TWI813106B - 雄性激素受體結合分子及其用途 - Google Patents
雄性激素受體結合分子及其用途 Download PDFInfo
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- TWI813106B TWI813106B TW110148478A TW110148478A TWI813106B TW I813106 B TWI813106 B TW I813106B TW 110148478 A TW110148478 A TW 110148478A TW 110148478 A TW110148478 A TW 110148478A TW I813106 B TWI813106 B TW I813106B
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- Taiwan
- Prior art keywords
- compound
- trifluoromethyl
- triazolo
- piperidin
- pyridazin
- Prior art date
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- 108010080146 androgen receptors Proteins 0.000 title claims abstract description 112
- 102000001307 androgen receptors Human genes 0.000 title claims abstract description 112
- 230000027455 binding Effects 0.000 title claims abstract description 61
- -1 trifluoromethylphenyl Chemical group 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims description 196
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- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- KBJXDTIYSSQJAI-UHFFFAOYSA-N propylcarbamic acid Chemical compound CCCNC(O)=O KBJXDTIYSSQJAI-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- IQHXABCGSFAKPN-UHFFFAOYSA-N pyrrolidine-3-carboxamide Chemical compound NC(=O)C1CCNC1 IQHXABCGSFAKPN-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000002330 subarachnoid space Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- LLYGVYMHHXQPJB-UHFFFAOYSA-N tert-butyl 2-[4-(4-methylphenyl)sulfonyloxybutoxy]acetate Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OCCCCOCC(=O)OC(C)(C)C LLYGVYMHHXQPJB-UHFFFAOYSA-N 0.000 description 1
- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 1
- LVOKHUJYWPPGKR-UHFFFAOYSA-N tert-butyl 4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetyl]piperazine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCN1C(COC1=CC=C(C(CC2)CCN2C2=NN3C(C(F)(F)F)=NN=C3CC2)C=C1)=O)=O LVOKHUJYWPPGKR-UHFFFAOYSA-N 0.000 description 1
- BWEQJNRBHWAQDA-UHFFFAOYSA-N tert-butyl 4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]ethynyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C#CC1=CC=C(C(CC2)CCN2C2=NN3C(C(F)(F)F)=NN=C3CC2)C=C1)=O BWEQJNRBHWAQDA-UHFFFAOYSA-N 0.000 description 1
- BCEVILDHCCWURH-UHFFFAOYSA-N tert-butyl 4-[4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]ethynyl]piperidin-1-yl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1N(CC1)CCC1C#CC1=CC=C(C(CC2)CCN2C2=NN3C(C(F)(F)F)=NN=C3CC2)C=C1)=O BCEVILDHCCWURH-UHFFFAOYSA-N 0.000 description 1
- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- ISTGQSQWSKCNFJ-UHFFFAOYSA-N tert-butyl n-ethylcarbamate Chemical compound CCNC(=O)OC(C)(C)C ISTGQSQWSKCNFJ-UHFFFAOYSA-N 0.000 description 1
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003754 zirconium Chemical class 0.000 description 1
Images
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- 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
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Description
本揭露係關於一種雄性激素受體結合分子與其用途,且特別是關於一種由其所製備之蛋白水解靶向嵌合體(proteolysis targeting chimera,PROTAC)的相關用途。
前列腺癌為全球男性的發病率第二高的癌症,居美國男性癌症死亡原因的第二位。
前列腺癌診斷的初期療效五年存活率可達90%以上。然而,90%之前列腺患者接受第一線雄性激素剝奪療法(androgen-deprivation therapy,ADT)治療後,僅2-5年後,其前列腺癌即會復發並演化成去勢療法抗性前列腺癌(castration-resistant prostate cancer,CRPC)。一旦轉變成去勢療法抗性前列腺癌,患者五年存活率下降至30%,其中50%患者具有雄性激素突變(AR mutation)、雄性激素擴增(AR amplification)或形成雄性激素變異體(AR-variants),因此導致雄性激素異常活化,且同時也造成患者對目前之用藥產生抗藥性,
特別是具有雄性激素受體可變剪接異變體7(androgen receptor splice variant 7,AR-V7)之患者為主。
因此極需新穎的治療藥物以解決去勢療法抗性前列腺癌之治療不足的困境。
本揭露提供一種雄性激素受體(androgen receptor,AR)結合分子,其具有以下所示之式(I)之結構:,其中,為,E與G獨立地為CH2或CH,為為OH、NH2、OTf或C-C三鍵,X為CF3或三氟甲基苯基,且Y與Z獨立地為CH2或CH;或為或為不存在,X為CF3,且Y與Z獨立地為CH2。
本揭露也提供一種化合物,其具有以下所示之式(α)之結構:A-R1-L-R2-E式(α)。A為一雄性激素受體結合域(binding
moiety),具有以下所示之式(I’)之結構:式(I’),其中,為,E與G獨立地為CH2或CH,為,X為CF3或三氟甲基苯基,且Y與Z獨立地為CH2或CH;或為或 為不存在,X為CF3,且Y與Z獨立地為CH2。R1與R2為接位點,其中,R1為O、N、C-C三鍵或C-C單鍵,又其中當為不存在時,R1不存在,且直接與L連接,而R2為NH、COO、C-C三鍵或C-C單鍵。L為一連接子,其包括下述之至少一者:總原子數為7-17之聚乙二醇(polyethylene glycol,PEG)、聚丙二醇(poly propylene glycol,PPG)、飽和碳鏈、醣、芳香環與雜環。E為E3泛素連接酶(E3 ubiquitin ligase)結合域,其包括下列所示之結構之一:
與
本揭露還提供一種醫藥組成物,其包括一化合物以及一藥學上可接受之載體和鹽類。該化合物具有以下所示之式(α)之結構:A-R1-L-R2-E式(α)。A為一雄性激素受體結合域,具有以下所示之式(I’)之結構:,其中,為,E與G獨立地為CH2或CH,為,X為CF3或三氟甲基苯基,且Y與Z獨立地為CH2或CH;或為或 為不存在,X為CF3,且Y與Z獨立地為CH2。R1與R2為接位
點,其中,R1為O、N、C-C三鍵或C-C單鍵,又其中當為不
存在時,R1不存在,且直接與L連接,而R2為NH、COO、C-C三鍵或C-C單鍵。L為一連接子,其包括下述之至少一者:總原子數為7-17之聚乙二醇、聚丙二醇、飽和碳鏈、醣、芳香環與雜環。E為E3泛素連接酶結合域,其包括下列所示之結構之一:
與
本揭露又提供一種雄性激素受體結合分子用於製備抑制雄性激素受體之試劑的用途。該雄性激素受體結合分子具有以下所示之式(I)之結構:,其中,為,E與G獨立地為CH2或CH,為
為OH、NH2、OTf或C-C三鍵,X為CF3或三氟甲基苯基,且Y與Z獨立地為CH2或CH;或為或為不存在,X為CF3,且Y與Z獨立地為CH2。
本揭露更提供一種雄性激素受體結合分子用於製備蛋白水解靶向嵌合體(proteolysis targeting chimera,PROTAC)的用途。該雄性激素受體結合分子具有以下所示之式(I)之結構:,其中,為,E與G獨立地為CH2或CH,為為OH、NH2、OTf或C-C三鍵,X為CF3或三氟甲基苯基,且Y與Z獨立地為CH2或CH;或為或為不存在,X為CF3,而Y與Z獨立地為CH2。
又,本揭露提供一種雄性激素受體結合分子用於製
備治療前列腺癌之藥物的用途。該雄性激素受體結合分子具有以下所示之式(I)之結構:,其中,為,E與G獨立地為CH2或CH,為為OH、NH2、OTf或C-C三鍵,X為CF3或三氟甲基苯基,且Y與Z獨立地為CH2或CH;或為或為不存在,X為CF3,而Y與Z獨立地為CH2。
此外,本揭露還提供一種化合物用於製備治療前列腺癌之藥物的用途。該化合物具有以下所示之式(α)之結構:A-R1-L-R2-E式(α)。A為一雄性激素受體結合域,具有以下所示之式(I’)之結構:,其中,為,E與G獨立地為CH2或CH,為,X
為CF3或三氟甲基苯基,且Y與Z獨立地為CH2或CH;或為或為不存在,X為CF3,且Y與Z獨立地為CH2。R1與R2為接位點,其中,R1為O、N、C-C三鍵或C-C單鍵,又其中當為不存在時,R1不存在,且直接與L連接,而R2為NH、COO、C-C三鍵或C-C單鍵。L為一連接子,其包括下述之至少一者:總原子數為7-17之聚乙二醇、聚丙二醇、飽和碳鏈、醣、芳香環與雜環。E為E3泛素連接酶結合域,其包括下列所示之結構之一:
與
為了讓本發明之上述和其他目的、特徵、和優點能更明顯易懂,下文特舉較佳實施例,並配合所附圖示,作詳細說明如下:
第1A圖顯示,經化合物30處理之細胞的細胞存活率。
第1B圖顯示,經化合物43處理之細胞的細胞存活率。
第2A圖顯示,分別經化合物1、化合物22與化合物30處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7(androgen receptor splice variant 7,AR-V7)的降解情況。
第2B圖顯示,分別經化合物1、化合物7與化合物29處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2C圖顯示,分別經化合物8、化合物19、化合物21與化合物22處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2D圖顯示,分別經化合物9、化合物36與化合物38處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2E圖顯示,經化合物14處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2F圖顯示,經化合物37處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2G圖顯示,分別經化合物39、化合物40、化合物41與化合物46處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2H圖顯示,經化合物42處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2I圖顯示,經化合物43處理之細胞之全長雄性激素受體與雄
性激素受體可變剪接異變體7的降解情況。
第2J圖顯示,分別經化合物44與化合物45處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2K圖顯示,分別經化合物47與化合物48處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2L圖顯示,經化合物49處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2M圖顯示,經化合物51處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2N圖顯示,經化合物52處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第2O圖顯示,經化合物53處理之細胞之全長雄性激素受體與雄性激素受體可變剪接異變體7的降解情況。
第3圖顯示,經化合物1處理之動物之腫瘤大小變化。
雄性激素受體(androgen receptor,AR)屬於核受體,其一般為分子量100,000道爾頓的蛋白質,且由N端轉錄啟動區(N-terminal domain,NTD)、DNA結合區(DNA-binding domain,DBD)、鉸鏈區與配體結合區(ligand-binding domain,LBD)之四個結構域所組成。
前列腺癌的復發與轉移主要經由雄性激素受體進行
訊息傳遞。針對前列腺癌的復發與轉移,現今的治療方式主要採用藥物來抑制雄性激素受體產生或是阻斷雄性激素受體與雄性激素受體結合,然而,在治療數個月後,復發之患者容易產生抗藥性而使腫瘤再度復發,而導致後續之治療難度增高。
而本揭露可提供一種新穎之雄性激素受體結合分子。
於本揭露中所述之“結合分子”係指一分子,其具有與另一分子或化合物結合之能力。例如,雄性激素受體結合分子,係指一具有與雄性激素受體結合之能力的分子。
上述本揭露之雄性激素受體結合分子,其可有效與雄性激素受體結合,進而抑制雄性激素受體之活性及/或阻斷雄性激素受體與雄性激素受體結合,且,其也可有效應用於與雄性激素受體之抑制或降解相關的各種藥物,如針對雄性激素受體之蛋白水解靶向嵌合體(proteolysis targeting chimera,PROTAC)的相關用途的製備,但不限於此。
蛋白水解靶向嵌合體為一種具有兩種不同功能配體(ligand)的小分子藥物,其中一個配體具有與目標蛋白質(protein of interest,POI)結合之能力,而另一個配體則是用來招募E3泛素連接酶(E3 ubiquitin ligase)。藉由蛋白水解靶向嵌合體與目標蛋白結合,E3泛素連接酶將得以靠近目標蛋白質並將其標記上泛素(ubiquitin)。經標記泛素的目標蛋白質會被蛋白酶體(proteasome)辨識並切割且降解為小片段胜肽,且因此蛋白水解靶
向嵌合體與目標蛋白質分離,而可以在細胞中循環再利用。
根據上述,本揭露之雄性激素受體結合分子,可作為以雄性激素受體為目標蛋白之蛋白水解靶向嵌合體中的具有與目標蛋白質結合之能力的配體。
上述本揭露之雄性激素受體結合分子可與一般全長之雄性激素受體結合,也可與各種雄性激素突變(AR mutation)、雄性激素擴增(AR amplification)、雄性激素受體可變剪接異變體(androgen receptor splice variant)等結合,並無特殊限制。
在一實施例中,上述本揭露之雄性激素受體結合分
子之結合標的可包括,但不限於,以下之至少一者:全長之雄性激素受體、雄性激素受體可變剪接異變體7(androgen receptor splice variant 7,AR-V7)等。
基於上述,本揭露也可提供一種上述本揭露之任何雄性激素受體結合分子用於製備抑制雄性激素受體之試劑的用途。
又,基於上述,本揭露也可提供一種上述本揭露之任何雄性激素受體結合分子用於製備蛋白水解靶向嵌合體的用途。
此外,基於上述,本揭露還可提供一種上述本揭露之任何雄性激素受體結合分子用於製備治療前列腺癌之藥物的用途。上述前列腺癌並無特別限制,可為一般前列腺癌、去勢療法抗性前列腺癌(castration-resistant prostate cancer,CRPC)等,或具有雄性激素突變(AR mutation)、雄性激素擴增(AR amplification)、雄性激素變異體(AR-variants),如雄性激素受體可變剪接異變體7之前列腺癌。
本揭露也可提供一種化合物。本揭露之化合物可用於一藥物或醫藥組成物之製備,而上述藥物或醫藥組成物可為一用於治療一與雄性激素受體過度表現相關之疾病,或一可藉由抑制雄性激素受體活性及/或降解而獲得減緩及/或治療的一疾病,或一癌症(如,前列腺癌)之藥物或醫藥組成物,但不限於此。或者,本揭露之化合物可用於一疾病之治療,而上述疾病可為與雄性激素受體過度表現相關之疾病,或一可藉由抑制雄性激素受體活性及/或降解而獲得減緩及/或治療的一疾病,或一癌症(如,前列腺癌),但
也不限於此。
上述本揭露之化合物可具有以下所示之式(α)之結構,但不限於此:A-R1-L-R2-E 式(α)。
於上方所示之式(α)中,A為一雄性激素受體結合域(binding moiety)。
於本揭露中所述“結合域”,意指於一分子或化合物中之一特定區域,其具有與另一分子或化合物結合之能力。例如,雄性激素受體結合域,係指一分子或化合物中之一特定區域,其具有與雄性激素受體結合的能力。
