TW202016084A - Selective estrogen receptor downregulators and uses thereof - Google Patents

Selective estrogen receptor downregulators and uses thereof Download PDF

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TW202016084A
TW202016084A TW108118751A TW108118751A TW202016084A TW 202016084 A TW202016084 A TW 202016084A TW 108118751 A TW108118751 A TW 108118751A TW 108118751 A TW108118751 A TW 108118751A TW 202016084 A TW202016084 A TW 202016084A
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methyl
compound
amine
fluoropropyl
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周全
鄒昊
祝偉
申長茂
王汝民
劉文耕
陳祥
漢忠 徐
楊振帆
小林 張
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大陸商迪哲（江蘇）醫藥有限公司
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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention relates to novel tetrahydroisoquinoline compounds that are selective estrogen receptor downregulators (SERDs). The present invention also relates to pharmaceutical compositions comprising one or more of the compounds as an active ingredient, and to the use of the compounds in the treatment of estrogen receptor (ER) mediated or dependent diseases or conditions, for example cancer such as breast cancer.

Description

選擇性雌激素受體下調劑和其用途Selective estrogen receptor down-regulator and its use

本發明涉及作為選擇性雌激素受體下調劑(SERD)的新型四氫異喹啉化合物。本發明還涉及包含所述化合物中的一種或多種作為活性成分的藥物組合物，和所述化合物在治療雌激素受體(ER)介導的或依賴性疾病或病況，例如癌症，如乳腺癌中的用途。The present invention relates to a novel tetrahydroisoquinoline compound as a selective estrogen receptor down-regulator (SERD). The present invention also relates to a pharmaceutical composition containing one or more of the compounds as an active ingredient, and the compound in the treatment of estrogen receptor (ER)-mediated or dependent diseases or conditions, such as cancer, such as breast cancer Use in.

ER是配體活化的轉錄調節蛋白，所述轉錄調節蛋白通過其與雌激素(例如內源性雌激素，如雌酮、雌二醇、雌三醇和雌四醇；或合成雌激素，例如炔雌醇、己烯雌酚等)的相互作用介導多種生物效應的誘發。已發現ER具有兩種同種型：ER-α(α)和ER-β(β)。兩種受體均與多種疾病或病況，如癌症(例如乳腺癌、卵巢癌、子宮內膜癌、子宮癌、肺癌、肝細胞癌、腎上腺皮質癌、胰腺癌、膀胱癌或胃癌等)以及其它疾病或病況(例如停經、肥胖和骨質疏鬆)有關。 大量結構上相異的化合物對ER有作用。這些可視其功能作用分成兩種不同類別：選擇性雌激素受體調節劑(SERM)，其為雌激素的競爭性結合劑但以組織和/或細胞選擇性方式具有雌激素或抗雌激素活性；和選擇性雌激素受體降解劑或下調劑(SERD)，其選擇性地結合至ER且致使ER降解且因此下調。SERM的實例包括但不限於：他莫昔芬(tamoxifen)、雷諾昔酚(raloxifene)、托瑞米芬(toremifene)、雙炔失碳酯(anordrin)、苯卓昔芬(bazedoxifene)、克羅米芬(clomifene)和奧培米芬(ospemifene)。氟維司群(Fulvestrant)為SERD的實例且能夠通過經由蛋白酶體路徑誘使ER快速下調來阻斷雌激素活性。 舉他莫昔芬作為SERM的組織選擇性的例子，其在乳房中是ER拮抗劑並且因此適用於乳腺癌治療，但為骨骼中的ER激動劑(由此防範骨質疏鬆)並在子宮內膜中是部分激動劑(提高子宮內膜癌的潛在風險)。不具有SERM的部分激動劑活性的SERD具有若干潛在優勢，包括降低的子宮內膜癌風險。因此，仍需要開發不具有部分激動劑活性的新型SERD，其在治療雌激素受體介導的或依賴性疾病或病況中具有活性。 先前已公開了某些四氫異喹啉衍生物。WO 2016/202161、WO 2017/107754和WO 2017/174757申請四氫異喹啉化合物的專利保護。這些化合物被描述為具有雌激素受體調節活性的SERM。 本文揭示新型四氫異喹啉化合物，其為SERD且不具有SERM的部分激動劑活性。其因此具有潛在改進的安全性和功效的特徵，尤其是就引起子宮內膜癌的風險而言。此外，這些化合物具有優良的下調特性，且具有改進的藥物動力學特徵(包括較低血漿蛋白結合、較長體內半衰期、較低的預測人體清除率和較平穩的游離藥物AUC覆蓋)以增加安全邊際，和/或可展現其它有利物理特性(例如較低親脂性、較高水溶性、較高滲透性和/或較大化學穩定性)。其還可具有相比於已知ER調節劑有利的毒性特徵(例如減少的hERG活性)，和/或有利的代謝或藥物動力學特徵。ER is a ligand-activated transcriptional regulator protein that interacts with estrogen (eg, endogenous estrogens, such as estrone, estradiol, estriol, and estriol); or synthetic estrogens, such as acetylene The interaction of estradiol, diethylstilbestrol, etc.) mediates the induction of various biological effects. It has been found that ER has two isotypes: ER-α (α) and ER-β (β). Both receptors are associated with a variety of diseases or conditions, such as cancer (eg breast cancer, ovarian cancer, endometrial cancer, uterine cancer, lung cancer, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, bladder cancer or gastric cancer, etc.) and others Disease or condition (such as menopause, obesity and osteoporosis). A large number of structurally different compounds have an effect on ER. These can be divided into two different categories depending on their functional effects: selective estrogen receptor modulators (SERM), which are competitive binding agents of estrogen but have estrogen or anti-estrogen activity in a tissue and/or cell selective manner ; And a selective estrogen receptor degrading agent or down-regulator (SERD), which selectively binds to the ER and causes the ER to degrade and thus down-regulate. Examples of SERM include, but are not limited to: tamoxifen, raloxifene, toremifene, anordrin, bazedoxifene, clomiphene (clomifene) and ospemifene (ospemifene). Fulvestrant is an example of SERD and is able to block estrogen activity by inducing rapid down-regulation of ER via the proteasome pathway. Take the example of tamoxifen as a tissue-selective SERM, which is an ER antagonist in the breast and is therefore suitable for breast cancer treatment, but is an ER agonist in the bone (thus preventing osteoporosis) and in the endometrium Among them are partial agonists (increasing the potential risk of endometrial cancer). SERD without partial agonist activity of SERM has several potential advantages, including a reduced risk of endometrial cancer. Therefore, there is still a need to develop new SERDs that do not have partial agonist activity, which are active in the treatment of estrogen receptor-mediated or dependent diseases or conditions. Some tetrahydroisoquinoline derivatives have been previously disclosed. WO 2016/202161, WO 2017/107754 and WO 2017/174757 apply for patent protection for tetrahydroisoquinoline compounds. These compounds are described as SERMs with estrogen receptor modulating activity. This article discloses a novel tetrahydroisoquinoline compound, which is SERD and does not have partial agonist activity of SERM. It therefore has the characteristics of potentially improved safety and efficacy, especially in terms of the risk of causing endometrial cancer. In addition, these compounds have excellent down-regulating properties and have improved pharmacokinetic characteristics (including lower plasma protein binding, longer in vivo half-life, lower predicted human clearance, and smoother free drug AUC coverage) to increase safety Margins, and/or may exhibit other favorable physical properties (eg, lower lipophilicity, higher water solubility, higher permeability, and/or greater chemical stability). It may also have advantageous toxicity characteristics (eg reduced hERG activity) compared to known ER modulators, and/or favorable metabolic or pharmacokinetic characteristics.

在一個方面，本發明提供一種由式(I)表示的化合物：

Figure 02_image001
式(I) 其中R1 、R2 、R3 、R4 、R5 、X、A1 、A2 、A3 、環B、環Q、m和n如本文中所定義，或其藥學上可接受的鹽。 在另一方面，本發明還涉及包含所述化合物中的一種或多種或其藥學上可接受的鹽作為活性成分的藥物組合物，和所述化合物或其藥學上可接受的鹽作為SERD在治療ER介導的或依賴性疾病或病況，例如癌症(如乳腺癌)中的用途。In one aspect, the present invention provides a compound represented by formula (I):
Figure 02_image001
Formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, A 1 , A 2 , A 3 , ring B, ring Q, m and n are as defined herein, or their pharmaceutical Acceptable salt. In another aspect, the invention also relates to a pharmaceutical composition comprising one or more of the compounds or a pharmaceutically acceptable salt thereof as an active ingredient, and the compound or a pharmaceutically acceptable salt thereof as a SERD in the treatment Use in ER-mediated or dependent diseases or conditions, such as cancer (eg breast cancer).

