JP2015221834A - Trkキナーゼ阻害剤としてのマクロ環化合物 - Google Patents
Trkキナーゼ阻害剤としてのマクロ環化合物 Download PDFInfo
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- JP2015221834A JP2015221834A JP2015174142A JP2015174142A JP2015221834A JP 2015221834 A JP2015221834 A JP 2015221834A JP 2015174142 A JP2015174142 A JP 2015174142A JP 2015174142 A JP2015174142 A JP 2015174142A JP 2015221834 A JP2015221834 A JP 2015221834A
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- Prior art keywords
- mmol
- fluoro
- alkyl
- pyrimidine
- pyrazolo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 229940043355 kinase inhibitor Drugs 0.000 title 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
Description
;非特許文献36)。
しかしながら、疼痛、特に慢性疼痛の治療のため、並びに癌、炎症、神経変性疾患及び特定の感染性疾患の治療のための化合物及び方法がなお必要とされている。
を有する環A−1、A−2及びA−3から選択され;
を有する環B−1及びB−2から選択され;
*−OC(=O)−であり、ここでアスタリスクはR3を担持している炭素へのZの結合点を示し;
を有する環B−2であり;
を有する環A−1であり;
を包含する。
を有する環A−2であり;
を有する環A−3であり;
を包含する。
に包含されるものはシクロプロピルC(O)−、シクロブチルC(O)−、シクロペンチルC(O)−及びシクロヘキシルC(O)−である。
であり;
ル又はヒドロキシ(1−6C)アルキルである。1つの実施形態において、R5はHであり、そしてR6はH、F、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである。
を包含する。
を有する環B−2である。
であり;
を有する環A−1、A−2及びA−3から選択され;
2及びR2aは共にOHではなく;
を有する環A−1、A−2及びA−3から選択され;
により表わされる環A−1であり;
により表わされる環B−1であり;
により表わされる環A−2であり;
により表わされる環B−1であり;
で表わされる環A−3であり;
で表わされる環B−1であり;
で表わされる環A−1であり;
で表わされる環B−1であり;
分枝鎖の1価の炭化水素ラジカルを指す。
位体の種類は、放射性であるか否かに関わらず、本発明の範囲内に包含されることを意図している。
下記式II:
であり、式中:
下記式III:
であり;
SO2)−L3、(3−6Cシクロアルキル)(SO2)−L3又はAr2(SO2)−L3を有する試薬、ただしL3は脱離原子であるものと、塩基の存在下にカップリングさせること;又は、
であり、
を有する環B−1であり;
in Organic Synthesis」第2版、New York;John Wiley&Sons,Inc.,1991に記載されているもので保護してよい。アミン保護基の例はアシル及びアルコキシカルボニル基、例えばt−ブトキシカルボニル(BOC)及び[2−(トリメチルシリル)エトキシ]メチル(SEM)を包含する。同様に、カルボキシル基も例えばGreene&Wuts編の「Protecting Groups in Organic Synthesis」第2版、New York;John Wiley&Sons,Inc.,1991に記載されている何れかの好都合なカルボキシル保護基で保護してよい。カルボキシル保護基の例は(1−6C)アルキル基、例えばメチル、エチル及びt−ブチルを包含する。アルコール基は例えばGreene&Wuts編の「Protecting Groups in Organic Synthesis」第2版、New York;John Wiley&Sons,Inc.,1991に記載されている何れかの好都合なアルコール保護基で保護してよい。アルコール保護基の例はベンジル、トリチル、シリル、エーテル等を包含する。
of Painにより定義される場合の急性の疼痛は疾患、炎症、又は組織への傷害から生じる。この種の疼痛は一般的に、例えば外傷又は手術の後に突然生じ、そして不安又はストレスを伴う場合がある。原因は通常は診断及び治療され、そして疼痛は所定の期間及び重症度に限定される。一部の稀な例においては、慢性となる可能性がある。
of Painにより定義される場合の慢性の疼痛は、広範には疾患自体を表わしていると考えられている。それは環境及び心理学的要因により遥かに悪化する場合がある。慢性の疼痛は急性の疼痛よりも長期間に渡って持続し、そして、一般的に3ヶ月を超えて、大部分の医学的治療に対して抵抗性である。患者に対する重度の問題を生じさせる場合があり、頻繁には実際に生じさせる。
製薬上許容しうるその塩の1つ以上を哺乳類に投与することを含む、哺乳類における炎症を治療又は防止する方法を提供する。1つの実施形態において、方法は哺乳類における疼痛を治療する方法を含む。1つの実施形態において、方法は哺乳類における疼痛を防止する方法を含む。
Iの化合物又は製薬上許容しうるその塩を提供する。1つの実施形態において、疼痛は慢性疼痛である。1つの実施形態において、疼痛は急性疼痛である。1つの実施形態において、疼痛は炎症性疼痛である。1つの実施形態において、疼痛は神経障害性疼痛である。1つの実施形態において、疼痛は癌に伴う疼痛である。1つの実施形態において、疼痛は手術に伴う疼痛である。1つの実施形態において、疼痛は骨折に伴う疼痛である。
(実施例A)
TrkAELISAアッセイ
メーターのロジスティック曲線適合の何れかを用いてIC50値を計算した。
(実施例B)
TrkA結合アッセイ
(R)−5−フルオロ−2−メトキシ−3−(ピロリジン−2−イル)ピリジン