依據上方段落中所述之本揭中之用語“結合域”的定義可知,本揭露之化合物中之“雄性激素受體結合域”,係指本揭露之化合物中具有與雄性激素受體結合之能力的一特定區域。
於上方所示之式(α)中,R1與R2可為接位點。R1可為O、N、C-C三鍵、C-C單鍵等,但不限於此。當為不存在時,R1不存在,且直接與L連接。而R2可為NH、COO、C-C三鍵、C-C單鍵等,但也不限於此。
於上方所示之式(α)中,L可為一連接子。而上述可為一連接子之L,可包括下述之至少一者,但不限於此:總原子數為7-17之聚乙二醇(polyethylene glycol,PEG)、聚丙二醇(poly propylene glycol,PPG)、飽和碳鏈、醣、芳香環、雜環等。
而依據上方段落中所述之本揭露中之用語“結合域”的定義可知,本揭露之化合物中之“E3泛素連接酶結合域”,係指本揭露之化合物中具有與E3泛素連接酶結合之能力的一特定區域。
在一實施例中,本揭露之化合物,可包括,但不限於以下表3中所示之化合物之一。
在一特定實施例中,本揭露之化合物可為上方所示之化合物1。在另一特定實施例中,本揭露之化合物可為上方所示之化合物30。在又另一特定實施例中,本揭露之化合物可為上方所示之化合物30。
依據上方所示本揭露之化合物之結構可知,本揭露之化合物可為一針對雄性激素受體之蛋白水解靶向嵌合體,而可有效與雄性激素受體結合,並因此使雄性激素受體被蛋白酶體(proteasome)辨識而被切割與降解。
上述本揭露之化合物可與一般全長之雄性激素受體結合,也可與各種雄性激素突變、雄性激素擴增、雄性激素受體可變剪接異變體等結合,並無特殊限制。
在一實施例中,上述本揭露之化合物之結合標的可包括,但不限於,以下之至少一者:全長之雄性激素受體、雄性激素受體可變剪接異變體7等。
基於上述,本揭露也可提供一種醫藥組成物,其可包括,但不限於,任何上述之本揭露之化合物與一藥學上可接受之載體或鹽類。
本揭露之醫藥組成物,可用於一疾病之治療,而上述疾病可為與雄性激素受體過度表現相關之疾病,或一可藉由抑制雄性激素受體活性及/或降解而獲得減緩及/或治療的一疾病,或一癌症(如,前列腺癌),但不限於此。在一實施例中,本揭露之醫藥組成物,可用於前列腺癌之治療,而上述前列腺癌並無特別限制,可為一般前列腺癌、去勢療法抗性前列腺癌等,或具有雄性激素突變、雄性激素擴增、雄性激素變異體,如雄性激素受體可變剪接異變體7之前列腺癌。
上述藥學上可接受之載體可包括,但不限於溶劑、分散媒(dispersion medium)、套膜(coating)、抗菌與抗真菌試劑與一等滲透壓與吸收延遲(absorption delaying)試劑等與藥學投予相容者。對於不同的給藥方式,可利用一般方法將藥學組合物配製成劑型(dosage form)。
又,上述藥學上可接受之鹽類可包括,但不限於鹽類包括無機陽離子,例如,鹼金屬鹽類,如鈉、鉀或胺鹽,鹼土金族鹽類,如鎂、鈣鹽,含二價或四價陽離子之鹽類,如鋅、鋁或鋯鹽。此外,也可是為有機鹽類,如二環己胺鹽類、甲基-D-葡糖胺,胺基酸鹽類,如精胺酸、離胺酸、組織胺酸、麩胺酸醯胺。
再者,本揭露之醫藥組成物可被投予至一需要此醫藥組成物之一個體,但不限於此。而本揭露之醫藥組成物的給藥途徑可包括非口服、口服、經由吸入噴霧(inhalation spray)或藉由植入貯存器(implanted reservoir)的方式,但不限於此。非口服可
包括,但不限於,皮下(subcutaneous)、皮內(intracutaneous)、靜脈內(intravenous)、肌肉內(intramuscular)、關節內(intraarticular)動脈(intraarterial)、滑囊(腔)內(intrasynovial)、胸骨內(intrasternal)、蜘蛛膜下腔(intrathecal)、疾病部位內(intralesional)注射以及灌注技術等。
此外,上述需要被投予此醫藥組成物之個體可包括,但不限於,一脊椎動物。又,上述脊椎動物可包括魚類、兩棲類、爬蟲類、鳥類或哺乳類,但不限於此。哺乳類的例子可包括,但不限於,人類、猩猩、猴子、馬、驢、狗、貓、兔子、天竺鼠、大鼠與小鼠。在一實施例中,上述個體可為人類。
實施例
2-(4-(4-(1-(3-(三氟甲基)-7,8-二氢-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙酸叔丁酯
(tert-butyl 2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetate)(1c)之製備
將4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯酚(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenol)(1a)(150mg,0.41mmol)及2-(4-(甲苯磺醯氧基)丁氧基)乙酸叔丁酯(tert-butyl 2-(4-(tosyloxy)butoxy)acetate)(1b)(162mg,0.45mmol)置於25mL圓底瓶中,並在室溫下將ACN(4.1mL)添加於上述圓底瓶中,並依序加入K2CO3(113mg,0.82mmol)與KI(17mg,0.20mmol)。將系統升溫至回流下反應8小時。反應完成後濾除固體,並將濾液濃縮獲得一粗產物。將粗產物經由管柱色層分析純化(MeOH/DCM=1/50)得到2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙酸叔丁酯(tert-butyl 2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetate)(1c)(150mg,66%)。
1-2. 2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙酸
(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetic acid)(1d)之製備
將2-(4-(4-(1-(3-(三氟甲基)-7,8-二氢-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙酸叔丁酯(1c)(146mg,0.26mmol)在室溫下以DCM(8.8mL)溶解。將系統移至冰浴下攪拌5分鐘後,慢慢滴入TFA(4.4mL)。持續攪拌5分鐘後移開冰浴,使系統於室溫下反應2小時。於反應完全後,將反應物減壓濃縮以抽乾,並以甲苯共沸3次(3mL x 3),之後再進行凍乾即可得到2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙酸(1d)(129mg,99%)。
1-3. (2S,4S)-1-((S)-3,3-二甲基-2-(2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(1)之製備
將2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三
唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙酸(1d)(145mg,0.29mmol)與VHL HCl鹽(150mg,0.32mmol)在室溫下注入DMF(2.9mL),並依序加入HATU(122mg,0.32mmol)與DIPEA(0.15mL,0.88mmol),並於室溫下攪拌10分鐘,且之後置於室溫下反應5小時。反應完後,將反應物加水以中和,並以乙酸乙酯與飽和食鹽水萃取。將所獲得之有機層以無水硫酸鈉除水過濾並濃縮以獲得粗產物。將粗產物以管柱色層分析(methanol/DCM=1/50→1/20)純化後可得(2S,4S)-1-((S)-3,3-二甲基-2-(2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺(1)(157mg,59%)。
1H-NMR(500MHz,CDCl3):δ 8.66(s,1H),7.36-7.32(m,5H),7.18(d,J=9.0Hz,1H),7.10(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H),4.72(t,J=7.5,8.5Hz,1H),4.57-4.53(m,2H),4.49(d,J=9.0Hz,1H),4.34(dd,J=5.5,15.3Hz,2H),4.09(d,J=11.0Hz,1H),3.97-3.89(m,4H),3.62-3.56(m,3H),3.21(t,J=8.0,8.0Hz,2H),3.02-2.95(m,2H),2.79(t,J=7.0,8.5Hz,2H),2.50(s,3H),2.14-2.09(m,1H),2.00-1.92(m,3H),1.86-1.78(m,7H),1.71-1.63(m,3H),1.25(s,1H),0.94(s,9H)。LCMS[M+H]+=908.3。
2-1. 6-(4-(4-碘苄氧基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(6-(4-(4-(4-iodobenzyloxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine)(2b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(flash chromatography)(MeOH/DCM=1/100)來純化粗產物,以得到標題化合物2b(174mg,73%)。
2-2. (2S,4S)-1-((S)-3,3-二甲基-2-(5-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)甲基)苯基)戊-4-炔乙酰胺基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺
((2S,4S)-1-((S)-3,3-dimethyl-2-(5-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)methyl)phenyl)pent-4-ynamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(2)之製備
將6-(4-(4-碘苄氧基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(2b)(80mg,0.14mmol)、(2S,4S)-1-((S)-3,3-二甲基-2-戊基-4-炔乙酰胺基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-pent-4-ynamidobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(2c)(77mg,0.15mmol)、CuI(5mg,0.03mmol)與PdCl2(PPh3)2(10mg,0.01mmol)置於高壓管內,在氬氣下加入DMF(0.7mL)與Et3N(0.7mL)。將反應升溫至90℃反應2小時,反應完全後移除溶劑獲得粗產物。將粗產物先以管柱色層分析(MeOH/DCM=4/25→1/19→1/15)初步純化,再以逆相製備性(reverse phase preparative)HPLC純化可獲得(2S,4S)-1-((S)-3,3-二甲基-2-(5-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)甲基)苯基)戊-4-炔乙酰胺基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺(2)(60mg,45%)。
1H-NMR(500MHz,CDCl3):δ 8.68(s,1H),
7.40-7.30(m,8H),7.26(s,1H),7.11(d,J=7.0Hz,2H),6.89(d,J=7.5Hz,2H),6.42(d,J=8.5Hz,1H),5.00(s,2H),4.65(t,J=8.0,7.5Hz,1H),4.60-4.53(m,3H),4.33(ABq,J=4.5,5.0Hz,2H),4.10(d,J=10.5Hz,1H),3.60(d,J=10.0Hz,1H),3.21(s,2H),3.00(t,J=13.5,13.0Hz,2H),2.80-2.73(m,5H),2.55-2.52(m,2H),2.50(s,3H),2.12-2.07(m,1H),1.94(d,J=13.0Hz,2H),1.69-1.67(m,4H),1.25(s,1H),0.92(s,9H)。LCMS[M+H]+=964.4。
3-1. 2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧乙酸叔丁酯(tert-butyl 2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetate)(3b)之
製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(乙酸乙酯/己烷=1/1→乙酸乙酯)來純化粗產物,以得到標題化合物3b(394mg,100%)。
3-2. 2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙酸(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetic acid)(3c)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(347mg,99%)。
3-3. 2-(3-(2-(4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧)乙醯胺)乙氧基)丙氧基)乙酸叔丁酯(tert-butyl 2-(3-(2-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetamido)ethoxy)propoxy)acetate)(3e)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法(DCM→MeOH/DCM=1/100→1/80→1/50→1/30)來純化粗產物,以得到標題化合物3e(103mg,71%)。
3-4. 2-(3-(2-(4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧)乙醯胺)乙氧基)丙氧基)
乙酸(2-(3-(2-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetamido)ethoxy)propoxy)acetic acid)(3f)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(93mg,99%)。
3-5. (2S,4S)-1-((S)-2-叔丁基-4,14-二側氧基-15-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基]哌啶-4-基)苯氧基)-6,10-二氧雜-3,13-二氮雜戊烷)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-2-tert-butyl-4,14-dioxo-15-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)-6,10-dioxa-3,13-diazapentadecane)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(3)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物3(12mg,7%)。
1H-NMR(500MHz,CD3OD):δ 8.88(s,1H),7.54(d,J=10.0Hz,1H),7.45(ABq,J=8.0,8.5Hz,4H),7.18(d,J=9.0Hz,2H),6.91(d,J=8.5Hz,2H),4.69(d,J=9.5Hz,1H),4.60-4.55(m,2H),4.55-4.46(m,2H),4.43(s,4H),4.36-4.33(m,2H),3.95(s,1H),3.93(s,1H),3.88-3.85(m,1H),3.80-3.79(m,1H),3.63-3.51(m,8H),3.47-3.43(m,
3H),3.35(s,1H),3.20(t,J=7.5,8.0Hz,3H),3.04(t,J=13.0,11.5Hz,2H),2.93(t,J=8.0,7.5Hz,3H),2.83-2.78(m,1H),2.46(s,3H),2.25-2.21(m,1H),2.11-2.06(m,1H),2.03(s,2H),1.89-1.81(m,5H),1.72-1.65(m,2H)。LCMS[M+H]+=995.4。
4-1. 4-(5-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)噠嗪-1-甲酸叔丁酯(tert-butyl 4-(5-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazol
o[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)pyridin-2-yl)piperazine-1-carboxylate)(4c)之製備
使用與用於製備化合物2之方法相似的方法來製備此化合物。藉由急速層析法(乙酸乙酯/己烷=1/1→乙酸乙酯)來純化粗產物,以得到標題化合物4c(149mg,86%)。
4-2. 6-(4-(4-((6-(哌嗪-1-基)吡啶-3-基)乙炔基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(6-(4-(4-((6-(piperazin-1-yl)pyridin-3-yl)ethynyl)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine)(4d)之製備
將於二噁烷(dioxane)中之4N HCl(2.3mL)倒入裝有4-(5-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)噠嗪-1-甲酸叔丁酯(4c)(149mg,0.23mmol)的圓底瓶中,於攪拌後發現化合物無法全溶,因此再加入約1mL的MeOH增加化合物之溶解度。將反應物於室溫攪拌3小時,於反應完全後濃縮抽乾,之後以甲苯(toluene)(3mL)共沸3次以去除殘餘的HCl,最後以凍乾機凍乾而獲得6-(4-(4-((6-(哌嗪-1-基)吡啶-3-基)乙炔基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(6-(4-(4-((6-(piperazin-1-yl)pyridin-3-yl)ethynyl)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine)(4d)(124mg,99%)。