在一個方面，本發明提供式(I)化合物：

Figure 02_image001
式(I) 或其藥學上可接受的鹽，其中： A1 、A2 和A3 各自獨立地為-C(R6 )=或-N=； 環Q為6元芳環，其中環原子獨立地選自碳或氮； 環B為5元或6元不飽和環，其可為碳連接的或氮連接的；其中如果所述5元或6元不飽和環含有-NH-部分，則所述氮可任選地經選自R7 的基團取代； X為-O-、-NR8 -、-C(R9 )(R10 )-或-S-； R1 和R3 為碳上的取代基且獨立地選自羥基、鹵素、硝基、氰基、羧基、胺基、胺甲醯基、巰基、胺磺醯基、甲基、乙基、氟甲基、二氟甲基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基、三氟乙氧基、甲胺基、二甲胺基或乙胺基；或鄰近原子上的兩個R1 基團形成五元或六元稠合碳環基或稠合雜環基環；其中所述五元或六元稠合碳環基或稠合雜環基環可任選地在碳上經R11 取代；且其中如果所述五元或六元稠合雜環基環含有-NH-部分，則所述氮可任選地經選自R12 的基團取代； R2 和R5 獨立地選自C1-12 烷基、3-10元飽和或不飽和碳環基，或3-10元飽和或不飽和雜環基；其中R2 和R5 可任選地在碳上經R13 取代；且其中如果所述3-10元飽和或不飽和雜環基含有-NH-部分，則所述氮可任選地經選自R14 的基團取代； R4 為C1-3 烷基或C3-4 環烷基；其中R4 可任選地經一個或多個羥基、鹵素或甲氧基取代； R8 為氫或任選地經一個或多個鹵基或羥基取代的C1-12 烷基； R6 、R9 和R10 各自獨立地為氫、羥基、鹵素、硝基、氰基、羧基、胺基、胺甲醯基、巰基、胺磺醯基、C1-12 烷基或C1-12 烷氧基；其中所述C1-12 烷基或C1-12 烷氧基可獨立地任選地經一個或多個鹵基或羥基取代； R11 和R13 為碳上的取代基並且各自獨立地選自羥基、鹵素、硝基、氰基、羧基、三氟甲氧基、胺基、胺甲醯基、巰基、胺磺醯基、C1-12 烷基、C1-12 烷氧基、C1-12 烷醯基、C1-12 烷醯氧基、N-(C1-12 烷基)胺基、N,N-(C1-12 烷基)2 胺基、C1-12 烷醯胺基、N-(C1-12 烷基)胺甲醯基、N,N-(C1-12 烷基)2 胺甲醯基、C1-12 烷基S(O)a ，其中a為0至2，C1-12 烷氧基羰基、N-(C1-12 烷基)胺磺醯基、N,N-(C1-12 烷基)2 胺磺醯基、C1-12 烷基磺醯胺基、C1-12 烷基-OH、C1-12 鹵烷基、-Si(Ra Rb Rc )、3-10元飽和或不飽和碳環基、或3-10元飽和或不飽和雜環基；其中R11 和R13 各自獨立地可在碳上任選地經一個或多個R15 取代；且其中如果所述3-10元飽和或不飽和雜環基含有-NH-部分，則所述氮可任選地經選自R16 的基團取代； R7 、R12 、R14 和R16 獨立地選自C1-12 烷基、C1-12 烷醯基、C1-12 烷基磺醯基、C1-12 烷氧基羰基、胺甲醯基、N-(C1-12 烷基)胺甲醯基、N,N-(C1-12 烷基)2 胺甲醯基、3-10元飽和或不飽和碳環基、3-10元飽和或不飽和雜環基、3-10元飽和或不飽和碳環基C1-12 烷基、3-10元飽和或不飽和雜環基C1-12 烷基、苯甲基、苯甲氧基羰基、苯甲醯基或苯基磺醯基；其中R7 、R12 、R14 和R16 可獨立地任選地在碳上經R17 取代； R15 和R17 各自獨立地選自羥基、鹵素、硝基、氰基、羧基、三氟甲氧基、胺基、胺甲醯基、巰基、胺磺醯基、C1-12 烷基、C1-12 烷氧基、C1-12 鹵烷基、N-(C1-12 烷基)胺基、N-(C1-12 鹵烷基)胺基或C1-12 烷基-OH； Ra 、Rb 和Rc 各自獨立地選自羥基、C1-12 烷基或C1-12 烷基-OH；且 m為0、1、2、3或4； n為0、1或2。 在本發明的一個方面中，A1 、A2 和A3 各自獨立地為 -C(R6 )=或-N=；其中R6 各自獨立地為氫或鹵素。 在本發明的一個方面中，A1 、A2 和A3 各自獨立地為 -C(R6 )=或-N=；其中R6 各自獨立地為氫或氟。 在本發明的一個方面中，A1 、A2 和A3 各自獨立地為 -C(R6 )=。 在本發明的一個方面中，A1 、A2 和A3 各自獨立地為 -C(R6 )=；其中R6 為氫。 在本發明的一個方面中，A1 為-N=且A2 和A3 各自獨立地為-C(R6 )=。 在本發明的一個方面中，A2 為-N=且A1 和A3 各自獨立地為-C(R6 )=。 在本發明的一個方面中，A3 為-N=且A1 和A2 各自獨立地為-C(R6 )=。 在本發明的一個方面中，環Q為苯基或吡啶基。 在本發明的一個方面中，環Q為吡啶基。 在本發明的一個方面中，環Q為苯基。 在本發明的一個方面中，環B為5元或6元不飽和環，其可為碳連接的或氮連接的；其中如果所述5元或6元不飽和環含有-NH-部分，則所述氮可任選地經選自R7 的基團取代；其中 R7 選自C1-12 烷基或環丙基；其中R7 可獨立地任選地在碳上經一個或多個R17 取代；且 R17 各自獨立地選自鹵素。 在本發明的一個方面中，環B為吡唑基、噁唑基、1,2,4-三唑-4-基、1,2,3-三唑-4-基、2,5-二氫噻吩-4-基1,1-二氧化物、嘧啶基、噠嗪基、吡啶基、吡咯基、四唑基或咪唑基；其中如果所述吡唑基、1,2,3-三唑基、吡咯基、四唑基、1,2,4-三唑基和咪唑基含有-NH-部分，則所述氮可任選地經選自R7 的基團取代；其中 R7 選自甲基、乙基或環丙基；其中R7 可獨立地任選地在碳上經一個或多個R17 取代；且 R17 各自獨立地選自氟。 在本發明的一個方面中，環B為1H-吡唑-1-基、1H-吡唑-3-基、1H-吡唑-4-基、噁唑-4-基、4H-1,2,4-三唑-4-基、2H-1,2,3-三唑-4-基、1H-1,2,4-三唑-3-基、2,5-二氫噻吩-4-基1,1-二氧化物、嘧啶-5-基、噠嗪-4-基、吡啶-3-基、吡啶-4-基、1H-吡咯-3-基、2H-四唑-5-基或1H-咪唑-2-基；其中所述1H-吡唑-3-基、1H-吡唑-4-基、2H-1,2,3-三唑-4-基、1H-吡咯-3-基、2H-四唑-5-基、1H-1,2,4-三唑-3-基和1H-咪唑-2-基可任選地在-NH-部分上經選自R7 的基團取代；其中 R7 選自甲基、二氟甲基、乙基或環丙基。 在本發明的一個方面中，環B為吡唑基、噁唑基、1,2,4-三唑-4-基、1,2,3-三唑-4-基、2,5-二氫噻吩-4-基1,1-二氧化物、嘧啶基、噠嗪基、吡啶基、吡咯基、四唑基或咪唑基；其中如果所述吡唑基、1,2,3-三唑基、吡咯基、四唑基、1,2,4-三唑基和咪唑基含有-NH-部分，則所述氮可任選地經選自R7 的基團取代。 在本發明的一個方面中，環B為1H-吡唑-1-基、1H-吡唑-3-基、1H-吡唑-4-基、噁唑-4-基、4H-1,2,4-三唑-4-基、2H-1,2,3-三唑-4-基、1H-1,2,4-三唑-3-基、2,5-二氫噻吩-4-基1,1-二氧化物、嘧啶-5-基、噠嗪-4-基、吡啶-3-基、吡啶-4-基、1H-吡咯-3-基、2H-四唑-5-基或1H-咪唑-2-基；其中所述1H-吡唑-3-基、1H-吡唑-4-基、2H-1,2,3-三唑-4-基、1H-吡咯-3-基、2H-四唑-5-基、1H-1,2,4-三唑-3-基和1H-咪唑-2-基可任選地在-NH-部分上經選自R7 的基團取代。 在本發明的一個方面中，X為-O-。 在本發明的一個方面中，X為-NR8 -。 在本發明的一個方面中，X為-NR8 -；其中R8 為氫。 在本發明的一個方面中，X為-C(R9 )(R10 )-。 在本發明的一個方面中，X為-C(R9 )(R10 )-；其中R9 和R10 各自獨立地為氫、羥基或鹵素。 在本發明的一個方面中，X為-S-。 在本發明的一個方面中，X為-O-、-NR8 -或-C(R9 )(R10 )-；其中 R8 為氫；且 R9 和R10 各自獨立地為氫、羥基或鹵素。 在本發明的一個方面中，X為-O-、-NH-、-CH2 -、 -CH(OH)-或-CH(F)-。 在本發明的一個方面中，R1 不為羥基。 在本發明的一個方面中，R1 為碳上的取代基並且獨立地選自羥基、鹵素或甲基。 在本發明的一個方面中，R1 為碳上的取代基並且獨立地選自鹵素或甲基。 在本發明的一個方面中，R1 為碳上的取代基並且獨立地選自羥基、氟或甲基。 在本發明的一個方面中，R1 為碳上的取代基並且獨立地選自氟或甲基。 