JP2017538766A - 縮合環ヘテロアリール化合物及びtrk抑制剤としての用途 - Google Patents
縮合環ヘテロアリール化合物及びtrk抑制剤としての用途 Download PDFInfo
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- JP2017538766A JP2017538766A JP2017533343A JP2017533343A JP2017538766A JP 2017538766 A JP2017538766 A JP 2017538766A JP 2017533343 A JP2017533343 A JP 2017533343A JP 2017533343 A JP2017533343 A JP 2017533343A JP 2017538766 A JP2017538766 A JP 2017538766A
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- 239000003112 inhibitor Substances 0.000 title abstract description 15
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- 238000000034 method Methods 0.000 claims description 42
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 41
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- 125000003118 aryl group Chemical group 0.000 claims description 30
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- 125000001424 substituent group Chemical group 0.000 claims description 26
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
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- 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 4
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 3
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- UHLSHMMWYQRKIR-MTGFJVSHSA-N 4-[(E)-3-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoyl]piperazin-2-one Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C1=NC=2N(C=C1)N=CC=2/C=C/C(=O)N1CC(NCC1)=O UHLSHMMWYQRKIR-MTGFJVSHSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
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- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
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- OIWAHBUCFODFNB-OAQYLSRUSA-N tert-butyl 4-[5-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C1=NC=2N(C=C1)N=CC=2C1=NN=C(O1)N1CCN(CC1)C(=O)OC(C)(C)C OIWAHBUCFODFNB-OAQYLSRUSA-N 0.000 description 1
- KQOALIQKEWIGJQ-JOCHJYFZSA-N tert-butyl 4-[[[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]carbamoyl]piperidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C1=NC=2N(C=C1)N=CC=2C(=O)NNC(=O)C1CCN(CC1)C(=O)OC(C)(C)C KQOALIQKEWIGJQ-JOCHJYFZSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