調製例B
(R)−5−(2−(5−フルオロ−2−メトキシピリジン−3−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸
3を除去した。残基をDCM(100mL)中に希釈し、そして氷水の入ったフラスコにゆっくり添加した。混合物を分離し、水層をDCM(2×200mL)で抽出した。合わせた有機層を乾燥(MgSO4)し、濾過し、濃縮して淡黄色の固体としてエチル5−クロロピラゾロ[1,5−a]ピリミジン−3−カルボキシレートを得た(24.2g、97.6%収率)。MS(apci)m/z=225.9(M+H)。
MS(apci)m/z=357.9(M+H)。
調製例C
(R)−4−((t−ブチルジメチルシリル)オキシ)−2−(5−フルオロ−2−メトキシフェニル)ピロリジン2,2,2−トリフルオロアセテート
濁液に、TBDMS−Cl(7.637g、50.67ミリモル)、次いでイミダゾール(4.978g、72.39ミリモル)を添加した。得られた混合物を周囲温度まで加温し、そして1時間攪拌し、次に攪拌しながら水100mLに注ぎ込んだ。得られた懸濁液を濾過し、そして固体を水で洗浄し、そして減圧下に乾燥し、得られた(R)−4−(t−ブチルジメチルシリルオキシ)ピロリジン−2−オン(10.14g、97.56%収率)は更に精製することなく直接使用した。
減圧下に濃縮し、得られた粗製の物質を2−10%MeOH/DCMを溶離剤とするシリカカラムクロマトグラフィーにより精製し、(R)−t−ブチル4−(t−ブチルジメチルシリルオキシ)−2−(5−フルオロ−2−メトキシフェニル)ピロリジン−1−カルボキシレート(シス及びトランス異性体の混合物と推定;2.648g、57.38%収率)を得た。LC/MS(ES+APCI)m/z=326.1(M+H−Boc)。
調製例D
(R)−5−(2−(5−フルオロ−2−ヒドロキシフェニル)−4−ヒドロキシピロリジン−1−yl)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸
ートの調製:0℃のTHF(1mL)中の(R)−エチル5−(4−(t−ブチルジメチルシリルオキシ)−2−(5−フルオロ−2−メトキシフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレート(シス及びトランス異性体の混合物として)(0.0487g、0.0946ミリモル)の溶液にTHF中1MのTBAF(0.104mL、0.104ミリモル)を添加した。反応混合物を周囲温度まで加温し、そして2.5時間攪拌した。反応混合物をEtOAc(10mL)で希釈し、MgSO4上に乾燥し、濾過し、そして減圧下に濃縮し、粗製の(R)−エチル5−(2−(5−フルオロ−2−メトキシフェニル)−4−ヒドロキシピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレート(シス及びトランス異性体の混合物として;37.9mg、100%収率)を得た。LC/MS(ES+APCI)m/z=401.1(M+H)。
実施例1
(6R)−9−フルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例2
(6R)−12−オキサ−2,16,20,21,24,26−ヘキサアザペンタシクロ[16.5.2.1 7,11 .0 2,6 .0 21,25 ]ヘキサコサ−1(24),7(26),8,10,18(25),19,22−ヘプタエン−17−オン
2−イル)プロポキシ)ピリジン−2−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレートの調製:DMF(2mL)中の(R)−エチル5−(2−(6−オキソ−1,6−ジヒドロピリジン−2−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレート(0.091g、0.26ミリモル)の懸濁液に、LiH(3.2mg、0.39ミリモル)を0℃で添加した。20分間攪拌した後、DMF(1mL)中の2−(3−ブロモプロピル)イソインドリン−1,3−ジオン(0.14g、0.52ミリモル)の溶液を添加し、そして反応混合物を周囲温度まで加温し、そして17時間攪拌した。0℃に冷却した後、反応混合物を氷水(30mL)でクエンチングし、そしてEtOAc(3×50mL)で抽出した。合わせた有機層を水及び塩水で洗浄し、乾燥(MgSO4)し、濾過し、そして濃縮した。粗製の物質を1.5%MeOH/DCMを溶離剤とするシリカカラムクロマトグラフィーにより精製し、所望の生成物を得た(0.117g、84%収率)。MS(apci)m/z=541.1(M+H)。
実施例3
(6R)−9−フルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例4
(6R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例5
(6R,13S)−9−フルオロ−13−ヒドロキシ−2,11,15,19,20,23−ヘキサアザペンタシクロ−[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例6
(6R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ−[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
リル/水)により白色固体(5mg、15%収率)として得られた単離最終生成物(6R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ−[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オンにおいては意外にも損なわれていたことがわかった(R/S比は約10:7であった)。MS(apci)m/z=399.2(M+H)。
実施例7
(6R,15R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ−[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例8
(6R,13R)−9−フルオロ−13−ヒドロキシ−2,11,15,19,20,2