在本發明的一個方面中，R2 選自C1-12 烷基或5元飽和碳環基；其中R2 可任選地在碳上經一個或多個R13 取代；其中 R13 為碳上的取代基且各自獨立地選自羥基、鹵素或C1-12 烷基。 在本發明的一個方面中，R2 選自乙基、丙基或雙環[1.1.1]戊-1-基；其中R2 可任選地在碳上經一個或多個R13 取代；其中 R13 為碳上的取代基且各自獨立地選自羥基、氟或甲基。 在本發明的一個方面中，R2 選自C1-12 烷基或5元飽和碳環基。 在本發明的一個方面中，R2 選自乙基、丙基或雙環[1.1.1]戊-1-基；其中R2 可任選地在碳上經一個或多個R13 取代。 在本發明的一個方面中，R3 為碳上的取代基且獨立地選自鹵素或甲氧基。 在本發明的一個方面中，R3 為碳上的取代基且獨立地選自氟或甲氧基。 在本發明的一個方面中，R4 為C1-3 烷基或C3-4 環烷基；其中R4 可任選地經一個或多個鹵素取代。 在本發明的一個方面中，R4 為甲基、乙基或環丙基；其中R4 可任選地經一個或多個氟取代。 在本發明的一個方面中，R4 為甲基、二氟甲基、乙基、2,2-二氟乙-2-基或環丙基。 在本發明的一個方面中，R4 為甲基。 在本發明的一個方面中，R5 選自C1-12 烷基或4元或5元飽和雜環基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中如果所述4元或5元飽和雜環基含有-NH-部分，則所述氮可任選地經選自R14 的基團取代；其中 R13 為碳上的取代基且獨立地選自N-(C1-12 烷基)胺基；其中R13 各自獨立地可任選地在碳上經一個或多個R15 取代； R14 獨立地選自C1-12 烷基；其中R14 可獨立地任選地在碳上經一個或多個R17 取代；且 R15 和R17 各自獨立地選自鹵素。 在本發明的一個方面中，R5 選自乙基、氮雜環丁烷-3-基或吡咯烷-3-基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中所述氮雜環丁烷-3-基或吡咯烷-3-基可任選地在-NH-部分上經選自R14 的基團取代；其中 R13 為碳上的取代基且獨立地選自丙胺基；其中R13 各自獨立地可任選地在碳上經一個或多個R15 取代； R14 獨立地選自丙基；其中R14 可獨立地任選地在碳上經一個或多個R17 取代；且 R15 和R17 各自獨立地選自氟。 在本發明的一個方面中，R5 選自C1-12 烷基或4元或5元飽和雜環基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中如果所述4元或5元飽和雜環基含有-NH-部分，則所述氮可任選地經選自R14 的基團取代。 在本發明的一個方面中，R5 選自乙基、氮雜環丁烷-3-基或吡咯烷-3-基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中所述氮雜環丁烷-3-基或吡咯烷-3-基可任選地在-NH-部分上經選自R14 的基團取代。 在本發明的一個方面中，R5 為1-(3-氟丙基)氮雜環丁烷-3-基。 在本發明的一個方面中，-X-R5 為[1-(3-氟丙基)氮雜環丁烷-3-基]胺基。 在本發明的一個方面中，R6 各自獨立地為氫或鹵素。 在本發明的一個方面中，R6 各自獨立地為氫或氟。 在本發明的一個方面中，R7 選自甲基、二氟甲基、乙基或環丙基。 在本發明的一個方面中，R8 為氫。 在本發明的一個方面中，R9 和R10 各自獨立地為氫、羥基或鹵素。 在本發明的一個方面中，R13 為碳上的取代基且各自獨立地選自羥基、鹵素或C1-12 烷基。 在本發明的一個方面中，R13 為碳上的取代基且各自獨立地選自羥基、氟或甲基。 在本發明的一個方面中，R13 為碳上的取代基且各自獨立地選自N-(C1-12 烷基)胺基；其中R13 各自獨立地可任選地在碳上經一個或多個R15 取代。 在本發明的一個方面中，R14 獨立地選自C1-12 烷基；其中R14 可獨立地任選地在碳上經一個或多個R17 取代。 在本發明的一個方面中，R15 和R17 各自獨立地選自鹵素。 m為0。 m為1。 m為2。 m為3。 m為4。 m為0或1。 n為0。 n為1。 n為2。 在本發明的一個方面中，提供式(I)化合物或其藥學上可接受的鹽，其中： A1 、A2 和A3 各自獨立地為-C(R6 )=或-N=；其中R6 各自獨立地為氫或鹵素； 環Q為苯基或吡啶基； 環B為5元或6元不飽和環，其可為碳或氮連接的；其中如果所述5元或6元不飽和環含有-NH-部分，則所述氮可任選地經選自R7 的基團取代；其中R7 選自C1-12 烷基或環丙基；其中R7 可獨立地任選地在碳上經一個或多個R17 取代；且R17 各自獨立地選自鹵素； X為-O-、-NR8 -或-C(R9 )(R10 )-；其中R8 為氫；且R9 和R10 各自獨立地為氫、羥基或鹵素； R1 為碳上的取代基且獨立地選自羥基、鹵素或甲基； R2 選自C1-12 烷基或5元飽和碳環基；其中R2 可任選地在碳上經一個或多個R13 取代；其中R13 為碳上的取代基且各自獨立地選自羥基、鹵素或C1-12 烷基； R3 為碳上的取代基且獨立地選自鹵素或甲氧基； R4 為C1-3 烷基或C3-4 環烷基；其中R4 可任選地經一個或多個鹵素取代； R5 選自C1-12 烷基或4元或5元飽和雜環基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中如果所述4元或5元飽和雜環基含有-NH-部分，則所述氮可任選地經選自R14 的基團取代；其中R13 為碳上的取代基且獨立地選自N-(C1-12 烷基)胺基；其中R13 各自獨立地可任選地在碳上經一個或多個R15 取代；R14 獨立地選自C1-12 烷基；其中R14 可獨立地任選地在碳上經一個或多個R17 取代；且R15 和R17 各自獨立地選自鹵素； m為0或1；且 n為0、1或2。 在本發明的一個方面中，提供式(I)化合物或其藥學上可接受的鹽，其中： A1 、A2 和A3 各自獨立地為-C(R6 )=或-N=；其中R6 各自獨立地為氫或氟； 環Q為苯基或吡啶基； 環B為吡唑基、噁唑基、1,2,4-三唑-4-基、1,2,3-三唑-4-基、2,5-二氫噻吩-4-基1,1-二氧化物、嘧啶基、噠嗪基、吡啶基、吡咯基、四唑基或咪唑基；其中如果所述吡唑基、1,2,3-三唑基、吡咯基、四唑基、1,2,4-三唑基和咪唑基含有-NH-部分，則所述氮可任選地經選自R7 的基團取代；其中R7 選自甲基、乙基或環丙基；其中R7 可獨立地任選地在碳上經一個或多個R17 取代；且R17 各自獨立地選自氟； X為-O-、-NH-、-CH2 -、-CH(OH)-或-CH(F)-； R1 為碳上的取代基且獨立地選自羥基、氟或甲基； R2 選自乙基、丙基或雙環[1.1.1]戊-1-基；其中R2 可任選地在碳上經一個或多個R13 取代；其中R13 為碳上的取代基且各自獨立地選自羥基、氟或甲基； R3 為碳上的取代基且獨立地選自氟或甲氧基； R4 為甲基、乙基或環丙基；其中R4 可任選地經一個或多個氟取代； R5 選自乙基、氮雜環丁烷-3-基或吡咯烷-3-基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中所述氮雜環丁烷-3-基或吡咯烷-3-基可任選地在-NH-部分上經選自R14 的基團取代；其中R13 為碳上的取代基且獨立地選自丙胺基；其中R13 各自獨立地可任選地在碳上經一個或多個R15 取代；R14 獨立地選自丙基；其中R14 可獨立地任選地在碳上經一個或多個R17 取代；且R15 和R17 各自獨立地選自氟； m為0或1；且 n為0、1或2。 在本發明的另一方面中，提供式(I)化合物，其為式(Ia)化合物：
Figure 02_image004
(Ia) 或其藥學上可接受的鹽，其中R1 、R2 、R3 、R4 、R5 、X、A1 、A2 、A3 、環B、環Q、m和n如本文中所定義。 在本發明的另一方面中，提供式(I)化合物，其為式(Ib)化合物：
Figure 02_image006
(Ib) 或其藥學上可接受的鹽，其中R1 、R2 、R3 、R4 、R5 、X、A1 、A2 、A3 、環B、環Q、m和n如本文中所定義。 在本發明的另一方面中，提供式(I)化合物，其為式(Ic)化合物：
Figure 02_image008
(Ic) 或其藥學上可接受的鹽，其中R1 、R2 、R3 、R4 、R5 、X、A1 、A2 、A3 、環B、環Q、m和n如本文中所定義。 在本發明的另一方面中，提供式(I)化合物，其為式(Id)化合物：