以下のセクションの見出しは単に体系化のために使用されただけで、技術的思想を制限すると解釈されてはならない。これらに制限されないが、特許、特許出願、記事、書籍、マニュアル及び論文など、本出願に引用された全ての文献または文献の一部は目的に応じてその全体内容が参照される。
特に定義されない限り、本願で使われた全ての技術的及び科学的用語は請求された技術的思想が属する技術分野の通常の技術者によって一般に理解される意味と同じ意味である。本明細書の全般にわたって言及された全ての特許、特許出願、公開された文献は、特に言及しない限り、全体が参考文献として引用される。ここで用語についての定義が多数存在する場合は、本セクションの定義が優先する。URLまたは他の識別子またはアドレスを言及する場合、該識別子は変更され得、インターネット上の特定情報が現われてから消えることがあるが、同じ情報がインターネットまたは他の適切な参照ソースを調べることで発見できるということを理解せねばならない。上述した参考文献はそのような情報の利用可能性及び大衆の普及を立証する。
本発明の実施例によれば、新規の化学的化合物は、化学式Iの化合物、その薬学的に許容可能な塩、溶媒和物、多形体、エステル、互変異性体またはプロドラッグを含む。
上述された新規化合物は、TrkA、TrkB及び/またはTrkCの抑制剤であり、疼痛、癌及び他の過剰増殖性疾病の治療に有用である。一態様において、本発明は、1つ以上の化学式Iの化学的化合物またはこれらの薬学的に許容可能な塩、溶媒和物、多形体、エステル、互変異性体またはプロドラッグを含む癌性疼痛及び他の過剰増殖性疾病治療用の薬学的組成物を提供する。
一部実施例において、本発明は、癌の治療または予防のための薬学的組成物の製造において、化学式Iまたはその薬学的に許容可能な塩、溶媒和物、多形体、エステル、互変異性体またはプロドラッグの用途に関する。
NMRスペクトルは、30℃、5mm O.D.チューブ(Norell社製、507−HP)でCDCl3及びDMSO−d6溶液で記録し、1H 400MHzでVarian VNMRS−400で収集した。化学シフト(δ)は、テトラメチルシラン(TMS=0.00ppm)を基準としてppmで表現した。LC/MSは、ESI(+)イオン化モードで作動するFINNIGAN Thermo LCQ Advantage MAX、Agilent LC 1200シリーズのイオントラップ質量分光計で行われた。流速=1.0mL/分。移動相=水またはCH3CN中の0.01%ヘプタフルオロ酪酸(HFBA)及び1.0%イソプロピルアルコール(IPA)。
(2R,4S)−tert−ブチル2−(2,5−ジフルオロフェニル)−4−フルオロピロリジン−1−カルボン酸塩(6a)に対し、1H−NMR(CDCl3,Varian,400MHz):δ1.21−1.46(9H,m)、1.94−2.10(1H,m)、2.71−2.79(1H,m)、3.62−3.75(1H,m)、3.98−4.14(1H,m)、5.09−5.48(2H,m)、6.92−7.01(3H,m)
(2S,4S)−tert−ブチル2−(2,5−ジフルオロフェニル)−4−フルオロピロリジン−1−カルボン酸塩(7a)に対し、1H−NMR(CDCl3,Varian,400MHz):δ1.20−1.49(9H,s)、2.25−2.35(1H,m)、2.48−2.60(1H,m)、3.71−4.03(1H,m)、5.19−5.33(2H,m)、6.88−6.99(3H,m)。
段階A:エチル5−オキソ−4,5−ジヒドロピラゾロ[1,5−a]ピリミジン−3−カルボン酸塩
段階B:エチル5−クロロピラゾロ[1,5−a]ピリミジン−3−カルボン酸塩
実施例15:化合物7の製造:2−シクロプロピル−5−(5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−1,3,4−オキサジアゾール
段階B:(R)−5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸
実施例29:化合物18の製造
段階B:tert−ブチル3−アジドピロリジン−1−カルボン酸塩
実施例65:化合物53の製造:(R,E)−3−(5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−1−(4−メチルピペラジン−1−イル)プロップ−2−エン−1−オン
実施例70:化合物58の製造:(R,E)−3−(5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−1−(4−ヒドロキシ−4−メチルピペリジン−1−イル)プロップ−2−エン−1−オン
