JP2021518836A - 抗癌剤としての置換されたアルキニレン化合物 - Google Patents
抗癌剤としての置換されたアルキニレン化合物 Download PDFInfo
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- JP2021518836A JP2021518836A JP2020536541A JP2020536541A JP2021518836A JP 2021518836 A JP2021518836 A JP 2021518836A JP 2020536541 A JP2020536541 A JP 2020536541A JP 2020536541 A JP2020536541 A JP 2020536541A JP 2021518836 A JP2021518836 A JP 2021518836A
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- alkyl
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- compound according
- cancer
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- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- HGLKMYOTFGKEDG-UHFFFAOYSA-N tert-butyl 5-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1C(N)C2 HGLKMYOTFGKEDG-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 238000004724 ultra fast liquid chromatography Methods 0.000 description 1
- 229940096998 ursolic acid Drugs 0.000 description 1
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- 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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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/28—Nitrogen atoms
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- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
本出願は、2018年1月17日に出願されたインド仮特許出願第201841001978号の優先権の利益を主張し、その内容は、参照によりその全体が本明細書に組み込まれる。
式中、
Aはアリールまたはヘテロアリールを表し;
Xは、N−Ryを表すか、あるいは存在しないことを表し;
Yは、O、S、あるいはNCNを表し;
Bは、アリール、シクロアルキル、あるいはヘテロシクロアルキルを表し;ここで、アリール、シクロアルキル、あるいはヘテロシクロアルキルは、アルキル、ハロ、およびオキソから選択される1つ以上の基で随意に置換され;
R1はアルキルを表し;R2は水素あるいはアルキルを表し;または、R1およびR2は、それらが結合する炭素原子と一体となって3〜5員のシクロアルキル環を形成し;
R3は、−C(O)Ra、−S(O)2Ra、−NHS(O)2Ra、−NRbC(O)Ra、=NORa、ヘテロアリール、ヘテロシクロアルキルあるいは(ヘテロシクロアルキル)アルキル−を表し;ここで、ヘテロアリールおよびヘテロシクロアルキルは、アルキル、ハロ、オキソおよび−C(O)Rxから選択される1つ以上の基で随意に置換され;
R4は、アルキル、ハロ、ハロアルキル、シアノ、アルコキシ、アリールオキシ、アルコキシアリール、ヒドロキシアルキル、アセチレン、アシル、ヒドロキシ、シクロアルキルあるいは−N(Rx)2を表し;ここで、シクロアルキルはアルキルで随意に置換され;
Raは、アルキル、アルケニル、ハロアルキル、シクロアルキルあるいはヘテロシクロアルキルを表し;ここで、アルキル、アルケニル、ハロアルキル、シクロアルキルおよびヘテロシクロアルキルは、アルキル、ハロ、アリール、シクロアルキル、ハロアルキル、アミノ、アミド、アルキルアミノ、アミノアルキル、ヒドロキシル、シアノ、アルコキシ、アルコキシアリール、アリールオキシ、ヒドロキシアルキル、カルボン酸、エステル、チオエステル、オキソ(=O)および−C(O)Rxから選択される1つ以上の基で随意に置換され;
Rxは、水素、アルキル、アルケニル、アシルあるいは−C(O)−シクロアルキルを表し;
Ryは、水素またはアルキルを表し;
Rbは、水素、アルキルあるいはアルケニルを表し;
「m」は、0、1、2、または3を表す。
式中、
Aはアリールまたはヘテロアリールを表し;
Xは、N−Ryを表すか、あるいは存在しないことを表し;
Yは、O、S、あるいはNCNを表し;
Bは、アリール、シクロアルキル、あるいはヘテロシクロアルキルを表し;ここで、アリール、シクロアルキル、あるいはヘテロシクロアルキルは、アルキル、ハロ、およびオキソから選択される1つ以上の基で随意に置換され;
R1はアルキルを表し;および、R2は水素あるいはアルキルを表し;または、R1およびR2は、それらが結合する炭素原子と一体となって3〜5員のシクロアルキル環を形成し;
R3は、−C(O)Ra、−S(O)2Ra、−NHS(O)2Ra、−NRbC(O)Ra、=NORa、ヘテロアリール、ヘテロシクロアルキルあるいは(ヘテロシクロアルキル)アルキル−を表し;ここで、ヘテロアリールおよびヘテロシクロアルキルは、アルキル、ハロ、オキソおよび−C(O)Rxから選択される1つ以上の基で随意に置換され;
R4は、アルキル、ハロ、ハロアルキル、シアノ、アルコキシ、アリールオキシ、アルコキシアリール、ヒドロキシアルキル、アセチレン、アシル、ヒドロキシ、シクロアルキルあるいは−N(Rx)2を表し;ここで、シクロアルキルはアルキルで随意に置換され;