Figure 02_image010
(Id) 或其藥學上可接受的鹽，其中R1 、R2 、R3 、R4 、R5 、X、A1 、A2 、A3 、環B、環Q、m和n如本文中所定義。 在本發明的另一方面中，提供式(I)化合物，其為式(Ie)化合物：
Figure 02_image012
式(Ie) 或其藥學上可接受的鹽，其中R1 、R2 、R3 、R4 、R5 、X、A1 、A2 、A3 、環B、m和n如本文中所定義。 在本發明的另一方面中，提供式(I)化合物，其為式(If)化合物：
Figure 02_image014
式(If) 或其藥學上可接受的鹽，其中R1 、R2 、R3 、R4 、R5 、X、A1 、A2 、A3 、環B、m和n如本文中所定義。 在本發明的一個方面中，提供選自以下的式(I)化合物或其藥學上可接受的鹽： N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 2,2-二氟-3-((1S,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-1-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-6-(異噁唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-((1S,3R)-6-(1-乙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3R)-6-(1-環丙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3R)-6-(1-(二氟甲基)-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1-甲基-1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(4H-1,2,4-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺；和 N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(2H-1,2,3-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺。 在本發明的一個方面中，提供選自以下的式(I)化合物或其藥學上可接受的鹽： N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-6-(1-甲基-1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 2,2-二氟-3-(1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-6-(1H-吡唑-1-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-6-(1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(6-(異噁唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-(6-(1-乙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-(6-(1-環丙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-(6-(1-(二氟甲基)-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-6-(1-甲基-1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-6-(4H-1,2,4-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺；和 N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-6-(2H-1,2,3-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺。 在本發明的一個方面中，提供選自以下的式(I)化合物或其藥學上可接受的鹽： N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 2,2-二氟-3-((1R,3S)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-3-甲基-6-(1H-吡唑-1-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-3-甲基-6-(1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-6-(異噁唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-((1R,3S)-6-(1-乙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1R,3S)-6-(1-環丙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1R,3S)-6-(1-(二氟甲基)-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-3-甲基-6-(1-甲基-1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-3-甲基-6-(4H-1,2,4-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺；和 N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3S)-3-甲基-6-(2H-1,2,3-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺。 在本發明的一個方面中，提供選自以下的式(I)化合物或其藥學上可接受的鹽： N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 2,2-二氟-3-((1R,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-3-甲基-6-(1H-吡唑-1-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-3-甲基-6-(1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-6-(異噁唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-((1R,3R)-6-(1-乙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1R,3R)-6-(1-環丙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1R,3R)-6-(1-(二氟甲基)-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-3-甲基-6-(1-甲基-1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-3-甲基-6-(4H-1,2,4-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺；和 N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1R,3R)-3-甲基-6-(2H-1,2,3-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺。 