3−ヘキサアザペンタシクロ−[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例9
(6R)−9−フルオロ−13−オキサ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
)及びCs2CO3(314mg、0.96ミリモル)の懸濁液を30分間85℃に加熱した。GF/F紙を通して濾過した後、反応混合物を水(40mL)及びNH4Cl(飽和、5mL)で希釈し、次にEtOAc(3×40mL)で抽出した。合わせた有機抽出物を乾燥(Na2SO4)し、濾過し、そして濃縮した。粗製の物質を逆相カラムクロマトグラフィー(Biotage SP4システムC−18、12+Mカラム、0〜73%アセトニトリル/水)で精製し、白色固体として表題生成物を得た(17mg、24%収率)。MS(apci)m/z=369.2(M+H)。
実施例10
(6R)−9−フルオロ−13−オキサ−2,11,18,22,23,26−ヘキサアザペンタシクロ[18.5.2.0 2,6 .0 7,12 .0 23,27 ]ヘプタコサ−1(26),7,9,11,20(27),21,24−ヘプタエン−19−オン
実施例11
(6R)−9−フルオロ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.1 7,11 .0 2,6 .0 21,25 ]ヘキサコサ−1(24),7,
9,18(25),19,22−ヘキサエン−17,26−ジオン
実施例12
(6R)−9−フルオロ−2,11,13,16,20,21,24−ヘプタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
(0.5g、35%収率)。MS(apci)m/z=201.1(M+H−Boc)。
ン酸塩酸塩の調製:HCl(4Nジオキサン、798μL)及びTFA(50%DCM、2mL)中の(R)−5−(2−(2−(2−(t−ブトキシカルボニルアミノ)エチルアミノ)−5−フルオロピリジン−3−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸(31mg、0.064ミリモル)の溶液を1時間周囲温度で攪拌した後、これを高真空下に濃縮及び乾燥させ、オフホワイトの固体として得られた所望の生成物を更に精製することなく直接次の工程で使用し、定量的変換と推定した。MS(apci)m/z=386.1(M+H)。
実施例13
(6R)−9−フルオロ−2,11,13,17,21,22,25−ヘプタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例14
(6R)−9−フルオロ−13,16−ジオキサ−2,11,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]−ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
SP4システムC18、25+M、5〜60%アセトニトリル/水)で直接精製し、所
望の生成物と不純物の混合物を得た。この混合物を10%ヘキサン/EtOAcを溶離剤としたBiotage SNAP KP−Sil 10g上の第2のカラムクロマトグラフィーにより処理し、白色固体として純粋な表題生成物を得た(11mg、22%収率)。MS(apci pos)m/z=370.2(M+H)。
実施例15
(6R)−9−フルオロ−14−オキサ−2,11,18,19,22−ペンタアザペンタシクロ[14.5.2.1 7,11 .0 2,6 .0 19,23 ]テトラコサ−1(22),7,9,16(23),17,20−ヘキサエン−15,24−ジオン
実施例16
(6R)−9−フルオロ−13,16−ジオキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
)及びHCl(4Nジオキサン、3.65mL、14.6ミリモル)の混合物を圧力チューブに密封し、3時間90℃に加熱した。次に反応混合物を冷却し、MeOHで希釈し、濃縮し、高真空下に乾燥し、得られた所望の生成物を更に精製することなく直接次の工程で使用し、定量的変換と推定した。
実施例17
(6R,13R)−9,13−ジフルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例18
(6R)−9−フルオロ−17−メチル−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例19
(6R)−9,15,15−トリフルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
−フルオロ−2−メトキシピリジン−3−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキサミドの調製:DCM(3mL)中の(R)−N−(3−クロロ−2−オキソプロピル)−5−(2−(5−フルオロ−2−メトキシピリジン−3−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキサミド(114mg、0.255ミリモル)の溶液にDeoxofluor(0.103mL、0.561ミリモル)を添加し、そして反応混合物を23時間周囲温度で攪拌した。反応混合物を飽和NaHCO3(5mL)でクエンチングし、DCM(5mL)で希釈し、そして30分間攪拌した。相分離の後、水相をDCM(10mL)で抽出した。合わせた有機相を濃縮し、そして5〜60%アセトニトリル/水を溶離剤とする逆相カラムクロマトグラフィーで精製し、白色固体として所望の生成物を得た(59mg、49%収率)。MS(apci)m/z=469.0(M+H)。
実施例20
(6R)−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
)m/z=182.1(M+H−Boc)。
製。(R)−エチル5−(2−(2−(3−アミノプロポキシ)−5−フルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレート(10mg、0.023ミリモル)及びDIEA(8.1μL、0.047ミリモル)を密封容器中乾燥EtOH(0.1mL)中で混合し、そして一夜200℃で加熱した。反応混合物を濃縮し、そして逆相カラムクロマトグラフィー(0〜70%アセトニトリル/H2O)により精製し、表題化合物を得た(4.5mg、50%収率)。MS(apci)m/z=382.2(M+H)。