Raは、アルキル、アルケニル、ハロアルキル、シクロアルキルあるいはヘテロシクロアルキルを表し;ここで、アルキル、アルケニル、ハロアルキル、シクロアルキルおよびヘテロシクロアルキルは、アルキル、ハロ、アリール、シクロアルキル、ハロアルキル、アミノ、アミド、アルキルアミノ、アミノアルキル、ヒドロキシル、シアノ、アルコキシ、アルコキシアリール、アリールオキシ、ヒドロキシアルキル、カルボン酸、エステル、チオエステル、オキソ(=O)および−C(O)Rxから選択される1つ以上の基で随意に置換され;
Rxは、水素、アルキル、アルケニル、アシルあるいは−C(O)−シクロアルキルを表し;
Ryは、水素またはアルキルを表し;
Rbは、水素、アルキルあるいはアルケニルを表し;
「m」は、0、1、2、または3を表す。
ある実施形態では、本発明は、式(I)の化合物およびその薬学的に許容可能な塩あるいは立体異性体、ならびに薬学的に許容可能な担体または賦形剤を含む医薬組成物を提供する。
ある実施形態では、本発明は、薬剤として使用するための化合物を提供する。
別段の定めのない限り、本明細書で使用される技術用語および科学用語はすべて、主題が属する当該技術分野の当業者によって一般に理解されるものと同じ意味を有する。本明細書および添付の特許請求の範囲で使用される場合、別段の定めがない限り、以下の用語は、本発明の理解を容易にするために示される意味を有する。
以下の一般的なガイドラインは、本明細書に記載されるすべての実験手順に提供される。別段の記載がない限り、実験が窒素の陽圧下で実施され、温度は、外部温度(つまり、油浴温度)を記載する。供給業者から受け取った試薬および溶剤を、さらに乾燥あるいは精製することなく、そのまま使用する。事前に標準液での滴定で確認していないため、溶液中の試薬について本明細書に記載されるモル濃度はおおよそである。反応はすべて、磁気撹拌棒の下で撹拌される。マイナスの温度への冷却は、アセトン/ドライアイスあるいは湿った氷/塩によって行われた。硫酸マグネシウムおよび硫酸ナトリウムは、反応後処理後に溶媒乾燥剤として使用され、交換可能である。減圧下あるいは真空内での溶媒の除去、であるいは反応混合物の濃縮は、ロータリーエバポレーター内の溶剤の蒸留を意味する。
特段明記されない限り、ワークアップは、有機質相と水相の間の反応混合物の分布、層の分離、無水硫酸ナトリウム上での有機層の乾燥、溶媒のろ過と蒸発を含む。精製は、特段明記されない限り、移動相として適切な極性の酢酸エチル/石油エーテルの混合物を通常使用して、シリカゲルクロマトグラフ法による精製を含む。
以下の化合物は典型的に市販で入手可能であるか、あるいは当業者に周知の技術によって作られてもよい。本発明の化合物および/またはその中間体の調製に生成物を使用した。
DMF(75mL)中の5−ブロモ−2−クロロ安息香酸(11.0g、46.72mmol)の撹拌溶液に、N,O−ジメチルヒドロキシルアミン塩酸塩(5.46g、56.07mmol)、HATU(26.6g、84.10mmol)およびDIPEA(18.1g、140.16mmol)を室温で加え、室温で16時間撹拌した。反応の完了後、それを氷水に注ぎ;得られた固体をろ過し、combiflash(登録商標)シリカゲルカラム(ヘキサン/EtOAc=90/10)によって精製して、表題化合物(11.0g、82%)を得た。LCMS: m/z = 277.5 [M]+.
THF(100mL)中の5−ブロモ−2−クロロ−N−メトキシ−N−メチルベンズアミド(工程−1)(11.0g、39.49mmol)の撹拌溶液に、不活性雰囲気下で、メチル臭化マグネシウム(THF中3.0M)(19.7mL、59.24mmol)を0°Cで加え、室温で16時間撹拌した。反応の完了後、それを1N HClによってクエンチし、ジエチルエーテルで抽出した。エーテル層を乾燥させ、濃縮し、combiflash(登録商標)シリカゲルカラム(ヘキサン/EtOAc=95/5)によって精製することで、表題化合物(7.0g、76.0%)を得た。LCMS:m/z=イオン化されない。得られた生成物を、精製することなく次の工程に進めた。
THF(50mL)中のメチルトリフェニルホスホニウムブロミド(26.8g、75.10mmol)の撹拌懸濁液に、0°Cでn−ブチル リチウム(ヘキサン中2.0M)(37.5mL、75.10mmol)を加えた。反応混合物を0°Cで5分間撹拌し、THF(50mL)中の1−(5−ブロモ−2−クロロフェニル)エタン−1−オン(工程−2)(7.0g、30.04mmol)を0°Cで加え、室温で16時間撹拌した。反応の完了後、それを1N HClによってクエンチし、ジエチルエーテルで抽出した。エーテル層を乾燥させ、濃縮して、粗製化合物を得た。粗製化合物をcombiflash(登録商標)シリカゲルカラム(ヘキサン/EtOAc=95/5)によって精製して、表題化合物(5.0g、71.42%)を得た。この化合物を精製することなく、さらなる工程に進めた。
DCM(25mL)中のジエチル亜鉛(ヘキサン中の1.0M)(43.2mL、43.2mmol)の撹拌溶液に、DCM(15mL)中のTFA(4.9g、43.2mmol)の溶液を0°Cでゆっくりと加え、0°Cで20分間撹拌した。DCM(30mL)中のジヨードメタン(11.5g、43.2mmol)の溶液を、反応混合物に0°Cで加え、0°Cで20分間撹拌した。DCM(30mL)中の4−ブロモ−1−クロロ−2−(プロプ−1−エン−2−イル)ベンゼン(工程−3)(2.0g、8.65mmol)の溶液を、室温で反応混合物に加え、室温で16時間撹拌した。その後、反応混合物をペンタンで希釈し、1N HCl、飽和NaHCO3溶液およびブラインで洗浄した。有機質層を乾燥させ、濃縮して、表題化合物(2.0g、94.3%)を得た。LCMS:m/z=イオン化されない。
特許US20140288045 A1で報告された手順に従って、表題中間体を合成し、次の工程に使用した。
濃塩酸(3.8mL)、水(3.8mL)中の4−クロロ−2−メトキシ−5−(1−メチルシクロプロピル)アニリン(0.8g、3.97mmol)の撹拌溶液に、−5°Cで水中のNaNO2(0.3g、4.53mmol)の溶液を加えた。15分間撹拌した後、ヨウ化カリウム(1.2g、7.55mmol)の溶液を加えた。反応混合物を室温で30分間撹拌した。反応混合物をEtOAc(2X50mL)で抽出し、Na2SO4の上で乾燥させ、濃縮し、combiflash(登録商標)シリカゲルカラム(ヘキサン/酢酸エチル=95/5)により精製することで、表題化合物(0.8g、74%)を得た、LCMS:m/z = 264.0[M+2]+.