4-3. 3-(2-(2-(4-(5-(4-(3-(三氟甲基)-7,8-二氫
-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)吡啶-2-基)哌嗪-1-基)乙氧基)乙氧基)丙酸叔丁酯(tert-butyl 3-(2-(2-(4-(5-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)propanoate)(4f)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/50→1/30→1/20)來純化粗產物,以得到標題化合物4f(50mg,23%)。
1H-NMR(500MHz,CDCl3):δ 8.32(s,1H),7.55(d,J=8.5Hz,1H),7.44(d,J=8.5Hz,2H),7.16(d,J=8.5Hz,2H),6.58(d,J=9Hz,1H),3.70(t,J=6.5,7.0Hz,2H),3.66(t,J=7.5,6.0Hz,2H),3.57(s,7H),3.20(t,J=8.0,7.5Hz,2H),3.00(t,J=12.5,12.5Hz,2H),2.78(t,J=7.0,8.0Hz,2H),2.65-2.61(m,5H),2.49(t,J=6.5,7.0Hz,2H),1.96(d,J=13.5Hz,2H),1.75-1.66(m,2H),1.43(s,9H)。
4.4. 3-(2-(2-(4-(5-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)吡啶-2-基)哌嗪-1-基)乙氧基)乙氧基)丙酸(3-(2-(2-(4-(5-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)propanoic acid)(4g)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(46mg,99%)。
4-5. (2S,4S)-1-((S)-3,3-二甲基-2-(3-(2-(2-(4-(5-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔)吡啶-2-基)哌嗪-1-基)乙氧基)乙氧基)丙醯胺)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(3-(2-(2-(4-(5-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)pyridin-2-yl)piperazin-1-yl)ethoxy)ethoxy)propanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(4)之製備
在室溫下將DMF(2.4mL)添加至3-(2-(2-(4-(5-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)吡啶-2-基)哌嗪-1-基)乙氧基)乙氧基)丙酸(4g)(83mg,0.12mmol)及VHL HCl鹽(84mg,0.18mmol)注入,並依序加入EDCI(46mg,0.24mmol)、HOBT(32mg,0.24mmol)與DIPEA(0.09mL,0.54mmol),室溫下反應8小時。反應完成後將水添加至反應物中以中和,之後將經中和之反應物以乙酸乙酯與飽和食鹽水萃取。將所獲得之有機層以無水硫酸鈉除水過濾濃縮後獲得粗產物。以管柱色層分析純化(MeOH/DCM=1/20→1/15→1/13→1/10→1/8→1/5)得產物(2S,4S)-1-((S)-3,3-二甲基
-2-(3-(2-(2-(4-(5-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔)吡啶-2-基)哌嗪-1-基)乙氧基)乙氧基)丙醯胺)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺(4)(31mg,23%)。
1H-NMR(500MHz,CD3OD):δ 8.85(s,1H),8.27(s,1H),7.65(d,J=10Hz,1H),7.44-7.41(m,8H),7.26(d,J=10Hz,2H),6.87(d,J=10Hz,1H),4.66(s,1H),4.49(s,2H),4.36(d,J=15Hz,2H),3.88(d,J=15Hz,1H),3.85-3.70(m,11H),3.65-3.60(m,5H),3.25-3.19(m,5H),3.12-3.04(m,7H),2.95(t,J=10,10Hz,3H),2.57-2.52(m,2H),2.49(s,3H),2.24-2.20(m,1H),2.10-2.06(s,1H),1.9(d,J=15Hz,2H),1.74(dd,J=15,22.5Hz,2H),1.04(s,9H)。LCMS:[M+H]+=1107.0。
5-1. 4-(2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙醯基)哌嗪-1-羧酸叔丁酯(tert-butyl 4-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetyl)piperazine-1-carboxylate)(5b)之製備
使用與用於製備化合物4之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/乙酸乙酯=1/100)來純化粗產物,以得到標題化合物5b(193mg,83%)。
5-2. 1-(哌嗪-1-基)-2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙酮(1-(piperazin-1-yl)-2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethanone)(5c)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(159mg,99%)。
5-3. 3-(2-(2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙醯基)哌嗪-1-基)乙氧基)乙氧基)丙酸叔丁酯(tert-butyl 3-(2-(2-(4-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetyl)piperazin-1-yl)ethoxy)ethoxy)propanoate)(5e)之製備
使用與用於製備化合物1c之方法相似的方法來製備
此化合物。藉由急速層析法(MeOH/DCM=1/30→1/15)來純化粗產物,以得到標題化合物5e(130mg,48%)。
5-4. 3-(2-(2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙醯基)哌嗪-1-基)乙氧基)乙氧)丙酸(3-(2-(2-(4-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetyl)piperazin-1-yl)ethoxy)ethoxy)propanoic acid)(5f)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(118mg,99%)。
5-5. (3R,5R)-1-((R)-3,3-二甲基-2-(3-(2-(2-(4-(2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙醯基)哌嗪-1-基)乙氧基)乙氧基)丙醯胺)丁醯基)-5-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-3-羧醯胺((3R,5R)-1-((R)-3,3-dimethyl-2-(3-(2-(2-(4-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetyl)piperazin-1-yl)ethoxy)ethoxy)propanamido)butanoyl)-5-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-3-carboxamide)(5)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/20→1/10→1/8)來純化粗產物,以得到標題化合物5(80mg,27%)。
1H-NMR(500MHz,CD3OD):δ 8.86(s,1H),7.42(ABq,JAB=10Hz,4H),7.16(d,J=10Hz,2H),6.89(d,J=10Hz,2H),4.76(s,2H),4.65(t,J=5,5Hz,1H),4.57-4.48(m,3H),4.34(d,J=15Hz,2H),3.88(d,J=10Hz,1H),3.8(dd,J=2.5,6Hz,1H),3.74-3.70(m,3H),3.68-3.61(m,10H),3.04(t,J=11.5,12Hz,3H),2.95-2.92(m,3H),2.66(t,J=4.5,9Hz,2H),2.61-2.54(m,4H),2.46(s,3H),1.87(d,J=12.5Hz,3H),1.72-1.70(m,3H),1.33(d,J=28Hz,2H),0.90(s,9H)。LCMS[M+H]+=1065.0。
6-1. 2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙基氨基甲
酸叔丁酯(tert-butyl 2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)ethylcarbamate)(6b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/60)來純化粗產物,以得到標題化合物6b(152mg,45%)。
1H-NMR(500MHz,CDCl3):δ 7.06(d,J=8.0Hz,2H),6.80(d,J=8.0Hz,2H),3.91(t,J=5.5,5.5Hz,2H),3.59-3.58(m,2H),3.46-3.43(m,6H),3.15(t,J=8.0,7.0Hz,2H),2.77-2.70(m,2H),1.89(d,J=13.0Hz,2H),1.80-1.78(m,2H),1.71-1.59(m,7H)。
6-2. 2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙胺(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)ethanamine)(6c)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(125mg,99%)。
6-3. (S)-1-(4-(4-甲基噻唑-5-基)苯基)-3-側氧基-3-(2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並-6-基)哌啶-4-基)苯氧基)丁氧基)乙氨基)丙基氨基甲酸叔丁酯((S)-tert-butyl 1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(2-(4-(4-(1-(3
-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)ethylamino)propylcarbamate)(6e)之製備
使用與用於製備化合物4之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/60→1/50→1/40→1/25)來純化粗產物,以得到標題化合物6e(84mg,39%)。
1H-NMR(500MHz,CDCl3):δ 8.63(s,1H),7.34(ABq,J=10.0,5.0Hz,4H),7.09(d,J=8.5Hz,2H),6.81(d,J=8.5Hz,2H),5.28(s,1H),3.90(t,J=5.5,6.5Hz,2H),3.41-3.32(m,6H),3.19(t,J=7.5,8.0Hz,2H),2.98(t,J=12.5,12.5Hz,2H),2.77(t,J=8.0,8.5Hz,3H),2.72(s,2H),2.49(s,3H),1.95-1.91(m,3H),1.77-1.72(m,3H),1.67-1.60(m,5H),1.40(s,9H)。
6-4. (S)-3-氨基-3-(4-(4-甲基噻唑-5-基)苯基)-N-(2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙基)丙醯胺((S)-3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)-N-(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)ethyl)propanamide)(6f)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(73mg,99%)。
6-5. (2S,4R)-4-羥基-1-((R)-3-甲基-2-(3-甲基異噁唑-5-基)丁醯基)-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)-3-側
氧基-3-(2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙氨基)丙基)吡咯烷-2-甲醯胺((2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)ethylamino)propyl)pyrrolidine-2-carboxamide)(6)之製備
使用與用於製備化合物4之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物6(10mg,6%)。
1H-NMR(500MHz,CD3OD):δ 8.82(s,1H),7.46-7.36(m,4H),7.13(d,J=9.0Hz,2H0,6.81(d,J=8.5Hz,2H),6.24-6.21(m,1H),4.59-4.31(m,5H),3.95-3.92(m,2H),3.86(d,J=8.5Hz,1H),3.77-3.57(m,2H),3.43-3.41(m,2H),3.37-3.34(m,2H),3.29-3.28(m,1H),3.21(t,J=15.5,8.0Hz,2H),3.04(t,J=12.5,12.0Hz,2H),2.93(t,J=8.0,7.5Hz,2H),2.86-2.84(m,1H),2.80-2.69(m,3H),2.46(s,3H),2.44-2.39(m,1H),2.23(d,J=14.5Hz,3H),2.00-1.95(m,1H),1.89(d,J=13.0,2H),1.77-1.72(m,2H),1.69-1.65(m,4H),1.31(s,2H),1.05(d,J=7.0Hz,3H),0.94-0.80(m,3H)。LCMS[M+H]+=1002.9。
7-1. 2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙酸叔丁酯(tert-butyl 2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetate)(7b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物7b(72mg,27%)。
7-2. 2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙酸(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetic acid)
(7c)之製備
使用與用於製備化合物4d之方法相似的方法來製備此化合物(66mg,95%)。
7-3. 1-(2-(2-((3R,4S,5R)-3,4-二羥基-5-((2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙醯氨基)甲基)四氫呋喃-2-基)乙醯氨基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺(1-(2-(2-((3R,4S,5R)-3,4-dihydroxy-5-((2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazo1o[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)acetamido)methyl)tetrahydrofuran-2-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(7)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物7(13mg,9%)。LCMS[M+H]+=1010.6。
8-1. 2-(4-(4-(1-(4-(三氟甲基)苯基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基]哌啶-4-基)苯氧基)丁氧基)乙酸叔丁酯(tert-butyl 2-(4-(4-(1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetate)(8b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/50→1/40)來純化粗產物,以得到標題化合物8b(32mg,23%)。
1H-NMR(500MHz,CDCl3):δ 8.42(d,J=8.5Hz,2H),7.70(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),6.85(d,J=8.5Hz,2H),4.29(d,J=12.0Hz,2H),3.97(dd,J=6.0,12.0Hz,4H),3.57(t,J=6.5,6.5Hz,2H),3.23(t,J=7.0,7.5Hz,2H),3.02(t,J=13.0,12.5Hz,1H),2.80-2.73
(m,2H),1.97(d,J=13.0,2H),1.91-1.85(m,3H),1.81-1.67(m,5H),1.46(s,9H)。
