッセイ系、ならびに受容体ＧＰＲ６と給餌挙動の間の関係に関して、当該業界の通常の熟練者は、受容体に対する小分子反アゴニスト、アゴニストおよび部分アゴニストを直接同定する能力があると信じられ、例えば、表現「小分子ＧＰＲ６反アゴニスト」が本明細書中に開示された特定の化合物に限定されないことを我々は注記する。
【０１９１】
本特許文書中に引用したすべての特許文書、出願、および印刷出版物は、仮出願および正常な特許出願を含めて、別途に特に断らない限り、引用することにより本明細書中にその全体が編入される。熟練した技術者の活動範囲内にある本開示特許の変形および拡張は、上記の開示および請求範囲の範囲に包含される。
【図面の簡単な説明】
【図１】
構成性信号伝達ＧＰＲ６およびＧＰＲ６：融合タンパク質に対する比較結果を示す細胞に基づくサイクリックＡＭＰアッセイの結果のグラフ表示である。
【図２】
ＧＰＲ６およびＧＰＲ６：融合タンパク質による構成性信号伝達に関する比較結果を示す〔^３５Ｓ〕ＧＴＰγＳアッセイの結果のグラフ表示である。
【図３】
ＧＰＲ６に対する数種の候補化合物の一次スクリーニングからの結果のグラフ表示である。化合物「ＡＲＥ１１２」の結果は、ウエルＨ６内に示される。
【図４】
ＧＰＲ６受容体に対する化合物ＡＲＥ１１２のＩＣ_５０曲線のグラフ表示であり、０．１５０１μＭのＩＣ_５０を示す。
【図５】
５Ａ、５Ｂおよび５Ｃは、２４時間絶食ラットに関する、累積飼料摂取（５Ａ）、水摂取（５Ｂ）および体重増加（５Ｃ）に対するＡＲＥ１１２の生体内投与（ＩＰ）の結果のグラフ表示である。
【図６】
６Ａ、６Ｂおよび６Ｃは、非絶食ラットに関する累積飼料摂取（６Ａ）、水摂取（６Ｂ）および体重増加（６Ｃ）に対するＡＲＥ１１２の生体内投与（ＩＰ）の結果のグラフ表示である。
【図７】
７Ａ、７Ｂおよび７Ｃは、２４時間絶食ラットに関する累積飼料摂取（７Ａ）、水摂取（７Ｂ）および体重増加（７Ｃ）に対するＡＲＥ１１２の生体内投与（ＩＣＶ）の結果のグラフ表示である。
【図８】
投与１６時間後のラットの歩行活動に対するＡＲＥ１１２の結果のグラフ表示である。
【図９】
９Ａおよび９Ｂは、２４時間絶食ラットに関する累積飼料摂取（９Ａ）および非絶食ラットに関する累積飼料摂取（９Ｂ）に対するＡＲＥ１１２の生体内投与（強制経口投与）の結果のグラフ表示である。
【図１０】
１０Ａ、１０Ｂおよび１０Ｃは、２４時間絶食ラットに関する、累積飼料摂取（１０Ａ）、水摂取（１０Ｂ）および体重増加（１０Ｃ）に対するＡＲＥ１１２の構造的類似体の生体内投与（強制経口投与）の結果のグラフ表示である。
【図１１】
絶食における体重の長期的低下を示す、ＡＲＥ１１２ラットの毎日反復した生体内（ＩＰ）投与の結果のグラフ表示である。
【図１２】
絶食ラットにおける驚愕反射の低下を示す、ＡＲＥ１１２の生体内（強制経口投与）投与の結果のグラフ表示である。[0001]
[Related application]
This patent document relates to commonly owned U.S. patent application Ser. No. 09 / 364,425, filed by express mail on Jul. 30, 1999. (1) Provisional patent application filed on Jul. 31, 1998. No. 60 / 094,879, (2) Provisional Patent Application No. 60 / 106,300 filed on Oct. 30, 1998, and (3) Provisional Patent Application No. 60 / 110,906 filed on Dec. 4, 1998. No., (4) Provisional Patent Application No. 60 / 121,851 filed on Feb. 26, 1999, (5) Provisional Patent Application No. 60 / 173,850 filed on Dec. 30, 1999, and (6) Claim the benefit of Provisional Patent Application No. 60 / 174,428 filed Jan. 4, 2000. The disclosure of each of the above patent documents is incorporated herein by reference in its entirety. The benefit of priority of the above-cited US patent application Ser. No. 09 / 364,425 and provisional patent applications (4), (5) and (6) is now claimed.
[0002]
FIELD OF THE INVENTION
The present invention relates to a small molecule modulator of the sixth G protein-coupled receptor (GPR6). Preferably, the small molecule modulator is preferentially selected for human GPR6. Most preferably, the small molecule modulator is an anti-agonist to human GPR6.
[0003]
BACKGROUND OF THE INVENTION
A. G protein-coupled receptor
G protein-coupled receptors (GPCRs) share a common structural motif. All these receptors have a seven sequence of 22-24 hydrophobic amino acids, each forming a seven alpha helix spanning the membrane. The transmembrane helix is connected by strands of amino acids that have large loops between the fourth and fifth transmembrane helices on the extracellular side of the membrane. Another large loop, consisting primarily of hydrophilic amino acids, connects the fifth and sixth transmembrane helices inside the cell on the membrane. The carboxy terminus of the receptor is intracellular and the amino terminus is in the extracellular space. It is thought that the loop connecting the fifth and sixth helices and the carboxy terminus interact with the G protein. Currently, Gp, Gs, Gi and Go are G proteins that have been identified.
[0004]
Under physiological conditions, GPCRs exist in the cell membrane in equilibrium between two different states or conformations, an "inactive" state and an "active" state. Receptors in an inactive state are unable to link to intracellular signaling pathways to generate a biological response. Changing the receptor conformation to the active state allows for linking to the transduction pathway and generates a biological response.
[0005]
The receptor is stabilized in an active state by an endogenous ligand or an exogenous agonist ligand. Recent discoveries, including but not limited to alterations in the amino acid sequence of the receptor, have provided alternative mechanisms other than ligands to stabilize the active state conformation. These methods effectively stabilize the receptor in an active state by simulating the effect of ligand binding to the receptor. Such stabilization by the ligand-independent method is called “constitutive receptor activation”. Receptors for which the endogenous ligand is unknown or have not been identified are termed "orphan receptors."
B. Conventional compound screening
In general, the use of orphan receptors for screening purposes to identify compounds that modulate the biological response associated with such receptors has not been possible. This requires that conventional wisdom regarding the screening of compounds requires that the ligand for the receptor be known, thereby competing with the receptor, i.e., blocking or blocking the binding of the natural ligand to the receptor. This is because a compound to be bound was selected. Thus, by definition, this method does not apply to orphan receptors. Thus, given the obsession of this canonical approach to therapeutic discovery, the art seems to abandon the use of orphan receptors essentially and until natural ligands to the receptor are found. And was taught. Pursuit of endogenous ligands for orphan receptors can take years and millions of dollars.
[0006]
In addition, and given that there are more than 2,000 putative GPCRs in the human genome, most of which are orphan receptors, the conventional belief is that creating methods for the discovery of therapeutics for these receptors has Severely restrict research.
[0007]
Many orphan G protein-coupled receptors are constitutively active in their endogenous state. GPR6 is a 362 amino acid homolog of GPR3. The endogenous ligand for GPR6 is unknown (Song Z.-H. et al., See FIG. 1 of the amino acid sequence reported above). GPR6 transcripts have been reported to be abundant in human putamen and less in the frontal cortex, hippocampus and hypothalamus (Heiber M. et al., DNA and Cell Biology (1995) 14 (1): 25, see FIG. 1 of the nucleic acid and amino acid sequences reported for GPR6).
C. obesity
Recently, our latest knowledge on human obesity has advanced rapidly. Previously, obesity was viewed as the hostile behavior of inadequate diet in providing delicious food. Studies of animal models of obesity, biochemical changes in both humans and animals, and the complex interactions of psychosocial and cultural factors that create receptivity to human obesity suggest that this disease in humans is multifaceted And is deeply rooted in biological systems. Thus, obesity has multiple causes. And it is almost certain that there are various forms of obesity.
[0008]
Children and adolescents are overweight. Although not all overweight children become overweight adults, an increase in the incidence of obesity in childhood may be reflected in an increase in obesity in adulthood. The widespread prevalence of obesity in our adult population and the potential for future obesity in the population requires a reconsideration of the health implications of this disease. See "Health Implications of Obesity, NIH Consens. Statement Online 1985 Feb. 11-13; 5 (9): 1-7".
[0009]
“Clinical obesity” is a measure of excess body fat relative to lean weight and is defined as weight that exceeds the ideal weight by more than 20%. Recent estimates suggest that one in two adults in the United States is clinically obese, an increase of more than 25% over the past decade (Flegal MD. Et al., 22 Int. Obes. Relat). Metab. Disor. 39 (1998)). Both overweight and clinical obesity are major health concerns around the world, and in particular, clinical obesity is often associated with a number of complications, hypertension and type II diabetes, which, on the other hand, are coronary artery disease , Stroke, late complications of diabetes and early death (see, eg, Nishina PM et al., 43 Metab. 554 (1994)).
[0010]
Although the etiological mechanism responsible for obesity requires further elucidation, the net effect of this mechanism results in an imbalance between energy intake and expenditure. Both genetic and environmental factors are thought to be involved in the pathogenesis of obesity. These include excessive caloric intake, low physical activity, and metabolic and secretory abnormalities.
[0011]
The treatment of overweight conditions and clinical obesity with medicaments is not only important with respect to the condition itself and also for example with respect to the potential for preventing other diseases associated with clinical obesity, but also at the same time as overweight or clinical obesity It is also important to increase the active awareness of the "self", often associated with those who have had significant weight loss.
[0012]
In view of the above considerations, it is clear that compounds that aid in the treatment of this disease are available in both research and clinical medicine and will bring about advances. The present invention addresses these and other important objectives.
[0013]
Summary of the Invention
The present invention relates to small molecule modulators of the GPR6 receptor. Most preferably, the GPR6 modulator has anti-agonist properties for the receptor.
[0014]
[Definition]
The scientific literature published on receptors uses a number of terms. For clarity and unity, the following definitions will be used throughout this patent document. In the event that these definitions conflict with other definitions for these terms, the definitions below will control.
[0015]
"Active ingredient" shall mean, within the scope of the "pharmaceutical composition", an ingredient of the "pharmaceutical composition" that provides a primary pharmacological benefit, and an "inactive ingredient" generally recognized as not providing a pharmacological benefit. Is the opposite of
[0016]
"Agonist" is intended to mean a moiety that activates an intracellular response when they bind to a receptor or enhances GTP binding to a membrane. Within the scope of the present disclosure, a “drug candidate” comprising a GPR6 “agonist” can be used to gain weight and / or metabolize such that the recipient gains weight and / or maintains weight. . This can be used within a range of abnormalities and / or diseases where weight loss is part of the disease and / or abnormalities such as, for example, anorexia, nervous breakdown, cancer, AIDS cachexia.
[0017]
A "partial agonist" activates an intracellular response to a lesser extent and / or extent when bound to a receptor, or increases GTP binding to a membrane to a lesser extent and / or extent than an agonist. It means the part to be made.
[0018]
An “antagonist” competitively binds to a receptor at the same site as an agonist, but does not activate an intracellular response initiated by the active form of the receptor, and thus an intracellular response by the agonist or partial agonist Means a portion that can inhibit An "antagonist" does not abrogate the basal intracellular response in the absence of an agonist or partial agonist.
[0019]
“Candidate compound” shall mean a small molecule to which screening techniques can be applied within the scope of the present disclosure.
[0020]
“Composition” shall mean a material comprising at least two compounds or two components, including, but not limited to, at least one “active ingredient” and at least one other component. The “pharmaceutical composition” comprising the components of the above is a “composition”.
[0021]
"Compound potency" shall mean a measure of the ability of a compound to inhibit or stimulate receptor functionality, as opposed to receptor binding affinity.
[0022]
“Constitutive receptor activation” shall mean the stabilization of an active receptor by means other than receptor binding, using an endogenous ligand or a chemical equivalent thereof.
[0023]
"Contacting" shall mean bringing at least two parts together, either in an in vitro system or an in vivo system.
[0024]
"Endogenous" shall mean a substance that is naturally produced by a mammal. The term "endogenous" in relation to the term "receptor" is intended to mean, without limitation, that which is naturally produced by a mammal (eg, but not limited to, a human) or a virus. . Conversely, "non-endogenous" shall mean within this range, not naturally produced by a mammal (eg, but not limited to, a human) or a virus. For example, and not by way of limitation, a receptor that is not constitutively active in its endogenous form, but which, when engineered, becomes constitutively active is most preferably referred to herein as "non-endogenous, constituent Sex activated receptor ". Both terms can be used for both "in vivo" and "in vitro" systems. For example, but not by way of limitation, in the case of a screening method, the endogenous or non-endogenous receptor may relate to an in vitro screening system. As another example, and not by way of limitation, when a mammalian genome has been engineered to contain a non-endogenous constitutively activated receptor, screening of candidate compounds using in vivo systems is possible.
[0025]
“G protein-coupled receptor fusion protein” and “GPCR fusion protein” are both within the scope of the invention disclosed herein, and are at least one G protein, most preferably such G protein Refers to a non-endogenous protein comprising an endogenous, constitutively activated orphan GPCR fused to an alpha (α) subunit of GTP, which binds to GTP, wherein the G protein is preferably Is the same type of G protein that naturally couples to the endogenous orphan GPCR. For example, but not by way of limitation, in the endogenous state, the G protein "Gsα" is predominantly conjugated to GPR6 such that the GPR6-based GPCR fusion protein is a non-endogenous protein comprising GPR6 fused to Gsα. G protein. G proteins can be fused directly to the C-terminus of an endogenous, constitutively active orphan GPCR, or they may have a spacer between the two.
[0026]
"Inhibition", in relation to the term "reaction", shall mean to reduce or prevent a response in the presence of a compound, as opposed to the absence of the compound.
[0027]
An "antagonist" binds to an endogenous form of the receptor and is initiated by an active endogenous form of the receptor below the normal basal level of activity observed in the absence of the endogenous ligand, agonist or partial agonist It is intended to mean a moiety that inhibits basal intracellular responses or reduces GTP bound to membranes. Preferably, the basal intracellular response is reduced by at least 30%, more preferably at least 50%, and most preferably at least 75%, in the presence of the anti-agonist, as compared to the basal response in the absence of the anti-agonist. . Biologically, a “GPR6 anti-agonist” is used to describe the interaction of a GPR6 with a GPR6 anti-agonist other than the accurate measurement of the portion interacting with GPR6, eg, when the moiety interacts in vivo with mammalian GPR6. It is intended to mean a moiety that can be assessed in vivo by factors that cause at least 5% weight loss of the mammal within 24 to 48 hours of contact is observed.
[0028]
"Ligand" is intended to mean an endogenously produced molecule specific for an endogenously produced receptor.
[0029]
A "pharmaceutical composition" comprises one "active ingredient" and at least one non- "active ingredient" (eg, but not limited to, a filler, a dye, or a sustained release mechanism). By means of a composition, the composition is suitable for studying specific and potent outcomes in mammals (eg, but not limited to humans). Those of ordinary skill in the art will understand and appreciate the techniques suitable to determine if an active ingredient has the desired efficacious outcome based on the needs of the skilled artisan.
[0030]
"Small molecule" is a non-protein based moiety within the scope of the invention disclosed herein. For example, and without limitation, ARE112 is a small molecule within the scope of the present invention, whereas the endogenous ligand for the receptor is not.
[0031]
DETAILED DESCRIPTION OF THE INVENTION
A. Introduction
Prior discoveries of the receptor suggest that the theoretical (historical) endogenous ligand must first be identified before research can proceed to the discovery of antagonists and other molecules that affect the receptor. The assumption is always being continued. The search continued immediately with the discovery of the endogenous ligand, even if the antagonist was first discovered. This mode of thinking persisted in receptor research, even after the discovery of constitutively activated receptors. What was not recognized is that this is most useful for the discovery of agonists, partial agonists and anti-agonists of the receptor, the active state of the receptor. For these diseases that result from overactive receptors, what is desired for therapeutic agents are compounds that act to reduce the receptor's active state, and are not necessarily antagonists to endogenous ligands. is not. This is because compounds that reduce the activity of the active receptor state (eg, therapeutics) need not bind to the same site as the endogenous ligand. Thus, as the method of the present invention teaches, every search for a therapeutic compound should start with screening the compound for a ligand-independent active state. Thus, the search is for an anti-agonist to the active receptor.
[0032]
For example, screening candidate compounds for orphan receptors, including, but not limited to, GPR6 and GPR6 fusion proteins, requires no prior knowledge or use of the receptor's endogenous ligands. Direct identification of candidate compounds that act on. By determining the region in the body where this receptor is expressed and / or overexpressed, it is possible to determine the relevant disease / abnormal condition associated with the expression and / or overexpression of these receptors, Such a method is disclosed in this patent document.
[0033]
B. Identification and / or selection of disease / abnormality
As described in detail below, most preferably, anti-agonists and agonists to GPR6 can be identified by the methodology of the present invention. Such anti-agonists and agonists are ideal candidates as lead compounds in drug discovery programs for the treatment of diseases associated with this receptor. Indeed, antagonists for such receptors (even if the ligand is known) will not work if the receptor is activated, even in the absence of ligand-receptor binding. The ability to directly identify anti-agonists and agonists for these receptors, and thereby enable the development of pharmaceutical compositions, allows for the search for diseases and disorders associated with these receptors. For example, GPR6 is expressed in the following regions of the brain. Lateral hypothalamus, hippocampus, nucleus accumbens, caudate and cerebral cortex. Given the high levels of expression in regions of the brain associated with ingestion behavior and metabolism, GPR6 appears to be involved in various abnormalities and diseases associated with abnormal food intake and / or metabolism, such as clinical obesity.
[0034]
C. Screening candidate compounds
1. Comprehensive GPCR screening assay technology
When the G protein receptor becomes constitutively active, it binds to G proteins (eg, Gq, Gs, Gi, Go) and stimulates GTP binding to G proteins. The G protein then acts as a GTPase and slowly hydrolyzes GTP to GDP, thereby deactivating the receptor under normal conditions. However, constitutively activated receptors continue to exchange GDP for GTP. It is a non-hydrolysable analog of GTP [ ³⁵ [S] GTPγS can be used to measure enhanced binding to membranes expressing constitutively activated receptors. [ ³⁵ It has been reported that [S] GTPγS can be used to measure G protein coupling to membranes in the presence or absence of ligand. Examples of this measurement are reported in 1995 by Traynor and Nahorski, among other examples well known and available in the art. In general, this preferred use of this assay system is a candidate because the system is generically applicable to all G-protein coupled receptors, regardless of the particular G-protein that interacts with the intracellular domain of the receptor. Suitable for initial screening of compounds.
2. Specific GPCR screening assay technology
Once a candidate compound was identified using the "inclusive" G protein-coupled receptor assay (ie, an assay that selects for compounds that are agonists, partial agonists or anti-agonists), the compound interacted at the receptor site. It is preferable to carry out screening for confirming further. For example, a compound identified by the "inclusive" assay may not bind to the receptor, but may instead simply "uncouple" G proteins from the intracellular domain. Thus, screening these candidate compounds identified using an "inclusive" assay in an agonist and / or antagonist competitive binding assay provides a further improvement in the selection process.
[0035]
In the case of this GPR6, it has been determined that this receptor couples to the G protein Gs. Gs stimulates the enzyme adenylyl cyclase (Gi conversely inhibits this enzyme). Adenylyl cyclase catalyzes the conversion of ATP to cAMP, and thus assays that detect cAMP can be used, for example and without limitation, in cell-based cAMP assays, where the candidate compound binds to the receptor. To determine if it is an anti-agonist (ie, such compounds that contact the receptor reduce cAMP levels as compared to the non-contact receptor). As a result, "cyclase-based assays" can be used to rescreen these compounds selected from agonist and / or antagonist competitive binding assays.
3. GPCR fusion protein
The use of an endogenous, constitutively activated orphan GPCR, such as GPR6, in screening candidate compounds for the direct identification of anti-agonists, agonists and partial agonists is, by definition, that the endogenous receptor is Is a unique challenge by being active even when there is no endogenous ligand that binds to. Thus, for example, to distinguish between an endogenous receptor in the presence of a candidate compound and an endogenous receptor in the absence of the compound, whether such a compound is an anti-agonist, agonist, partial agonist For the purpose of such a distinction to allow an understanding as to whether or not it has an effect on the receptor, the use of a method which can increase such a distinction is preferred. A preferred method is the use of a GPCR fusion protein.
[0036]
In general, once the endogenous orphan GPCR is determined to be constitutively activated using the assay techniques described above (as well as other methods), a dominant G protein coupled to the endogenous GPCR can be determined. Coupling of a G protein to a GPCR provides an evaluable signaling pathway. Such systems are expected to have endogenous G proteins therein, as it is most preferred to perform screening using mammalian expression systems. Thus, by definition, in such a system, the endogenous, constitutively active orphan GPCR will continuously generate a signal. In this regard, it is believed that this signal can be readily distinguished when the receptor is contacted with an anti-agonist, for example, in the presence of an anti-agonist for the receptor, especially within the scope of screening between receptors. It is preferred that it be strengthened as follows.
[0037]
GPCR fusion proteins are intended to enhance the efficacy of G proteins that couple to endogenous GPCRs. GPCR fusion proteins may be important for screening using endogenous, constitutively activated GPCRs, as such methods increase the signals most preferably used in this screening technique. This is important because it facilitates a significant "signal to noise" ratio. Significant ratios are preferred for screening for candidate compounds described herein.
[0038]