在本發明的一個方面中，提供選自以下的式(I)化合物或其藥學上可接受的鹽： N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 2,2-二氟-3-((1S,3S)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-3-甲基-6-(1H-吡唑-1-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-3-甲基-6-(1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-6-(異噁唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-((1S,3S)-6-(1-乙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3S)-6-(1-環丙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3S)-6-(1-(二氟甲基)-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-3-甲基-6-(1-甲基-1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-3-甲基-6-(4H-1,2,4-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺；和 N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3S)-3-甲基-6-(2H-1,2,3-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺。 示例性的式(I)化合物1-54陳述於下表1中。
Figure 02_image016
Figure 02_image018
Figure 02_image020
Figure 02_image022
Figure 02_image024
Figure 02_image026
Figure 02_image028
應瞭解，為清楚起見而在單獨實施方式的上下文中描述的本發明的某些特徵也可在單一實施方式中組合。相反地，為簡潔起見描述於單個實施方式的情形中的本發明的各種特徵還可以分開地或以任何合適的子組合形式提供。 在本文中的多處，描述了鍵聯取代基。在結構明確需要連接基團的情況下，關於所述基團所列的馬庫什變數(markush variable)應理解為連接基團。例如，如果結構需要連接基團且所述變數的馬庫什組定義列舉“烷基”，則應理解，所述“烷基”表示連線性的亞烷基。 如本文所用，當提及化學基團時，術語“經取代”意指所述化學基團有一個或多個氫原子被移除且經取代基置換。如本文所用，術語“取代基”具有本領域中已知的普通含義並且是指共價連接至，或在適當時，稠合至母基團的化學部分。如本文所用，術語“任選地經取代”或“任選地…經取代”意指化學基團可不具有取代基(亦即未經取代)或可具有一個或多個取代基(亦即經取代)。應理解，在給定原子處的取代受價態限制。 如本文所用，術語“Ci-j ”指示碳原子數目的範圍，其中i和j為整數且碳原子數目的範圍包括端點(即i和j)以及之間的每個整數點，且其中j大於i。例如，C1-6 指示一到六個碳原子的範圍，包括一個碳原子、兩個碳原子、三個碳原子、四個碳原子、五個碳原子和六個碳原子。在一些實施例中，術語“C1-12 ”指示1至12，尤其1至10，尤其1至8，尤其1至6，尤其1至5，尤其1至4，尤其1至3或尤其1至2個碳原子。 如本文所用，術語“烷基”無論作為另一術語的一部分或獨立地使用，都是指飽和或不飽和烴鏈，而後者可以進一步細分成具有至少一個雙鍵或三鍵的烴鏈(烯基或炔基)。以上提到的烴鏈可以是直鏈的或分支鏈的。術語“Ci-j 烷基”是指具有i至j個碳原子的烷基。飽和烷基的實例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、叔丁基、異丁基、仲丁基；高級同系物，如2-甲基-1-丁基、正戊基、3-戊基、正己基、1,2,2-三甲基丁基等。不飽和烷基的實例包括但不限於乙烯基、正丙烯基、異丙烯基、正丁烯基、仲丁烯基、乙炔基、丙炔-1-基、丙炔-2-基等。“C1-12 烷基”的實例為甲基、乙基、丙基和丁基。“C1-3 烷基”的實例為甲基、乙基、丙基和異丙基。 如本文所用，術語“鹵基”和“鹵素”是指選自氟、氯、溴和碘的原子。 如本文所用，術語“烷氧基”無論是作為另一術語的一部分或獨立地使用，都是指式-O-烷基的基團。術語“Ci-j 烷氧基”意指烷氧基的烷基部分具有i至j個碳原子。烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(例如正丙氧基和異丙氧基)、叔丁氧基等。“C1-12 烷氧基”的實例為甲氧基、乙氧基和丙氧基。 如本文所用，術語“Ci-j 烷基-OH”是指式“-C1-12 烷基-OH”的基團，其中所述基團的烷基部分具有i至j個碳原子，且一個或多個羥基可連接至烷基部分中的任何碳原子。“C1-12 烷基-OH”的實例為羥甲基、1-羥乙基、2-羥乙基和1-羥異丙基。 如本文所用，術語“Ci-j 鹵烷基”是指鹵素取代的(單取代或多取代的)Ci-j 烷基。“C1-12 鹵烷基”的實例為氟甲基、三氟甲基、2-氯乙基和1-溴異丙基。“N-(C1-12 鹵烷基)胺基”的實例為氟甲胺基、三氟甲胺基、2-氯乙胺基和1-溴異丙胺基。 “C1-12 烷醯基”的實例為丙醯基和乙醯基。“C1-12 烷醯胺基”的實例為甲醯胺基、乙醯胺基和丙醯胺基。“C1-12 烷醯氧基”的實例為乙醯氧基。“C1-12 烷氧基羰基”的實例為甲氧基羰基、乙氧基羰基、正丁氧基羰基和叔丁氧基羰基。“C1-12 烷基(O)a ，其中a為0至2”的實例為甲硫基、乙硫基、甲基亞硫醯基、乙基亞硫醯基、甲磺醯基和乙基磺醯基。“C1-12 烷基磺醯基”的實例為甲磺醯基、乙基磺醯基和異丙基磺醯基。“C1-12 烷基磺醯胺基”的實例為甲磺醯胺基、乙基磺醯胺基和異丙基磺醯胺基。“N-(C1-12 烷基)胺基”的實例為甲胺基和乙胺基。“N-(C1-12 烷基)胺甲醯基”的實例為甲基胺基羰基和乙基胺基羰基。“N-(C1-12 烷基)胺磺醯基”的實例為N-(甲基)胺磺醯基和N-(乙基)胺磺醯基。“N,N-(C1-12 烷基)2 胺基”的實例為二-N-甲基胺基、二-(N-乙基)胺基和N-乙基-N-甲基胺基。“N,N-(C1-12 烷基)2 胺甲醯基”的實例為二甲基胺基羰基和甲基乙基胺基羰基。“N,N-(C1-12 烷基)2 胺磺醯基”的實例為N,N-(二甲基)胺磺醯基和N-(甲基)-N(乙基)-胺磺醯基。“三氟乙氧基”的實例為2,2,2-三氟乙氧基和1,2,2-三氟乙氧基。“三氟乙基”的實例為2,2,2-三氟乙基和1,2,2-三氟乙基。 如本文所用，術語“碳環基”無論作為另一術語的一部分還是獨立地使用，均指任何環，包括單環或多環(例如具有2或3個稠環、橋環或螺環)，其中所有環原子為碳且含有至少三個成環碳原子。在一些實施方式中，碳環基可含有3至10個成環碳原子、3至9個成環碳原子或4至8個成環碳原子。碳環基可為飽和、部分不飽和或完全不飽和的。在一些實施方式中，碳環基可為飽和環狀烷基。在一些實施方式中，碳環基可為在環系統中含有至少一個雙鍵的不飽和環狀烷基。在一些實施例中，不飽和碳環基可含有一個或多個芳環。在一些實施方式中，環-CH2 -基團可經環-C(O)-基團置換。 單環碳環基的實例包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環戊烯基、環己烯基、環己二烯基、環庚三烯基等。如本文所用，術語“螺環”是指兩個環通過單一共同原子連接的環系統；術語“稠環”是指兩個環共用兩個相鄰原子的環系統；並且術語“橋環”是指兩個環共用三個或更多個原子的環系統。螺碳環基的實例包括但不限於螺[5.5]十一烷基、螺戊二烯基、螺[3.6]癸基等。稠合碳環基的實例包括但不限於萘基、苯並芘基、蒽基、苊基、茀基等。橋連碳環基的實例包括但不限於雙環[1,1,1]戊烯基、雙環[2,2,1]庚烯基、雙環[2.2.1]庚基、雙環[2.2.2]辛基、雙環[3.3.1]壬基、雙環[3.3.3]十一烷基等。 “3-10元飽和或不飽和碳環基”為具有3至10個環碳原子的飽和、部分不飽和或完全不飽和的單環或多環系統，其中-CH2 -基團可任選地經-C(O)-置換。 “5元飽和碳環基”為具有5個環碳原子的飽和單環系統，其中-CH2 -基團可任選地經-C(O)-置換。 