ADP−Gloアッセイキットはプロメガ(Promega)社から購入した。ポリ(Glu,Tyr)、マグネシウムスルファート、ウシ血清アルブミン(Bovine Serum Albumin;BSA)及びジメチルスルホキシド(DMSO)はシグマアルドリッチ(Sigma−Aldrich)社から購入した。トリス−HClバッファーはBD Gentest社から購入した。HTRF KinEASE−TKキットはシスバイオ(Cisbio)社から購入した。TRKA、B&Cキナーゼはカルナバイオサイエンス(Carna Bioscience)社から購入した。
プロテインキナーゼアッセイは、30℃で化合物1〜61に対して行った。レシピとして、キナーゼは0.4ng/μLのTrKA、0.5ng/μLのTrKB及び3ng/μLのTrKCをそれぞれ含み、1ug/μLのポリ(glu、Tyr)ストック溶液5μL、化合物またはアッセイバッファー5μL、ATP(125μMストック溶液)5μLを含む。
HTRF KinEASE−TKアッセイは、384ウェルローボリュームマイクロプレート(グライナー(Greiner)社製)で化合物1〜61に対して行った。前記HTRF KinEASE−TKアッセイフォーマットは2段階を含む。第一段階は、キナーゼ反応段階である。該キナーゼ反応段階は、以下のようなアッセイ反応レシピによって室温で最終ボリューム10μLに行われた:10μLのキナーゼ混合物(キナーゼ(2μL)+ATP(2μL)+基質(2μL)+化合物(4μL))。キナーゼ最終濃度は、それぞれTRKA0.3ng/μL、TRKB0.1ng/μL、TRKC0.03ng/μLであった。ATP最終濃度は、それぞれ14.7μM(TRKA)、4.77μM(TRKB)、25.6μM(TRKC)であった。TK−基質最終濃度は、0.3ng/μLであった。化合物を0〜100Nmの用量反応濃度(Dose Response Concentration;DRC)化合物に40分間露出させた。キナーゼ反応段階の間、キナーゼ反応はATPの追加によって始まった。キナーゼは基質をリン酸化する。
第二段階は、検出段階である。10μLの検出試薬(EDTA中の5μLのSa−XL665+EDTA中の5μLのTK抗体−Eu)をキナーゼ混合物に添加した。該段階は室温で1時間行われた。検出試薬はリン酸化された基質を検出する。
ドキソルビシンはシグマアルドリッチ(D1515)から購入した。全ての化合物はDMSO(シグマアルドリッチ社製、D2650)で希釈した。AlamarBlue(登録商標)細胞生死判定試薬はThermo Scientific(88952)から購入した。CellTiter96(登録商標)AQueous One Solution細胞増殖アッセイはプロメガ社から購入した。KM12−luc細胞はJCRB(日本、東京、国立医薬品食品衛生研究所 )から確保した。これらは10%ウシ胎児血清(Gibco社製、16000−044)及びMEM非必須アミノ酸溶液(Thermo Scientific、11140−050)を添加したDMEM培地(GIB−11965−118)中に維持した。TF−1細胞はATCCから確保した。これらは10%ウシ胎児血清(Gibco社製、16000−044)、GM−CSF(Thermo Scientific、11140−050)及びβ−NGF(R&D systems)を添加したRPMI培地(GIB−A10491)中に維持した。トリプシン/EDTAはGibco社(GIB−25300−054、0.05%)から購入した。96ウェルプレートはコーニング社から購入した。
増殖アッセイは、AlamarBlue(登録商標)細胞生死判定試薬またはCellTiter96(登録商標)AQueous One Solution細胞増殖アッセイキットを使用して、10%FBSを添加した培地で化合物1〜61に対して行った。細胞は5%CO2の加湿培養器で37℃で培養された。化合物の抗増殖活性を測定するため、TF−1細胞を16時間GM−CSFフリー培地(RPMI、10%FBS及び1%ペニシリン−ストレプトマイシン)で調整し、培地(RPMI、10%FBS、1%ペニシリン−ストレプトマイシン及び10ng/mlヒトβ−NGF)を有する30,000細胞/ウェルの96ウェルプレートに接種した。KM12−lucはウェル当り10,000細胞で96ウェルプレート中に接種した。一晩培養した後、化合物の段階希釈物を3個のウェルに添加して、細胞を72時間露出させた。DMSOの最終濃度を培地で0.5%に調整した。2種類の試薬を使用して細胞増殖を定量評価した。培養液体積の10%に該当する20μLのAlamarBlue(登録商標)試薬を各ウェルに入れて、2時間5%CO2の加湿培養器で37℃で培養した。または、20μLのCellTiter96(登録商標)試薬を各ウェルに添加し、上述した同様の条件で培養した。データをプロットして、グラフパッドソフトウェアを使用してGI50値を計算した。下記表1はアッセイ結果を含む。
Claims (18)
- 化学式Iの化合物またはその塩;