The construction of constructs that can be used for expression of a GPCR fusion protein is within the knowledge of a person of ordinary skill in the art. Commercially available expression vectors and systems provide a variety of tools that can be tailored to the specific needs of researchers. The criteria for the importance of such a GPCR fusion protein construct is that the endogenous GPCR sequence and the G protein sequence are both in frame (preferably the sequence of the endogenous GPCR is upstream of the G protein sequence), and The "stop" codon of the GPCR must be deleted or replaced so that the G protein can also be expressed upon expression of the GPCR. The GPCR may be directly linked to the G protein or may have a spacer residue between them (preferably not more than about 12, although this number is readily ascertainable by one of ordinary skill in the art). it can). Both methods have been evaluated and the results are essentially the same for measuring the activity of GPCRs. However, it is preferred (for convenience) to use a spacer so that some unused restriction sites are effectively spacers during expression. Most preferably, the G protein that couples to the endogenous GPCR is identified prior to the creation of the GPCR fusion protein construct. Since only a small number of G proteins have been identified, it is preferred that constructs comprising sequences of G proteins (ie, universal G protein constructs) can be used for insertion of endogenous GPCR sequences therein, This provides efficacy within large-scale screening of a variety of different endogenous GPCRs having different sequences.
[0039]
D. Pharmaceutical composition
Candidate compounds selected in subsequent developments as active ingredients can be incorporated into pharmaceutical compositions using techniques well known in the art. Suitable pharmaceutically acceptable carriers are available from within the art. For example, "Remington's Pharmaceutical Sciences, 16th edition, 1980, Mack Publishing Co., Oslo et al., Eds."
[0040]
【Example】
The following examples are offered by way of illustration of the invention, and not by way of limitation. The order of the specific screening techniques described below are ordered for convenience of explanation. Although specific nucleic acids and amino acids are disclosed herein, those of ordinary skill in the art believe that they are capable of making these sequence changes, which achieve the same or essentially the same results, as reported below.
[0041]
Example 1
Receptor expression
1. cDNA and vector
An expression vector comprising the GPR6 cDNA was generously supplied by Brian O'Dow (University of Toronto). The vector used for GPR6 was pRcCMV (the coding region of GPR6 was subcloned into CMV at the HindIII-Xbal site). See SEQ ID NO: 1 for the nucleic acid sequence of GPR6 and SEQ ID NO: 2 for the derived amino acid sequence.
2. Transfection procedure
On the first day, 1X10 per 150mm plate ⁷ 293 cells were plated out. On the second day, two reaction tubes were prepared (the following ratios for each tube are per plate). Tube A was prepared by mixing 20 μg DNA (eg, pCMV vector; pCMV vector GPR6 cDNA, pCMV vector GPR6: fusion protein) in 1.2 ml of serum-free DMEM (Irvine Scientific, Irvine, CA). Tube B was prepared by mixing 120 μl Lipofectamine (Gibco BRL) in 1.2 ml DMEM without serum. Tubes A and B were then mixed by inversion (several times) and then incubated at room temperature for 30-45 minutes. This mixture is called "transfection mixture". Plated 293 cells were mixed with 1 × PBS and then 10 ml of serum-free DMEM was added. Then, 2.4 ml of the transfection mixture was added to the cells, followed by 4 hours at 37 ° C./5% CO 2. ₂ And incubated. The transfection mixture was then aspirated off and 25 ml of DMEM / 10% fetal bovine serum was added. The cells are then incubated at 37 ° C / 5% CO ₂ And incubated. After a 27 hour incubation, the cells were then harvested and used for analysis.
[0042]
Example 2
GPCR fusion protein preparation
The design of the GPC6 fusion protein construct was as follows. The 5 ′ and 3 ′ ends of the rat G protein Gsα (long form; Itoh, H. et al., 83 PNAS 3776 (1986)) were made to contain HindIII (5′-AAGCTT-3 ′) thereon. Operated. After confirming the correct sequence (including the flanking HindIII sequence), the entire sequence was shuttled into pcDNA3.1 (-) (Invitrogen, catalog number V775-20) by subcloning using the HindIII restriction site of the vector. The correct orientation of the Gsα sequence was determined after subcloning into pcDNA3.1 (-). Next, a modified pcDNA3.1 (-) containing the rat Gsα gene in the HindIII sequence was confirmed. This vector is now available as a “universal” Gsα protein vector. The pcDNA3.1 (-) vector contains various well-known restriction sites upstream of the HindIII sequence, and thus advantageously provides the ability to insert the coding sequence of an endogenous, constitutively active GPCR upstream of the Gs protein. . This same method can be used to create other "universal" G protein vectors, and of course, other commercially available or proprietary vectors well known to the skilled artisan can be used, and the key criteria are GPCR Is upstream and in frame with the sequence of the G protein.
[0043]
The GPR6-Gsα fusion protein construct was made as follows. The primers used were as follows.
5'-gatchTCTAGAATGCAGGGTGCAAATCCGGCC-3 '(SEQ ID NO: 3, sense)
5'-ctagGGTACCCGGACCTCCGCTGGGAGACCTGGAAC-3 '(SEQ ID NO: 4, antisense).
[0044]
The sense and antisense primers contained restriction sites for XbaI and KpnI, respectively. These restriction sites are also available upstream of the HindIII site in the pcDNA3.1 (-) vector.
[0045]
PCR was then used to secure the respective receptor sequence for fusion in the Gsα universal vector disclosed above, each using the following protocol. 100 ng cDNA for GPR6 was added to 2 μl of each primer (sense and antisense) in 3 μl of 10 mM dNTP, 10 × T Taq Plus ^TM 10 μL of Precision buffer, Taq Plus ^TM 1 μL of Precision Polymerase (Strategene, # 600211) and 80 μL of water were added to separate tubes. The reaction temperature and cycle time were as follows. The first denaturation step was repeated 30 times at 96 ° C for 7 minutes and at 96 ° C for 30 seconds, 55 ° C for 30 seconds, and 72 ° C for 2 minutes 30 times. A final extension time of 72 ° C. for 10 minutes was performed on GPR6. The GPR6 PCR product was run on a 1% agarose gel and then purified (data not shown). The purified product was digested with XbaI and KpnI (New England Biolabs), and the desired insert was isolated, purified and ligated into a Gs universal vector at each binding site. Positive clones were isolated, then transformed and determined by restriction enzyme digestion. Expression using 293 cells was performed according to the protocol described below. A positive clone of the GPR6: Gsα-fusion protein was sequenced and used for direct identification of candidate compounds. GPR6: See SEQ ID NO: 5 for the nucleic acid sequence of the Gsα-fusion protein and SEQ ID NO: 6 for the derived amino acid sequence.
[0046]
Example 3A
Evaluation of constitutive activity using an adenylyl cyclase assay
Flash plates designed for cell-based assays ^TM ・ Adenylyl cyclase kit (Flash Plate) ^TM The Adenylyl Cycle Kit (New England Nuclear; catalog number SMA004A) can be modified for use with crude plasma membranes. Flash plate wells can include a scintillation agent coating that also contains a specific antibody that recognizes cAMP. CAMP produced in the wells can be quantified by direct competition for binding of the radioactive cAMP tracer to the cAMP antibody. The following serves as a protocol for measuring changes in cAMP levels in whole cells expressing a receptor such as GPR6 or GPR6: Gsα-fusion protein.
[0047]
Transfected cells are harvested approximately 24 hours after transient transfection. Carefully aspirate and discard the media. Gently add 10 ml of PBS to each dish of cells and then carefully aspirate. Add 1 ml Sigma cell dissociation buffer and 3 ml PBS to each plate. The cells are pipetted off the plate and the cell suspension is collected in a 50 ml conical centrifuge tube. The cells are then centrifuged at room temperature, 1.100 rpm for 5 minutes. Carefully resuspend the cell pellet in the appropriate volume of PBS (about 3 ml / plate). The cells are then counted using a hemocytometer and additional PBS is added to give the appropriate number of cells (final concentration about 50 × 10 5 ⁴ / Well).
[0048]
cAMP standard and detection buffer (tracer to 11 ml of detection buffer [ ¹²⁵ IcAMP (comprising 1 μCi of 50 μl) was prepared and maintained according to the manufacturer's guidelines. Stimulation buffer (preferably freshly prepared) for screening contains 50 μl stimulation buffer, 3 μl test compound (12 μM final assay concentration) and 50 μl cells, and the stimulation buffer can be stored on ice until use. The assay can be started by adding 50 μl of cAMP standard to the appropriate wells and then adding 50 μl of PBSA to wells H-11 and H-12. 50 μl of stimulation buffer was added to all wells. DMSO (or selected candidate compounds) was added to the appropriate wells using a pin device capable of dispensing 3 μl of the compound solution to a final concentration of test compound of 12 μM and a total assay volume of 100 μl. The cells were then added to the wells and incubated for 60 minutes at room temperature. Then 100 μl of detection buffer containing tracer cAMP was added to all wells. Plates were then incubated for a further 2 hours and then counted on a Wallac MicroBeta scintillation counter. The cAMP / well values contained in each assay plate were then extrapolated from a standard cAMP curve.
[0049]
The GPR6 and GPR6: Gsα-fusion proteins were analyzed as described above and confirmed to be constitutively active, demonstrating that the GPR6: fusion proteins had about a 4-fold increase in cAMP over GPR6. (See FIG. 1). Within the scope of screening candidate compounds, it is preferred to maximize the signal-to-noise ratio when the goal is to identify anti-agonists, agonists or partial agonists (especially when screening for anti-agonists). Thus, it is possible to use GPR6 itself, but given the substantial increase in this ratio, the use of a GPR6: fusion protein is particularly preferred (a person of ordinary skill in the art will appreciate the particular needs of the technician). Though it is believed that we will choose a method based on Furthermore, despite the signal rise seen in FIG. 1, these constructs further confirm that there is no "upper limit" or "ceiling" for the signal so that it can be used in a screen for the measurement of GPR6 agonists. (Ie, the agonist will further increase the signal).
[0050]
Example 3B
Evaluation of constitutive activity using GTP membrane-bound scintillation proximal assay
For measuring constitutive activation ³⁵ S] The use of GTPγS binding is described in (a) [ ³⁵ S] GTPγS binding is universally applied to all G protein-coupled receptors, and (b) [ ³⁵ [S] GTPγS binding may be advantageous because the binding is likely to be proximal at the membrane surface, thereby not taking up molecules that affect the intracellular cascade. Preferably, a GPCR: fusion protein is used. This assay is directed to membranes expressing the relevant receptor. ³⁵ [S] Utilizes the ability of G protein-coupled receptors to stimulate GTPγS binding. Thus, this assay may be used to screen compounds directly at the disclosed GPR6 receptor.
[0051]
Proximal scintillation assays are performed, for example, on membranes expressing endogenous human GPR6: Gs-fusion protein (expressed in 293 cells). ³⁵ S] GTPγS was used to measure binding. In summary, a preferred protocol for the assay is 20 mM HEPES, pH 7.4, binding buffer (100 mM NaCl and 10 mM MgCl 2). ₂ ) Within 0.6 nM [ ³⁵ [S] Assay with 60 min incubation with GTPγS and 12.5 μG membrane protein and 0.1 μM GDP. The assay plate was then centrifuged at 4000 rpm for 15 minutes at room temperature, then aspirated and counted in a scintillation counter.
[0052]
Using this assay, control vectors alone or on membranes prepared from 293 cells expressing the human GPR6: Gsα-fusion protein receptor [ ³⁵ [S] Enhanced binding of GTPγS was relatively observed. The total protein concentration used in this assay was determined for each receptor [ ³⁵ S] affected the total amount of GTPγS binding. C. Between the transfected pCMV and the constitutively active GPR6: Gsα-fusion protein receptor. p. m. Difference (at 12.5 μg / ml) is about 6000 c. p. m. From about 11,600 c. p. m. Increased protein concentration.
[0053]
The results are shown in FIG. 2 and demonstrate that the GPR6 receptor (GPR6: Gsα-fusion protein receptor) has increased activity compared to controls. This increased activity is not a result of the autocrine stimulus for which data was obtained from the membrane preparation, which is the opposite of the whole cell preparation.
[0054]
Example 4A
[ ³⁵ S] Direct identification of anti-agonists and agonists using the GTPγS assay We used endogenous, constitutively active GPR6 for direct identification of candidate compounds as anti-agonists, but for reasons not completely understood, Fluctuations may increase. Thus, preferably, the GPCR fusion proteins disclosed above are used. When using this protein, the intra-assay variability appears to stabilize in essence, resulting in an effective signal to noise ratio. This has the advantageous result of allowing more reliable direct identification of the candidate compound. The following protocol is preferred.
1. Membrane preparation
GPCR: A membrane expressing the Gsα-fusion protein (see Example 2) and for use in direct identification of candidate compounds as anti-agonists, agonists or partial agonists was prepared as follows.
(A) Material
Membrane scrape buffer comprised 20 mM HEPES and 10 mM EDTA, pH 7.4. The membrane wash buffer comprised 20 mM HEPES and 0.1 mM EDTA, pH 7.4. The binding buffer was 20 mM HEPES, 100 mM NaCl, and 10 mM MgCl. ₂ , PH 7.4.
(B) Operation
All materials were kept on ice at all times during the run. First, the medium was aspirated from the combined monolayers of cells, then washed with 10 ml of cold PBS and then aspirated. Thereafter, 5 ml of membrane scraping buffer was added to the scraped cells, and the cell extract was transferred to a 50 ml centrifuge tube (centrifugation at 20,000 rpm for 17 minutes at 4 ° C.). Thereafter, the supernatant was aspirated and the pellet was resuspended in 30 ml membrane wash buffer and then centrifuged at 20,000 rpm for 17 minutes at 4 ° C. The supernatant was then aspirated and the pellet was resuspended in binding buffer. Then, Brinkman polytron (Brinkman polytron) ^TM Homogenized using a homogenizer (15-20 second burst until all material was suspended). This is referred to herein as "membrane protein".
2. Bradford protein assay
Following homogenization, the protein concentration of the membrane was determined using a Bradford protein assay (protein could be diluted to about 1.5 mg / ml, sampled and frozen (-80 ° C) for future use) When frozen, the protocol for use is as follows: On the day of the assay, the frozen membrane protein is thawed at room temperature, then vortexed, and then vortexed using a Polytron at about 12 x 1,000 rpm for about 5 hours. Homogenize for 秒 間 10 seconds, note that for multiple preparations, the homogenizer must be thoroughly cleaned during homogenization of different preparations). Reconfirm membrane protein concentration and normalize to CMV with optimal protein concentration between 0.25 μg / μl and 0.30 μg / μl.
(A) Material
Binding buffer (as described above); Bradford dye reagent, Bradford protein standards were used according to the manufacturer's guidelines (Biorad, catalog number 500-0006).
(B) Operation
Two tubes were prepared, one containing the membrane and one as the control "blank". All contained 800 μl of binding buffer. Thereafter, 10 μl of Bradford protein standard (1 mg / ml) was added to each tube, and 10 μl of membrane protein was added to one tube only (excluding blanks). Thereafter, 200 μl of Bradford Dye Reagent was added to each tube and each vortexed. After 5 minutes, the tube was again vortexed and the material therein was transferred to a cuvette. The cuvette was then read using a CECIL 3041 spectrometer at a wavelength of 595.
3. Direct identification assay
(A) Material
The GDP buffer consisted of 37.5 ml of binding buffer and 2 mg of GDP (Sigma, catalog number G-7127), followed by a series of dilutions in binding buffer to obtain 0.2 μM GDP (in each well). Final concentration of GDP was 0.1 μM GDP). Each well comprising the candidate compound contains 100 μl GDP buffer in binding buffer (final concentration 0.1 μM GDP), 50 μl membrane protein (12.5 μg), and 50 μl in binding buffer [ ³⁵ S] GTPγS (0.6 nM) (2.5 μl per 10 ml binding buffer [ ³⁵ S] GTPγS) had a final volume of 200 μl.
(B) Operation
Candidate compounds (Tripos, Inc., St. Louis, MO) were added to 96 well plates (these can be frozen at -80 ° C). The membrane protein (or membrane with expression vector, excluding GPR6: Gsα-fusion protein as control) was briefly homogenized until suspended. The protein concentration was then measured using the Bradford protein assay described above. The membrane protein (and control) was then diluted in binding buffer to 0.25 mg / ml (final assay concentration 12.5 μg / well). Thereafter, 100 μl of the GDP buffer was added to Wallac Scintistrip. ^TM (Wallac) was added to each well. A 5 μl pin instrument was then used to transfer 5 μl of the candidate compound into this well (ie, 5 μl in a total assay volume of 200 μl was a 1:40 ratio, resulting in a final screening concentration of 10 μM for the candidate compound). Again, to prevent contamination, after each transfer step, the pin device is washed in three containers comprising water (1 ×), ethanol (1 ×) and water (2 ×), and excess liquid is added to each container. Shake off after washing, and paper towel and Kimwipe ^TM And dried. Thereafter, 50 μl of membrane protein was added to each well (a control well comprising a membrane without GPCR fusion protein was also used) and preincubated for 5-10 minutes at room temperature (candidate compound obtained from Tripos). Was light sensitive, so the plate was covered with foil). Then, the binding buffer [ ³⁵ 50 μl of [S] GTPγS (0.6 nM) was added to each well and then incubated on a shaker at room temperature for 60 minutes (again, the plate was covered with foil). The assay was then stopped by spinning the plate at 22 ° C. for 15 minutes at 4000 rpm. The plate was then aspirated using an 8-channel manifold and sealed using a plastic plate cover. The plate was then read on a Wallac 1450 using the setting "Protocol # 37" (according to the manufacturer's guidelines).
[0055]
Example 4B
Direct identification of "Leads"
We believe it is important to note that using the orphan receptor to achieve the following results, i.e., using the techniques disclosed herein as data support, Candidate compounds that modulate orphan receptors as agonists, agonists and partial agonists can be identified directly from primary screening. Indeed, the methods disclosed herein are sensitive enough to allow direct identification of both anti-agonists and agonist modulators on the same assay plate.
[0056]
For example, an initial or “primary” screen designed to directly identify human GPR6 receptor anti-agonists consists of the membrane-based GTPγS binding assay of Example 4A using membranes prepared from 293 stable cells. Candidate compounds identified directly as inhibiting the receptor-mediated increase in GTPγS described below are considered active “Leeds”. The primary assay series is then retested in the same assay to reconfirm these anti-agonist activities. If the primary hit is reconfirmed as active (50% or more inhibition), and thus, for example, is directly identified as an anti-agonist, another candidate compound is synthesized based on the structure of this reconfirmed hit (forward). , For example, improving the properties of the compounds), and library compounds directed thereby (Arena Pharmaceuticals, Inc., San Diego, CA) were then evaluated. The last step in the secondary assay evaluation was to determine if the test compound was capable of inhibiting cAMP accumulation (ie, an adenylate cyclase-based assay, disclosed below in Example 4C). This final assay confirms that the directly identified compound retains anti-agonist properties.
[0057]
The results of a representative screening assay plate (96-well format) are shown in FIG. Each bar shows the results for the various compounds and GPR6: Gs fusion protein in each well. The representative results shown in FIG. 3 include the standard deviation based on the average result ("m") for each plate and the sum of twice the average and standard deviation ("m + 2sd") and twice the standard deviation from the average. The subtraction ("m-2sd") is also shown. Our discretionary selection for the selection of an anti-agonist as the "Leeds" from the primary screen involves the selection of candidate compounds that reduce the response rate by at least twice the standard deviation from the average plate response. Based on this selection method, the following candidate compounds in the wells were directly identified as putative anti-agonists for the GPR6 receptor: A7, B2, F6, G6 and H6. Additional evaluation of the compounds specified in wells A7, B2, F6 and G6 (using non-GPR6 receptors) indicates that these compounds are non-specific for the GPR6: Gs fusion protein and therefore It was shown to act to uncouple the G protein from the GPR6 receptor (data not shown). Thus, a candidate compound for well H6, called "ARE112", was selected for subsequent evaluation.
[0058]
Following such identification, the IC ₅₀ (Anti-agonist) or EC ₅₀ It is preferred to determine the (agonist) value. Those having ordinary skill in the art are particularly skilled ICs. ₅₀ And EC ₅₀ It is believed that the assay protocol will be used. FIG. 4 shows a representative IC for compound ARE112 using the assay protocol of Example 4A. ₅₀ It is a curve.
[0059]
Example 4C
Clinical AMP confirmation assay
Preferably, the confirmation assay is performed using an independent assay for obtaining confirmation of the directly identified candidate compound as described above. In this case, the preferred confirmation assay is a membrane-based cyclic AMP (cAMP) assay.
[0060]
Modified flash plate ^TM The adenylyl cyclase kit (New England Nuclear, catalog number SMP004A) was used for the identification of candidate compounds directly identified as anti-agonists and agonists for endogenous, constitutively activated orphan GPCR according to the following protocol. .
[0061]
Transfected stable cells were harvested about 3 days after transfection. The membrane was made of 20 mM HEPES, pH 7.4 and 10 mM MgCl ₂ Prepared by homogenization of cells suspended in a buffer containing Homogenization is performed by Brinkman Polytron. ^TM For about 10 seconds on ice. The resulting homogenate was centrifuged at 20,000 rpm for 20 minutes at 4 ° C. The resulting pellet was then resuspended in a buffer containing 20 mM HEPES, pH 7.4 and 0.1 mM EDTA, homogenized for 10 seconds, and then centrifuged at 20,000 rpm for 20 minutes at 4 ° C. The resulting pellet can be stored at -80C until use. On the day of the direct identification screen, the membrane pellet was slowly thawed at room temperature and 20 mM HEPES, pH 7.4, 100 mM NaCl and 10 mM MgCl2. ₂ To a final protein concentration of 0.60 mg / ml (resuspended membrane was kept on ice until use).
[0062]
cAMP standard and detection buffer (tracer for 11 ml detection buffer [ ¹²⁵ IcAMP (comprising 50 μl] of 2 μCi) was prepared and maintained according to the manufacturer's guidelines. Assay buffer was prepared fresh for screening, 20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl. ₂ , 20 mM phosphocreatine (Sigma), 0.1 units / ml creatine phosphokinase (Sigma), 50 μM GTP (Sigma), 0.2 mM ATP (Sigma) and 0.6 mM isobutyl-methylxanthine (IBMX). . Assay buffer can be stored on ice until use.
[0063]
The candidate compounds identified above (thaw at room temperature if frozen) are placed in plate wells (3 μl / well, final assay concentration 12 μM), 50 μl membrane protein (30 μg / well) and 50 μl assay buffer. Added with The mixture was then incubated for 30 minutes at room temperature with gentle shaking.
[0064]
Following incubation, 100 μl of detection buffer was added to each well and then incubated for 2-20 hours. Subsequently, the plate was aspirated and then Wallac Microbeta using "Protocol # 31". ^TM Counted in plate reader (follow manufacturer's guidelines).
[0065]
Table A below shows the IC determined using the cAMP assay described above. ₅₀ Display the value.
[0066]
[Table 1]