1,4−ジオキサン(10.0mL)中の1−アミノシクロペンタン−1−カルボン酸(1.00g、7.742mmol)の撹拌懸濁液に、水(26.0mL)中の1N NaOH溶液、およびジ−tert−ブチル ジカーボネート(1.40mL、6.101mmol)を室温で加え、それを14時間撹拌した。反応混合物を氷水に注ぎ、DCMで抽出した。組み合わせたDCM層を水とブラインで洗浄し;硫酸ナトリウムで乾燥させ;減圧下で蒸発させて、表題化合物(1.201g、粗製)を得た。LCMS: m/z = 230.3[M+H]+1.
ジメトキシエタン(30.0mL)中の1−((tert−ブトキシカルボニル)アミノ)シクロペンタン−1−カルボン酸(1.20g、5.234mmol)の撹拌懸濁液に、4−メチルモルホリン(0.58mL、5.286mmol)、クロロギ酸イソブチル(0.68mL、5.286mmol)を−15°Cで加え、1時間撹拌した。反応混合物をRTに温め、それをさらに1時間撹拌し、反応混合物を減圧下で蒸発させることで、表題化合物(1.782g、粗製)を得た。得られた粗製物をさらに精製することなく、次の工程に進めた。
ジメトキシエタン(20.0mL)中の1−((tert−ブトキシカルボニル)アミノ)シクロペンタン−1−カルボキシリック(炭酸イソブチル)無水物(1.780g、5.404mmol)の撹拌懸濁液に、水(3.0mL)中の水素化ホウ素ナトリウム(0.78g、27.019mmol)を−5°Cで、滴下で加え、それを室温で1時間撹拌した。反応混合物を氷水へと注ぎ、酢酸エチルで抽出した。組み合わせた酢酸エチル層を水、ブラインで洗浄し;硫酸ナトリウム上で乾燥させ、減圧下で蒸発させて、表題化合物(0.903g、77.84%)を得た。上で得られた化合物をさらに分析することなく、次の工程に進めた。
ジクロロメタン(25.0mL)中のtert−ブチル(1−(ヒドロキシメチル)シクロペンチル)カルバメート(0.980g、4.552mmol)の撹拌懸濁液に、デス・マーチン・ペルヨージナン(2.51g、5.918mmol)を0°Cで少しずつ加え、室温で2時間撹拌した。反応混合物をヘキサンへと注ぎ;セライト(登録商標)を介してろ過し、DCMで洗浄した。集めた濾液を硫酸ナトリウム上で乾燥させ、減圧下で蒸発させた。得られた残留物をシリカゲル(ヘキサン/酢酸エチル=90/10)上でCombiflash(登録商標)によって精製して、表題化合物(0.540g、55.67%)を得た。上で得られた化合物をさらに分析することなく、次の工程に進めた。
アセトニトリル(30.0mL)中の4−アセトアミドベンゼンスルホニル アジド(0.732g、3.047mmol)の撹拌懸濁液に、ジメチル(2−オキソプロピル)ホスホネート(0.466g、2.813mmol)を0°Cで加え、それを室温で2時間撹拌した。メタノール(30.0mL)中のtert−ブチル(1−ホルミルシクロペンチル)カルバメート(0.980g、4.552mmol)を、室温で反応混合物に滴下で加え、それを2時間撹拌した。反応混合物をセライト(登録商標)パッドを介してろ過した。集めた濾液を減圧下で蒸発させた。得られた残留物をシリカゲル(ヘキサン/酢酸エチル=95/05)上でCombiflash(登録商標)によって精製して、表題化合物(0.300g、61.22%)を得た。LCMS:イオン化されていない。得られた生成物を精製することなくさらに使用した。
ジクロロメタン(10mL)中のtert−ブチル5−アミノ−2−アザビシクロ[2.2.1]ヘプタン−2−カルボキシレート(±)(0.300g、1.41mmol)、およびトリエチルアミン(0.580mL、4.23mmol)の懸濁液に、0°Cで塩化アクリロイル(0.127g、1.41mmol)を加え、室温で1時間撹拌した。反応混合物をジクロロメタンで希釈し、無飽和NaHCO3溶液で洗浄し、水硫酸ナトリウム上で乾燥させて濃縮した。得られた粗製物をシリカゲル(酢酸エチル=100%)上のCombiFlash(登録商標)によって精製して、表題化合物(0.180g、48%)を得た。LCMS: m/z = 167.3 [M−100]+
ジクロロメタン(5mL)中のtert−ブチル5−アクリルアミド−2−アザビシクロ[2.2.1]ヘプタン−2−カルボキシレート(±)(0.180g、0.670mmol)の溶液に、TFA(0.2mL)を0°Cで加え、室温で4時間撹拌し、反応混合物を濃縮することで、表題化合物(0.280g、粗製)を得た。LCMS:m/z = 167.1 [M−100]+
tert−ブチル5−アミノ−2−アザビシクロ[2.2.1]ヘプタン−2−カルボキシレート(±)(0.500g、2.350mmol)およびトリエチルアミン(0.970mL、7.060mmol)の懸濁液に、クロロエチル スルホニルクロリド(0.383g、2.35mmol)を0°Cで加え、室温で1時間撹拌した。反応混合物をジクロロメタンで希釈し、飽和NaHCO3溶液で洗浄し、無水硫酸ナトリウム上で乾燥させ、濃縮して、粗製化合物を得て、それをCombiFlash(登録商標)(酢酸エチル=100%)によって精製することで表題化合物(0.250g、358%)を得た。LCMS:m/z = 203.2 [M+H−100]+.