當“鄰近原子上的兩個R1 基團形成五元或六元稠合碳環基”時，所述碳環基為具有5或6個環碳原子的飽和、部分不飽和或完全不飽和的單環系統，其中-CH2 -基團可任選地經-C(O)-置換。 “3-10元飽和或不飽和碳環基”的實例為環丙基、環己基、環己烯基、苯基、萘基和雙環[1.1.1]戊-1-基。“5元飽和碳環基”的實例為環戊基。 “3-10元飽和或不飽和碳環基C1-12 烷基”的實例為環丙基甲基、環己基乙基、1-環己烯基丙-2-基、苯甲基、1-萘乙基和雙環[1.1.1]戊-1-基甲基。 “C3-4 環烷基”的實例為環丙基和環丁基。 “鄰近原子上的兩個R1 基團形成五元或六元稠合碳環基”的實例為稠合環己烯基，稠合苯基為稠合環戊基。 如本文所用，術語“雜環基”是指碳環基，其中一個或多個(例如1、2或3個)環原子經包括但不限於氧、硫、氮、磷等的雜原子置換。在一些實施方式中，雜環基為飽和雜環基。在一些實施方式中，雜環基為在其環系統中具有一個或多個雙鍵的不飽和雜環基。在一些實施方式中，雜環基為部分不飽和雜環基。在一些實施方式中，雜環基為在其環系統中具有一個或多個雙鍵的完全不飽和雜環基。在一些實施方式中，不飽和雜環基可含有一個或多個芳環。在一些實施方式中，環硫原子可任選地經氧化以形成S-氧化物。在一些實施方式中，雜環為碳連接的。在一些實施方式中，雜環為氮連接的。 示例性單環雜環基包括但不限於呱啶基、吡咯烷基、四氫呋喃基、呱啶基、呱嗪基、嗎啉基等。螺雜環基的實例包括但不限於螺吡喃基、螺噁嗪基等。稠合雜環基的實例包括但不限於喹啉基、異喹啉基、喹嗪基、喹唑啉基、喋啶基、色烯基、異色烯基、吲哚基、異吲哚基、吲哚嗪基、吲唑基、嘌呤基、苯並呋喃基、異苯並呋喃基、苯並咪唑基、苯並噻吩基、哢唑基、吩嗪基、吩噻嗪基、菲啶基等。橋連雜環基的實例包括但不限於嗎吩烷基(morphanyl)、六亞甲基四胺基(hexamethylenetetramine)、8-氮雜雙環[3.2.1]辛烷、1-氮雜雙環[2.2.2]辛烷、1,4-二氮雜雙環[2.2.2]辛烷(DABCO)等。 “3-10元飽和或不飽和雜環基”為具有3至10個環原子(其中至少一個原子選自氮、硫或氧)的飽和、部分不飽和或完全不飽和的單環或多環系統，除非另外說明，否則其可為碳或氮連接的，其中-CH2 -基團可任選地經-C(O)-置換且環硫原子可任選地經氧化以形成S-氧化物。 “4元或5元飽和雜環基”為具有4或5個環原子(其中至少一個原子選自氮、硫或氧)的飽和單環系統，除非另外說明，否則其可為碳或氮連接的，其中-CH2 -基團可任選地經-C(O)-置換且環硫原子可任選地經氧化以形成S-氧化物。 “可為碳或氮連接的5元或6元不飽和環”為具有5或6個環原子(其中環原子選自碳、氮、硫或氧)的部分不飽和或完全不飽和單環系統，除非另外說明，否則其可為碳或氮連接的，其中-CH2 -基團可任選地經-C(O)-置換且環硫原子可任選地經氧化以形成S-氧化物。 當鄰近原子上的兩個R1 基團形成五元或六元稠合雜環基環時，所述雜環基環為具有5或6個環原子(其中至少一個原子選自氮、硫或氧)的飽和、部分不飽和或完全不飽和的單環系統，其中-CH2 -基團可任選地經-C(O)-置換且環硫原子可任選地經氧化以形成S-氧化物。 “3-10元飽和或不飽和雜環基”的實例為吡咯基、吡唑基、氧硫雜環戊烷基、異噁唑基、嘧啶基和噠嗪基。 “3-10元飽和或不飽和雜環基C1-12 烷基”的實例為吡咯基甲基、1-吡唑基乙基、氧硫雜環戊烷基甲基、1-異噁唑基丙-2-基、嘧啶基甲基和噠嗪基丁基。 “4元或5元飽和雜環基”的實例為氮雜環丁基和1,3-二氧戊環基。 “可為碳或氮連接的5元或6元不飽和環”的實例為苯基、咪唑基、吡唑基、吡啶基、嘧啶基、2-吡咯啉基和2-吡唑啉基。 鄰近原子上的兩個R1 基團形成五元或六元稠合雜環基環的實例為稠合嘧啶基、稠合噠嗪基、稠合呋喃基、稠合異噻唑基和稠合三唑基。 “6元芳環，其中環原子獨立地選自碳或氮”是指在成環原子之間具有交替雙鍵和單鍵的單環碳環基或雜環基部分。示例性“6元芳環，其中環原子獨立地選自碳或氮”為苯基、吡啶基、吡嗪基、嘧啶基、三嗪基和噠嗪基。 除非另外說明，否則本發明的“化合物”意圖涵蓋所描繪的結構的所有立體異構體、幾何異構體和互變異構體。 術語“立體異構體”是指不對稱化合物(例如具有一個或多個不對稱取代的碳原子或“不對稱中心”的化合物)的各種立體異構構型(例如對映異構體、非對映異構體和外消旋體)中的任一種。含有不對稱中心的本發明化合物可以分離為有光學活性(對映異構體或非對映異構體)或無光學活性(外消旋)形式。術語“對映異構體”包括不互為可重疊的鏡像的立體異構體對。一對對映異構體的1:1混合物為“外消旋混合物”。術語“非對映異構體(diastereomer或diastereoisomer)”包括具有至少兩個不對稱原子但不互為鏡像的立體異構體。含有一個或多個不對稱中心的某些化合物可產生對映異構體、非對映異構體或其它立體異構形式，其可根據Cahn-Ingold-Prelog R-S系統，在各不對稱中心處依據絕對構型定義為(R)-或(S)-。可在不對稱中心處使用術語“或”標識絕對構型未知的經拆分的化合物。關於如何自外消旋混合物製備光學活性形式的方法是本領域中已知的，如通過HPLC拆分或立體選擇性合成。 術語“幾何異構體”或“順式和反式異構體”是指具有相同式但其官能團在三維空間中旋轉至不同取向的化合物。 術語“互變異構體”包括處於具有相同式和總電荷的化合物的異構質子化狀態的質子轉移互變異構體。質子轉移互變異構體的實例包括但不限於酮-烯醇對、醯胺-亞胺酸對、內醯胺-內醯亞胺對、烯胺-亞胺對，以及環狀形式，其中質子可佔據雜環系統的兩個或更多個位置，例如1H-咪唑和3H-咪唑、1H-1,2,4-三唑、2H-1,2,4-三唑和4H-1,2,4-三唑、1H-異吲哚和2H-異吲哚，以及1H-吡唑和2H-吡唑。互變異構體可處於平衡狀態或通過適當取代而空間鎖定成一種形式。除非另外說明，否則通過名稱或結構識別為一種特定互變異構形式的本發明化合物意圖包括其它互變異構形式。 本發明的“化合物”還意圖涵蓋化合物中原子的所有同位素。原子的同位素包括具有相同原子序數但質量數不同的原子。例如，除非另外說明，否則本發明的“化合物”中的氫、碳、氮、氧、磷、硫、氟、氯、溴或碘意圖還包括其同位素，如但不限於1 H、2 H、3 H、11 C、12 C、13 C、14 C、14 N、15 N、16 O、17 O、18 O、31 P、32 P、32 S、33 S、34 S、36 S、17 F、19 F、35 Cl、37 Cl、79 Br、81 Br、127 I和131 I。在一些實施方式中，氫包括氕、氘和氚。在一些實施方式中，術語“經氘取代”或“氘取代的”是指用氘置換化學基團中的氫的另一種同位素(例如氕)。在一些實施方式中，碳包括12 C和13 C。 還應理解，本發明的“化合物”可以溶劑化形式以及非溶劑化形式，例如水合形式、固體形式存在，並且本發明意圖涵蓋所有此類溶劑化形式和非溶劑化形式。 還應理解，本發明的“化合物”可以藥學上可接受的鹽形式存在。 如本文所用，術語“藥學上可接受的”是指在合理醫學判斷的範圍內，適用於與人類和動物的組織接觸，而無過度毒性、刺激、過敏反應或其它問題或併發症，與合理的效益/風險比相稱的化合物、材料、組合物和/或劑型。在一些實施例中，藥學上可接受的化合物、材料、組合物和/或劑型是指被管理機構(如美國食品藥品監督管理局(U.S. Food and Drug Administration)、中國國家食品藥品監督管理總局(China Food and Drug Administration)或歐洲藥品管理局(European Medicines Agency))批准或在公認藥典(如美國藥典(U.S.Pharmacopoeia)、中國藥典(China Pharmacopoeia)或歐洲藥典(European Pharmacopoeia))中列出的用於動物，且更確切地說用於人體內的那些。 如本文所用，“藥學上可接受的鹽”是指本發明化合物的衍生物，其中母體化合物通過將現有的酸性部分(例如羧基等)或鹼部分(例如胺、鹼金屬等)轉化為其鹽形式而改性。在許多情況下，本發明化合物能夠憑藉胺基和/或羧基或其類似基團的存在而形成酸和/或鹼鹽。並且藥學上可接受的鹽是保留母體化合物的生物有效性和特性的酸鹽和/或鹼鹽，其通常不會在生物學上或其它方面有不良影響。合適的本發明化合物的藥學上可接受的鹽包括例如酸加成鹽，其可衍生自例如無機酸(例如鹽酸、氫溴酸、硫酸、硝酸、磷酸等)或有機酸(例如甲酸、乙酸、丙酸、乙醇酸、草酸、順丁烯二酸、丙二酸、琥珀酸、反丁烯二酸、酒石酸、苯均三酸、檸檬酸、乳酸、苯乙酸、苯甲酸、扁桃酸、甲烷磺酸、萘二磺酸、乙烷磺酸、甲苯磺酸、三氟乙酸、水楊酸、磺基水楊酸等)。