[0067]
Preferably, the IC ₅₀ For the determination, the dose response range at the maximum is in the range of 80-120 percent of the control ("% control"), and is minimal and 20--20 percent of the control. The exact parameters are the choice of the skilled worker and depend on the particular requirements of the skilled worker.
[0068]
Example 5
Screening libraries for orientation
Based on the above results, the structure-activity analysis of the ARE112 compound indicated a series of ARE112 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,3-dithiazole-3-ylidene). Of ARE111 N- (2-thioxo-imidazolidine-1-carbothioyl) will have similar GPR6 anti-agonist activity and selectivity. Derivatives of N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,3-dithiazol-3-ylidene) and derivatives of N- (2-thioxo-imidazolidin-1-carbothioyl) An oriented library was synthesized (see Examples 8 and 9 below). IC ₅₀ Values were determined by calculating the mean ± standard deviation of the number of assays (in parentheses) using the following assay. These were also evaluated using the protocol described above, and the results are summarized in Table B.
[0069]
[Table 2]

[0070]
[Table 3]

[0071]
Example 6
In vivo analysis
1. 24-hour fasted animal feed / water intake and body weight
The profile of ARE112 from the in vivo functional assay suggested that the compound exhibited selective GPR6 anti-agonist properties. In vivo assessment of GPR6 anti-agonists was performed by measuring the effect of ARE112 on food intake after fasting in rats. Fasting was used to induce a higher than normal feeding behavior (eg, control / vehicle treated animals had hyperphagia).
[0072]
Animals (male Sprague-Dawley rats were used for the following tests) were fasted for 24 hours and then intraperitoneally (IP) at 0, 6.75, 13.5, 27 and 54 mg / kg. Compound ARE112 was injected. Thirty minutes later, the rats were given standard rat feed pellets and then observed for 6.5 hours after injection.
[0073]
The data revealed that animals treated IP with compound ARE112 exhibited reduced food intake, water intake and weight gain. In FIG. 5A, 1.5 hours after injection, vehicle-treated animals received about 6 grams of food, while ARE112-treated animals (54 mg / kg) received 3 grams of food. Over time, the data show that vehicle-treated animals consume substantially more food (<14 g at 6.5 hours post-injection), while ARE112-treated animals, especially 54 mg / kg ARE112-treated animals, weigh 4 g. It shows that it was ingested (see FIG. 5A). The data also showed a 4 and 5 fold reduction in water intake at the 27 and 54 mg / kg doses, respectively, as evidenced by the data, which appeared to parallel the reduction in food intake ingested. (See FIG. 5B). Vehicle-treated rats showed a weight gain of 20 g, whereas ARE112-treated rats revealed the following: 13.5 mg / kg treatment gained 11 g body weight, 27 and 54 mg / kg treatment did not gain body weight (see FIG. 5C).
2. Basal diet / water intake and body weight in non-fasting animals
Animals were also observed during their most active period (dark cycle), and both basal food intake and water were measured. In this test, the animals did not fast and instead observed normal activity.
[0074]
Animals were IP administered 0, 6.75, 13.5, 27, and 54 mg / kg of compound ARE112 30 minutes prior to the onset of the dark cycle (ie, 6:30 pm) and then fed a standard rat diet pellet ( That is, 30 minutes after the administration of the compound) and 15.5 hours after the administration. The data shown in FIG. 6A demonstrates that animals receiving ARE112 did not take as much as vehicle-treated animals. For example, vehicle-treated animals received 9 g of diet during 4 hours, while animals treated at doses of 13.5 mg / kg and 54 mg / kg consumed less than half during the same period (4 and 2 mg of diet, respectively). / Kg). Like fasted rats, non-fasted rats also showed reduced water intake and weight gain (see FIGS. 6B and 6C).
[0075]
The long-term effect of ARE112 (60 days) was also tested. Animals (treatment n = 4, control n = 5) were treated with ARE112 intraperitoneally once daily for 22 days and evaluated for 60 days. On days 1-3, animals treated with 13.5 mg / kg lost weight initially and animals gradually gained weight between days 4 and 31, but were lower than vehicle-treated animals. Was. From day 31 to day 60, the data support the opinion that there is a significant difference in body weight between treated and vehicle animals. The data support the conclusion that daily repeated administration of ARE112 (13.5 mg / kg) induces prolonged weight loss in non-fasted rats. See FIG.
3. Intraventricular (ICV) administration of ARE112 to fasted animals
a surgery
Animals were prepared using an ICV cannula targeted over the lateral ventricle. For this surgery, animals were placed under general anesthesia using continuous inhalation of isoflurane and fixed in a head stereotaxic apparatus. Surgery was performed in a dedicated room using sterile instruments, surgical gloves and aseptic procedures to prevent clinical infection. Surgical sites were shaved and disinfected using butazine solution and alcohol. The animals were continuously monitored for the level of anesthesia by examining the animal's response across the tail or limbs. Coordinates of a cannula made of a 23 gauge stainless steel tube (length 7 mm) using A / P-0.6 mm from Bregma, M / L +/- 2.0 mm from Bregma, and D / V 3.2 mm from below the skull surface. It was lowered to a point 1 mm above the ventricle. The guide was fixed to the skull using three stainless steel screws and dental cement. The coordinates were based on a stereotaxic map such as a Paxinos and Watson stereotaxic map (Paxinos, G. and Watson, C. The Rat Brain, New York, Academic Press, 1982). After implantation of the cannula, a 30 gauge stainless steel dummy stylet was inserted into the cannula. At the end of the surgery, a heat source (heat lamp facing half of the recovery cage) was used to maintain body temperature, while the animals were allowed to recover from anesthesia. Compounds were given an ICV injection after at least one week of recovery following surgery.
b. Administration of ARE112
Animals were fasted for 24 hours prior to compound administration.
[0076]
For ICV injection, a dummy stylet was removed from the implanted cannula, and a 30 gauge stainless steel injection cannula containing a suspension of ARE112 in a 45% cyclodextrin solution was placed with the implanted cannula's ventral tip. It was inserted to a depth exceeding 1.5 mm. The end of the other (uninserted) injection cannula was attached to a 60 cm PE10 tube containing the compound suspension and attached to a 25 μl Hamilton syringe at the free end of the tube. Then, 10 μl of the ARE112 suspension (containing 0, 25, 50, 100 nmol) was delivered by lightly rather mechanical pressure to the plunger of a Hamilton syringe. The volume injected was confirmed by a mark on a pre-calibrated PE tube using a 10 μl Hamilton syringe. At the end of the injection, any fluid observed from the dorsal tip of the implanted cannula during withdrawal of the injection cannula was recorded and inserted into the implanted cannula with a dummy stylet.
[0077]
The data revealed that 2 hours after administration of all doses of ARE112, animals consumed substantially less food (approximately 6 times less food). Three hours later, vehicle rats ingested about 2.5 g of food, while ARE112-treated rats ingested about 1.0 g or less. See FIG. 7A. Test animals (25 and 50 nmol) drank as much water as the vehicle, ie, about 17 g. At higher doses (eg, 100 nmol), less than half were ingested (see FIG. 7C). The data are consistent with data generated using IP administration of a 100 nmol dose of ARE112, with ICV-treated animals having substantially less weight gain when compared to vehicle-treated animals that had gained about 12 g. (Eg, 5 g). See FIG. 7C.
4. Effect of ARE112 on motor function
The effect of ARE112 on motor function was also tested. Motor function was evaluated using an automated walking activity cage. Animals were placed in standard rodent cages surrounded by photovoltaic cells that allowed automatic recording of locomotor activity. Animals were free of stimulating forcing and were able to move freely around the cage.
[0078]
Male Sprague-Dawley rats (n = 4-9 per dose) were administered ARE112 (IP) before being placed in a locomotion cage. The data is shown in FIG. Based on the data, it can be concluded that ARE112 had no effect on locomotor activity when animals were housed in a locomotor activity cage for 1.5 hours immediately after ARE112 injection. The data support the conclusion that ARE112 reduces locomotor activity 16 hours after dosing (see FIG. 8), and thus ARE112 has some sedation (eg, animals appear flaccid and appear anxious). Little sedation is shown), indicating that this sedative effect is mild and due to reduced food intake, and not possible by itself.
[0079]
As another evidence of this mild sedation, animals were measured to determine their startle reflex. In this assay, ARE112 was administered orally to rats that had not fasted for 4.5 hours prior to testing. The animals were given a 12 db pre-pulse followed by a 120 db pulse, followed by measuring the animal's jump height. FIG. 12 shows the average startle width of the treated rats (ie, 6.75, 13.5 and 54 mg / kg). Compared to vehicle and 6.75 mg / kg low dose treated rats, 13.5 and 54 mg / kg treated rats did not jump as high in response to the pulse. This data further suggests that at high doses of ARE112, animals show mild sedative activity.
5. Oral efficacy: ARE112
Based on the in vivo data generated, the oral bioavailability of compound ARE112 was determined. Compounds were given by oral gavage to give doses ranging from 6.75 to 54 mg / kg. The data presented in FIGS. 9A and 9B support the conclusion that oral administration of ARE112 also reduces food intake in both fasted and non-fasted rats. The effect of ARE112 is dose dependent and comparable to that observed after IP administration. In FIG. 9A, rats were fasted 24 hours prior to oral administration of compound. In this assay, vehicle-treated rats ingested about 6 g of food in 2.5 hours, while injected rats, especially rats administered 25 and 54 mg / kg of ARE112, ingested about 6 and 4 g, respectively. did. Over time, vehicle-treated rats ingested even larger amounts, about 14 g 8 hours post-dose, while treated rats (27 and 54 mg / kg) received about 8 g and 6 g, respectively (see FIG. 9A).
[0080]
In the second assay, rats were treated with ARE112 by gavage but did not fast. The data reveal even greater reductions in food intake, for example, 18 hours after administration of the compound, vehicle rats receive about 15 g of food, while injected rats (at all doses) lose 5 g or less. Ingested. Treatment with compound ARE112 reduces food intake by about 3-fold (see FIG. 9B). These data support the conclusion that ARE112 is orally active.
6. Evaluation of other compounds
Several other GPR6 anti-agonists were also evaluated under oral fasting conditions using oral administration. The analogs listed below were tested at 200 μmol / kg, equivalent to 54 mg / kg. ARE114 was also evaluated at 100 μmol / kg (27 mg / kg). The data is summarized in Table C below.
[0081]
[Table 4]

[0082]
In a second assay, tested under the same conditions, several other analogs were evaluated at 100 μmol / kg. The data is summarized in Table D below.
[0083]
[Table 5]

[0084]
In FIG. 10, rats were fasted 24 hours before oral administration of the compound. In this assay, the analogs ARE130, ARE135, ARE136 and ARE140 were administered at 100 μmol / kg. In particular, the three analogs, ARE130, ARE136, and ARE140, demonstrate a slow intake of food (eg, about 1-1.5 g per 2 hours) over a period of 8 hours post-dose, while vehicle rats exhibit a rate of About 2 to 2.5 g were ingested. Similar to the vehicle rat, the open-ring analog ARE135 was shown to increase in rats by about 2.5 g per 2 hours for 8 hours after administration (see FIG. 10A). . In addition, vehicle rats and rats receiving the analog ARE135 gained about 19.5 g body weight. Conversely, the closed ring structure revealed a decrease in weight gain as described below. ARE112-6g, ARE130-9g, ARE136-11g and ARE140-14g. See FIG. 10C.
[0085]
Treated rats, especially ARE130 and ARE136, drink even less water compared to vehicle animals, ie, about 10 g and 4 g respectively. In contrast, analogs ARE135 and ARE140 drank comparable amounts (ie, about 19 g). See FIG. 10B. These data suggest that the closed ring structure, preferably ARE112, ARE130, ARE136 and ARE140, more preferably ARE112 and ARE130, and most preferably ARE112 is specific for the 6G protein-coupled receptor.
[0086]
Table E below shows several ICs for analogs of ARE112. ₅₀ Is displayed. IC ₅₀ Values were derived using the GTP assay disclosed in Example 4A. At low concentrations of the analogs ARE130, ARE136 and ARE140, GPR6 is activated and thus stimulates the conversion of GTP to GDP. This data supports the suggestion that the closed ring structure is a selective anti-agonist for GPR6.
[0087]
[Table 6]

[0088]
Example 7
GPR6 anti-agonist
Based on the patent disclosure and information provided herein, one of ordinary skill in the art is believed to be capable of directly identifying candidate compounds that are anti-agonists, agonists and partial agonists of GPR6. More preferably, they are small molecule compounds that have not demonstrated their properties (eg selectivity for GPR6) prior to such direct identification. For agonists, the goal in screening is to find small molecules that increase the measured signal.
[0089]
In the following we disclose our most preferred small molecule GPR6 anti-agonist. It is recognized that there are various stereoisomers of the compounds disclosed herein. The present invention is intended to include the racemates, individual enantiomers, and mixtures thereof.
1. Open-chain aryl series
As a first series of GPR6 inverse agonists, an "open chain aryl" is disclosed which is structurally represented as follows (note: R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Racem mixtures, mixtures of diastereomers, and separated (+) and (-) enantiomers or diastereomers when one or more of Are within the disclosed series and within the claims that follow):
[0090]
Embedded image

[0091]
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl part of the aryl group may be optionally substituted by up to four substituents at any position of the aryl, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring, and when the aryl ring is substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ Can be joined by a chain selected from O to form a bicyclic structure; or
R ^Thirteen And R ¹⁴ Forms part of a 5, 6 or 7 membered ring structure which may be either saturated or unsaturated and may contain up to 4 heteroatoms selected from O, N and S And the ring structure may be at any position:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Optionally substituted with up to 4 substituents independently selected from; or
Where R ^Thirteen And R ¹⁴ Form one aryl ring substituted at two adjacent positions on the aryl ring, said two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl.
[0092]
The following conditions, which are stated preferentially, can thereby be fulfilled: ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Are all H, then R ¹ , R ² , R ³ And R ⁴ At least one is other than H; ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Are all H, then R ³ Is Cl, CH ₃ Or OCH ₃ But also R ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Are all H, then R ² , R ³ And R ⁴ Is OCH ₃ Not.
[0093]
An "aryl moiety" is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle. There can be.
[0094]
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Throughout this specification, the term "alkylaryl" is intended to mean an alkyl moiety having an aryl moiety attached thereto (eg, a benzyl group).
[0095]
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0096]
Further disclosed is a method of modulating a GPR6 receptor by contacting the receptor with a small molecule that is structurally represented as follows:
[0097]
Embedded image