8-2. 2-(4-(1-(3-(4-(三氟甲基)苯基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙酸(2-(4-(4-(1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetic acid)(8c)之製備
使用與用於製備化合物1d之方法相似的方法來製備此化合物(29mg,100%)。
8-3. (2S,4S)-1-((S)-3,3-二甲基-2-(2-(4-(4-(1-(3-(4-(三氟甲基)苯基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(1-(3-(4-(trifluoromethyl)phenyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(8)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物8(27mg,54%)。
1H-NMR(500MHz,CDCl3):δ 8.66(s,1H),8.42(d,J=8.0Hz,2H),7.70(d,J=8.5Hz,2H),7.37-7.30(m,5H),7.18(d,J=9.0Hz,1H),7.12(d,J=8.5Hz,2H),
6.84(d,J=8.5Hz,2H),4.72(t,J=8.5,9.0Hz,1H),4.58-4.55(m,2H),4.50(d,J=8.5Hz,1H),4.35-4.28(m,3H),4.11(d,J=11.5Hz,1H),3.96-3.89(m,4H),3.62-3.56(m,3H),3.24(t,J=7.5,7.5Hz,2H),3.02(t,J=13.0,12.0Hz,2H),2.80-2.73(m,3H),2.59-2.53(m,1H),2.50(s,3H),2.14-2.10(m,1H),1.98-1.75(m,10 H)。LCMS[M+H]+=983.9。
9-1. 4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)-[1,4'-聯吡啶]-1'-甲酸叔丁酯(tert-butyl
4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate)(9b)之製備
使用與用於製備化合物2之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物9b(92mg,37%)。
9-2. 6-(4-(4-([1,4'-二哌啶]-4-乙炔基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(6-(4-(4-([1,4'-bipiperidin]-4-ylethynyl)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine)(9c)之製備
使用與用於製備化合物4d之方法相似的方法來製備此化合物(90mg,98%)。
9-3. (S)-(1-(4-(4-甲基噻唑-5-基)苯基)-3-側氧基-3-(4-((4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基-[1,4'-二哌啶]-1'-基]丙基)氨基甲酸叔丁酯(tert-butyl(S)-(1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)propyl)carbamate)(9d)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物9d。
9-4. (S)-3-胺-3-((4-甲基噻唑-5-基)-4l7,5l5-環己-1,3,5-三乙四胺-4-炔-1-基)-1-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)-[1,4'-二哌啶]-1'-基)丙-1酮((S)-3-amino-3-((4-methylthiazol-5-yl)-4l7,5l5-cyclohexa-1,3,5-trien-4-yn-1-yl)-1-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)propan-1-one)(9e)之製備
使用與用於製備化合物4d之方法相似的方法來製備此化合物(35mg,27%,2步驟)。
9-5. (2S,4R)-4-羥基-1-((R)-3-甲基-2-(3-甲基異噁唑-5-基)丁醯基)-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)-3-側氧基-3-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)-[1,4'-二哌啶]-1'-基)丙基)吡咯烷-2-羧醯胺((2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)propyl)pyrrolidine-2-carboxamide)(9)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合
物9(22mg,49%)。LCMS[M+H]+=1063.5。
上方所示之化合物10與11之製備流程可由上方所示化合物4之製備流程推得。
上方所示之化合物12之製備流程可由後方所示化合物52之製備流程推得。
12-1. 4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-羧酸叔丁酯(tert-butyl 4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidine-1-carboxylate)(13b)之製備
使用與用於製備化合物2之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物13b(155mg,69%)。
12-2. 6-(4-(4-(哌啶-4-基乙炔基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(6-(4-(4-(piperidin-4-ylethynyl)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine)(13c)之製備
使用與用於製備化合物4d之方法相似的方法來製備
此化合物(130mg,95%)。
12-3. 4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丁酸酯甲酯(methyl 4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidin-1-yl)butanoate)(13e)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→1/95)來純化粗產物,以得到標題化合物13e(70mg,56%)。
12-4. 4-(4-((4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丁酸(4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidin-1-yl)butanoic acid)(13f)之製備
將4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丁酸酯甲酯(13e)(70.4mg,0.126mmol)溶在H2O/THF(1mL/1mL)並攪拌,再加入LiOH(6mg,0.25mmol),並於室溫下反應。於反應2小時之後,將THF自反應物移除,添加些許水於反應物中。之後,將反應物以1N檸檬酸(citric acid)進行酸化,再以DCM萃取。將所獲得之有機層以無水硫酸鎂除水,過濾,之後進行減壓濃縮,而獲得4-(4-((4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丁酸(13f)
(40.9mg,60%)。
12-5. (2S,4S)-1-((S)-3,3-二甲基-2-(4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丁醯胺)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidin-1-yl)butanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(13)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物13(11mg,16%)。
1H-NMR(CD3OD,500MHz)δ 8.95(s,1H),7.47(d,J=8.0Hz,2H),7.42-7.28(m,4H),7.32(d,J=7.5Hz,1H),7.23(dd,J=8.0,8.0Hz,2H),4.6-4.3(m,8H),3.92(t,J=10.0Hz,1H),3.85-3.75(m,1H),3.70-3.49(m,3H),3.30-2.80(m,16H),2.60-2.40(m,6H),2.3-2.0(m,10H),1.9-1.8(m,4H),1.8-1.6(m,2H),1.06(s,9H)。LCMS[M+H]+=956.6。
13-1. (S)-(1-(4-(4-甲基噻唑-5-基)苯基)-3-側氧基-3-(4-((4-(1-(3-(三氟甲基)-7,8-二氢-[1,2,4]三唑並[4,3-b]哒嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丙基)氨基甲酸叔丁酯(tert-butyl(S)-(1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidin-1-yl)propyl)carbamate)(14a)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物14a(37mg,29%)。
13-2. (S)-3-氨基-3-(4-(4-甲基噻唑-5-基)苯基)-1-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丙烷-1-酮((S)-3-amino-3-(4-(4-methylthiazol-5-yl)phenyl)-1-(4-((4-
(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidin-1-yl)propan-1-one)(14b)之製備
使用與用於製備化合物4d之方法相似的方法來製備此化合物(31mg,89%)。
13-3. (2S,4R)-4-羥基-1-((R)-3-甲基-2-(3-甲基異噁唑-5-基)丁醯基)-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)-3-側氧基-3-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-基)丙基)吡咯烷-2-羧醯胺((2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)-3-oxo-3-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidin-1-yl)propyl)pyrrolidine-2-carboxamide)(14)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物14(10mg,25%)。LCMS[M+H]+=980.6。
使用與用於製備化合物1之方法相似的方法來製備這些化合物。
14-1. (2S,4S)-1-((S)-3,3-二甲基-2-(2-(2-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)乙氧基)乙醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(2-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(19)
1H-NMR(500MHz,CD3OD):δ 8.86(1H,s),7.47(2H,d,J=6.5Hz),7.40(2H,d,J=7.5Hz),7.09(2H,d,J=7.5Hz),6.95(2H,d,J=6.5HZ),4.72(1H,s),4.59(2H,
d,J=14.0Hz),4.51(1H,s),4.42-4.31(2H,m),4.16(2H,s),4.11(2H,s),3.91-3,80(4H,m),3.19(2H,d,J=7.5Hz),3.01(2H,t,J=11.5,13.0Hz),2.93(2H,d,J=7.0Hz),2.81-2.70(1H,s),2.43(3H,s),2.24-2.08(2H,m),1.82(2H,d,J=13.0Hz),1.66-1.59(2H,m),1.03(9H,s)。LCMS[M+H]+=879.9。
14-2. (2S,4S)-1-((S)-3,3-二甲基-2-(2-(3-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丙氧基)乙醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(2-(3-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)propoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(20)
1H-NMR(500MHz,CDCl3):δ 8.67(s,1H),7.35(ABX,J=8.5,7.5Hz,4H),7.30(t,J=6.0,6.0Hz,1H),7.15(d,J=8.0Hz,1H),7.10(d,J=8.0Hz,2H),6.85(d,J=8.5Hz,2H),4.72(t,J=8.0,7.5Hz,1H),4.58-4.54(m,2H),4.48(d,J=9.0Hz,1H),4.34(dd,J=5.0,15.25Hz,2H),4.10(d,J=11.0Hz,1H),4.04(t,J=5.5,6.5Hz,2H),3.94(d,J=4.5Hz,2H),3.73-3.68(m,2H),3.61(dd,J=3.0,11.25Hz,1H),3.21(t,J=8.0,8.0Hz,2H),3.06-2.94(m,2H),2.78(t,J=7.5,8.0Hz,2H),2.73-2.71(m,1H),2.59-2.53(m,1H),
2.51(s,3H),2.14-2.05(m,3H),1.92(d,J=12.5Hz,2H),1.69-1.63(m,10H),0.93(s,9H)。LCMS[M+H]+=895.0。
14-3. 5-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)戊基((S)-1-((2S,4S)-4-羥基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲醯基)吡咯烷-1-基)-3,3-二甲基-1-側氧基丁烷-2-基)氨基甲酸酯(5-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)pentyl((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate)(21)
1H-NMR(500MHz,CD3OD):δ 8.84(1H,s),7.44(2H,s),7.40(2H,d,J=6.5Hz),7.10(2H,d,J=7.0Hz),6.81(2H,d,J=7.5Hz),4.69(1H,s),4.56(2H,d,J=9.0Hz),4.51(1H,d,J=6.0Hz),4.35-4.32(2H,m),4.01-3.96(4H,m),3.87(1H,d,J=10.5Hz),3.80(1H,d,J=11.0Hz),3.58(2H,s),3.18(2H,d,J=7.0Hz),3.03(2H,s),2.93(2H,s),2.76(1H,t,J=11.5,10.0Hz),2.45(3H,s),2.25-2.21(1H,m),2.11-2.07(1H,m),1.87-1.80(4H,m),1.71-1.60(6H,m)。LCMS[M+H]+=921.9。
14-4. 6-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)己基((S)-1-((2S,4S)-4-羥基-2-((4-(4-甲基噻唑-5-基)苄基)氨基甲醯基)吡咯烷-1-基)-3,3-二甲基-1-側氧基丁烷-2-基)氨基甲酸酯
(6-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)hexyl((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate)(22)
1H-NMR(500MHz,CD3OD):δ 8.83(1H,s),7.44(2H,s),7.40(2H,d,J=6.5Hz),7.11(2H,d,J=7.5Hz),6.80(2H,d,J=7.5Hz),4.68(1H,s),4.56(2H,d,J=13.5Hz),4.51(1H,s),4.00-3.92(4H,m),3.87(1H,d,J=10.5Hz),3.80(1H,d,J=11.0Hz),3.56(2H,s),3.19(2H,s),3.03(2H,t,J=12.0,11.5Hz),2.95(2H,s),2.77(1H,t,J=11.0,9.5Hz),2.45(3H,s),2.25-2.20(1H,m),2.11-2.07(1H,m),1.87(2H,d,J=12.5Hz),1.76(2H,s),1.68(4H,d,J=8.0Hz),1.51(4H,s),0.96(9H,s)。LCMS[M+H]+=935.9。
14-5. (2S,4S)-1-((S)-3,3-二甲基-2-(2-((7-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)庚基)氧基)乙醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(2-((7-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)heptyl)oxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(23)
1H-NMR(500MHz,CDCl3):δ 8.66(s,1H),