ジクロロメタン(10mL)中のtert−ブチル5−(ビニルスルホンアミド)−2−アザビシクロ[2.2.1]ヘプタン−2−カルボキシレート(±)(0.250g、0.827mmol)の溶液に、TFA(0.5mL)を0°Cで加え、室温で4時間撹拌した。反応混合物を濃縮して、表題化合物(0.300g、粗製)を得た。LCMS:m/z = 203.2 [M+H−100]+.
アセトニトリル(50.0mL)中の2−シアン酢酸(2.85g、33.548mmol)の撹拌懸濁液に、TBTU(10.77g、33.548mmol)を室温で加え、それを2時間撹拌した。2時間後、tert−ブチル ピペラジン−1−カルボキシレート(5.00g、26.838mmol)を室温で加え、それを14時間さらに撹拌した。反応混合物を減圧下で蒸発させ、得られた残留物を水とEtOAc(1:1)とに分けた。組み合わせたEtOAc層を水およびブラインで洗浄した。Na2SO4上で乾燥させ、減圧下で蒸発させた。得られた残留物を シリカゲル(DCM/MeOH=99/1)上でCombiflash(登録商標)によって精製することで、表題化合物(2.80g、41.27%)を得た。LCMS:m/z = 254.30[M]+.
DMF(10.0mL)中のtert−ブチル4−(2−シアノアセチル)ピペラジン−1−カルボキシレート(1.00g、3.947mmol)の撹拌懸濁液に、DMF−DMA(10.0mL、75.277mmol)を室温で加え、それを100°Cで5時間加熱した。反応混合物を氷水へと注ぎ、EtOAcで抽出した。組み合わせたEtOAc層をブライン、水で洗浄した。Na2SO4上で乾燥させ、減圧下で蒸発させ、表題化合物(0.902g、粗製)を得た。LCMS:m/z = 309.38[M+H]+.
工程−3:(E)−3−(ジメチルアミノ)−2−(ピペラジン−1−カルボニル)アクリロニトリル.TFA塩
DCM(5.0mL)中のtert−ブチル4−(2−シアノ−3−(ジメチルアミノ)アクリロイル)ピペラジン−1−カルボキシレート(0.20g、0.648mmol)の撹拌懸濁液に、TFA(0.50mL、6.529mmol)を室温で加え、それ5時間撹拌した。反応混合物を減圧下で蒸発させ、得られた残留物をジエチルエーテルを用いて粉末にすることで、表題化合物(0.195g、粗製)を得た。LCMS:m/z = 209.30[M+H]+.
K2CO3(0.133g、0.480mmol)を加え、室温で1時間撹拌した。反応混合物を濃縮し、シリカゲル(ヘキサン/EtOAc=60/40)上でCombiflash(登録商標)によって精製して、表題化合物(0.070g、不純)を得た。LCMS:m/z = 428.3[M+H].
中間体16d:tert−ブチル(1−((4−(3,4−ジクロロフェニル)ブト−3−イン−2−イル)カルバモイル)シクロペンチル)カルバメート(±).
1H NMR (400 MHz,CDCl3): δ 7.53 (d, J = 1.86 Hz, 1H), 7.40 (d, J = 8.31 Hz, 1H), 7.31 − 7.22 (m, 1H), 6.59 (dd, J = 10.49, 16.79 Hz, 1H), 6.37 (dd, J = 1.82, 16.87 Hz, 1H), 5.78 (dd, J = 1.84, 10.52 Hz, 1H), 4.97 (q, J = 7.14 Hz, 1H), 4.67 (d, J = 7.87 Hz, 1H), 3.84 − 3.37 (m, 8H), 1.53 (d, J = 6.87 Hz, 3H)
方法:
カラム:LUX AMYLOSE−2(21.2X250mm−5μm);
移動相:ヘキサン(A)、エタノール中の0.1%のTFA(B)
流量:20mL/分
アイソクラティック:80:20
収率:46.0%; HPLC: 99.09%; LCMS: m/z =379.9 [M+H]+;
収率=0.005g(33.3%)LCMS:m/z = 449.2[M+H]+;HPLC:99.1%;キラルHPLC:95.2%(保持時間=5.067分)。
収率:0.005g、(33.3%)。LCMS:m/z = 449.2 [M+H]+;HPLC:95.7%;キラルHPLC:97.8%(保持時間=5.138分)。
表題化合物を、中間体17o、および実施例−43あるいは実施例−44の合成に記載されるような2−シアノ酢酸から合成した。収率:77.6%;LCMS:m/z = 405.2 [M+H]+.
IPA(3mL)中の4−(2−シアノアセチル)−N−(1−((3,4−ジクロロフェニル)エチニル)シクロプロピル)ピペラジン−1−カルボキサミド(0.100g、246mmol)の撹拌懸濁液に、イソブチルアルデヒド(0.022g、0.313mmol)、ピペリジンアセテート(0.007g、0.049mmol)を室温で加えた。室温で5時間撹拌した後に、反応混合物を減圧下で濃縮した。分取TLC法(ジクロロメタン/メタノール:98/2)を2回実行することによって粗製生成物を精製して、表題化合物(0.020g、22.1%)を得た。HPLC:96.8%;LCMS: m/z = 459.3 [M]+. 1H NMR (300 MHz, Chloroform−d): δ 7.47 (d, J = 1.9 Hz, 1H), 7.35 − 7.30 (m, 1H), 7.23 − 7.17 (m, 1H), 6.99 (d, J = 10.5 Hz, 1H), 5.13 (s, 1H), 3.64 (dd, J = 6.5, 4.0 Hz, 4H), 3.47 (s, 4H), 1.39 − 1.31 (m, 1H), 1.23 − 1.17 (m, 2H), 1.15 (d, J = 6.7 Hz, 6H), 1.07 (d, J = 6.7 Hz, 2H).