[0098]
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl part of the aryl group may be optionally substituted by up to four substituents at any position of the aryl, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring, and when the aryl ring is substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ Can be joined by a chain selected from O to form a bicyclic structure; or
R ^Thirteen And R ¹⁴ Forms part of a 5, 6 or 7 membered ring structure which may be either saturated or unsaturated and may contain up to 4 heteroatoms selected from O, N and S And the ring structure may be at any position:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Optionally substituted with up to 4 substituents independently selected from; or
Where R ^Thirteen And R ¹⁴ Forms one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl.
2. Closed aryl series
The second series of GPR6 inverse agonists are "closed chain aryls", which are structurally represented as follows:
[0099]
Embedded image

[0100]
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl part of the aryl group may be at any position: F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; or
R ^Thirteen And R ¹⁴ May form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure having four members selected from O, N and S Up to 4 heteroatoms, and each ring structure may be optionally substituted at any position with up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Forms one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl;
The following conditions, which are stated preferentially, can then be fulfilled: ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Are all H, then R ¹ , R ² , R ³ And R ⁴ At least one is other than H; and R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Are all H, then R ³ Is Cl, CH ₃ Or OCH ₃ Not; and R ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Are all H, then R ² , R ³ And R ⁴ Is OCH ₃ Not.
[0101]
An "aryl moiety" is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle. There can be.
[0102]
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
[0103]
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0104]
Further disclosed is a method of modulating a GPR6 receptor by contacting the receptor with a small molecule that is structurally represented as follows:
[0105]
Embedded image

[0106]
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl part of the aryl group may be at any position: F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains the one aryl group substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; or
R ^Thirteen And R ¹⁴ May form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure having four members selected from O, N and S Up to 4 heteroatoms, and each ring structure may be optionally substituted at any position with up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO2C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Forms one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl;
3. Open-chain 6-membered heteroaryl series
A third series of GPR6 inverse agonists are "open-chain 6-membered heteroaryls" which are structurally represented as follows:
[0107]
Embedded image

[0108]
Wherein at least one of V, W, X, Y and Z is selected from N, and each of V, W, X, Y and Z which is not N is CR ¹ , CR ² , CR ³ , CR ⁴ And CR ⁵ Independently selected from, with the proviso that at least two of V, W, X, Y and Z are other than N;
R ¹ , R ² , R ³ , R ⁴ And R ⁵ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl2R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl part of the aryl group may be at any position: F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C2H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; or
R ^Thirteen And R ¹⁴ Form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure having up to 4 members selected from O, N and S Optionally containing a heteroatom, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Form one aryl ring substituted at two adjacent positions on the aryl ring, said two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl;
The aryl moiety is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle Can be;
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
[0109]
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0110]
Further disclosed is a method of modulating a GPR6 receptor by contacting the GPR6 receptor with a small molecule structurally represented by the aforementioned open-chain 6-membered heteroaryl series.
4. Closed 6-membered heteroaryl series
A fourth series of GPR6 inverse agonists are "closed 6-membered heteroaryls" which are structurally represented as follows:
[0111]
Embedded image

[0112]
Wherein at least one of V, W, X, Y and Z is selected from N, and each of V, W, X, Y and Z which is not N is CR ¹ , CR ² , CR ³ , CR ⁴ And CR ⁵ Independently selected from, with the proviso that at least two of V, W, X, Y and Z are other than N;
R ¹ , R ² , R ³ , R ⁴ And R ⁵ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl moiety of the aryl group may be at any position:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H5, OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; or
R ^Thirteen And R ¹⁴ Form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure having up to 4 members selected from O, N and S Optionally containing a heteroatom, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Forms one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl;
The aryl moiety is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle Can be;
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl;
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0113]
Further disclosed are methods of modulating the GPR6 receptor by contacting the GPR6 receptor with a small molecule structurally represented by the closed 6-membered heteroaryl series described above.
5. Open-chained 5-membered heteroaryl (subseries a)
The fifth series of GPR6 inverse agonists are "open-chain five-membered heteroaryls" which are structurally represented as follows:
[0114]
Embedded image

[0115]
Where Z is NR ⁴ , O and S;
W, X or Y is N, CR ¹ , CR ² And CR ³ Where Z is O and Y is N, then W is CR ¹ And X is CR ² And;
R ¹ , R ² And R ³ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, COR ⁵ , CSR ⁵ And SO ₂ R ⁵ Selected from;
R ⁵ , R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl or cycloalkyl, or alkylcycloalkyl, cycloalkylalkyl, or aryl and CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl moiety of the aryl group may be at any position:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring substituted at two adjacent positions on the aryl ring, said two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; ^Thirteen And R ¹⁴ Form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure having up to 4 members selected from O, N and S Optionally containing a heteroatom, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H7) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Forms one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl.
[0116]
The aryl moiety is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle Can be;
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
[0117]
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0118]
Further disclosed is a method of modulating a GPR6 receptor by contacting the GPR6 receptor with a small molecule structurally represented by the open-chain 5-membered heteroaryl series described above.
6. Closed 5-membered heteroaryl (subseries a)
As a sixth series of GPR6 inverse agonists, disclosed are "closed 5-membered heteroaryl sub-series a" which is structurally represented as follows:
[0119]
Embedded image

[0120]
Where Z is NR ⁴ , O and S;
W, X or Y is N, CR ¹ , CR ² And CR ³ Where Z is O and Y is N, then W is CR ¹ And X is CR ² And;
R ¹ , R ² And R ³ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, COR ⁵ , CSR ⁵ And SO ₂ R ⁵ Selected from;
R ⁵ , R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H, (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 or m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl moiety of the aryl group may be at any position:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring substituted at two adjacent positions on the aryl ring, said two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; ^Thirteen And R ¹⁴ Form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure having up to 4 members selected from O, N and S Optionally containing a heteroatom, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Forms one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4- 9 alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl.
[0121]
The aryl moiety is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle Can be;
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
[0122]
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0123]
Further disclosed are methods of modulating the GPR6 receptor by contacting the GPR6 receptor with a small molecule structurally represented by the closed 5-membered heteroaryl series described above.
7. Open-chain 5-membered heteroaryl (subseries b)
Disclosed as a seventh series of GPR6 inverse agonists is an "open five-membered heteroaryl subseries b" that is structurally represented as follows:
[0124]
Embedded image

[0125]
Where Y is NR ⁴ , O or S;
W, X or Z is N or CR ¹ , CR ² Or CR ³ , Where Y is O and Z is N, W is CR ¹ And X is CR ² And;
R ¹ , R ² And R ³ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, COR ⁵ , CSR ⁵ And SO ₂ R ⁵ And;
R ⁵ , R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl moiety of the aryl group may be at any position:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring substituted at two adjacent positions on the aryl ring, said two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; ^Thirteen And R ¹⁴ Form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, wherein each such structure has up to 4 members selected from O, N and S Optionally containing a heteroatom, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C2H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Form one aryl ring substituted at two adjacent positions on the aryl ring, said two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl.
[0126]
The aryl moiety is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle Can be;
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
[0127]
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0128]
Further disclosed is a method of modulating a GPR6 receptor by contacting the GPR6 receptor with a small molecule structurally represented by the open-chain 5-membered heteroaryl series described above.
8. Closed 5-membered heteroaryl (subseries b)
As an eighth series of GPR6 inverse agonists is disclosed a "closed 5-membered heteroaryl sub-series b" which is structurally represented as follows:
[0129]
Embedded image