在一些實施方式中，本發明化合物的藥學上可接受的鹽為甲酸鹽。在一些實施例中，本發明化合物的藥學上可接受的鹽為TFA鹽。 合適的本發明化合物的藥學上可接受的鹽還包括例如鹼加成鹽，其可衍生自例如無機鹼(例如週期表的第I至XII欄的金屬，如鈣、鎂、鐵、銀、鋅、銅等的鈉、鉀、銨鹽和氫氧化物、碳酸鹽、碳酸氫鹽)或有機鹼(例如伯胺、仲胺和叔胺、取代胺(包括天然存在的取代胺)、環胺、鹼性離子交換樹脂等)。某些有機胺包括但不限於異丙胺、苯乍生(benzathine)、膽酸鹽、二乙醇胺、二乙胺、賴胺酸、葡甲胺、呱嗪以及緩血酸胺。本領域技術人員應理解，也能夠加入除實例中所顯示的酸或鹼外的其它酸或鹼以用於形成酸/鹼加成鹽。其它合適鹽的列表可見於例如《雷明頓氏藥物科學(Remington's Pharmaceutical Sciences)》，第20版，Mack Publishing Company, Easton, Pa., (1985)；以及Stahl和Wermuth的《藥用鹽手冊：特性、選擇和應用(Handbook of Pharmaceutical Salts: Properties, Selection, and Use)》(Wiley-VCH, Weinheim, Germany, 2002)中。 本發明還包括本發明化合物的活性中間物、活性代謝物和前藥。如本文所用，“活性中間物”是指合成方法中的中間化合物，其展現與最終合成的化合物相同或基本上相同的生物活性。 如本文所用，“活性代謝物”是指通過在動物或人體內代謝或生物轉化產生的本發明化合物或其鹽或前藥的分解或最終產物，其展現與指定化合物相同或基本上相同的生物活性。此類代謝物可由例如施用的化合物或鹽或前藥的氧化、還原、水解、醯胺化、脫醯胺、酯化、脫酯化、酶裂解等產生。 如本文所用，“前藥”是指當施用至動物或人類個體時釋放活性母體藥物的任何化合物或偶聯物。前藥可通過修飾化合物中存在的官能團來製備，其方式使得該修飾在常規操作中或在體內被剪切而釋放出母體化合物。前藥包括這樣的化合物，其中羥基、胺基、硫氫基或羧基鍵結至任何基團，使得當將其施用至哺乳動物個體時分別剪切形成游離羥基、胺基、硫氫基或羧基的化合物。前藥的實例包括但不限於本發明化合物中醇和胺官能團的乙酸酯、甲酸酯和苯甲酸酯衍生物。前藥的製備和使用論述於T. Higuchi和V. Stella, “作為新型遞送系統的前藥(Pro-drugs as Novel Delivery Systems)”，《美國化學會會議論文集(A. C. S. Symposium Series)》第14卷，以及《藥物設計中的生物可逆載體(Bioreversible Carriers in Drug Design)》, Edward B. Roche編，American Pharmaceutical Association and Pergamon Press, 1987，二者特此以全文引用的方式併入。合成方法 本文提供的化合物，包括其藥學上可接受的鹽的合成說明於實例中的合成流程中。本文提供的化合物可使用任何已知的有機合成技術製備並且可以根據多種可能的合成途徑中的任一種合成，因此，這些方案只是說明性的且不打算限制可用於製備本文提供的化合物的其它可能的方法。此外，所述方案中的步驟是為了更好地說明且在適當時可以改變。出於研究和可能提交給管理機構的目的而合成實施例中的化合物實例。 用於製備本發明化合物的反應可在合適的溶劑中進行，所述溶劑可由有機合成領域的技術人員容易地選擇。合適的溶劑可在反應進行的溫度下，例如在溶劑的冷凍溫度至溶劑的沸騰溫度範圍內的溫度下基本上不與起始物質(反應物)、中間物或產物反應。指定反應可在一種溶劑或多於一種溶劑的混合物中進行。取決於特定反應步驟，用於特定反應步驟的合適溶劑可由熟練技術人員選擇。 本發明化合物的製備可涉及各種化學基團的保護和脫保護。對於保護和脫保護的需求，以及適當保護基的選擇可以由本領域技術人員容易地確定。保護基的化學性質可見於例如T. W. Greene和P. G. M. Wuts，《有機合成中的保護基(Protective Groups in Organic Synthesis)》，第3版，Wiley & Sons, Inc., New York (1999)，其以全文引用的方式併入本文中。 反應可根據本領域中已知的任何合適方法監測。例如，可通過頻譜手段，如核磁共振光譜(NMR，例如1 H或13 C)、紅外光譜(IR)、分光光度法(例如紫外-可見光)、質譜，或通過層析法，如高效液相層析(HPLC)、液相層析-質譜(LCMS)或薄層層析(TLC)來監測產物形成。本領域的技術人員可通過多種方法，包括高效液相層析法(HPLC) (“製備型LC-MS純化：改善的化合物特異性方法優化(Preparative LC-MS Purification: Improved Compound Specific Method Optimization)”, Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs，《組合化學雜誌(J. Combi. Chem.)》, 2004, 6(6), 874-883，其以全文引用的方式併入本文中)和正相二氧化矽層析法來純化化合物。 實例中的化合物的結構是通過核磁共振(NMR)或/和液相層析-質譜(LC-MS)來表徵。NMR化學位移(δ )是以10-6 (ppm)為單位給出。1 H-NMR譜是在Bruker AVANCE NMR (400 MHz)譜儀上使用ICON-NMR(在TopSpin程式控制下)，或在Varian 400MR NMR或Varian VNMR400 NMR(400 MHz)譜儀上(在VnmrJ程式控制下)，在二甲亞碸-d6 (DMSO-d6 )或CDCl3 或CD3 OD或D2 O或丙酮_d6 或CD3 CN(來自Aldrich或Cambridge Isotope Lab., Inc.)中記錄獲得，其中以四甲基矽烷作為內標。 MS測量是使用Shimadzu 2010質譜儀或Agilent 6110A MSD或1969A TOF質譜儀，使用電噴霧、化學和電子碰撞電離方法由一系列儀器進行。 高效液相層析(HPLC)測量是在Shimadzu LC-20A系統或Shimadzu LC-2010HT系列，或Agilent 1200 LC或Agilent 1100系列上，使用Ultimate XB-C18柱(3.0×50 mm，3 μm或3.0×150 mm，3 μm)，或Xbridge shieldRP18柱(5 μm，50 mm×2.1 mm)，或Xtimate C18柱(3 μm，2.1×30 mm)，或MERCK RP18 2.5-2 mm等進行。 薄層層析是使用Yantai Huanghai HSGF254矽膠或Anhui Liang Chen Gui Yuan板進行。用於薄層層析(TLC)的矽膠板為0.15 mm-0.2 mm。通過TLC分離和純化產物所使用的矽膠板為0.4 mm-0.5 mm。 純化層析柱使用矽膠作為載體(100-200、200-300或300-400目，由Yantai Huanghai co.或Anhui Liang Chen Gui Yuan co.等製造)，或Teledyne ISCO combi-flash或Biotage快速層析系統中的快速柱(由Agela Technologies製造的二氧化矽-CS快速柱40-60 μm，或逆相C18柱20-35 μm等)或由Agela Technologies製造的快速柱二氧化矽-CS(40-60 μm)或C18柱(20-40 μm)。層析柱的大小根據化合物的量進行調整。 本發明的已知起始物質可通過使用或根據本領域中已知的方法合成，或可購自Alfa Aesar、TCI、Aldrich、Bepharm和Scochem(或PharmaBlock、Bide、Amatek、Stru Chem、Firster Pharmaceutical、Titan(Adamas)等)。 除非另外說明，否則反應全部在氬氣或氮氣氣氛下進行。氬氣或氮氣氣氛是指，反應燒瓶被連接至體積為約1 L的氬氣或氮氣球。氫化通常是在壓力下進行。除非另外說明，否則實例中的反應溫度為環境溫度，其為10℃-30℃。 通過TLC或/和LC-MS監測反應進展。用於反應的洗提劑系統包括二氯甲烷-甲醇系統和石油醚-乙酸乙酯系統。溶劑的體積比是根據化合物的不同極性進行調整。 用於純化化合物的柱層析的洗提系統以及TLC的洗提劑系統包括二氯甲烷-甲醇系統和石油醚-乙酸乙酯系統。溶劑的體積比是根據化合物的不同極性進行調整。可添加少量鹼性或酸性試劑(0.1%-1%)，如甲酸、或乙酸、或TFA、或氨水以進行調整。 在本文提供的化合物的合成中使用的化學試劑的縮寫列於下文：