実施例21
(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン
、0.487ミリモル)、t−ブチル2−ブロモエチルカルバメート(131mg、0.585ミリモル)、炭酸カリウム(202mg、1.46ミリモル)及びDMF(1mL)の混合物を密封容器中で混合し、そして一夜周囲温度で、そして次に3時間60℃で攪拌した。DCM(20mL)で希釈した後、反応混合物をCelite(登録商標)を通して濾過し、濃縮し、そして0〜70%アセトニトリル/H2Oを溶離剤とする逆相カラムクロマトグラフィーで精製し、黄色味を帯びた固体として(R)−t−ブチル2−(4−フルオロ−2−(1−(3−ホルミルピラゾロ[1,5−a]ピリミジン−5−イル)ピロリジン−2−イル)フェノキシ)エチルカルバメートを得た(198mg、86.6%収率)MS(apci)m/z=370.4(M+H−Boc)。
実施例22
1−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]エタン−1−オン
02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン(実施例21、5.0mg、0.014ミリモル)のDCM(0.5mL)溶液に添加し、その後DIEA(7.4μL、0.042ミリモル)を添加した。一夜周囲温度で攪拌した後、反応混合物を濃縮し、そして0〜80%アセトニトリル/H2Oを溶離剤とする逆相カラムクロマトグラフィーで精製し、表題生成物を得た(3.9mg、70%収率)。MS(apci)m/z=396.2(M+H)。
実施例23
1−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]−2−ヒドロキシエタン−1−オン
実施例24
(6R)−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン
実施例25
(6R)−9−フルオロ−16−メタンスルホニル−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン
24),7,9,11,18(25),19,22−ヘプタエン(実施例21、5mg、0.0141ミリモル)のDCM(5mL)溶液に、DIEA(2.46μL、0.0141ミリモル)、次いでメタンスルホニルクロリド(1.10μL、0.0141ミリモル)を添加した。反応混合物を1時間周囲温度で攪拌し、その後MeOH(0.1mL)を添加した。反応混合物を濃縮し、そして0〜80%アセトニトリル/H2Oを溶離剤とする逆相カラムクロマトグラフィーで精製し、表題生成物を得た(3.1mg、50.8%収率)。MS(apci)m/z=432.3(M+H)。
実施例26
2−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]酢酸
実施例27
(6R)−9−フルオロ−17−メタンスルホニル−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン
実施例28
(6R)−N−エチル−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ 17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−17−カルボキサミド
実施例29
(6R)−N−エチル−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ−[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−カルボキサミド
実施例30
(6S)−9−フルオロ−4,13−ジオキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−3,18−ジオン
−イル)エチル)−2−メチルプロパン−2−スルフィンアミド(1.40g、3.46ミリモル)の溶液に4NのHCl/ジオキサン(8.65mL、34.6ミリモル)を添加した。溶液を16時間周囲温度で攪拌し、次に濃縮し、そして真空下に乾燥することにより黄色油状物として得られた(S)−2−アミノ−2−(5−フルオロ−2−メトキシピリジン−3−イル)エタノール2塩酸塩を更に精製することなく使用し、100%収率と推定した。
MS(apci)m/z=186.9(M+H)。
得た(121mg、45%収率)。MS(apci)m/z=347.9(M+H)。
エン−3,18−ジオンの調製:DMF(3mL)中の(S)−N−(3−クロロプロピル)−5−(4−(5−フルオロ−2−オキソ−1,2−ジヒドロピリジン−3−イル)−2−オキソオキサゾリジン−3−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキサミド(35mg、0.08ミリモル)の溶液に炭酸セシウム(79mg、0.24ミリモル)を添加した。混合物を30分間65℃で、次に48時間周囲温度で攪拌した。混合物を水(30mL)で処理し、そしてEtOAc(3x10mL)で抽出した。合わせた有機相を水(5x10mL)及び塩水(10mL)で洗浄し、次にNa2SO4上で乾燥し、濾過し、そして濃縮した。残留物を2%MeOH/DCMを溶離剤とするフラッシュカラムクロマトグラフィーで精製し、不定形の白色固体として表題化合物を得た(13mg、41%収率)。MS(apci)m/z=399.2(M+H)。
実施例31
(6S)−9−フルオロ−4,13−ジオキサ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7(12),8,10,18(25),19,22−ヘプタエン−3,17−ジオン