7.36(ABX,J=8.0,7.5Hz,5H),7.18(d,J=8.5Hz,1H),7.10(d,J=7.5Hz,2H),6.84(d,J=7.5Hz,2H),4.74(t,J=8.0,7.5Hz,1H),4.58-4.53(m,2H),4.47(d,J=8.5Hz,1H),4.33(dd,J=5.0,15.0,2H),4.11(d,J=11.5Hz,1H),3.93-3.87(m,4H),3.61(dd,J=2.5,11.25Hz,1H),3.51-3.47(m,2H),3.21(t,J=8.0,8.0Hz,2H),3.00(t,J=12.5,13.0Hz,2H),2.79(t,J=7.5,8.0Hz,2H),2.73(d,J=12.0Hz,1H),2.58-2.53(m,1H),2.51(s,3H),2.12(dd,J=9.0,12.25Hz,1H),1.94(d,J=12.5Hz,2H),1.79-1.60(m,14H),1.45-1.38(m,3H),0.82(s,9H)。LCMS[M+H]+=950.0。
上方所示之化合物24-27之製備流程可由上方所示化合物6之製備流程推得。
上方所示之化合物28之製備流程可由上方所示化合物1之製備流程推得。
17-1. 2-((3aS,6R,6aR)-2,2-二甲基-6-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並-6-基)哌啶-4-基)苯氧基)甲基)四氫呋喃[3,4-d][1,3]二噁醇-4-基)乙酸甲酯(methyl 2-((3aS,6R,6aR)-2,2-dimethyl-6-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate)(29b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→1/95)來純化粗產物,以得到標題化合物29b(305mg,55%)。
17-2. 2-((3aS,6R,6aR)-2,2-二甲基-6-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)甲基)四氫呋喃[3,4-d][1,3]二噁醇-4-基)乙酸(2-((3aS,6R,6aR)-2,2-dimethyl-6-((4-(1-(3-(trifluoromethy
l)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetic acid)(29c)之製備
將2-((3aS,6R,6aR)-2,2-二甲基-6-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並-6-基)哌啶-4-基)苯氧基)甲基)四氫呋喃[3,4-d][1,3]二噁醇-4-基)乙酸甲酯(methyl 2-((3aS,6R,6aR)-2,2-dimethyl-6-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetate)(29b)(305.2mg,0.51mmol)溶在MeOH/H2O(1/1),並攪拌,且加入NaOH(41mg,1.02mol)於室溫下反應2小時。之後利用減壓濃縮將MeOH從反應物去除。將反應物以1M檸檬酸進行酸化至pH值4-5,並以乙酸乙酯萃取。將所獲得之有機層以無水硫酸鎂除水,過濾,並減壓濃縮而獲得2-((3aS,6R,6aR)-2,2-二甲基-6-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)甲基)四氫呋喃[3,4-d][1,3]二噁醇-4-基)乙酸(29c)(275mg,92%)。
17-3. 1-(2-(2-((3R,4S,5R)-3,4-二羥基-5-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)甲基)四氫呋喃-2-基)乙醯氨基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺(1-(2-(2-((3R,4S,5R)-3,4-dihydroxy-5-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)p
iperidin-4-yl)phenoxy)methyl)tetrahydrofuran-2-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(29)之製備
將2-((3aS,6R,6aR)-2,2-二甲基-6-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)甲基)四氫呋喃[3,4-d][1,3]二噁醇-4-基)乙酸(2-((3aS,6R,6aR)-2,2-dimethyl-6-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acetic acid)(29c)(275mg,0.471mmol)溶在DMAC中,並攪拌,接著加入HATU(216mg,0.856mmol)與DIPEA(0.15mL,0.856mmol)室溫下攪拌10分鐘。然後再將VHL-HCl(200mg,0.428mmol)加入反應物中並於室溫下反應4小時。之後進行逆相製備性HPLC純化(50% ACN/50% H2O+0.1% TFA,24mL/分鐘,210nm),然後進行減壓濃縮以去除反應物中之ACN。將剩下的水溶液放置在室溫,以去除醣類保護基。待等保護基完全去後將水溶液凍乾,而獲得1-(2-(2-((3R,4S,5R)-3,4-二羥基-5-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)甲基)四氫呋喃-2-基)乙醯氨基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺(29)(252mg,62%)。LCMS[M+H]+=953.5。
使用與用於製備化合物1之方法相似的方法來製備此化合物。
N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)-2-(4-(4-(1-(3-(三氟甲基)-7,8)-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯胺(N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetamide)(30)
1H-NMR(500MHz,CDCl3):δ 8.30(s,1H),8.07(s,1H),7.74(dd,J=2.5,7.5Hz,2H),7.49(t,J=8.0,8.0Hz,1H),7.10(d,J=8.0Hz,2H),6.84(d,J=8.5Hz,2H),5.18(dd,J=5.0,13.25Hz,1H),4.46(d,J=8.0Hz,2H),4.11(s,2H),4.01(t,J=6.0,5.5Hz,2H),3.59(t,J=6.0,5.5Hz,2H),3.21(t,J=8.0,7.5Hz,2H),2.99(t,J=13.0,12.0Hz,2H),2.84-2.70(m,4H),2.32(ddd,J=5.5,12.5,26.0Hz,1H),2.19-2.16(m,1H),1.93-1.87(m,5H),1.70-1.62(m,7H)。LCMS[M+H]+=737.0。
19-1. 6-(4-(4-(己-5-炔基氧基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(6-(4-(4-(hex-5-ynyloxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine)(31b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法來純化粗產物,以得到標題化合物31b。
19-2. 3-(1-側氧基-4-(6-(4-(1-(3-(三氟甲基))-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)己-1-炔基)異吲哚啉-2-基)哌啶-2,6-二酮(3-(1-oxo-4-(6-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)hex-1-ynyl)isoindolin-2-yl)piperidine-2,6-dione)(31)之製備
使用與用於製備化合物2之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物31。
1H-NMR(500MHz,DMSO-d6):δ 10.98(s,1H,NH),7.70(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),7.51(t,J=7.5Hz,1H),7.15-7.13(m,2H),6.87-6.84(m,2H),5.13(dd,J=5.5,13.0Hz,1H),4.44(d,J=17.5Hz,1H),4.33-4.27(m,3H),3.99(t,J=6.5Hz,2H),3.18-3.07(m,4H),2.98-2.89(m,4H),2.77-2.72(m,1H),2.57-2.55(m,2H),2.47-2.40(m,1H),2.08-1.97(m,1H),1.89-1.84(m,2H),1.81-1.71(m,3H),1.58-1.55(m,3H)。LCMS[M+H]+=687.9。
使用與用於製備化合物1之方法相似的方法來製備此化合物。
N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)-2-((6-(4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)己基)氧基)乙醯胺(N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((
6-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)hexyl)oxy)acetamide)(32)
1H-NMR(500MHz,CDCl3):δ 8.28(s,1H),8.06(s,1H),7.74(t,J=7.0,7.0Hz,2H),7.49(t,J=8.0,8.0Hz,2H),7.10(d,J=7.5Hz,2H),6.84(d,J=8.0Hz,2H),5.21(dd,J=5.0,13.0Hz,1H),4.44(d,J=6.5Hz,2H),4.30(s,2H),4.09(s,2H),3.97-3.93(m,2H),3.66-3.62(m,2H),3.22(t,J=7.5,7.5Hz,2H),3.00(t,J=13.0,12.5Hz,2H),2.90-2.87(m,2H),2.84-2.72(m,5H),2.36(dd,J=5.0,13.25Hz,1H),2.23-2.21(m,1H),1.94(d,J=12.5Hz,3H),1.80-1.79(m,9H),1.74-1.60(m,6H),1.57-1.44(m,5H)。LCMS[M+H]+=765.9。
21-1. 4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-羰基)苯甲酸甲酯(methyl 4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazol
o[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidine-1-carbonyl)benzoate)(33b)
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物33b(30mg,24%)。
21-2. 4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-羰基)苯甲酸4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidine-1-carbonyl)benzoic acid(33c)之製備
使用與用於製備化合物13f之方法相似的方法來製備此化合物(12mg,41%)。
21-3. 1-(3,3-二甲基-2-(4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-羰基)苯甲醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺(1-(3,3-dimethyl-2-(4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)piperidine-1-carbonyl)benzamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(33)
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合
物33(13mg,64%)。
1H-NMR(CD3OD,500MHz)δ 8.99(s,1H),7.9(d,J=8.5Hz,2H),7.52(d,J=8.5Hz,2H),7.49(d,J=8.5Hz,2H),7.44(d,J=8.5Hz,2H),7.33(d,J=8.0Hz,2H),7.21(d,J=8.5Hz,2H),5.34(t,J=5.0Hz,1H),4.92(d,J=9.5Hz,1H),4.50-4.65(m,4H),4.40-4.50(m,3H),3.99(d,J=11.5Hz,1H),3.80-3.90(m,1H),3.21(t,J=7.5Hz,2H),2.90-3.10(m,7H),2.49(s,3H),2.0-2.3(m,6H),1.50-1.95(m,10H),1.11(s,9H)。LCMS[M+H]+=1018.6。
使用與用於製備化合物33之方法相似的方法來製備此化合物。
1-(3,3-二甲基-2-(4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)哌啶-1-羰基)環己烷-1-羧基醯胺)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺(1-(3,3-dimethyl-2-(4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)
phenyl)ethynyl)piperidine-1-carbonyl)cyclohexane-1-carboxamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(34)
1H-NMR(CD3OD,500MHz)δ 9.04(s,1H),7.48(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),7.32(d,J=8.5Hz,2H),7.20(d,J=8.5Hz,2H),4.7-4.3(m,9H),4.0-3.8(m,5H),4.50-4.65(m,4H),3.21(t,J=8.0Hz 2H),3.06(t,J=11Hz,2H),3.0-2.8(m,5H),2.75-2.65(m,1H),2.50(s,3H),2.45-2.3(m,2H),2.25-2.15(m,1H),2.15-1.5(m,24H),1.11(s,9H)。LCMS[M+H]+=1024.7。
1H NMR(CD3OD,500MHz)δ 8.92(s,1H),7.5-7.4(m,4H),7.31(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),4.7-4.65(m,1H),4.6-4.3(m,6H),4.0-3.8(m,4H),3.20(t,J=8.0Hz 2H),3.06(t,J=12.5Hz,2H),3.0-2.7(m,6H),2.75-2.65(m,1H),2.48(s,3H),2.25-2.2(m,1H),2.1-1.8(m,11H),1.8-1.5(m,10H),1.11(s,9H)。LCMS[M+H]+=1024.7。
23-1. (2R,4R)-1-((S)-2-氨基-3,3-二甲基丁醯基)-4-羥基-N-(2-羥基-4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺((2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(35b)之製備
將於1,4-二噁烷(0.6mL,2.4mmol)中之4N HCl添加至在CH2Cl2(1.2mL)中之(S)-1-((2R,4R)-4-羥基-2-(2-羥基-4-(4-甲基噻唑-5-基)芐基氨基甲醯基)吡咯烷-1-基)-3,3-二甲基-1-側氧基丁-2-基氨基甲酸叔丁酯(tert-butyl(S)-1-((2R,4R)-4-hydroxy-2-(2-hydroxy-4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate)(35a)(100mg,0.2mmol)與1,4-二噁烷(1.2mL)的一混合物。將反應混合物隔夜攪拌。然後將反應混合物在減壓下濃縮並與PhMe(3 x 3mL)共沸。得到(2R,4R)-1-((S)-2-氨基-3,3-二甲基丁醯基)-4-羥基-N-(2-羥基-4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺((2R,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy
-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(35b)為黃色固體(80mg,99%)。
23-2. (2S,4S)-1-((S)-3,3-二甲基-2-(2-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯氨基)丁醯基)-4-羥基-N-(2-羥基-4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetamido)butanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(35)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物35(66mg,42%)。
1H-NMR(500MHz,CDCl3):δ 8.64(s,1H),7.12(ABX,J=8.0,8.0Hz,5H),6.97(s,1H),6.85(t,J=8.5,8.0Hz,3H),4.72(t,J=7.5,8.0Hz,1H),4.52-4.46(m,3H),4.39(d,J=8.5Hz,1H),4.30(s,2H),4.13(dd,J=5.5,14.5Hz,1H),4.06(d,J=11,5,4H),3.97-3.86(m,5H),3.56-3.55(m,4H),3.21(t,J=7.5,8.0Hz,2H),3.00(t,J=10.5,15.0Hz,3H),2.78(t,J=7.5,8.0Hz,3H),2.74-2.72(m,1H),2.51(s,4H),2.09-2.05(m,1H),1.93(d,J=12.5Hz,3H),1.85-1.75(m,10H),1.72-1.64(m,5H),0.83(s,9H)。LCMS[M+H]+=925.1。