方法:カラム:Xbridge−C−18(19x150)mm;水:アセトニトリル;流量15mL/分。HPLC: 98.27% , LCMS: m/z = 429.9 [M+H]+.1H NMR (400 MHz, DMSOd6): δ 7.75 − 7.49 (m, 2H), 7.47 − 7.29 (m, 2H), 6.93 (d, J = 8.18 Hz, 1H), 6.76 (ddd, J = 0.86, 9.94, 16.52 Hz, 1H), 6.11 − 5.86 (m, 2H), 4.75 (p, J = 7.13 Hz, 1H), 3.94 − 3.72 (m, 2H), 3.17 (tdd, J = 4.73, 7.05, 8.84, 10.58 Hz, 2H), 2.78 (ddt, J = 5.89, 11.88, 15.23 Hz, 2H), 1.74 (d, J = 12.57 Hz, 2H), 1.34 − 1.22 (m, 3H).
THF:MeOH:H2O(1:1:8)混合物中の実施例57(0.200g、0.440mmol)の撹拌溶液に、LiOH.H2O(0.093g、2.220mmol)を加え、室温で12時間撹拌した。反応混合物を減圧下で濃縮し、水(25mL)で希釈し、ジエチルエーテル(2×50mL)で洗浄した。水層を分離し、PHを、希塩酸でわずかに酸性に調節し、EtOAc(50mL×2)で抽出した。有機質層を無水Na2SO4上で乾燥させ;減圧下で濃縮して、オフホワイトの固形物(0.08g、42.6%)を得た。LCMS: m/z 456.2 [M+H+38]+.
DMF中のEt3Nの存在下で、EDC.HClおよびHOBtを用いて、実施例−42の記載された手段に従って、工程−1の中間体および塩化アンモニウムから表題化合物を合成した。収率:18.7%; HPLC: 98.4%; LCMS: m/z = 423.0 [M]+;1H NMR (400 MHz, DMSOd6) δ 7.66 (d, J = 1.96 Hz, 1H), 7.62 (d, J = 8.38 Hz, 1H), 7.41 − 7.35 (m, 1H), 7.25 (d, J = 15.06 Hz, 1H), 6.78 (d, J = 15.09 Hz, 1H), 4.77 (p, J = 7.17 Hz, 1H), 3.61 − 3.44 (m, 4H), 3.33 − 3.17 (m, 4H), 3.18 (s, 1H), 1.24 (d, J = 17.61 Hz, 3H),
実施例−25の合成で記載された手順に従って、中間体17oを、0°Cの1−(tert−ブトキシカルボニル)アゼチジン−3−カルボン酸、トリエチルアミン、HOBT、EDCIと反応させて、表題化合物(0.455g、粗製)を得た。LCMS: m/z = 421.2 [M+H−100]+.
ジオキサン(5mL)中のtert−ブチル3−(4−((1−((3,4−ジクロロフェニル)エチニル)シクロプロピル)−カルバモイル)ピペラジン−1−カルボニル)アゼチジン−1−カルボキシレート(0.45g、0.86mmol)の撹拌溶液に、室温でジオキサン.HCl(10mL)を滴下で加えた。反応混合物を2時間室温で撹拌した。溶媒を減圧下で蒸発させて、生成物(0.390g、粗製)を得た;LCMS: m/z = 421 [M−36]+。
DCM(10mL)中の4−(アゼチジン−3−カルボニル)−N−(1−((3,4−ジクロロフェニル)エチニル)−シクロプロピル)ピペラジン−1−カルボキサミド塩酸塩(工程−2)(0.25g、0.54mmol)の撹拌溶液に、NaHCO3溶液(10mL)および塩化アクリロイル(45μL、0.54mmol)を室温で加え、1時間撹拌した。DCM層を分離し、ブライン溶液で洗浄し、無水Na2SO4上で乾燥させて濃縮した。得られた残留物を分取HPLCによって精製し、表題化合物(0.080g、30.8%)を得た;LCMS: m/z = 475.3 [M]+ , HPLC: 99%, 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 1.87 Hz, 1H), 7.33 (d, J = 8.30 Hz, 1H), 7.20 (dd, J = 1.90, 8.30 Hz, 1H), 6.34 (dd, J = 1.82, 16.98 Hz, 1H), 6.18 (dd, J = 10.25, 16.99 Hz, 1H), 5.69 (dd, J = 1.84, 10.29 Hz, 1H), 5.16 (s, 1H), 4.31 (q, J = 9.20, 9.84 Hz, 2H), 4.14 (dd, J = 6.31, 9.88 Hz, 1H), 3.48 (q, J = 6.95 Hz, 4H), 3.33 (p, J = 5.28 Hz, 4H), 1.42 − 1.31 (m, 2H), 1.31 − 1.12 (m, 4H).