3−カルボキサミドの調製:DCM(10mL)中の5−クロロピラゾロ[1,5−a]ピリミジン−3−カルボニルクロリド(284mg、1.31ミリモル)の懸濁液にDIEA(1.14mL、6.57ミリモル)を添加した。溶液を0℃に冷却し、次に2−クロロエチルアミン塩酸塩(183mg、1.58ミリモル)で処理し、そして1時間攪拌した。混合物を水(30mL)とDCM(30mL)の間に分配し、そして層を分離させた。水層をDCM(2x20mL)で抽出し、そして合わせた有機相を塩水(20mL)で洗浄し、Na2SO4上で乾燥し、濾過し、そして濃縮することにより、ベージュ色の固体として5−クロロ−N−(2−クロロエチル)ピラゾロ[1,5−a]ピリミジン−3−カルボキサミドを得た(290mg、85%収率)。MS(apci)m/z=258.9(M+H)。
実施例32
(6R)−9−フルオロ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
)。MS(apci)m/z=385.0(M+H)。
実施例33
(6R)−9−フルオロ−15−メチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例34
(6R,13R)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
。反応混合物を減圧下に濃縮し、そして残留物をDCM(100mL)に溶解し、そして飽和NaHCO3(40mL)で洗浄した。有機層をNa2SO4上で乾燥し、濾過し、そして減圧下に濃縮し、粗製の所望の生成物を得た(4.67g、93.2%収率)。MS(apci)m/z=357.9(M+H)。
収率)。MS(apci)m/z=397.3(M+H)。
実施例35
(6R,13S)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例36
(6R)−9−フルオロ−15,15−ジメチル−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例37
(6R)−9−フルオロ−15,15−ジメチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
リミジン−3−カルボキシレートの調製:DMF(20mL)中の(R)−メチル5−(2−(5−フルオロ−2−ヒドロキシピリジン−3−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレート(実施例34、工程Aに従って調製;2.31g、6.46ミリモル)の溶液に、1,1,1−トリフルオロ−N−フェニル−N−(トリフルオロメチル−スルホニル)メタンスルホンアミド(2.54g、7.11ミリモル)及びトリエチルアミン(0.785g、7.76ミリモル)を添加した。反応混合物を18時間攪拌した。溶媒を減圧下に除去し、そして残留物を33%EtOAc/ヘキサンを溶離剤とするシリカカラムクロマトグラフィーにより精製し、所望の生成物を得た(2.36g、74.6%収率)。MS(apci)m/z=490.0(M+H)。
実施例38
(6R)−9−フルオロ−13−オキサ−2,11,16,17,21,25,26,29−オクタアザヘキサシクロ[21.5.2.0 2,6 .0 7,12 .0 16,20 .0 26,30 ]トリアコンタ−1(29),7,9,11,17,19,23(30),24,27−ノナエン−22−オン
カルボキサミドにTHF(20mL)、DEAD(53.9μL、0.342ミリモル)及びトリフェニルホスフィン(89.8mg、0.342ミリモル)を添加した。反応混合物を18時間攪拌し、次に真空下に濃縮した。残留物を10%MeOH/DCMを溶離剤とするシリカカラムクロマトグラフィーにより精製し、表題化合物を得た(1.8mg、1.5%収率)。MS(apci)m/z=435.3(M+H)。
実施例39
(6R)−9−フルオロ−13−オキサ−2,11,19,21,25,26,29−ヘプタアザヘキサシクロ[21.5.2.0 2,6 .0 7,12 .0 15,20 .0 26,30 ]トリアコンタ−1(29),7,9,11,15(20),16,18,23(30),24,27−デカエン−22−オン
そして有機層を飽和NaHCO3(5mL)、水(5mL)及び塩水(5mL)で洗浄した。有機層を減圧下に濃縮することにより得られた粗製の(R)−N−(3−(クロロメチル)ピリジン−2−イル)−5−(2−(5−フルオロ−2−ヒドロキシピリジン−3−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキサミドにDMF(10mL)及びCs2CO3(276mg、0.848ミリモル)を添加した。反応混合物を4時間60℃に加熱し、次に周囲温度に冷却し、そして減圧下に濃縮した。残留物を10%MeOH/DCMを溶離剤とするシリカカラムクロマトグラフィーにより精製し、表題化合物を得た(8.0mg、2.2%収率)。MS(apci)m/z=432.3(M+H)。
実施例40
(6R)−9−フルオロ−13,13−ジメチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例41
(4R,6R,15S)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
a]ピリミジン−3−カルボキサミド(0.0407g、0.0778ミリモル)及びCs2CO3(0.127g、0.389ミリモル)の混合物を30分間85℃に加熱した。反応混合物を周囲温度に冷却し、そして濾過した。濾液を減圧下に濃縮して得られた粗製の物質を0〜20%MeOH/EtOAcを溶離剤とするシリカカラムクロマトグラフィーにより精製し、粗生成物を得た。粗製の物質をキラルカラムクロマトグラフィー(Chiral Tech OD−Hカラム、ヘキサン中20%EtOH)を用いて精製した。約21.8分の保持時間を有する物質の単離により表題化合物を得た(0.0052g、16.2%収率)。表題化合物の立体化学的特徴は1H−NMR nOe実験により確認した。LC/MS(ES+APCI)m/z=414.1(M+H)。
実施例41−B
(4R,6S,15S)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例42
(4R,6R)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例42−B
(4R,6S)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例43