24-1. 7-(4-(1-(3-(三氟甲基)-7,8-二氢-[1,2,4]三唑并[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)庚基4-甲基苯磺酸酯(7-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)heptyl 4-methylbenzenesulfonate)(36b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。
24-2. (2R,4R)-1-((S)-2-(1-氟環丙烷-1-羧醯胺)-3,3-二甲基丁醯)-4-羥基-N-(4-(4-甲基噻唑-5-基)-2-((7-(4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基]哌啶-4-基)苯氧基)庚基)氧基)苄基)吡咯烷-2-羧醯胺((2R,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-((7-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)heptyl)oxy)benzyl)pyrrolidine-2-carboxamide)之製備(36)
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物36(22mg,37%)。
1H-NMR(5000MHz,CDCl3):δ 8.67(s,1H),7.32(d,J=8.0Hz,1H),7.22(t,J=5.5,6.0Hz,1H),7.11(d,J=16.5Hz,2H),7.17(d,J=5.5Hz,1H),6.94(d,J=8.0Hz,1H),6.85(d,J=9.0Hz,3H),4.73(t,J=7.5,7.5Hz,1H),4.54-4.50(m,3H),4.41(dd,J=5.5,14.75Hz,1H),4.30(s,2H),4.01(d,J=6.0Hz,3H),3.94(t,J=7.0,6.5Hz,2H),3.61(d,J=7.0Hz,1H),3.21(t,J=8.0,8.0Hz,2H),3.00(t,J=12.0,13.0Hz,1H),2.80-2.72(m,3H),2.60-2.55(m,1H),2.52(s,3H),2.09-2.05(m,1H),1.94(d,J=13.0Hz,3H),1.89-1.82(m,3H),1.80-1.76(m,6H),1.72-1.65(m,4H),1.56-1.45(m,7H),1.37-1.24(m,5H),0.93(s,9H)。LCMS[M+H]+=994.3。
使用與用於製備化合物1之方法相似的方法來製備此化合物。
(2S,4S)-1-((S)-3,3-二甲基-2-(2-(4-(1-(3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯胺)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧醯胺((2S,4S)-1-((S)-3,3-dimethyl-2-(2-(4-(4-(1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(37)
1H-NMR(500MHz,CDCl3):δ 8.66(s,1H),7.92(d,J=10.5Hz,1H),7.34(ABX,J=8.0,7.5Hz,5H),7.18-7.11(m,4H),6.84(d,J=8.0Hz,2H),4.73(t,J=8.0,7.5Hz,1H),4.58-4.53(m,2H),4.48(d,J=9.0Hz,1H),4.38-4.31(m,3H),4.12-4.06(m,2H),3.97-2.92(m,4H),3.62-3.51(m,4H),3.11(t,J=13.0,12.5Hz,3H),2.77(t,J=12.0,12.0Hz,1H),2.59-2.54(m,1H),2.50(s,3H),2.11(dd,J=8.0,12.75Hz,1H),1.98(d,J=12.0Hz,2H),1.86-1.76(m,8H),1.74-1.70(m,8H),0.94(s,9H)。LCMS[M+H]+=906.4。
使用與用於製備化合物1之方法相似的方法來製備此化合物。
N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)-2-(4-(4-(3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯胺(N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-(4-(4-(1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetamide)(38)
1H-NMR(500MHz,DMSO-d6):δ 10.99(s,1H),9.72(s,1H),8.23(d,J=10.0Hz,1H),7.74(d,J=7.5Hz,1H),7.64(d,J=10.0Hz,1H),7.56(d,J=7.0Hz,1H),7.51(t,J=7.5,7.5Hz,1H),7.14(d,J=7.5Hz,2H),6.84(d,J=8.0Hz,2H),5.12(dd,J=5.5,13.25Hz,1H),4.41-4.32(m,4H),4.13(s,2H),3.96(t,J=6.5,6.0Hz,2H),3.58(t,J=6.5,6.0Hz,2H),3.08(t,J=12.5,12.0Hz,2H),2.93-2.86(m,1H),2.78(t,J=11.5,12.5Hz,1H),2.58(d,J=16.0Hz,1H),2.35(ddd,J=4.0,13.25,26.375Hz,1H),2.01-1.98(m,1H),1.86(d,J=12.0Hz,2H),1.81-1.70(m,4H),1.68-1.60(m,3H)。LCMS[M+H]+=735.3。
27-1. 7-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)庚酸甲酯(methyl 7-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)heptanoate)(39b)之製備
使用與用於製備化合物1c之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/100→1/60)來純化粗產物,以得到標題化合物39b(458mg,66%)。
27-2. 7-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)庚烷酸(7-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)heptanoic acid)(39c)之製備
使用與用於製備化合物29c之方法相似的方法來製
備此化合物(97mg,100%)。
27-3. N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-4-基)-7-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)庚醯胺(N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-7-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)heptanamide)(39)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物39(16mg,24%)。
1H-NMR(500MHz,DMSO-d6):δ 11.00(s,1H),9.77(s,1H),7.81(d,J=7.0Hz,1H),7.51-7.48(m,2H),7.13(d,J=8.5Hz,2H),6.83(d,J=8.0Hz,2H),5.13(dd,J=5.0,13.25Hz,1H),4.35(ABX,J=17.5,17.5Hz,2H),4.27(s,1H),3.92(t,J=6.5,6.0Hz,2H),3.14(t,J=7.5,8.0Hz,2H),3.00-2.87(m,5H),2.75(t,J=12.0,11.5Hz,1H),2.59(d,J=17.5Hz,1H),2.38-2.28(m,3H),2.02-2.00(m,1H),1.80(d,J=12.0Hz,2H),1.79-1.64(m,2H),1.63-1.55(m,4H)。LCMS[M+H]+=735.3。
28-1. 4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚啉-5-基)-3,6-二氫吡啶-1(2H)-羧酸叔丁酯(tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate)(40c)之製備
對4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-5,6-二氫吡啶-1(2H)-甲酸叔丁酯(tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate)(40a)(150mg,0.49mmol)在DMF(2.4mL)中的一溶液添加3-(5-溴-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione)(40b)(188mg,0.59mmol)、Pd(dppf)2Cl2(54mg,0.07mmol)與K3PO4(124mg,0.59mmol),且在氬氣(argon)下,將混合物在90℃下攪拌22小時。於冷卻至室溫後,將反應溶液濃縮至乾燥,並將殘留物經由急速層析法(乙酸乙酯/己烷=1/1→3/1→4/1→乙酸乙酯)純化以獲得4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲
哚-5-基)-5,6-二氫吡啶-1(2H)-羧酸叔丁酯(tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate)(40c)(111mg,54%)為一白色固體。
28-2. 3-(1-側氧基-5-(1,2,3,6-四氫吡啶-4-基)異吲哚啉-2-基)哌啶-2,6-二酮(3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione)(40d)之製備
使用與用於製備化合物35b之方法相似的方法來製備此化合物(49mg,100%)。
28-3. 3-(1-側氧基-5-(1-(2-(4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯基)-1,2,3,6-四氫吡啶-4-基)異吲哚啉-2-基)哌啶-2,6-二酮(3-(1-oxo-5-(1-(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-2-yl)piperidine-2,6-dione)(40)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物40(52mg,43%)。
1H-NMR(500MHz,CDCl3):δ 8.22(s,1H),7.83(d,J=7.5Hz,1H),7.50-7.43(m,2H),7.09(d,J=8.5Hz,2H),6.83(d,J=8.0Hz,2H),6.14(d,J=37.5Hz,1H),5.22
(dd,J=5.5,13.25Hz,1H),4.48(d,J=16.5Hz,1H),4.39-4.20(m,7H),3.98-3.95(m,2H),3.86-3.85(m,1H),3.75(t,J=5.5,5.0Hz,1H),3.61(t,J=6.0,5.0Hz,2H),3.21(t,J=8.0,7.5Hz,2H),3.02-2.90(m,3H),2.88-2.81(m,2H),2.80-2.71(m,4H),2.62-2.58(m,2H),2.35(ddd,J=4.5,12.75,26.25Hz,1H),2.23-2.20(m,1H),1.94-1.80(m,7H),1.71-1.63(m,9H)。LCMS[M+H]+=803.2。
29-1. 4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚-5-基)哌啶-1-羧酸叔丁酯(tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate)(41a)之製備
對4-(2-(2,6-二側氧哌啶-3-基)-1-側氧基異吲哚啉-5-基)-5,6-二氫吡啶-1(2H)-羧酸叔丁酯(tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindo1in-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate)(40c)(50mg,0.12
mmol)在MeOH(1.2mL)之一溶液添加20%濕Pd/C(10mg),並在H2下將混合物於60℃隔夜攪拌。於冷卻至室溫後,經由Celite墊過濾並於減壓下濃縮。得到4-(2-(2,6-二側氧基哌啶-3-基)-1-側氧基異吲哚-5-基)哌啶-1-羧酸叔丁酯(41a)(45mg,90%)為一白色固體。
29-2. 3-(1-側氧基-5-(哌啶-4-基)異吲哚啉-2-基)哌啶-2,6-二酮(3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione)(41b)之製備
使用與用於製備化合物35b之方法相似的方法來製備此化合物(34mg,100%)。
25-3. 3-(1-側氧基-5-(1-(2-(4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯基)哌啶-4-基)異吲哚啉-2-基)哌啶-2,6-二酮(3-(1-oxo-5-(1-(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione)(41)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物41(34mg,27%)。
1H-NMR(500MHz,CDCl3):δ 8.05(s,1H),7.81(d,J=8.0Hz,1H),7.32-7.26(m,2H),7.10(d,J=7.0Hz,2H),6.84(d,J=7.0Hz,2H),5.20(d,J=11.0Hz,1H),4.76
(d,J=11.5Hz,1H),4.46(d,J=16.0Hz,1H),4.31(d,J=15.5Hz,3H),4.23-4.08(m,4H),3.97(t,J=5.0,6.0Hz,2H),3.62-3.59(m,2H),3.21(t,J=8.0,8.0Hz,2H),3.14(t,J=12.5,13.0Hz,1H),3.02-2.83(m,6H),2.80-2.66(m,5H),2.38-2.30(m,1H),2.22-2.19(m,1H),1.94-1.86(m,7H),1.82-1.79(m,3H),1.70-1.65(m,5H),1.62(s,10H)。LCMS[M+H]+=805.2。
使用與用於製備化合物1之方法相似的方法來製備此化合物。
1H-NMR(500MHz,DMSO-d6):δ 11.00(s,1H,NH),7.71-7.70(m,2H),7.56(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,2H),6.84(d,J=8.0Hz,2H),5.12(dd,J=5.0,13.0Hz,1H),4.47-4.42(m,3H),4.35-4.27(m,3H),3.96(t,J=6.5Hz,2H),3.59(t,J=6.5Hz,2H),3.16-3.06(m,6H),3.00-2.87(m,3H),2.78-2.74(m,1H),2.61-2.58(m,1H),2.41-2.37(m,1H),1.80-1.76(m,3H),1.71-1.68(m,2H),1.60-1.56(m,2H)。LCMS[M+H]+=718.2。
27-1. 2-(2,6-二側氧基哌啶-3-基)-4-((2-側氧基-2-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)-[1,4'-二哌啶]-1'-基)乙基)氨基)異吲哚啉-1,3-二酮(2-(2,6-dioxopiperidin-3-yl)-4-((2-oxo-2-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)ethyl)amino)isoindoline-1,3-dione)(43)之製備
1H-NMR(DMSO-d6,500MHz)δ 7.45-7.60(m,1H),7.39(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),7.20-7.23(m,2H),6.90-7.18(m,2H),5.15-5.0(m,1Hz),4.6-4.15(m,6H),3.8-3.4(m,6H),3.4-2.6(m,20H),2.4-1.6(m,16H)。LCMS[M+H]+=854.5。
2-(2,6-二氧哌啶-3-基)-4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]哌啶[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)-[1,4'-二哌啶]-1'-基)異吲哚啉-1,3-二酮(2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)ethynyl)-[1,4'-bipiperidin]-1'-yl)isoindoline-1,3-dione)(44)
將6-(4-(4-([1,4'-二哌啶]-4-乙炔基)苯基)哌啶-1-基)-3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪(9c)(40.3mg,0.223mmol)溶在DMAC中並攪拌,之後加入2-(2,6-二側氧基哌啶-3-基)-4-氟異吲哚啉-1,3-二酮(2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione)(44a)(23mg,0.245mmol)與K2CO3(21mg,0.335mmol),且加熱至100℃反應1天。接著,將水與DCM加入反應物以進行萃取,並以硫酸鎂除水。然後,將粗產物藉由逆相製備性HPLC來純