ブト−3−イン−2−イルメタンスルホネート(±)(1.0g、6.75mmol)を、アンモニア水(10mL)において室温で16時間撹拌した。反応混合物をDCM(25mL)で抽出した。DCM層をNa2SO4上で乾燥させてろ過した。上で得られたDCM溶液4−アクリルアミド安息香酸(US2008/300268 A1に記載される手順に従って調製された)(0.990gm、5.19mmol、1.0eq)に、DIPEA(3.58mL、20.22mmol)およびHATU(3.86gm、10.12mmol、1.5eq)を室温で加え、結果として生じる反応混合物を室温で16時間撹拌した。反応混合物を水(20mL)で洗浄し、その後ブライン(20mL)で洗浄した。DCM層を乾燥させ、濃縮して、粗製化合物を得た。得られた残留物をシリカゲル(ヘキサン/酢酸エチル=60/40)上のCombiflash(登録商標)によって精製して、表題化合物(0.650gm、40%)を得た。LCMS:m/z = 243.4 [M+H]+.
4−アクリルアミド−N−(ブト−3−イン−2−イル)ベンズアミド(±)(0.65g、2.68mmol)を、中間体8の調製のための手順に記載されるような1,2−ジクロロ−4−ヨードベンゼン(0.487g、1.79mmol)で処理して、表題化合物を得た(収率:0.12g、11.5%)。LCMS: m/z = 387.0 [M+H]+. HPLC: 95.13%; 1H NMR (400 MHz, DMSOd6): δ 10.39 (s, 1H), 8.87 (d, J = 7.89 Hz, 1H), 7.93 − 7.85 (m, 2H), 7.77 − 7.69 (m, 3H), 7.64 (d, J = 8.38 Hz, 1H), 7.42 (dd, J = 1.99, 8.32 Hz, 1H), 6.45 (dd, J = 10.04, 16.96 Hz, 1H), 6.29 (dd, J = 2.04, 16.90 Hz, 1H), 5.80 (dd, J = 2.06, 10.05 Hz, 1H), 5.11 (p, J = 7.04 Hz, 1H), 1.50 (d, J = 6.97 Hz, 3H).
N,N−ジメチルホルムアミド(7.0mL)中のtert−ブチル4−アクリロイルピペラジン−1−カルボキシレート(0.200g、0.832mmol)の撹拌懸濁液に、ヒドロキシカルボンイミド酸ジブロミド(hydroxycarbonimidic dibromide)(0.253g、1.248mmol)およびKHCO3水溶液(0.250g、2.496mmol、2mL)を0°Cで加えた。反応混合物を、室温で14時間撹拌した後に、水で希釈し、酢酸エチルで抽出した。組み合わせた有機質層をブラインで洗浄し、硫酸ナトリウム上で乾燥させ、および減圧下で蒸発させた。得られた粗製物を、シリカゲル(ヘキサン/酢酸エチル=99.9/0.1)上のCombiflash(登録商標)により精製して、液体として表題化合物(0.160g、53.15%)を得た。LCMS: m/z = 448.35 [M+H]+.
ジクロロメタン(5.0mL)中のtert−ブチル4−(3−ブロモ−4、5−ジヒドロイソオキサゾール−5−カルボニル)ピペラジン−1−カルボキシレート(0.20g、0.552mmol)の撹拌懸濁液に、TFA(0.20mL、2.612mmol)を室温で加え、14時間撹拌した。反応混合物を減圧下で蒸発させ、得られた残留物を、ジエチルエーテルを用いて粉末にすることで、表題化合物(0.199g、粗製)を得た。LCMS:m/z = 262.11 [M]+.
実施例−54に記載される方法に従って、上記の表題化合物を調製した。収率:53.15%; HPLC: 99.7%; LCMS: m/z = 448.35 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.52 − 7.46 (m, 1H), 7.34 (d, J = 8.31 Hz, 1H), 7.23 − 7.18 (m, 1H), 5.28 (dd, J = 7.62, 11.27 Hz, 1H), 5.00 − 4.84 (m, 1H), 4.61 (d, J = 7.87 Hz, 1H), 3.89 − 3.76−(m,2H), 3.66 − 3.38 (m, 6H), 3.25 (dd, J = 11.29, 17.52 Hz, 2H), 1.46 (d, J = 6.87 Hz, 3H).
完全なRPMI培地を使用して、NCI−H1792細胞(ATCC CRL−5895)を96ウェル平底クリアボトムプレート(Corning, Cat.No 3596)において、2000の細胞/ウェルでプレーティングした。24時間後、DMSO(Sigma Cat no. D2650)で作られた20mMのストックからの細胞に、本発明の化合物を加えた。DMSO濃度が細胞内の0.3の最終パーセンテージを超えないように、各濃度の化合物を3回繰り返して試験した。CO2インキュベーターにおける72時間のインキュベーション後、XTT(Invitrogen、Cat.no X6493)をウェルに加えた。XTTを1mg/mlの無血清培地に溶解し、吸光度を465nmの分光光度計で得た。グラフパッドプリズムソフトウェアを使用してデータを分析した。陽性対照(100%の生存)=0.3%のDMSOを有する完全培地中の細胞;陰性対照/ブランク(0%の生存)=0.3%のDMSOを含む培地のみ。
Claims (34)
- 式(I)の化合物
式中、
Aはアリールまたはヘテロアリールを表し;
Xは、N−Ryを表すか、あるいは存在しないことを表し;
Yは、O、S、あるいはNCNを表し;
Bは、アリール、シクロアルキル、あるいはヘテロシクロアルキルを表し;ここで、アリール、シクロアルキル、あるいはヘテロシクロアルキルは、アルキル、ハロ、およびオキソから選択される1つ以上の基で随意に置換され;
R1はアルキルを表し;R2は、水素またはアルキルを表し;あるいは、R1およびR2は、それらが結合する炭素原子と一体となって3〜5員のシクロアルキル環を形成し;
R3は、−C(O)Ra、−S(O)2Ra、−NHS(O)2Ra、−NRbC(O)Ra、=NORa、ヘテロアリール、ヘテロシクロアルキルあるいは(ヘテロシクロアルキル)アルキル−を表し;ここで、ヘテロアリールおよびヘテロシクロアルキルは、アルキル、ハロ、オキソおよび−C(O)Rxから選択される1つ以上の基で随意に置換され;
R4は、アルキル、ハロ、ハロアルキル、シアノ、アルコキシ、アリールオキシ、アルコキシアリール、ヒドロキシアルキル、アセチレン、アシル、ヒドロキシ、シクロアルキルあるいは−N(Rx)2を表し;ここで、シクロアルキルはアルキルで随意に置換され;