R1は、フッ素、メトキシ及びエトキシからなる群より独立して選択された1つ以上の置換基で置換されたフェニル環であり;R2はHであり;Xは−CH2−、−CH2CH2−、−CH2O−及び−CH(Z)−からなる群より選択され、ここでZはハロゲンであり;Qは、−CH=CR3C(O)NR4R5、−C≡CC(O)NR4R5及び
R1は、少なくともフッ素及びメトキシからなる群より選択された1つで置換されたピリジン環であり;R2はHであり;Xは−CH2−、−CH2CH2−、−CH2O−及び−CH(Z)−からなる群より選択され、ここでZはハロゲンであり;Qは、−CH=CR3C(O)NR4R5、−C≡CC(O)NR4R5及び
前記化学式Iの化合物は、(R,E)−4−(3−(5−(2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)アクリロイル)ピペラジン−2−オン(化合物51)または(E)−3−(5−((R)−2−(2,5−ジフルオロフェニル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−イル)−1−(3−(2−ヒドロキシプロパン−2−イル)ピペラジン−1−イル)プロップ−2−エン−1−オン(化合物52)である。 - R1はフッ素、メトキシ及びエトキシからなる群より独立して選択された1つ以上の置換基で置換されたフェニル環であり、R2及びR3はHであり、R5はH、メチル、エチル、イソプロピル、シクロプロピル、t−ブチル、メトキシエチル及びヒドロキシエチルからなる群より選択される、請求項1に記載の化学式Iの化合物またはその塩。
- R1はフッ素及びメトキシからなる群より選択された少なくとも1つで置換されたピリジン環であり、R2及びR3はHであり、R5はH、メチル、エチル、イソプロピル、シクロプロピル、t−ブチル、メトキシエチル及びヒドロキシエチルからなる群より選択される、請求項1に記載の化学式Iの化合物またはその塩。
- −NR4R5が環構造を形成しない場合、R4は水素、直鎖C1−C6アルキル及び分岐C1−C6アルキルからなる群より選択され、R5は直鎖C1−C6フルオロアルキル、分岐C1−C6フルオロアルキル、直鎖C1−C6ジフルオロアルキル、分岐C1−C6ジフルオロアルキル、直鎖C1−C6トリフルオロアルキル、分岐C1−C6トリフルオロアルキル、直鎖C1−C6ヒドロキシアルキル、分岐C1−C6ヒドロキシアルキル、直鎖C2−C6ジフルオロアルキル及び分岐C2−C6ジフルオロアルキルからなる群より選択される、請求項1に記載の化学式Iの化合物またはその塩。
- 4−7員複素環を形成する−NR4R5は、4−7員ヘテロシクロアルキル環である、請求項1に記載の化学式Iの化合物またはその塩。
- −NR4R5が4−7員複素環を形成する場合、4−7員複素環内の第2ヘテロ原子は窒素、酸素及び硫黄からなる群より選択される、請求項1に記載の化学式Iの化合物またはその塩。
- 前記塩は、アセテート、ベンゾエート、ベシレート、ビタルタレート、ブロマイド、カーボネート、クロライド、エデテート、エジシレート、エストレート、フマレート、グルセプテート、グルコネート、ハイドロブロマイド、ハイドロクロライド、ヨージド、ラクテート、ラクトビオネート、マレート、マレエート、マンデレート、メシレート、メチルブロマイド、メチルスルファート、ムケート、ナプシレート、ニトレート、オキサレート、パモエート、ホスファイト、ジホスファイト、サリチレート、ジサリチレート、ステアレート、サクシネート、スルファート、タルトレート、トシレート、トリエチオダイド、トリフルオロアセテート及びバレレートからなる群より選択される、請求項1に記載の化学式Iの化合物またはその塩。
- 請求項1に記載の化合物またはその薬学的に許容可能な塩の薬学的に効果的な量を、甲状腺乳頭癌、膵臓癌、肺癌、結腸癌、乳癌、神経芽細胞腫、疼痛、悪液質、皮膚炎及び喘息からなる群より選択されたTRK媒介疾患の治療が必要な個体に投与する段階を含む、TRK媒介疾患の治療または予防方法。
- 請求項1に記載の化合物またはその薬学的に許容可能な塩の薬学的に効果的な量を、TRK酵素の抑制が必要な個体に投与する段階を含む、TRK酵素の抑制方法。
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MX2017007748A (es) | 2018-01-30 |
BR112017012755A2 (pt) | 2017-12-26 |
BR112017012755B1 (pt) | 2023-11-14 |
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US9701681B2 (en) | 2017-07-11 |
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