(4R,6R)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例43−B
(4R,6S)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例44
(4R,6R,15R)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
nOe実験により確認した。LC/MS(ES+APCI)m/z=414.0(M+H)。
実施例44−B
(4R,6S,15R)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例45
(15S)−4,4,9−トリフルオロ−15−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オンのジアステレオマー1及びジアステレオマー2
ルオロ−2−メトキシフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレート(0.126g、0.267ミリモル)の溶液にCH2Cl2中1MのBBr3(1.50mL、1.50ミリモル)を添加した。得られた混合物を周囲温度まで加温し、そして18時間攪拌した。反応混合物をCH2Cl2(5mL)で希釈し、そして氷と飽和水性NaHCO3(3mL)の混合物中に注ぎ込んだ。次に水層を1N水性HClで約pH3まで酸性化した。水層をCH2Cl2(3x10mL)で抽出した。合わせた有機層をMgSO4上に乾燥し、濾過し、そして減圧下に濃縮し、エチル5−(4,4−ジフルオロ−2−(5−フルオロ−2−ヒドロキシフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキシレートと5−(4,4−ジフルオロ−2−(5−フルオロ−2−ヒドロキシフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸の混合物を得た。この混合物を周囲温度でMeOH−THF(0.25mL/0.75mL)に溶解回収し、そして2N水性LiOH(0.667mL、1.33ミリモル)を添加した。得られた混合物を24時間50℃に加熱した。反応混合物を周囲温度に冷却し、そして減圧下に濃縮し、有機溶媒を除去した。残留物を5mLのEtOAcで希釈し、そして攪拌しながら6Nの水性HClでpH3〜4まで酸性化した。有機層を分離し、そして酸性の水層をEtOAc(2x5mL)で抽出した。合わせた有機層をMgSO4上に乾燥し、濾過し、そして減圧下に濃縮し、5−(4,4−ジフルオロ−2−(5−フルオロ−2−ヒドロキシフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸を得た(0.094g、93.1%収率)。MS(APCI)m/z=378.9(M+H)。
(項目1)
下記一般式I:
[式中:
環Aは下記構造:
[式中、1と標記された波線は環Aの環Bへの結合点を示し、そして2と標記された波線は環AのWへの結合点を示す
]を有する環A−1、A−2及びA−3から選択され;
XはN又はCHであり;
YはH又はFであり;
R 1 はH、(1−3C)アルコキシ又はハロゲンであり;
環Bは下記構造:
[式中、3と標記された波線は環Aへの結合点を示し、そして4と標記された波線は式Iのピラゾロ[1,5−a]ピリミジン環への結合点を示す]を有する環B−1及びB−2から選択され;
WはO、NH又はCH 2 であり、ここで環AがA−2である場合は、WはCH 2 であり;mは0、1又は2であり;
Dは炭素であり、R 2 及びR 2a は独立してH、F、(1−3C)アルキル又はOH(ただしR 2 及びR 2a は共にOHではない)であり、そしてR 3 及びR 3a は独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルであるか、又は
Dは炭素又は窒素であり、R 2 及びR 3 は存在せず、そしてR 2a 及びR 3a はそれらが結合している原子と一緒になって1〜2個の環ヘテロ原子を有する5〜6員のヘテロアリール環を形成し;
Zは * −NR 4a C(=O)−、 * −ONHC(=O)−、 * −NR 4b CH 2 −又は * −OC(=O)−であり、ここでアスタリスクはR 3 を担持している炭素へのZの結合点を示し;
R 4a はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)であり;
R 4b はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)、ジヒドロキシ(2−6Cアルキル)、(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−、HOCH 2 C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、Ar 2 (SO 2 )−、HO 2 CCH 2 −又は(1−6Cアルキル)NH(CO)−であり;
Ar 1 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;
Ar 2 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;そして、
R 5 及びR 6 は独立してH、ハロゲン、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである]の化合物又は製薬上許容しうるその塩。
(項目2)
下記一般式:
[式中、環Aは下記構造:
[式中1と標記された波線は環Aの式Iのピロリジン環への結合点を示し、そして2と標記された波線は環AのWへの結合点を示す]を有する環A−1、A−2及びA−3から選択され;
XはN又はCHであり;
YはH又はFであり;
R 1 はH、(1−3C)アルコキシ又はハロゲンであり;
WはO、NH又はCH 2 であり、ここで環AがA−2である場合は、WはCH 2 であり;mは0、1又は2であり;
R 2 及びR 2a は独立してH、F又はOHであるが、ただしR 2 及びR 2a は共にOHではなく;
R 3 はH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキル;