[0130]
Where Y is NR ⁴ , O or S;
W, X or Z is N or CR ¹ , CR ² Or CR ³ , Where Y is O and Z is N, W is CR ¹ And X is CR ² And;
R ¹ , R ² And R ³ The following:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ^Thirteen R ¹⁴ , NR ^Fifteen COR ¹² , NR ^Fifteen SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , SCF ₂ CF ₂ R ¹² , SCOR ¹² , SO ₃ R ¹² , SO ₂ NR ^Thirteen R ¹⁴ , PO (OR ¹² ) ₃ , PO (OR ¹² ) ₂ R ¹² , NO ₂ , CN, CNR ^Fifteen (NR ^Thirteen R ¹⁴ ), CNR ^Fifteen (SR ¹² ), COOR ¹² , COSR ¹² , CONR ^Thirteen R ¹⁴ Each independently selected from, and
Where R ¹ , R ² , R ³ , R ⁴ And R ⁵ Any two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure;
R ⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, COR ⁵ , CSR ⁵ And SO ₂ R ⁵ Selected from;
R ⁵ , R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ And R ⁷ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl
R ⁸ , R ⁹ , R ¹⁰ And R ¹¹ Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ¹² Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4- 9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Alkenyl, aryl, alkylaryl, (CH ₂ ) _n NR ^Thirteen R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H wherein n is 2 to 6 and m is 1 to 6;
R ^Thirteen And R ¹⁴ Is H, C _1-8 Linear alkyl, branched alkyl, C _2-8 Alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ Each independently selected from aryl, wherein each of said aryl groups or CH ₂ The aryl moiety of the aryl group may be at any position:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ And may be optionally substituted by up to four substituents independently selected from
Where R ^Thirteen And / or R ¹⁴ Contains one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CHCH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; or
R ^Thirteen And R ¹⁴ Form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure having up to 4 members selected from O, N and S Optionally containing a heteroatom, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHC ₂ H ₅ , N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H ₇ , OC ₄ H ₉ , OC ₅ H ₉ , OC ₅ H ₁₁ , OC ₆ H ₁₁ , OC ₆ H _Thirteen , OCF ₃ , OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OSO ₂ CH ₃ , OSO ₂ C ₂ H ₅ , OSO ₂ C ₃ H ₇ , OSO ₂ C ₄ H ₉ , SH, SCH ₃ , SC ₂ H ₅ , SC ₃ H ₇ , SC ₄ H ₇ , SC ₄ H ₉ , SC ₅ H ₉ , SC ₅ H ₁₁ , SC ₆ H ₁₁ , SC ₆ H _Thirteen , SCF ₃ , SCOCH ₃ , SCOC ₂ H ₅ , SCOC ₃ H ₇ , SCOC ₄ H ₉ , SO ₃ CH ₃ , SO ₃ C ₂ H ₅ , SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COOC ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ Independently selected from and
Where R ^Thirteen And R ¹⁴ Form one aryl ring substituted at two adjacent positions on the aryl ring, said two adjacent positions are CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O can be joined by a chain selected from O to form a bicyclic structure; and
R ^Fifteen Is H, C _1-8 Linear alkyl, branched alkyl, C _3-8 Cycloalkyl, C _4-9 Alkylcycloalkyl or cycloalkylalkyl and C _2-8 Selected from alkenyl.
[0131]
The aryl moiety is a 5- or 6-membered aromatic heterocycle (containing up to 4 heteroatoms independently selected from N, O or S) or a 6-membered aromatic non-heterocycle or polycycle Can be;
Suitable C _1-8 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
[0132]
Examples of 5- or 6-membered ring moieties include, but are not limited to, phenyl, furanyl, thienyl, imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, thiazolyl and isothiazolyl. Examples of polycyclic moieties include, but are not limited to, naphthyl, benzothiazolyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, indolyl, quinoxalinyl, quinazolinyl, and benzothienyl.
[0133]
Further disclosed are methods of modulating the GPR6 receptor by contacting the GPR6 receptor with a small molecule structurally represented by the closed 5-membered heteroaryl sub-series described above.
[0134]
Example 8A
Synthetic approach
The compounds disclosed in the present invention can be readily prepared according to a variety of synthetic procedures, all of which will be familiar to those skilled in the art. In the general synthesis shown below, the labeled substituent "R" has the same identity as shown in the definition of the compound disclosed below.
[0135]
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[0136]
In the approaches disclosed below, "Protocol A" is a synthetic approach up to formula (III) and "Protocol B" is a synthetic approach up to formula (V). In each of these approaches, it is shown that the compound prepared by Protocol A is then used in turn as a starting material for the compound prepared by Protocol B.
[0137]
The compounds of formulas (III) and (V), or solvates or physiologically functional derivatives thereof, can be used as active ingredients in pharmaceutical compositions, especially as GPR6 inverse agonists. The data disclosed herein indicate that GPR6 inverse agonists should be used to treat or prevent clinical obesity or overweight disorders in mammals, including but not limited to humans. I support the conclusion. The compounds of formulas (III) and (V) may be administered orally, sublingually, parenterally, rectally, topically or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an effective manner with minimal degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure-sensitive adhesive and a removable protective layer with a release backing. Those of skill in the art will understand and appreciate the appropriate technology for producing transdermal patches with the desired efficacy based on the needs of the skilled artisan.
[0138]
In addition to the neutral forms of the compounds of formulas (III) and (V), the appropriate addition of ionizable substituents which do not alter the receptor specificity of the compound allows the physiologically acceptable salts of the compound to be formed. It can also be formed and used as a therapeutic. Various amounts of the compounds of formulas (III) and (V) may be required to achieve the desired biological effect. The amount will depend on factors such as the particular compound, the intended use for it, the means of administration and the condition of the individual to be treated (all of these dosing parameters are within the level of ordinary skill in the pharmaceutical arts). be able to. A typical dose may be expected to be in the range of 0.001 to 200 mg / kg of mammal. A unit dose may contain from 1 to 200 mg of the compound of formula (III) or (V) and may be administered individually or in a complex one or more times daily. In the case of salts or solvates of the compounds of formulas (III) and (V), the dosage is based on the cation (for the salt) or the unsolvated compound.
[0139]
Without limitation, at least one compound of Formulas (III) and (V) as an active ingredient in combination with at least one carrier or excipient (eg, a pharmaceutical carrier or excipient) and And / or a composition that can include a pharmaceutical composition comprising an acceptable salt or solvate thereof (eg, a pharmaceutically acceptable salt or solvate). The pharmaceutical composition may be used in the treatment of a clinical condition in which a GPR6 inverse agonist is indicated. At least one compound of formulas (III) and (V) may be combined with carriers, either solid or liquid, in unit dosage form. Pharmaceutical carriers must be compatible with the other ingredients in the composition and must be more tolerable by the individual recipient. If desired, and if such components are compatible with the other components in the composition, other physiologically active ingredients may be incorporated into the pharmaceutical compositions of the present invention. The formulations are typically prepared by uniformly mixing the active ingredient (s) with the liquid or finely divided solid carrier or both in the required proportions, and Thereafter, if necessary, the mixture may be produced by forming the resulting mixture into a desired shape.
[0140]
Conventional excipients such as binders, fillers, acceptable wetting agents, tableting lubricants and disintegrating agents may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral formulation may be in the form of a dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and additional additives such as flavoring and coloring agents may be added to the liquid formulation. Parenteral dosage forms may be made by dissolving the compound of the invention in a suitable liquid vehicle, filter sterilizing before filling with the solution, and sealing appropriate vials or ampules. These are just a few of the many suitable methods known in the art for producing dosage forms.
[0141]
The use of GPR6 inverse agonists as active ingredients in pharmaceutical compositions indicates that they are intended not only for humans, but for use in other non-human mammals as well. Indeed, recent advances in the area of animal health care have led to the adoption of GPR6 inverse agonists for the treatment of obesity in domestic animals (eg, cats and dogs), and other domesticated animals in which the disease or disorder is not apparent. It dictates that the use of GPR6 agonists in animals (e.g., food-oriented animals such as cows, chickens, fish, etc.) be considered. It is readily believed that one skilled in the art would understand the utility of such compounds in such settings.
[0142]
The following is a representation of the structure of the compound determined to exhibit GPR6 inverse agonist activity and selectivity similar to that of compound ARE112.
[0143]
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[0144]
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[0145]
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[0146]
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[0147]
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[0148]
Example 8B
Preparation of Compounds ARE111-ARE156
Mass spectra were obtained on a PE Sciex API 150 EX mass spectrometer coupled to a Shimazu dual pump (2 LC8 pumps) HPLC using a CombiScreen C18 reversed phase column (50 mm x 4.6 mm ID) HPLC. Recorded. Gradient elution was at 3.5 ml / min from 5% acetonitrile with 0.05% TFA / 5% acetonitrile with 0.35% TFA to 100% acetonitrile in 5 minutes. Unless otherwise specified, samples eluted from HPLC were usually measured at 220 nm using a Shimadzu SPD-10AVP detector. All reagents were purchased from commercial sources.
Preparation method 1
ARE111 N- (2-thioxo-imidazolidin-1-carbothioyl) -thiophen-2-carboxamide and
ARE112 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -thiophen-2-carboxamide
Preparation and analysis
The following synthesis protocol was used for the production of each of the following compounds.
Protocol A:
To a freshly prepared solution of potassium thiocyanate (2.14 g, 22 mmol) in dry acetone (80 ml) was added thiophene-2-carbonyl chloride (2.93 g, 20 mmol) dropwise at room temperature. The reaction mixture is then heated at reflux for 15 minutes to give thiophen-2-carbonyl isothiocyanate in situ as a yellow suspension. The heat was turned off and 2-imidazolidinthione (2.04 g, 20 mmol) was added. The mixture was then heated at reflux for a further 4 hours, then allowed to cool and then stirred at room temperature overnight (15 hours). 50 ml of water were added and the mixture was further stirred at room temperature for several minutes. The resulting precipitate was collected by filtration and washed with water, water / methanol (1: 1) and methanol to give compound ARE111 (2.865 g, yield = 53%).
[0149]
Mass spectrum: m / z (%): 272.0 (M + H, 100), C ₉ H ₉ N ₃ OS ₃ Calculated as = 270.98
HPLC retention time: 2.97 minutes
Protocol B:
To a suspension of ARE111 (2 g, 7.37 mmol) in ethanol (30 ml) was added concentrated hydrochloric acid (0.75 ml) and 30% hydrogen peroxide (2 ml). The reaction mixture is heated at reflux in an oil bath for 2 hours, turning the yellow suspension white. The resulting precipitate is collected by filtration and washed with ethanol to give the hydrochloride salt, which is then suspended in ethanol (20 ml) and treated with 28-30% ammonium hydroxide (1 ml) Then, a free base is generated. The reaction mixture was stirred at room temperature for 20 minutes, then the resulting precipitate was collected by filtration, washed with ethanol and dried to give compound ARE112 (1.304 g, yield = 66%) as a yellowish solid. Can be
[0150]
MS (ES +): m / z (%): 270 (M + H, 100)
Mass spectrum: m / z (%): 270.0 (M + H, 100), C ₉ H ₇ N ₃ OS ₃ Calculated as = 269.98
HPLC retention time: 2.36 minutes
Preparation method 2
ARE113 N- (2-thioxo-imidazolidin-1-carbothioyl) -benzamide and
ARE114 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -benzamide
Preparation and analysis
Following the procedure of Protocol A above using benzoyl chloride instead of thiophene-2-carbonyl chloride, ARE113 is formed as a yellowish solid.
[0151]
Mass spectrum: m / z (%): 266.0 (M + H, 100), C ₁₁ H ₁₁ N ₃ OS ₂ = 265.02
HPLC retention time: 3.29 minutes
Following the procedure of Protocol B above, using ARE 113 instead of ARE 111, produces ARE 114 as a white solid.
[0152]
Mass spectrum: m / z (%): 263.8 (M + H, 61), C ₁₁ H ₉ N ₃ OS ₂ = 263.02
HPLC retention time: 2.53 minutes
Preparation method 3
ARE115 N- (2-thioxo-imidazolidin-1-carbothioyl) -4-trifluoromethylbenzamide and
ARE116 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -4-trifluoromethylbenzamide;
Preparation and analysis
According to Protocol A using 4- (trifluoromethyl) benzoyl chloride instead of thiophene-2-carbonyl chloride, ARE115 is formed as a yellowish solid.
[0153]
Mass spectrum: m / z (%): 173.0 (100), 334.2 (M + H, 83), C ₁₂ H ₁₀ F ₃ N ₃ OS ₂ = 333.01 calculated
HPLC retention time: 3.69 minutes
Following Protocol B using ARE 115 instead of ARE 111 produces ARE 116 as a white solid.
[0154]
Mass spectrum: m / z (%): 332.0 (M + H, 100), C ₁₂ H ₁₂ F ₃ N ₃ OS ₂ Calculated as = 331.01
HPLC retention time: 3.28 minutes
Preparation method 4
ARE117 N- (2-thioxo-imidazolidine-1-carbothioyl) -4-t-butylbenzamide and
ARE118 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -4-t-butylbenzamide
Preparation and analysis
According to Protocol A, using tert-butylbenzoyl chloride instead of thiophene-2-carbonyl chloride, ARE117 is formed as a yellowish solid.
[0155]
Mass spectrum: m / z (%): 161.0 (100), 322.0 (M + H, 53), C _Fifteen H ₁₉ N ₃ OS ₂ = 321.45 calculated
HPLC retention time: 3.97 minutes
Following Protocol B using ARE117 instead of ARE111 produces ARE118 as a white solid.
[0156]
Mass spectrum: m / z (%): 320.0 (M + H, 100), C _Fifteen H ₁₇ N ₃ OS ₂ = 319.45 calculated
HPLC retention time: 3.72 minutes
Preparation method 5
ARE119 N- (2-thioxo-imidazolidin-1-carbothioyl) -4-chlorobenzamide and
ARE120 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazole-3-ylidene) -4-chlorobenzamide
Preparation and analysis
According to Protocol A, using 4-chlorobenzoyl chloride instead of thiophene-2-carbonyl chloride, ARE119 is formed as a yellowish solid.
[0157]
Mass spectrum: m / z (%): 139.0 (100), 300.0 (M + H, 56), C ₁₁ H ₁₀ ClN ₃ OS ₂ Calculated as = 298.98
HPLC retention time: 3.52 minutes
Following Protocol B using ARE 119 instead of ARE 111 produces ARE 120 as a white solid.
[0158]