Raは、アルキル、アルケニル、ハロアルキル、シクロアルキルあるいはヘテロシクロアルキルを表し;ここで、アルキル、アルケニル、ハロアルキル、シクロアルキルおよびヘテロシクロアルキルは、アルキル、ハロ、アリール、シクロアルキル、ハロアルキル、アミノ、アミド、アルキルアミノ、アミノアルキル、ヒドロキシル、シアノ、アルコキシ、アルコキシアリール、アリールオキシ、ヒドロキシアルキル、カルボン酸、エステル、チオエステル、オキソ(=O)および−C(O)Rxから選択される1つ以上の基で随意に置換され;
Rxは、水素、アルキル、アルケニル、アシルあるいは−C(O)−シクロアルキルを表し;
Ryは、水素またはアルキルを表し;
Rbは、水素、アルキルあるいはアルケニルを表し;
「m」は、0、1、2、または3を表す、
化合物。 - Bはヘテロシクロアルキルを表す、請求項1に記載の化合物。
- R1はアルキルを表し;およびR2は水素を表す、請求項1に記載の化合物。
- R1およびR2は、それらが結合する炭素原子と一体となってシクロプロピル環あるいはシクロペンチル環を形成する、請求項1に記載の化合物。
- Aはアリールを表す、請求項1−5のいずれか1つに記載の化合物。
- Bは5員または6員のシクロアルキルを表す、請求項7に記載の化合物。
- Bは5員または6員のヘテロシクロアルキルを表す、請求項7に記載の化合物。
- Aはアリールを表す、請求項7−9のいずれか1つに記載の化合物。
- R3は−NHS(O)2Raあるいは−NRbC(O)Raを表し;ここで、RaおよびRbは請求項1で定義される通りである、請求項7−10のいずれか1つに記載の化合物。
- Bは、アルキル、ハロあるいはオキソから選択される1つ以上の基で随意に置換されたヘテロシクロアルキルを表す、請求項1に記載の化合物。
- Bは5員または6員のヘテロシクロアルキルを表す、請求項12に記載の化合物。
- R1はアルキルを表し;および、R2は、水素またはアルキルを表す、請求項15に記載の化合物。
- R1およびR2は、それらが結合する炭素原子と一体となってシクロプロピルあるいはシクロペンチルを形成する、請求項15に記載の化合物。
- R3は、−C(O)Rxで随意に置換されたヘテロシクロアルキルを表す、請求項15−17のいずれか1つに記載の化合物。
- R4は、アルキル、ハロ、ハロアルキルあるいはシクロアルキルを表し、ここで、シクロアルキルはアルキルで随意に置換される、請求項15−18のいずれか1つに記載の化合物。
- Raは、アルケニル、シクロアルキルあるいはヘテロシクロアルキルを表し;ここで、アルケニル、シクロアルキルおよびヘテロシクロアルキルは、ハロ、アリール、ハロアルキルあるいはカルボン酸から選択される1つ以上の基で随意に置換される、請求項20に記載の化合物。
- Raは、アルキルあるいはハロアルキルで置換されたアルケニルを表す、請求項21に記載の化合物。
- 請求項1−25のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩あるいは立体異性体、および薬学的に許容可能な担体あるいは賦形剤を含む、医薬組成物。
- 抗癌剤、化学療法薬剤、および抗増殖性化合物から選択される少なくとも1つの追加の薬剤をさらに含む、請求項26に記載の医薬組成物。
- 薬剤として使用するための、請求項1−25のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩あるいは立体異性体。
- 請求項1−25に記載の治療上有効な量の式(I)の化合物またはその薬学的に許容可能な塩あるいは立体異性体の投与を含む、癌または増殖性疾患を処置する方法。
- 癌または増殖性疾患は、固形腫瘍、良性腫瘍または悪性腫瘍、脳、腎臓、肝臓、胃、膣、卵巣、胃腫瘍、乳房、膀胱、結腸、前立腺、膵臓、肺、頚部、精巣、皮膚、骨あるいは甲状腺の細胞腫;肉腫、膠芽腫、神経芽細胞腫、多発性骨髄腫、胃腸癌、頭頸部の腫瘍、上皮過剰増殖、乾癬、前立腺肥大、新生物、腺腫、腺癌、角化棘細胞腫、類表皮癌、大細胞癌、非小細胞肺癌、リンパ腫、ホジキンと非ホジキン、乳癌、濾胞癌、乳頭癌、精上皮腫、黒色腫;白血病、びまん性大細胞型B細胞リンパ腫(DLBCL)、活性化B細胞様DLBCL、慢性リンパ性白血病リンパ球腫(CLL)、慢性のリンパ球性リンパ腫、原発性滲出性リンパ腫、バーキットリンパ腫/白血病、急性リンパ性白血病、B細胞前リンパ性白血病、小リンパ球性リンパ腫、リンパ形質細胞性リンパ腫、ワルデンシュトレームマクログロブリン血症(WM)、脾辺縁帯リンパ腫、血管内大細胞型B細胞リンパ腫、形質細胞腫および多発性骨髄腫から選択される血液悪性腫瘍から選択される、請求項29に記載の方法。
- 癌または増殖性疾患は、リンパ腫、白血病、乳癌、肺癌(非小細胞肺癌)、結腸癌、大腸癌、脳癌(神経膠腫、髄芽腫および上衣腫)、家族性大腸腺腫症(FAP)、ならびにバレット食道から選択される、請求項29に記載の方法。
- 癌、炎症性疾患、自己免疫疾患、慢性移植片対宿主病、代謝疾患、遺伝病、ホルモン関連疾患、免疫不全疾患、細胞死に関連する疾患、破壊性骨障害、トロンビン誘発性血小板凝集、肝疾患あるいは心血管疾患の処置に使用するための、請求項1−25のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩あるいは立体異性体。
- CAR−T治療を含むT細胞結合療法に関連するサイトカイン放出症候群の管理に使用するための、請求項1−25のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩あるいは立体異性体。
- 癌、炎症性疾患、自己免疫疾患、慢性移植片対宿主病、代謝疾患、遺伝病、ホルモン関連疾患、免疫不全疾患、細胞死に関連する疾患、破壊性骨障害、トロンビン誘発性血小板凝集、肝疾患あるいは心血管疾患の処置のための薬剤の製造における、請求項1−25のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩あるいは立体異性体の使用。
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IL276013B2 (en) | 2018-01-17 | 2024-03-01 | Glaxosmithkline Ip Dev Ltd | PI4KIIIBETA inhibitors |
EP4163273A1 (en) | 2021-10-07 | 2023-04-12 | Universita' Degli Studi Di Pavia | Substituted vinyl piperazine-piperidine urea derivatives as anticancer agents |
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JP2007502838A (ja) * | 2003-08-20 | 2007-02-15 | アクシス・ファーマシューティカルズ・インコーポレイテッド | ヒストンデアセチラーゼのインヒビターとしてのアセチレン誘導体 |