Zは * −NR 4a C(=O)−、 * −ONHC(=O)−、 * −NR 4b CH 2 −又は*−OC(=O)−であり、ここでアスタリスクはR 3 を担持している炭素へのZの結合点を示し;
R 4a はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)であり;
R 4b はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)、ジヒドロキシ(2−6Cアルキル)、(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−、HOCH 2 C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、Ar 2 (SO 2 )−、HO 2 CCH 2 −又は(1−6Cアルキル)NH(CO)−であり;
Ar 1 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;
Ar 2 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;そして、
R 5 及びR 6 は独立してH、ハロゲン、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである]を有する上記項目1記載の化合物又は製薬上許容しうるその塩。
(項目3)
環Aが下記構造:
を有する環A−1である上記項目1又は2記載の化合物。
(項目4)
XがCHである上記項目3記載の化合物。
(項目5)
XがNである上記項目3記載の化合物。
(項目6)
環Aが下記構造:
を有する環A−3である上記項目1又は2記載の化合物。
(項目7)
WがOである上記項目1〜6の何れかに記載の化合物。
(項目8)
WがNHである上記項目1〜6の何れかに記載の化合物。
(項目9)
WがCHである上記項目1〜6の何れかに記載の化合物。
(項目10)
環Aが下記構造:
を有する環A−2である上記項目1又は2記載の化合物。
(項目11)
YがFである上記項目1〜10の何れかに記載の化合物。
(項目12)
YがHである上記項目1〜10の何れかに記載の化合物。
(項目13)
R 1 がHである上記項目1〜12の何れかに記載の化合物。
(項目14)
R 1 が(1−3C)アルキル又は(1−3C)アルコキシである上記項目1〜12の何れかに記載の化合物。
(項目15)
R 1 がメチル又はメトキシである上記項目14記載の化合物。
(項目16)
R 1 がハロゲンである上記項目1〜12の何れかに記載の化合物。
(項目17)
R 1 がフルオロである上記項目16記載の化合物。
(項目18)
Zが * −NR 4a C(=O)−である上記項目1〜17の何れかに記載の化合物。
(項目19)
R 4a が水素である上記項目18記載の化合物。
(項目20)
R 4a が(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)である上記項目18記載の化合物。
(項目21)
R 4a が(1−6C)アルキルである上記項目20記載の化合物。
(項目22)
Zが * −ONHC(=O)−である上記項目1〜17の何れかに記載の化合物。
(項目23)
Zが * −NR 4b CH 2 −である上記項目1〜17の何れかに記載の化合物。
(項目24)
R 4b がHである上記項目23記載の化合物。
(項目25)
R 4b が(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル及びトリフルオロ(1−6C)アルキルから選択される上記項目23記載の化合物。
(項目26)
R 4b が(1−6C)アルキルである上記項目25記載の化合物。
(項目27)
R 4b が(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−及びHOCH 2 C(O)−から選択される上記項目23記載の化合物。
(項目28)
R 4b が(1−6Cアルキル)C(O)−である上記項目27記載の化合物。
(項目29)
R 4b が(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル及びAr 2 (SO 2 )−から選択される上記項目23記載の化合物。
(項目30)
R 4b が(1−6Cアルキル)スルホニルである上記項目29記載の化合物。
(項目31)
R 4b がHO 2 CCH 2 −である上記項目23記載の化合物。
(項目32)
R 4b が(1−6Cアルキル)NH(CO)−である上記項目23記載の化合物。
(項目33)
Dが炭素であり、R 2 及びR 2a は独立してH、F、(1−3C)アルキル又はOH(ただしR 2 及びR 2a は共にOHではない)であり、そしてR 3 及びR 3a は独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルである上記項目1又は3〜32の何れかに記載の化合物。
(項目34)
R 2 及びR 2a が各々水素である上記項目1〜33の何れかに記載の化合物。
(項目35)
R 2 及びR 2a が各々フルオロである上記項目1〜33の何れかに記載の化合物。
(項目36)
R 2 が水素であり、そしてR 2a がフルオロである上記項目1〜33の何れかに記載の化合物。
(項目37)
R 2 が水素であり、そしてR 2a がOHである上記項目1〜33の何れかに記載の化合物。
(項目38)
R 2 がHであり、そしてR 2a がメチルであるか、又はR 2 及びR 2a が共にメチルである上記項目1又は3〜33記載の化合物。
(項目39)
R 3 及びR 3a がHであるか;又は、
R 3a がメチルであり、そしてR 3 がHであるか;又は、
R 3a 及びR 3a が共にメチルである;
上記項目1又は3〜33記載の化合物。
(項目40)
Dは炭素又は窒素であり、R 2 及びR 3 は存在せず、そしてR 2a 及びR 3a はそれらが結合している原子と一緒になって1〜2個の環ヘテロ原子を有する5〜6員のヘテロアリール環を形成する上記項目1又は3〜32記載の化合物。
(項目41)
環Bが下記環B−1:
であり;