Mass spectrum: m / z (%): 139.0 (100), 298.0 (M + H, 72), C ₁₁ H ₈ ClN ₃ OS ₂ Calculated as = 296.98
HPLC retention time: 3.01 minutes
Preparation method 6
ARE121 N- (2-thioxo-imidazolidin-1-carbothioyl) -4-methoxybenzamide and
ARE122 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -4-methoxybenzamide
Preparation and analysis
4-methoxybenzoyl instead of thiophene-2-carbonyl chloride
According to Protocol A with chloride, ARE121 is produced as a yellowish solid.
[0159]
Mass spectrum: m / z (%): 135.0 (100), 296.2 (M + H, 39), C ₁₂ H _Thirteen N ₃ O ₂ S ₂ Calculated as = 295.03
HPLC retention time: 3.37 minutes
Following Protocol B using ARE 121 instead of ARE 111 produces ARE 122 as a white solid.
[0160]
Mass spectrum: m / z (%): 294.0 (M + H, 100), C ₁₂ H ₁₁ N ₃ O ₂ S ₂ Calculated as = 293.03
HPLC retention time: 2.89 minutes
Preparation method 7
ARE123 N- (2-thioxo-imidazolidine-1-carbothioyl) -3-methoxybenzamide and
ARE124 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazole-3-ylidene) -3-methoxybenzamide
Preparation and analysis
3-methoxybenzoyl instead of thiophene-2-carbonyl chloride
According to Protocol A with chloride, ARE123 is produced as a yellowish solid.
[0161]
Mass spectrum: m / z (%): 135.2 (100), 296.2 (M + H, 53), C ₁₂ H _Thirteen N ₃ O ₂ S ₂ Calculated as = 295.03
HPLC retention time: 3.20 minutes
Following Protocol B using ARE123 instead of ARE111 produces ARE124 as a white solid.
[0162]
Mass spectrum: m / z (%): 294.0 (M + H, 100), C ₁₂ H ₁₁ N ₃ O ₂ S ₂ Calculated as = 293.03
HPLC retention time: 2.94 minutes
Preparation method 8
ARE125 N- (2-thioxo-imidazolidin-1-carbothioyl) -3-methylbenzamide and
ARE126 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -3-methylbenzamide
Preparation and analysis
According to Protocol A using 3-methylbenzoyl chloride instead of thiophene-2-carbonyl chloride, ARE125 is formed as a yellowish solid.
[0163]
Mass spectrum: m / z (%): 119.4 (100), 280.0 (M + H, 47), C ₁₂ H _Thirteen N ₃ OS ₂ Calculated as = 279.03
HPLC retention time: 3.59 minutes
Following Protocol B using ARE 125 instead of ARE 111 produces ARE 126 as a white solid.
[0164]
Mass spectrum: m / z (%): 278.0 (M + H, 100), C ₁₂ H ₁₁ N ₃ OS ₂ Calculated as = 277.03
HPLC retention time: 3.11 minutes
Preparation Method 9
ARE127 N- (2-thioxo-imidazolidine-1-carbothioyl) -4-fluorobenzamide and
ARE128 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -4-fluorobenzamide
Preparation and analysis
4-fluorobenzoyl instead of thiophene-2-carbonyl chloride
According to Protocol A with chloride, ARE127 is produced as a yellowish solid.
[0165]
Mass spectrum: m / z (%): 123.2 (100), 284.2 (M + H, 75), C ₁₁ H ₁₀ FN ₃ OS ₂ Calculated as = 283.01
Following Protocol B using ARE 127 instead of ARE 111 produces ARE 128 as a white solid.
[0166]
Mass spectrum: m / z (%): 123.2 (100), 282.2 (M + H, 90), C ₁₁ H ₈ FN ₃ OS ₂ = 281.01 calculated
HPLC retention time: 2.68 minutes
Preparation method 10
ARE129 N- (2-thioxo-imidazolidin-1-carbothioyl) -3-fluorobenzamide and
ARE130 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -3-fluorobenzamide
Preparation and analysis
3-fluorobenzoyl instead of thiophene-2-carbonyl chloride
According to Protocol A with chloride, ARE129 is produced as a yellowish solid.
[0167]
Mass spectrum: m / z (%): 123.2 (100), 284.3 (M + H, 61), C ₁₁ H ₁₀ FN ₃ OS ₂ Calculated as = 283.01
HPLC retention time: 3.24 minutes
Following Protocol B using ARE 129 instead of ARE 111 produces ARE 130 as a white solid.
[0168]
Mass spectrum: m / z (%): 282.2 (M + H, 100), C ₁₁ H ₈ FN ₃ OS ₂ = 281.01 calculated
HPLC retention time: 2.97 minutes
Preparation method 11
ARE131 N- (2-thioxo-imidazolidin-1-carbothioyl) -2-fluorobenzamide and
ARE132 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -2-fluorobenzamide
Preparation and analysis
2-fluorobenzoyl instead of thiophene-2-carbonyl chloride
According to Protocol A with chloride, ARE131 is produced as a yellowish solid.
[0169]
Mass spectrum: m / z (%): 123.2 (100), 284.0 (M + H, 67), C ₁₁ H ₁₀ FN ₃ OS ₂ Calculated as = 283.01
HPLC retention time: 3.07 minutes
Following Protocol B using ARE 131 instead of ARE 111 produces ARE 132 as a white solid.
[0170]
Mass spectrum: m / z (%): 282.2 (M + H, 100), C ₁₁ H ₈ FN ₃ OS ₂ = 281.01 calculated
HPLC retention time: 2.72 minutes
Preparation method 12
ARE133 N- (2-thioxo-imidazolidin-1-carbothioyl) -2,4-difluorobenzamide and
ARE134 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -2,4-difluorobenzamide
Preparation and analysis
According to Protocol A using 2,4-difluorobenzoyl chloride instead of thiophene-2-carbonyl chloride, ARE133 is formed as a yellow solid.
[0171]
Mass spectrum: m / z (%): 141.0 (100), 302.2 (M + H, 39), C ₁₁ H ₉ F ₂ N ₃ OS ₂ = Calculated as 301.01
HPLC retention time: 3.23 minutes
Following Protocol B using ARE 133 instead of ARE 111 produces ARE 134 as a white solid.
[0172]
Mass spectrum: m / z (%): 300.0 (M + H, 100), C ₁₁ H ₇ F ₂ N ₃ OS ₂ = Calculate as 299.00
HPLC retention time: 2.86 minutes
Preparation method 13
ARE135 N- (2-thioxo-imidazolidin-1-carbothioyl) -naphthyl-2-carboxamide and
ARE136 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -naphthyl-carboxamide
Preparation and analysis
According to Protocol A, using 2-naphthoyl chloride instead of thiophene-2-carbonyl chloride, ARE135 is formed as a yellowish solid.
[0173]
Mass spectrum: m / z (%): 155.0 (100), 316.0 (M + H, 56), C _Fifteen H _Thirteen N ₃ OS ₂ Calculated as = 315.40
HPLC retention time: 3.88 minutes
Following Protocol B using ARE 135 instead of ARE 111 produces ARE 136 as a white solid.
[0174]
Mass spectrum: m / z (%): 314.0 (M + H, 100), C _Fifteen H ₁₁ N ₃ OS ₂ Calculated as = 313.40
HPLC retention time: 3.41 minutes
Preparation method 14
ARE137 N- (2-thioxo-imidazolidin-1-carbothioyl) -naphthyl-1-carboxamide and
ARE138 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -naphthyl-1-carboxamide
Preparation and analysis
According to Protocol A using 1-naphthoyl chloride instead of thiophene-2-carbonyl chloride, ARE137 is produced as a yellow solid.
[0175]
Mass spectrum: m / z (%): 155.0 (100), 316.0 (M + H, 39), C _Fifteen H _Thirteen N ₃ OS ₂ Calculated as = 315.40
HPLC retention time: 3.80 minutes
Following Protocol B using ARE 137 instead of ARE 111 produces ARE 138 as a white solid.
[0176]
Mass spectrum: m / z (%): 314.0 (M + H, 100), C _Fifteen H ₁₁ N ₃ OS ₂ Calculated as = 313.05
HPLC retention time: 3.38 minutes
Preparation method 15
ARE139 N- (2-thioxo-imidazolidine-1-carbothioyl) -benzothiophene-2-carboxamide and
ARE140 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -benzothiophen-2-carboxamide
Preparation and analysis
According to Protocol A, using benzo [b] thiophen-2-carbonyl chloride instead of thiophen-2-carbonyl chloride, ARE139 is formed as a yellowish solid.
[0177]
Mass spectrum: m / z (%): 160.8 (100), 321.8 (M + H, 51), C _Thirteen H ₁₁ N ₃ OS ₃ Calculated as = 320.99
HPLC retention time: 3.92 minutes
Following Protocol B using ARE 139 instead of ARE 111 produces ARE 140 as a white solid.
[0178]
Mass spectrum: m / z (%): 320.0 (M + H, 100), C _Thirteen H ₉ N ₃ OS ₃ Calculated as = 318.99
HPLC retention time: 3.47 minutes
Preparation method 16
ARE143 N- (2-thioxo-imidazolidin-1-carbothioyl) -furan-2-carboxamide and
ARE144 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -furan-2-carboxamide
Preparation and analysis
According to Protocol A using 2-furoyl chloride instead of thiophene-2-carbonyl chloride, ARE143 is formed as a yellowish solid.
[0179]
Mass spectrum: m / z (%): 256.0 (M + H, 100), C ₉ H ₉ N ₃ O ₂ S ₂ Calculated as = 255.00
HPLC retention time: 2.86 minutes
Following Protocol B using ARE 143 instead of ARE 111 produces ARE 144 as a white solid.
[0180]
Mass spectrum: m / z (%): 254.2 (M + H, 100), C ₉ H ₉ N ₃ O ₂ S ₂ = 253.00
HPLC retention time: 2.13 minutes
Preparation method 17
ARE148 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -2,5-dimethylisoxazole-4-carboxamide
Preparation and analysis
According to Protocol A using 2,5-dimethylisoxazole-4-carbonyl chloride instead of thiophene-2-carbonyl chloride, the compound N- (2-thioxo-imidazolidin-1-carbothioyl) -2,5-dimethyl Isoxazole-4-carboxamide is formed as a yellowish solid.
[0181]
Following Protocol B using the above compound in place of ARE111 produces ARE148 as a white solid.
[0182]
Mass spectrum: m / z (%): 283.0 (M + H, 100), C ₁₀ H ₁₀ N ₄ O ₂ S ₂ Calculated as = 282.02
HPLC retention time: 2.53 minutes
Preparation method 18
ARE149 N- (2-thioxo-imidazolidin-1-carbothioyl) -isoxazole-3-carboxamide and
ARE150 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazole-3-ylidene) -isoxazole-3-carboxamide
Preparation and analysis
According to Protocol A using isoxazole-3-carbonyl chloride instead of thiophene-2-carbonyl chloride, ARE149 is formed as a yellowish solid.
[0183]
Mass spectrum: m / z (%): 257.0 (M + H, 100), C ₈ H ₈ N ₄ O ₂ S ₂ = Calculate as 255.99
HPLC retention time: 2.76 minutes
Following Protocol B using ARE 149 instead of ARE 111 produces ARE 150 as a white solid.
[0184]
Mass spectrum: m / z (%): 255.2 (M + H, 100), C ₈ H ₆ N ₄ O ₂ S ₂ = 253.99 calculated
HPLC retention time: 2.09 minutes
Preparation Method 19
ARE151 N- (2-thioxo-imidazolidin-1-carbothioyl) -2- (4-chlorophenyl) -3- (trifluoromethyl) pyrazole-4-carboxamide and
ARE152 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -2- (4-chlorophenyl) -3- (trifluoromethyl) pyrazole- 4-carboxamide
Preparation and analysis
According to Protocol A using 2- (4-chlorophenyl) -3- (trifluoromethyl) pyrazole-4-carbonyl chloride instead of thiophene-2-carbonyl chloride, ARE151 is formed as a yellowish solid.
[0185]
Mass spectrum: m / z (%): 273.0 (100), 434.0 (M + H, 76), C _Fifteen H ₁₁ ClF ₃ N ₄ O ₂ S ₂ Calculated as = 432.99
HPLC retention time: 4.25 minutes
Following Protocol B using ARE 151 instead of ARE 111 produces ARE 152 as a white solid.
[0186]
Mass spectrum: m / z (%): 431.8 (M + H, 100), C _Fifteen H ₉ ClF ₃ N ₅ OS ₂ Calculated as = 431.8
HPLC retention time: 3.77 minutes
Preparation method 20
ARE153 Preparation and analysis of N- (2-thioxo-imidazolidine-1-carbothioyl) -2- (4-chlorophenyl) -3- (trifluoromethyl) pyrazole-4-carboxamide
According to Protocol A using 2-methyl-5-phenylisoxazole-4-carbonyl chloride instead of thiophene-2-carbonyl chloride, ARE153 is formed as a yellowish solid.
[0187]
Mass spectrum: m / z (%): 344.8 (M + H, 100), C _Fifteen H ₁₂ N ₄ O ₂ S ₂ = 344.42
HPLC retention time: 4.57 minutes
Preparation method 21
ARE154 Preparation and analysis of N- (2-thioxo-imidazolidin-1-carbothioyl) -pyridine-2-methylthio-3-carboxamide
According to Protocol A using pyridine-2-methylthio-3-carbonyl chloride instead of thiophene-2-carbonyl chloride, ARE 154 is formed as a yellowish solid.
[0188]
Mass spectrum: m / z (%): 152.2 (100), 313.2 (M + H, 100), C ₁₁ H ₁₂ N ₄ OS ₃ Calculated as = 312.02
HPLC retention time: 3.31 minutes
Preparation Method 22
ARE155 N- (2-thioxo-imidazolidine-1-carbothioyl) -pyridine-3-carboxamide and
ARE156 N- (5,6-dihydro-3H-imidazo [2,1-c] -1,2,4-dithiazol-3-ylidene) -pyridine-3-carboxamide
Preparation and analysis
Pyridine-3-carbonyl instead of thiophene-2-carbonyl chloride
According to Protocol A with chloride, ARE155 is produced as a yellowish solid.
[0189]
Mass spectrum: m / z (%): 165.0 (100), 267.0 (M + H, 50), C ₁₀ H ₁₀ N ₄ OS ₂ = 266.03
HPLC retention time: 2.29 minutes
Following Protocol B using ARE 155 instead of ARE 111 produces ARE 156 as a white solid.
[0190]
Mass spectrum: m / z (%): 265.0 (M + H, 100), C ₁₀ H ₈ N ₄ OS ₂ = 264.01 and calculated
HPLC retention time: 1.87 minutes
Various embodiments of the invention consist of various constitutively active receptors, expression systems, various assays, and various compounds. Those skilled in the art will understand which receptors to use with which expression systems and assay methods. All are considered to be within the teachings of the present invention. In addition, those skilled in the art will recognize that various changes, additions, substitutions, and variations to the illustrative embodiments described herein are possible without departing from the spirit of the invention, It will be appreciated that it is considered to be within the scope of the present invention. Indeed, with respect to the assay systems disclosed above, and the relationship between receptor GPR6 and feeding behavior, one of ordinary skill in the art would have the ability to directly identify small molecule anti-agonists, agonists and partial agonists for the receptor. We believe that, for example, we note that the expression “small molecule GPR6 anti-agonist” is not limited to the specific compounds disclosed herein.
[0191]
All patent documents, applications, and printed publications cited in this patent document, including provisional applications and normal patent applications, are hereby incorporated by reference in their entirety, unless otherwise indicated. Will be transferred. Variations and extensions of this disclosure patent that are within the skill of the artisan are within the scope of the above disclosure and claims.
[Brief description of the drawings]
FIG.
FIG. 5 is a graphical representation of the results of a cell-based cyclic AMP assay showing constitutive signaling GPR6 and GPR6: fusion protein results.
FIG. 2
GPR6 and GPR6: Comparative results on constitutive signaling by fusion proteins are shown [ ³⁵ S] Graphical representation of the results of a GTPγS assay.
FIG. 3
FIG. 2 is a graphical representation of the results from the primary screening of several candidate compounds for GPR6. The results for compound "ARE112" are shown in well H6.
FIG. 4
Compound ARE112 IC for GPR6 receptor ₅₀ It is a graph display of a curve, IC of 0.1501 μM ₅₀ Is shown.
FIG. 5
5A, 5B and 5C are graphical representations of the results of in vivo administration (IP) of ARE112 on cumulative feed intake (5A), water intake (5B) and weight gain (5C) for 24-hour fasted rats.
FIG. 6
6A, 6B and 6C are graphical representations of the results of in vivo administration (IP) of ARE112 on cumulative feed intake (6A), water intake (6B) and weight gain (6C) for non-fasted rats.
FIG. 7
7A, 7B and 7C are graphical representations of the results of in vivo administration of ARE112 (ICV) on cumulative feed intake (7A), water intake (7B) and weight gain (7C) for 24-hour fasted rats.
FIG. 8
It is a graphic display of the result of ARE112 with respect to the gait activity of the rat 16 hours after administration.
FIG. 9
9A and 9B are graphical representations of the results of in vivo administration (gavage) of ARE112 on cumulative food intake (9A) for 24-hour fasted rats and cumulative food intake (9B) for non-fasted rats.
FIG. 10
10A, 10B and 10C show the results of in vivo (gavage) administration of a structural analog of ARE112 on cumulative feed intake (10A), water intake (10B) and weight gain (10C) for 24 hour fasted rats. This is a graph display.
FIG. 11
FIG. 9 is a graphical representation of the results of daily repeated in vivo (IP) administration of ARE112 rats showing long-term weight loss on fasting.
FIG.
Figure 6 is a graphical representation of the results of in vivo (gavage) administration of ARE112, showing reduced startle reflex in fasted rats.