JP2010501014A (ja) * | 2006-08-18 | 2010-01-14 | レオ ファーマ アクティーゼルスカブ | 疾病の処置に有用な置換アセチレン化合物 |
WO2011153049A1 (en) * | 2010-06-02 | 2011-12-08 | The Trustees Of The University Of Pennsylvania | Methods and use of compounds that bind to her2/neu receptor complex |
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US7638513B2 (en) * | 2004-06-02 | 2009-12-29 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
US8193225B2 (en) * | 2006-10-13 | 2012-06-05 | The Board Of Regents Of The University Of Texas System | Isoxazole amides, derivatives and methods of chemical induction of neurogenesis |
CN103420977B (zh) | 2012-05-16 | 2016-06-22 | 上海医药集团股份有限公司 | 具有抗肿瘤活性的乙炔衍生物 |
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- 2019-01-17 MX MX2020007535A patent/MX2020007535A/es unknown
- 2019-01-17 CN CN201980016754.7A patent/CN111902403B/zh active Active
- 2019-01-17 US US16/962,941 patent/US11633394B2/en active Active
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- 2019-01-17 PE PE2020000981A patent/PE20210173A1/es unknown
- 2019-01-17 WO PCT/IB2019/050387 patent/WO2019142126A1/en unknown
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2020
- 2020-06-29 PH PH12020500572A patent/PH12020500572A1/en unknown
- 2020-07-14 MX MX2023007985A patent/MX2023007985A/es unknown
- 2020-07-17 CL CL2020001882A patent/CL2020001882A1/es unknown
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2023
- 2023-03-10 US US18/120,149 patent/US20230210847A1/en not_active Abandoned
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US20030082830A1 (en) * | 1996-10-16 | 2003-05-01 | Schreiber Stuart L. | Synthesis of combinatorial libraries of compounds reminiscent of natural products |
JP2007502838A (ja) * | 2003-08-20 | 2007-02-15 | アクシス・ファーマシューティカルズ・インコーポレイテッド | ヒストンデアセチラーゼのインヒビターとしてのアセチレン誘導体 |
JP2010501014A (ja) * | 2006-08-18 | 2010-01-14 | レオ ファーマ アクティーゼルスカブ | 疾病の処置に有用な置換アセチレン化合物 |
WO2011153049A1 (en) * | 2010-06-02 | 2011-12-08 | The Trustees Of The University Of Pennsylvania | Methods and use of compounds that bind to her2/neu receptor complex |
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US11633394B2 (en) | 2023-04-25 |
AU2019208515A1 (en) | 2020-09-03 |
SG11202006246PA (en) | 2020-07-29 |
CO2020010042A2 (es) | 2020-11-20 |
BR112020014421A2 (pt) | 2020-12-01 |
CU20200047A7 (es) | 2021-03-11 |
WO2019142126A1 (en) | 2019-07-25 |
PH12020500572A1 (en) | 2021-05-17 |
CL2020001882A1 (es) | 2020-10-02 |
CN111902403A (zh) | 2020-11-06 |
UA128087C2 (uk) | 2024-04-03 |
CA3087130A1 (en) | 2019-07-25 |
EP3740473A1 (en) | 2020-11-25 |
PE20210173A1 (es) | 2021-01-29 |
MX2020007535A (es) | 2020-12-07 |
MX2023007985A (es) | 2023-07-18 |
CN111902403B (zh) | 2024-05-17 |
IL275766B2 (en) | 2024-05-01 |
EA202091481A1 (ru) | 2020-12-03 |
IL275766A (en) | 2020-08-31 |
EP3740473A4 (en) | 2021-11-10 |
IL275766B1 (en) | 2024-01-01 |
CU24661B1 (es) | 2023-05-11 |
US20210379055A1 (en) | 2021-12-09 |
KR20200143669A (ko) | 2020-12-24 |
US20230210847A1 (en) | 2023-07-06 |
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