化(35% ACN+0.1% TFA,24mL/分鐘,210nm),並進行減壓濃縮去除CAN,之後凍乾而獲得2-(2,6-二氧哌啶-3-基)-4-(4-((4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]哌啶[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)乙炔基)-[1,4'-二哌啶]-1'-基)異吲哚啉-1,3-二酮(44)(5.4mg,9%)。LCMS[M+H]+=797.4。
2-(2,6-二側氧基哌啶-3-基)-4-(4-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯氧基)丁氧基)乙醯基)哌嗪-1-基)異吲哚啉-1,3-二酮(2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-(4-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)butoxy)acetyl)piperazin-1-yl)isoindoline-1,3-dione(45)
使用與用於製備化合物1之方法相似的方法來製備
此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物45(114mg,26%)。
1H-NMR(500MHz,CDCl3):δ 7.67-7.64(m,2H),7.42(d,J=7.0Hz,1H),7.24(d,J=8.5Hz,1H),7.09(d,J=8.5Hz,2H),6.82(d,J=8.5Hz,2H),5.05-5.02(m,1H),4.22(s,2H),3.98(t,J=6.0,6.0Hz,2H),3.78(s,2H),3.73(s,2H),3.60(t,J=6.0,6.0Hz,3H),3.35-3.33(m,2H),3.23(t,J=7.5,8.0Hz,2H),3.04-3.01(m,2H),2.91(t,J=8.0,8.0Hz,2H),2.82-2.73(m,4H),2.13-2.11(m,1H),1.90-1.78(m,7H),1.69-1.61(m,2H)。LCMS[M+H]+=820.3。
34-1. ((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)氨基甲酸叔丁酯(tert-butyl((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)carbamate)(46c)之製備
將((1r,3r)-3-羥基-2,2,4,4-四甲基環丁基)氨基甲酸叔丁酯(tert-butyl((1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate)(46b)(1.1g,4.56mmol)在DMF中的一溶液於0℃在氬氣下以氫化鈉(sodium hydride)(130mg,5.42mmol,油中60%分散體)處理。使反應在1小時內升溫至室溫。然後將反應瓶冷卻到0℃,在溫度保持在0℃以下的情況下,對此溶液滴加6-氯-3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪(6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine)(46a)(1.1g,4.94mmol)。將混合物在室溫下攪拌24小時。之後以水淬熄(quenched)。將有機相分離,並以鹽水(brine)清洗且以無水碳酸鈉(anhydrous sodium carbonate)乾燥。然後將樣
本於真空濃縮。藉由急速層析法(MeOH/DCM=1/99→5/95)純化,而獲得((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)氨基甲酸叔丁酯(46c)(890mg,46%)為一無色油。
34-2. (1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁烷-1-胺((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutan-1-amine)(46d)之製備
使用與用於製備化合物4d之方法相似的方法來製備此化合物(800mg,98%)。
30-3. 4-溴-N-((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)苯甲醯胺(4-bromo-N-((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)benzamide)(46f)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物46f(310mg,55%)。
34-4. 4-((4-(((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)氨基甲醯基)苯基)乙炔基)哌啶-1-羧酸叔丁酯(tert-butyl 4-((4-(((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)carba
moyl)phenyl)ethynyl)piperidine-1-carboxylate)(46g)之製備
使用與用於製備化合物2之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物46g(47mg,38%)。
34-5. 4-(哌啶-4-乙炔基)-N-((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)苯甲醯胺(4-(piperidin-4-ylethynyl)-N-((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)benzamide)(46h)之製備
使用與用於製備化合物4d之方法相似的方法來製備此化合物(50mg,98%)。
34-6. 4-((1-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)哌啶-4-基)乙炔基)-N-((1r,3r)-2,2,4,4-四甲基-3((3-三氟甲基-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)苯甲醯胺(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethynyl)-N-((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)benzamide)(46)之製備
使用與用於製備化合物44之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物46(2mg,3%)。LCMS[M+H]+=798.4。
35-1. 4-(5-(((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)氨基甲醯基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(tert-butyl 4-(5-(((1r,4r)-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclohexyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate)(47c)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/100→1/80→1/40)來純化粗產物,以得到標題化合物47c(396mg,76%)。
35-2. 6-(哌嗪-1-基)-N-((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)煙醯胺(6-(piperazin-1-yl)-N-((1r,4r)-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclohexyl)nicotinamide)(47d)之製備
使用與用於製備化合物35b之方法相似的方法來製備此化合物(240mg,98%)。
35-3. 6-(4-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)哌嗪-1-基)-N-((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)煙醯胺(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo1in-4-yl)piperazin-1-yl)-N-((1r,4r)-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclohexyl)nicotinamide)(47)之製備
將6-(哌嗪-1-基)-N-((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)煙醯胺(47d)(82mg,0.17mmol)、2-(2,6-二側氧基哌啶-3-基)-4-氟異吲哚啉-1,3-二酮(44a)(51mg,0.18mmol)與DIPEA(0.09mL,0.51mmol)於1,4-二噁烷(1.7mL)中的一混合物於回流下隔夜攪拌。將混合物濃縮,並藉由逆相製備性HPLC來純化,而獲得6-(4-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)哌嗪-1-基)-N-((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)煙醯胺(47)(14mg,11%)為一黃色固體。LCMS[M+H]+=747.3。
36-1. 4-((4-(5-(((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)氨基甲醯基)吡啶-2-基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯(tert-butyl 4-((4-(5-(((1r,4r)-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclohexyl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate)(48b)之製備
將6-(哌嗪-1-基)-N-((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)煙醯胺(47d)(160mg,0.33mmol)添加至對應之4-甲醯基哌啶-1-甲酸叔丁酯(tert-butyl 4-formylpiperidine-1-carboxylate)(48a)(104mg,0.49mmol)、醋酸(2.0mL)與三乙醯氧基硼氫化鈉(sodiumtriacetoxyborohydride)(207mg,0.98mmol)於2.0mL之乾DCE中的一溶液。將反應混合物於室溫隔夜攪拌,之後將粗反應混合物於真空蒸發,並以NaHCO3(aq)中和至PH=8。以DCM萃取粗產物並於真空蒸發而無純化而獲得4-((4-(5-(((1r,4r)-4-((3-(三氟
甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)氨基甲醯基)吡啶-2-基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯(48b)。
32-2. 6-(4-(哌啶-4-基甲基)哌嗪-1-基)-N-((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)煙醯胺(6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-N-((1r,4r)-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclohexyl)nicotinamide)(48c)之製備
使用與用於製備化合物35b之方法相似的方法來製備此化合物(34mg,18%,2步驟)。
32-3. 6-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)哌啶-4-基)哌啶-4-基)甲基)哌嗪-1-基)-N-((1r,4r)-4-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環己基)煙醯胺(6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-N-((1r,4r)-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclohexyl)nicotinamide)(48)之製備
使用與用於製備化合物47之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物48(7mg,14%)。LCMS[M+H]+=844.5。
4-((1-((2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)甘氨醯)哌啶-4-基)乙炔基)-N-((1r,3r))-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)苯甲醯胺(4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)piperidin-4-yl)ethynyl)-N-((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)benzamide)(49)
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物49(33mg,38%)。
1H-NMR(500MHz,DMSO-d6)δ 10.99(s,1H),8.36(d,J=10.0Hz,1H),7.90(d,J=10.0Hz,1H),7.75(d,J=8.0Hz,2H),7.51(dd,J=8.0,8.0Hz,1H),7.41(d,J=8.5Hz,2H),7.25(d,J=9.5Hz,1H),7.00(dd,J=8.5,8.5Hz,1H),4.97(dd,J=5.5,5.5Hz,1H),4.55(s,1H),4.11(s,2H),3.99(d,J=10Hz,1H),3.80-3.90(m,1H),3.60-3.70(m,1H),2.85-2.95(m,1H),2.70-2.85(m,1H),1.75-2.00(m,3H),1.4-1.65(m,2H),1.13(s,6H),1.11(s,6H)。LCMS[M+H]+=855.4。
上方所示之化合物50之製備流程可由上方所示化合物48之製備流程推得。
39-1. 5-溴-N-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)吡啶醯胺(5-bromo-N-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]
triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)picolinamide)(51c)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法來純化粗產物,以得到標題化合物51c(410mg,91%)。
39-2. 4-((6-((4-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)氨基甲醯基)吡啶-3-基)乙炔基)-[1,4'-二哌啶]-1'-羧酸叔丁酯(tert-butyl 4-((6-((4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)carbamoyl)pyridin-3-yl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate)(51d)之製備
使用與用於製備化合物2之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/100→1/20)來純化粗產物,以得到標題化合物51d(400mg,64%)。
39-3. 5-([1,4'-二哌啶]-4-基乙炔基)-N-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)吡啶醯胺(5-([1,4'-bipiperidin]-4-ylethynyl)-N-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)picolinamide)(51f)之製備
使用與用於製備化合物35b之方法相似的方法來製備此化合物(345mg,99%)。
39-4. 5-((1'-((2-(2,6-二側氧基哌啶-3-基)-1,3-
二側氧基異吲哚啉-4-基)甘氨醯)-[1,4'-二哌啶]-4-基)乙炔基)-N-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)吡啶醯胺(5-((1'-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-[1,4'-bipiperidin]-4-yl)ethynyl)-N-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)picolinamide)(51)之製備
將2-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基异吲哚啉-4-基氨基)乙酸(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)acetic acid)(43a)(174mg,0.53mmol)於DMSO(10.5mL)中之一混合物添加HOAt(143mg,1.05mmol)、EDCI(163mg,1.05mmol)與NMM(0.3mL,2.65mmol)並於室溫攪拌15分鐘,且之後添加5-([1,4'-二哌啶]-4-基乙炔基)-N-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)吡啶醯胺(51f)(345mg,0.52mmol)。將混合物於室溫隔夜攪拌。將混合物以H2O(10mL)稀釋並以DCM(10mL x 2)萃取。將組合之有機相以鹽水(10mL)清洗,經由Na2SO4乾燥、濃縮,並藉由急速管柱純化,而獲得5-((1'-(2-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基氨基)乙醯基)-1,4'-二哌啶-4-基)乙炔基)-N-(4-(1-(3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)哌啶-4-基)苯基)吡啶醯胺(5-((1'-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)acetyl)-1,4'-bipiperidin-4-yl)ethynyl)-N-(4-(1-