Claims (20)

Small molecule GPR6 inverse agonist. A method for regulating G protein-coupled receptor GPR6 by inverse agonism, comprising the step of contacting GPR6 with a small molecule GPR6 inverse agonist. Less than:

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, are each independently selected from aryl and alkyl ^{aryl; R 8, R 9, R} 10 and ^{R 11,} _H, straight chain alkyl of _{C 1-8,} branched _{alkyl, C 3 -8 cycloalkyl, C 4- 9} independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, from (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, where n is 2 to 6 and m is 1 to 6 Selected;
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ aryl. Wherein the aryl portion of each aryl group or CH ₂ aryl group may be optionally substituted with up to four substituents at any position of the aryl, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and / or R ¹⁴ contains one aryl ring, and the aryl ring is substituted at two adjacent positions on the aryl ring, the two adjacent positions is selected _{CHCHCHCH, CH 2 CH 2 CH 2} CH 2, CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, from OCH ₂ O and _OCH 2 CH ₂ O Can be joined by two chains to form a bicyclic structure; or
R ¹³ and R ¹⁴ may be either saturated or unsaturated and have a 5, 6 or 7 membered ring structure which may contain up to 4 heteroatoms selected from O, N and S. May form part and the ring structure may be at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ ; or Here, when R ¹³ and R ¹⁴ form one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2,} CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, OCH 2 O or _OCH 2 CH Linked by a chain chosen from O and can form a bicyclic ring; and ^{R 15} is, _H, straight chain alkyl of _{C 1-8,} branched _{alkyl, C 3-8} cycloalkyl, _{C 4 -9} selected from alkylcycloalkyl or cycloalkylalkyl and C _2-8 alkenyl;
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. Small molecule GPR6 inverse agonists include:

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl; H, C _1-8 straight-chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4- Independently selected from ₉ alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, from (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, where n is 2 to 6 and m is 1 to 6 Selected;
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ aryl. Wherein the aryl portion of each aryl group or CH ₂ aryl group may be optionally substituted with up to four substituents at any position of the aryl, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and / or R ¹⁴ contains one aryl ring, and the aryl ring is substituted at two adjacent positions on the aryl ring, the two adjacent positions is selected _{CHCHCHCH, CH 2 CH 2 CH 2} CH 2, CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, from OCH ₂ O and _OCH 2 CH ₂ O Can be joined by two chains to form a bicyclic structure; or
R ¹³ and R ¹⁴ may be either saturated or unsaturated and may contain up to four heteroatoms selected from O, N and S, and may be a member of a 5, 6 or 7 membered ring structure. And the ring structure may be at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC4H 7, SC 4 H 9, SC 5 H 9 _{, SC 5 H 11, SC 6} H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5, SO _{3 C 3 H 7, SO 3} C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) 2, SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, COO C ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ ; and ,
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: Less than:

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be linked by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, Each independently selected from _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, from (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, where n is 2 to 6 and m is 1 to 6 Selected;
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ aryl. Wherein the aryl moiety of each aryl group or CH ₂ aryl group is at any position: F, Cl, Br, I, CF ₃ , CCl ₃ , CH ₃ , C ₂ H ₅ , C _{3 H 7, C 4 H 9} , NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C 2 H 5) 2, NHC 3 H 7, N (C 3 H 7) 2, _{NHC 4 H 9, N (C} 4 H 9) 2, NHCOH, NHCOCH 3, NHCOC 2 H 5, NHCOC 3 H 7, NHCOC 4 H 9, NHSO 2 CH 3, NHS _{2 C 2 H 5, NHSO 2} C 3 H 7, NHSO 2 C 4 H 9, OH, OCH 3, OC 2 H 5, OC 3 H 7, OC 4 H 7, OC 4 H 9, OC 5 H 9, _{OC 5 H 11, OC 6 H} 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO 2 CH 3, OSO 2 C 2 H 5, OSO 2 _{C 3 H 7, OSO 2 C} 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 H 9, SC 5 H 11, SC 6 H _{11, SC 6 H 13, SCF} 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5, SO 3 C 3 H 7, SO 3 C _{4 9, SO 2 NH 2, SO} 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) 2, SO 2 NHC 3 H 7, SO 2 N ( _{C 3 H 7) 2, SO} 2 NHC 4 H 9, SO 2 N (C 4 H 9) 2, NO 2, CN, COOCH 3, COOC 2 H 5, COOC 3 H 7, COOC 4 H 9, COSCH 3 , COSC ₂ H ₅ , COSC ₃ H ₇ , CONS ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , CONHC ₃ H ₇ , CON ( C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , which may be optionally substituted by up to four substituents independently selected, and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ¹⁴ may form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being O, N and S Optionally contains up to four selected heteroatoms, wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. The GPR6 inverse agonist comprises:

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be linked by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, Each independently selected from _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, wherein n is 2 to 6 and m is 1 to 6 );
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH 2 aryl. Wherein the aryl moiety of each aryl group or CH ₂ aryl group is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl group substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ¹⁴ may form part of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being O, N and S Optionally contains up to four selected heteroatoms and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: Less than:

Wherein at least one of V, W, X, Y and Z is selected from N and each of non-N V, W, X, Y and Z is CR ¹ , CR ² , CR ³ , CR ⁴ and Independently selected from CR ⁵ with the proviso that at least two of V, W, X, Y and Z are other than N;
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as follows:
_{^{H, F, Cl, Br,}} I, R 12, CF 3, CF 2 R 12, CF 2 CF 2, CCl 3, CCl2R 12, CCl 2 CCl 2 R 12, NR 13 R 14, NR 15 COR 12, NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R ¹² , _{^{SCF 2 CF 2 R 12, SCOR}} 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R 14 ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, Each independently selected from _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, wherein n is 2 to 6 and m is 1 to 6 );
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ aryl. Wherein the aryl moiety of each of the aryl groups or CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C2H 5, SO _{3 C 3 H 7, SO 3} C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) 2, SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, COO C ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. Small molecule GPR6 inverse agonists include:

Wherein at least one of V, W, X, Y and Z is selected from N and each of non-N V, W, X, Y and Z is CR ¹ , CR ² , CR ³ , CR ⁴ and Independently selected from CR ⁵ with the proviso that at least two of V, W, X, Y and Z are other than N;
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as follows:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, Each independently selected from _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, wherein n is 2 to 6 and m is 1 to 6 );
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ aryl. Wherein the aryl moiety of each of the aryl groups or CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: Less than:

Wherein at least one of V, W, X, Y and Z is selected from N and each of non-N V, W, X, Y and Z is CR ¹ , CR ² , CR ³ , CR ⁴ and Independently selected from CR ⁵ with the proviso that at least two of V, W, X, Y and Z are other than N;
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as follows:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, Each independently selected from _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, wherein n is 2 to 6 and m is 1 to 6 );
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ aryl. Wherein the aryl moiety of each of the aryl groups or CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. Small molecule GPR6 inverse agonists include:

Wherein at least one of V, W, X, Y and Z is selected from N and each of non-N V, W, X, Y and Z is CR ¹ , CR ² , CR ³ , CR ⁴ and Independently selected from CR ⁵ with the proviso that at least two of V, W, X, Y and Z are other than N;
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as follows:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, Each independently selected from _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, wherein n is 2 to 6 and m is 1 to 6 );
R ¹³ and R ¹⁴ are each independently selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl and CH ₂ aryl. Wherein the aryl moiety of each of the aryl groups or CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: Less than:

Wherein Z is selected from NR ⁴ , O and S;
W, X or Y is independently selected from N, CR ¹ , CR ² and CR ³ with the proviso that when Z is O and Y is N, W is CR ¹ and X is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ₁₃ R ₁₄ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, wherein n is 2 to 6 and m is 1 to 6 );
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH ₂ aryl, respectively. Independently selected, wherein the aryl moiety of each of the aryl groups or the CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O and _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. The small molecule GPR6 inverse agonist comprises:

Wherein Z is selected from NR ⁴ , O and S;
W, X or Y is independently selected from N, CR ¹ , CR ² and CR ³ with the proviso that when Z is O and Y is N, W is CR ¹ and X is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, wherein n is 2 to 6 and m is 1 to 6 );
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl and CH ₂ aryl, respectively. Independently selected, wherein the aryl moiety of each of the aryl groups or the CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O and _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: Less than:

Wherein Z is selected from NR ⁴ , O and S;
W, X or Y is independently selected from N, CR ¹ , CR ² and CR ³ with the proviso that when Z is O and Y is N, W is CR ¹ and X is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H, (CH ₂ ) _m CO ₂ H (where n is 2 to 6 or m is 1 to 6) );
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ aryl, respectively. Independently selected, wherein the aryl moiety of each of the aryl groups or the CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. Small molecule GPR6 inverse agonists include:

Wherein Z is selected from NR ⁴ , O and S;
W, X or Y is independently selected from N, CR ¹ , CR ² and CR ³ with the proviso that when Z is O and Y is N, W is CR ¹ and X is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be joined by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O and OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is, _H, straight chain alkyl of _{C 1-8,} branched _{alkyl, C 3-8 cycloalkyl,} alkylcycloalkyl or cycloalkylalkyl _{C 4-9,} alkenyl of _{C 2-8,} aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H, (CH ₂ ) _m CO ₂ H (where n is 2 to 6 or m is 1 to 6) );
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ aryl, respectively. Independently selected, wherein the aryl moiety of each of the aryl groups or the CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: Less than:

Wherein Y is selected from NR ⁴ , O or S;
W, X or Z is independently selected from N or CR ¹ , CR ² or CR ³ with the proviso that when Y is O and Z is N, W is CR ¹ and X Is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be linked by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, where n is 2 to 6 and m is 1 to 6 Selected;
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ aryl, respectively. Independently selected, wherein the aryl group or the aryl moiety of the CH ₂ aryl group is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. Small molecule GPR6 inverse agonists include:

Wherein Y is selected from NR ⁴ , O or S;
W, X or Z is independently selected from N or CR ¹ , CR ² or CR ³ with the proviso that when Y is O and Z is N, W is CR ¹ and X Is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be linked by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, where n is 2 to 6 and m is 1 to 6 Selected from;
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ aryl, respectively. Independently selected, wherein the aryl moiety of each of the aryl groups or the CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, _{N (C 2 H 5) 2} , NHC 3 H 7, N (C 3 H7) 2, NHC 4 H 9, N (C 4 H 9) 2, NHCOH, NHCOCH 3, NHCOC 2 H 5, NHCOC 3 H 7 , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC ₄ H _{7, OC 4 H 9, OC} 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO 2 CH _{, OSO 2 C 2 H 5,} OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 H _{9, SC 5 H 11, SC} 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5, SO ₃ C ₃ H ₇ , SO ₃ C ₄ H ₉ , SO ₂ NH ₂ , SO ₂ NHCH ₃ , SO ₂ N (CH ₃ ) ₂ , SO ₂ NHC ₂ H ₅ , SO ₂ N (C ₂ H ₅ ) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H ₇ , COO C ₄ H ₉ , COSCH ₃ , COSC ₂ H ₅ , COSC ₃ H ₇ , COSC ₄ H ₉ , CONH ₂ , CONHCH ₃ , CON (CH ₃ ) ₂ , CONHC ₂ H ₅ , CON (C ₂ H ₅ ) ₂ , Independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O or _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: Less than:

Wherein Y is selected from NR ⁴ , O or S;
W, X or Z is independently selected from N or CR ¹ , CR ² or CR ³ with the proviso that when Y is O and Z is N, W is CR ¹ and X Is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be linked by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, from (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, where n is 2 to 6 and m is 1 to 6 Selected;
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ aryl, respectively. Independently selected, wherein the aryl moiety of each of the aryl groups or the CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Optionally containing up to 4 heteroatoms, wherein each said ring structure may be optionally substituted at any position by up to 4 substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O and _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
The small molecule GPR6 inverse agonist according to claim 1, which is structurally represented as follows. Small molecule GPR6 inverse agonists include:

Wherein Y is selected from NR ⁴ , O or S;
W, X or Z is independently selected from N or CR ¹ , CR ² or CR ³ with the proviso that when Y is O and Z is N, W is CR ¹ and X Is CR ² ;
R ¹ , R ² and R ³ are:
H, F, Cl, Br, I, R ¹² , CF ₃ , CF ₂ R ¹² , CF ₂ CF ₂ , CCl ₃ , CCl ₂ R ¹² , CCl ₂ CCl ₂ R ¹² , NR ¹³ R ¹⁴ , NR ¹⁵ COR ¹² , NR ¹⁵ SO ₂ R ¹² , OR ¹² , OCF ₃ , OCF ₂ R ¹² , OCF ₂ CF ₂ R ¹² , OCOR ¹² , OSO ₂ R ¹² , OPO (OR ¹² ) ₂ , SR ¹² , SCF ₃ , SCF ₂ R _{^{12, SCF 2 CF 2 R 12}} , SCOR 12, SO 3 R 12, SO 2 NR 13 R 14, PO (OR 12) 3, PO (OR 12) 2 R 12, NO 2, CN, CNR 15 (NR 13 R ¹⁴ ), CNR ¹⁵ (SR ¹² ), COOR ¹² , COSR ¹² , CONR ¹³ R ¹⁴ are each independently selected, and
Here, any two adjacent positions of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent CHCHCHCH, CH ₂ CH ₂ CH ₂ CH ₂ , CHCHCH ₂ , CH ₂ CH ₂ CH ₂ , Can be linked by a chain selected from CH ₂ CH ₂ , SCH ₂ S, SCH ₂ CH ₂ S, OCH ₂ O or OCH ₂ CH ₂ O to form a bicyclic structure;
R ⁴ is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkylaryl , COR ⁵ , CSR ⁵ and SO ₂ R ⁵ ;
R ⁵ , R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 Each independently selected from alkenyl, aryl and alkylaryl;
R ⁶ and R ⁷ are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently selected from aryl and alkylaryl are H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 Each independently selected from alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl and alkylaryl;
R ¹² is H, C _1-8 linear alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl, C _2-8 alkenyl, aryl, alkyl Aryl, from (CH ₂ ) _n NR ¹³ R ¹⁴ , (CH ₂ ) _m SO ₃ H and (CH ₂ ) _m CO ₂ H, where n is 2 to 6 and m is 1 to 6 Selected;
R ¹³ and R ¹⁴ are each selected from H, C _1-8 straight chain alkyl, branched alkyl, C _2-8 alkenyl or cycloalkyl, or alkylcycloalkyl, or cycloalkylalkyl, or aryl or CH ₂ aryl, respectively. Independently selected, wherein the aryl moiety of each of the aryl groups or the CH ₂ aryl groups is at any position:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, May be optionally substituted by up to four substituents independently selected from CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) ₂ , and
Here, when R ¹³ and / or R ¹⁴ contains the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, _{CH 2 CH 2 CH 2 CH 2} , CHCHCH 2, CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S bond, _SCH 2 CH 2 S, the chain selected from OCH ₂ O or _OCH 2 CH ₂ O To form a bicyclic structure; or
R ¹³ and R ^{14 form part} of a 5, 6 or 7 membered saturated ring structure or a 5, 6 or 7 membered unsaturated ring structure, each such structure being selected from O, N and S. Up to four heteroatoms, and wherein each said ring structure may be optionally substituted at any position by up to four substituents, wherein each position is:
_{F, Cl, Br, I,} CF 3, CCl 3, CH 3, C 2 H 5, C 3 H 7, C 4 H 9, NH 2, NHCH 3, N (CH 3) 2, NHC 2 H 5, N (C ₂ H ₅ ) ₂ , NHC ₃ H ₇ , N (C ₃ H ₇ ) ₂ , NHC ₄ H ₉ , N (C ₄ H ₉ ) ₂ , NHCOH, NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₄ H ₉ , NHSO ₂ CH ₃ , NHSO ₂ C ₂ H ₅ , NHSO ₂ C ₃ H ₇ , NHSO ₂ C ₄ H ₉ , OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ , OC _{4 H 7, OC 4 H 9,} OC 5 H 9, OC 5 H 11, OC 6 H 11, OC 6 H 13, OCF 3, OCOCH 3, OCOC 2 H 5, OCOC 3 H 7, OCOC 4 H 9, OSO ₂ CH _{3, OSO 2 C 2 H 5} , OSO 2 C 3 H 7, OSO 2 C 4 H 9, SH, SCH 3, SC 2 H 5, SC 3 H 7, SC 4 H 7, SC 4 H 9, SC 5 _{H 9, SC 5 H 11,} SC 6 H 11, SC 6 H 13, SCF 3, SCOCH 3, SCOC 2 H 5, SCOC 3 H 7, SCOC 4 H 9, SO 3 CH 3, SO 3 C 2 H 5 _{, SO 3 C 3 H 7,} SO 3 C 4 H 9, SO 2 NH 2, SO 2 NHCH 3, SO 2 N (CH 3) 2, SO 2 NHC 2 H 5, SO 2 N (C 2 H 5) ₂ , SO ₂ NHC ₃ H ₇ , SO ₂ N (C ₃ H ₇ ) ₂ , SO ₂ NHC ₄ H ₉ , SO ₂ N (C ₄ H ₉ ) ₂ , NO ₂ , CN, COOCH ₃ , COOC ₂ H ₅ , COOC ₃ H _7, CO _{C 4 H 9, COSCH 3,} COSC 2 H 5, COSC 3 H 7, COSC 4 H 9, CONH 2, CONHCH 3, CON (CH 3) 2, CONHC 2 H 5, CON (C 2 H 5) 2, CONHC ₃ H ₇ , CON (C ₃ H ₇ ) ₂ , CONHC ₄ H ₉ , CON (C ₄ H ₉ ) _2, and is independently selected from:
Here, when R ¹³ and R ¹⁴ form the one aryl ring substituted at two adjacent positions on the aryl ring, the two adjacent positions are CHCHCHCH, CH ₂ CH _{2 CH 2 CH 2, CHCHCH 2} , CH 2 CH 2 CH 2, CH 2 CH 2, SCH 2 S, SCH 2 CH 2 S, are linked by a chain chosen from OCH ₂ O and _OCH 2 CH ₂ O two A ring structure can be formed; and R ¹⁵ is H, C _1-8 straight chain alkyl, branched alkyl, C _3-8 cycloalkyl, C _4-9 alkylcycloalkyl or cycloalkylalkyl and Selected from C _2-8 alkenyl,
3. The method of claim 2, wherein the method is represented structurally as: The following structure:

A small molecule GPR6 inverse agonist selected from the group consisting of:

A method for regulating G protein-coupled receptor GPR6 by inverse agonism, comprising contacting GPR6 with a small molecule GPR6 inverse agonist selected from the group consisting of:

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