R 5 及びR 6 は独立してH、F、OH、メチル、エチル、HOCH 2 −又はHOCH 2 CH 2 −である上記項目1〜40の何れかに記載の化合物。
(項目42)
R 5 が水素であり、そしてR 6 がH、F、OH、メチル、エチル、HOCH 2 −又はHOCH 2 CH 2 −である上記項目41記載の化合物。
(項目43)
R 6 がHである上記項目42記載の化合物。
(項目44)
環Bが下記環B−2:
である上記項目1又は3〜40記載の化合物。
(項目45)
mが0である上記項目1〜44の何れかに記載の化合物。
(項目46)
mが1である上記項目1〜44の何れかに記載の化合物。
(項目47)
mが2である上記項目1〜44の何れかに記載の化合物。
(項目48)
下記図1−a:
の絶対配置を有する上記項目1〜47の何れかに記載の化合物。
(項目49)
下記式図1−b:
の絶対配置を有する上記項目1〜47の何れかに記載の化合物。
(項目50)
上記項目1〜49の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩、及び、製薬上許容しうる希釈剤又は担体を含む医薬組成物。
(項目51)
上記項目1〜49の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩の治療有効量を哺乳類に投与することを含む、該哺乳類における疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症から選択される疾患又は障害を治療するための方法。
(項目52)
疾患又は障害が疼痛である上記項目51記載の方法。
(項目53)
疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症の治療において使用するための上記項目1〜49の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩。
(項目54)
下記工程:
(a)Zが * −NHC(=O)−であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式II:
[式中P 1 はH又はカルボキシル保護基である]を有する相当する化合物をカップリング試薬及び塩基の存在下に環化すること;又は、
(b)WがOであり、環Aが下記式A−1:
[式中nは1、2、3又は4であり、そしてL 1 は脱離基又は原子である]を有する相当する化合物を塩基の存在下に環化すること;又は、
(c)WがCH 2 であり、環Aが下記式A−2:
であり、そして環B、Z、D、Y、R 1 、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式IV:
[式中L 2 は脱離基又は原子である]を有する相当する化合物を塩基の存在下に環化すること;又は、
(d)Zが * −NHC(=O)−であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式V:
(e)Zが * −NHCH 2 −であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式VI:
を有する相当する化合物を還元剤の存在下に環化すること;又は、
(f)Zが * −NHCH 2 −であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式VII:
を有する相当する化合物をトリフェニルホスフィンの存在下に環化すること;又は、
(g)環A、環B、W、D、m、R 2 、R 2a 、R 3 、及びR 3a が式Iに関して定義したとおりであり、Zが * −NR 4b CH 2 −であり、そしてR 4b が(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−、HOCH 2 C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、又はAr 2 (SO 2 )−である式Iの化合物に関しては、下記式VIII:
を有する相当する化合物を式(1−6Cアルキル)C(O)−L 3 、(3−6Cシクロアルキル)C(O)−L 3 、Ar 1 C(O)−L 3 、HOCH 2 C(O)−L 3 、(1−6Cアルキル)(SO 2 )−L 3 、(3−6Cシクロアルキル)(SO 2 )−L 3 又はAr 2 (SO 2 )−L 3 (それぞれ式中L 3 は脱離原子である)を有する試薬と塩基の存在下にカップリングさせること;又は、
(h)環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりであり、Zが * −NR 4b CH 2 −であり、そしてR 4b が(1−6Cアルキル)NH(CO)−である式Iの化合物に関しては、下記式VIII:
を有する化合物を式(1−6Cアルキル)N=C=Oを有する試薬と塩基の存在下に反応させること;又は、
(i)R 2 がFであり、R 2a がHであり、そして環A、環B、Z、W、D、R 3 、R 3a 、及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式IX:
を有する相当する化合物をフッ素化試薬と反応させること;
(j)WがOであり、環Aが下記式A−1:
であり、XがCHであり、そしてY、R 1 、D、環B、Z,R 2 、R 2a 、R 3 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式X:
[式中nは1、2、3又は4であり、そしてL 1 は脱離基又は原子である]を有する相当する化合物を塩基の存在下に環化すること;及び、
場合により何れかの保護基を除去すること、及び、場合によりその塩を調製すること;
を含む上記項目1記載の化合物の調製のためのプロセス。
(項目55)
環Bが下記構造:
を有する環B−1であり;
Dが炭素であり;
R 2 及びR 2a は独立してH、F、(1−3C)アルキル又はOHであるが、ただしR 2 及びR 2a は共にOHではなく;そして、
R 3 及びR 3a は独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルである;
上記項目54記載のプロセス。
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