(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenyl)picolinamide)(51)(85mg,17%)。
1H-NMR(500MHz,DMSO-d6):δ 11.10(s,1H),10.58(s,1H),8.69(s,1H),8.07(dd,J=8.5,34.25Hz,1H),7.80(d,J=8.5Hz,2H),7.60(t,J=8.0,7.5Hz,1H),7.24(d,J=8.5Hz,2H),7.11-7.06(m,3H),5.06(dd,J=5.5,13.0Hz,1H),4.43(d,J=11.0Hz,1H),4.29(s,1H),4.20(ABX,J=14.0,6.0Hz,2H),3.94(d,J=11.0Hz,1H),3.15(t,J=7.5,8.0Hz,2H),3.06-3.02(m,9H),2.93(t,J=8.0,7.5Hz,3H),2.88-2.79(m,4H),2.67-2.54(m,4H),2.04-2.02(m,1H),1.98-1.91(m,2H),1.85-1.83(m,4H),1.67-1.61(m,4H),1.17(t,J=7.0,7.5Hz,7H).LCMS[M+H]+=973.6。
40-1. 4-((4-(((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)
氨基甲醯基)苯基)乙炔基)-[1,4'-二哌啶]-1'-羧酸叔丁酯(tert-butyl 4-((4-(((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)carbamoyl)phenyl)ethynyl)-[1,4'-bipiperidine]-1'-carboxylate)(52b)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物52b(236mg,75%)。
40-2. 4-([1,4'-二哌啶]-4-乙炔基)-N-((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)苯甲醯胺(4-([1,4'-bipiperidin]-4-ylethynyl)-N-((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)benzamide)(52c)之製備
使用與用於製備化合物4d之方法相似的方法來製備(238mg,98%)。
40-3. 4-((1'-((2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)甘氨醯)-[1,4'-二哌啶]-4-基)乙炔基)-N-((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-7,8-二氫-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)苯甲醯胺(4-((1'-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycyl)-[1,4'-bipiperidin]-4-yl)ethynyl)-N-((1r,3r)-2,2,
4,4-tetramethyl-3-((3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)benzamide)(52)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物52(1mg,1%)。
1H-NMR(CD3OD,500MHz)δ 7.8-7.65(m,2H),7.6-7.4(m,3H),7.1-7.0(m,2H),5.2-5.0(m,2H),4.63(s,1H),4.4-4.1(m,4H),3.6-3.4(m,4H),3.2-2.6(m,9H),2.4-1.6(m,10H),1.26(s,6H),1.25(s,6H)。
41-1. 4-羥基-N-((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)苯甲醯胺
(4-hydroxy-N-((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)benzamide)(53b)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由快速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物53b(310mg,55%)。
41-2. 2-(4-(4-((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)氨基甲醯基)苯氧基)丁氧基)乙酸叔丁酯(tert-butyl 2-(4-(4-(((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)carbamoyl)phenoxy)butoxy)acetate)(53d)之製備
使用與用於製備化合物44之方法相似的方法來製備此化合物。藉由急速層析法(MeOH/DCM=1/99→5/95)來純化粗產物,以得到標題化合物53d。
41-3. 2-(4-(4-((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)氨基甲醯基)苯氧基)丁氧基)乙酸(2-(4-(4-(((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)carbamoyl)phenoxy)butoxy)acetic acid)(53e)之製備
使用與用於製備化合物4d之方法相似的方法來製備此化合物(82mg,98%)。
41-4. 1-(3,3-二甲基
-2-(2-(4-(4-(((1r,3r)-2,2,4,4-四甲基-3-((3-(三氟甲基)-[1,2,4]三唑並[4,3-b]噠嗪-6-基)氧基)環丁基)氨基甲醯基)苯氧基)丁氧基)乙醯氨基)丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)芐基)吡咯烷-2-羧醯胺(1-(3,3-dimethyl-2-(2-(4-(4-(((1r,3r)-2,2,4,4-tetramethyl-3-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)cyclobutyl)carbamoyl)phenoxy)butoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)(53)之製備
使用與用於製備化合物1之方法相似的方法來製備此化合物。藉由逆相製備性HPLC來純化粗產物,以得到標題化合物53(53mg,59%)。LCMS[M+H]+=993.6。
實施例2
體外實驗
A.材料
22Rv1(ATCC® CRL-2505TM)、RPMI-1640培養基(Gibco,11875-093)、杜爾貝科改良伊格爾培養基(Dulbecco’s Modified Eagle’s Medium,DMEM)、胎牛血清(Gibco,10437-028)、青黴素(penicillin)/鏈黴菌素(streptomycin)(Gibco,15140-122)。
B.方法
1.化合物測試樣本的製備
用100%的DMSO溶液製備10mM的化合物儲備溶液(stock solution),並震盪10-15秒。在12000rpm(13523rcf.)下離心5分鐘,並以照片快照(photo snapshot)記錄渾濁或沉澱狀態。藉由震盪10-15秒使化合物儲備溶液重新懸浮,並以100%DMSO溶液連續將化合物濃度稀釋到1000μM,再稀釋到100,10及1μM,然後,以培養基10倍稀釋至100、10、1、0.1μM(最終10%DMSO/培養基)以完成化合物測試樣本之製備。對在96孔盤之各孔洞中的細胞加入10μL化合物測試樣本以進行化合物處理(最終1%DMSO/培養基)。
2.化合物之細胞毒性試驗
將細胞(CWR22Rv1細胞或VCaP細胞)培養於添加有10%胎牛血清、10,000U/mL青黴素與10,000μg/mL鏈黴素的RPMI-1640培養中。將細胞培養於37℃,於潮濕5%CO2之培養箱中。
將細胞接種於96孔盤(1x104細胞/孔洞)。隔天在96孔盤之各孔加入10μL之上述化合物測試樣本。於化合物處理72小時後,在每個96孔中加入10μL之AlamaBlue試劑,培養4小時。以微孔盤讀取儀讀取Ex/Em=560/590nm處的螢光值,並計算細胞毒性(%)。
3.化合物對全長之雄性激素受體或雄性激素受體可變剪接異變體7的降解能力的分析
3-1.西方墨點(Western blot)
將CWR22Rv1細胞在37℃、5%CO2的濕潤環境中,維持於添加有10%胎牛血清與1%青黴素-鏈黴素的RPMI培養基中。
將CWR22Rv1(5x105個細胞)接種於在6孔盤之各孔中,並隔夜培養過夜。在化合物處理前,將孔洞中之培養液置換為新培養液。將細胞以不同濃度的化合物隔夜處理。隨後,經由加入冷的PBS與刮除細胞來收穫細胞。依據一般程序裂解細胞並進行西方墨點檢測以評估化合物對全長之雄性激素受體或雄性激素受體可變剪接異變體7的降解能力。將細胞或細胞裂解液始終保持在冰上。
本實驗中使用了以下試劑。磷酸鹽緩衝鹽水(phosphate buffered saline,PBS)(Hyclone,SH30028.02)、胎牛血清(Hyclone,SH30084.23,Lot AC14563276),青黴素-鏈黴素溶液(Hyclone,SV30010)、0.5%胰蛋白酶-EDTA(Trypsin-EDTA)(Gibco,15400-054)、CST裂解緩衝液(CST-9803),HaltTM蛋白酶與磷酸酶抑制劑(ThermoFisher,78442)、考馬斯(布拉德福)蛋白質分析(Coomassie(Bradford)protein assay)(ThermoFisher,23200)、雄性激素受體抗體(Cell Siginaling,CST-5153S)、GAPDH抗體(Cell Siginaling,CST-5174S)、HRP-山羊-抗-兔(Jackson Immuno Research,111-035-003)、脫脂牛奶、SuperSignal West Pico Maximum Sensitivity substrate(ThermoFisher,34080)。
B.結果
1.化合物之細胞毒性試驗
依據上述方法,將上方所製備之化合物以CWR22RV1細胞與VCaP細胞進行細胞毒性試驗。
結果如表4及第1A圖與第1B圖所示。
根據表4及第1A圖與第1B圖可知,本揭露之化合物大都具有殺死前列腺癌細胞之能力。
2.化合物對全長之雄性激素受體或雄性激素受體可變剪接異變體7的降解能力的分析
依據上方項目B.3-2中所示方法,經由西方墨點法來分析上方所製備之化合物對CWR22RV1細胞之全長之雄性激素受體與雄性激素受體可變剪接異變體7的降解能力。
結果如表5及第2A圖至第2O圖所示。
根據表5及第2A圖至第2O圖可知,本揭露之化合物對於全長之雄性激素受體與雄性激素受體可變剪接異變體7兩者大都具有降解能力。
實施例3
動物實驗
A.方法
小鼠:雄性SCID小鼠(CB17/Icr-Prkdcscid/IcrIcoCrlBltw,週齡4-6週,購自樂斯科生物科技股份有限公司(BioLASCO Taiwan Co.,Ilan,Taiwan.)。
將CWR22Rv1細胞或VCaP細胞培養至指數生長期時即收取細胞,接著將細胞以PBS洗滌兩次。之後,對於CWR22Rv1細胞,將5×106個細胞懸浮於100μL含有33% Matrigel之PBS中形成細胞懸浮液;對於VCaP細胞,將3×106個細胞懸浮於100μL含有50% Matrigel之PBS中形成細胞懸浮液。然後,以25G針將上述細胞懸浮液皮下植入到雄性SCID小鼠右背。
在細胞接種後,當平均腫瘤體積達到100-150cm3或是腫瘤明確開始生長時,將小鼠分為載劑處理組(n=4~8)、5mg/kg化合物1處理組(n=4~8)與30mg/kg化合物1處理組(n=4~8),並以腹腔注射(IP),每日兩次(BID)來給藥。載劑為10% N-甲基吡咯烷酮(NMP,N-Methyl-2-pyrrolidone)與20%蓖麻油聚氧乙烯醚(Cremophor EL)於PBS緩衝溶液中。給藥後每週三次測定腫瘤體積與動物的體重。
腫瘤大小用卡尺測量並轉換成腫瘤體積(cm3;V),使用公式:V=0.5×[長度×(寬度)2]。
抗腫瘤活性以腫瘤生長抑制率(TGI)表示。計算方式為[1-(治療組最終腫瘤體積-治療組起始腫瘤體積)/(對照組最
終腫瘤體積-對照組起始腫瘤體積)]×100%。
數據以平均值(mean)±標準差(SEM)表示。
本研究所有相關的動物處理,護理和治療的程序皆經過動物照顧與使用委員會(IACUC)通過,通過案號ITRI-IACUC-2020-011及ITRI-IACUC-2020-014。
B.結果
結果如第3圖所示。
依據第3圖可以得知,相較於載劑處理,經由本揭露化合物1處理之動物的腫瘤尺寸之增加有減緩之趨勢。
然本發明已以較佳實施例揭露如上,然其並非用以限定本發明,任何熟習此技藝者,在不脫離本發明之精神和範圍內,當可作些許之更動與潤飾,因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
Claims (14)
- 如請求項6之用途,其中該雄性激素受體包括全長之雄性激素受體或雄性激素受體可變剪接異變體7(androgen receptor splice variant 7,AR-V7)。
- 如請求項9之用途,其中該雄性激素受體結合分子之結合標的包括全長之雄性激素受體及/或雄性激素受體可變剪接異變體7。
- 如請求項12之用途,其中該前列腺癌為具有一般雄性激素受體及/或雄性激素受體可變剪接異變體7之前列腺癌。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200301117A (en) * | 2001-11-23 | 2003-07-01 | Schering Ag | Piperazine derivatives that destabilize androgen receptors |
WO2009081197A1 (en) * | 2007-12-21 | 2009-07-02 | Astrazeneca Ab | Bicyclic derivatives for use in the treatment of androgen receptor associated conditions |
WO2010092371A1 (en) * | 2009-02-10 | 2010-08-19 | Astrazeneca Ab | Triazolo [4,3-b] pyridazine derivatives and their uses for prostate cancer |
US20150291562A1 (en) * | 2014-04-14 | 2015-10-15 | Arvinas, Inc. | Imide-based modulators of proteolysis and associated methods of use |
WO2017176708A1 (en) * | 2016-04-05 | 2017-10-12 | Arvinas, Inc. | Protein-protein interaction inducing technology |
US20180346461A1 (en) * | 2015-01-20 | 2018-12-06 | Arvinas, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
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US20170327469A1 (en) * | 2015-01-20 | 2017-11-16 | Arvinas, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
JP7029777B2 (ja) * | 2016-03-28 | 2022-03-04 | 国立大学法人金沢大学 | アンドロゲン依存性又は非依存性前立腺癌細胞の抑制用の組成物及びそれを含有する前立腺癌の医薬製剤 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200301117A (en) * | 2001-11-23 | 2003-07-01 | Schering Ag | Piperazine derivatives that destabilize androgen receptors |
WO2009081197A1 (en) * | 2007-12-21 | 2009-07-02 | Astrazeneca Ab | Bicyclic derivatives for use in the treatment of androgen receptor associated conditions |
WO2010092371A1 (en) * | 2009-02-10 | 2010-08-19 | Astrazeneca Ab | Triazolo [4,3-b] pyridazine derivatives and their uses for prostate cancer |
US20150291562A1 (en) * | 2014-04-14 | 2015-10-15 | Arvinas, Inc. | Imide-based modulators of proteolysis and associated methods of use |
US20180346461A1 (en) * | 2015-01-20 | 2018-12-06 | Arvinas, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
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