Figure 02_image030
藥物組合物 本發明提供包含至少一種本發明的化合物的藥物組合物，或其藥學上可接受的鹽。在一些實施方式中，藥物組合物包含多於一種本發明的化合物，或其藥學上可接受的鹽。在一些實施方式中，藥物組合物包含一種或多種本發明的化合物，或其藥學上可接受的鹽，和藥學上可接受的載體。 一般來說，藥學上可接受的載體是本領域中的常規藥物載體，其可以藥學領域中眾所周知的方式製備。在一些實施方式中，本發明的化合物或其藥學上可接受的鹽可與藥學上可接受的載體摻合以製備藥物組合物。 藥物組合物的形式取決於多種標準，包括但不限於施用途徑、疾病程度或欲施用的劑量。所述藥物組合物可以被配製成經口、經鼻、經直腸、經皮、靜脈內或肌肉內施用。根據所需的施用途徑，所述藥物組合物可以被配製成片劑、膠囊、丸劑、散劑、顆粒劑、藥囊、扁囊劑、口含錠、懸浮液、乳液、溶液、糖漿、氣霧劑(呈固體形式或在液體介質中)、噴霧劑、油膏、糊漿、乳膏、洗劑、凝膠、貼片、吸入劑或栓劑形式。 在某些實施方式中，藥物組合物包含約1 mg至約500 mg，確切地說1 mg至約50 mg本發明的化合物，或其藥學上可接受的鹽。 在一些實施方式中，藥物組合物包含一種或多種本發明的化合物或其藥學上可接受的鹽作為第一活性成分，並且進一步包含第二活性成分。第二活性成分可以是本領域中已知的任何抗腫瘤劑，例如化學治療劑、細胞信號轉導抑制劑、烷化劑、拓撲異構酶抑制劑、免疫治療劑、有絲分裂抑制劑、抗激素藥劑、化學療法藥物、EGFR抑制劑、CTLA-4抑制劑、CDK 4/6抑制劑、MEK抑制劑、PD-L1抑制劑、OX40激動劑、抗雄激素抑制劑、IgG4同型抗體、酪胺酸激酶抑制劑、DNA甲基轉移酶抑制劑、Hsp90抑制劑、FGFR抑制劑、mTOR抑制劑、芳香酶抑制劑、VEGF抑制劑、LHRH拮抗劑、PI3K抑制劑、AKT抑制劑、極光激酶抑制劑、MEK抑制劑、HDAC抑制劑、BET抑制劑、PIK3CA抑制劑、蛋白酶體抑制劑、其它SERD、法尼基轉移酶抑制劑、VEGF-A抗體、ErbB3(Her3)抗體、蛋白酶體抑制劑、蛋白激酶Cβ抑制劑、抗PD-L1抗體、抗IGF-1R抗體、抗HER2抗體、SERM、IGF抑制劑、抗IgG抗體等。用於治療癌症或腫瘤的抗腫瘤劑的代表性實例可包括但不限於索拉非尼(sorafenib)、來那替尼(neratinib)、舒尼替尼(sunitinib)、達沙替尼(dasatinib)、伏立諾他(vorinostat)、坦羅莫司(temsirolimus)、依維莫司(everolimus)、帕唑帕尼(pazopanib)、曲妥珠單抗(trastuzumab)、阿多-曲妥珠單抗恩他新(ado-trastuzumab emtansine)、帕妥珠單抗(pertuzumab)、貝伐單抗(bevacizumab)、西妥昔單抗(cetuximab)、蘭比珠單抗(ranibizumab)、呱加他尼(pegaptanib)、帕尼單抗(panitumumab)、曲美單抗(tremelimumab)、帕博利珠單抗(pembrolizumab)、納武單抗(nivolumab)、伊匹單抗(ipilimumab)、阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)、度伐單抗(durvalumab)、克卓替尼(crizotinib)、蘆可替尼(ruxolitinib)、紫杉醇、長春新鹼、長春鹼、順鉑、卡鉑、吉西他濱(gemcitabine)、他莫昔芬(tamoxifen)、雷諾昔酚(raloxifene)、環磷醯胺、苯丁酸氮芥(chromabucil)、卡莫司汀(carmustine)、甲胺喋呤、氟尿嘧啶、放線菌素、多柔比星(doxorubicin)、表柔比星(epirubicin)、蒽環黴素、博萊黴素、絲裂黴素-C、伊立替康(irinotecan)、拓朴替康(topotecan)、替尼泊甙(teniposide)白介素、干擾素、帕博西裡(palbociclib)、玻瑪西林(abemaciclib)、恩雜魯胺、多韋替尼(dovitinib)、拉帕替尼(lapatinib)、埃羅替尼(erlotinib)、CC-486、加利特皮(ganetespib)、Debio 1347、伊達替尼(erdafitinib)、維圖塞替(vitusertib)、薩帕塞替(sapanisertib)、GDC-0980、吉達昔布(gedatolisib)、阿那曲唑(anastrazole)、西地尼布、戈舍瑞林、阿普昔布(alpelisib)、BKM120、考帕昔布(copanlisib)、AZD8835、GDC-0941、塔瑟昔布(taselisib)、AZD5363、MK2206、阿立塞替(alisertib)、司美替尼(selumetinib)、恩替諾特(entinostat)、GS-5829、GSK525762、G1T38、瑞博西林、MLN9708、GDC-0810、多烯紫杉醇、AFP464、替吡法尼(tipifarnib)、塞利班單抗(seribantumab)、硼替佐米、恩紮妥林(enzastaurin)、吉非替尼(gefitinib)、AVE1642、森吐珠單抗(xentuzumab)、達羅吐珠單抗(dalotuzumab)、他莫昔芬、AMG 479、MCLA-128等。在一些實施方式中，第二活性劑為CDK 4/6抑制劑，例如帕博西裡或玻瑪西林。 根據本發明的這一方面，提供適用於治療癌症的組合，其包含如上文所定義的式(I)化合物或其藥學上可接受的鹽和以上列出的抗腫瘤劑中的任一種。 因此，在本發明的另一方面中，提供式(I)化合物或其藥學上可接受的鹽與選自以上所列的一者的抗腫瘤劑的組合。 本文中，當使用術語“組合”時，應理解，這是指同時、分別或依序施用。在本發明的一個方面中，“組合”是指同時施用。在本發明的另一個方面中，“組合”是指分別施用。在本發明的另一個方面中，“組合”是指依序施用。當依序或分別施用時，施用第二組分的延遲不應使得失去所述組合的有益作用。 根據本發明的另一方面，提供一種藥物組合物，其包含式(I)化合物或其藥學上可接受的鹽與選自以上所列的一者的抗腫瘤劑的組合，以及藥學上可接受的稀釋劑或載體。 根據本發明的另一方面，提供一種藥物組合物，其包含式(I)化合物或其藥學上可接受的鹽與選自以上所列的一者的抗腫瘤劑的組合，以及藥學上可接受的稀釋劑或載體，用於產生抗癌效應。 根據本發明的另一方面，提供一種藥物組合物，其包含式(I)化合物或其藥學上可接受的鹽與選自以上所列的一者的抗腫瘤劑的組合，以及藥學上可接受的稀釋劑或載體，用於治療乳腺癌(等)。 根據本發明的另一方面，提供一種試劑盒，其包含式(I)化合物或其藥學上可接受的鹽與選自以上所列的一者的抗腫瘤劑的組合。 根據本發明的另一方面，提供一種試劑盒，其包含： a)呈第一單位劑型的式(I)化合物或其藥學上可接受的鹽； b)呈第二單位劑型的選自以上所列的一者的抗腫瘤劑；和 c)用於容納所述第一和第二劑型的容器裝置。 除了用於治療藥物以外，式(I)化合物或其藥學上可接受的鹽還適用作體外和體內測試系統的開發和標準化中的藥理學工具，所述測試系統用於評估SERD活性在例如貓、狗、兔、猴、大鼠和小鼠的實驗動物中的作用，作為尋找新治療劑的一部分。 在以上其它藥物組合物、過程、方法、用途和藥物製造特徵中，本文所述的本發明化合物的替代和優選實施方式也適用。治療方法 本發明的化合物為選擇性雌激素受體下調劑(SERD)。在一些實施方式中，本發明的化合物或其藥學上可接受的鹽在早期癌症、活躍進展癌症、轉移性癌症和/或耐藥性癌症中具有強效抗癌活性。另外，本發明的化合物或其藥學上可接受的鹽可適用於治療其它疾病和病況，例如衰老(例如停經)、代謝疾病(例如糖尿病、骨質疏鬆)、心血管疾病和其它疾病，尤其是骨質疏鬆，尤其是衰老。 本發明提供一種通過施用本發明的選擇性ER下調化合物或其藥學上可接受的鹽，或藥物組合物治療疾病或病況的方法。 確切地說，癌症包括但不限於乳腺癌、卵巢癌、子宮內膜癌、子宮癌、肺癌、肝細胞癌、腎上腺皮質癌、胰腺癌、膀胱癌或胃癌。 在一些實施方式中，癌症為乳腺癌、子宮癌、卵巢癌、子宮內膜癌或肺癌。在一些實施方式中，癌症為乳腺癌。在一些實施方式中，癌症為激素受體陽性乳腺癌。在一些實施方式中，癌症為在內分泌療法之後疾病進展的停經後婦女中的激素受體陽性乳腺癌。在一些實施方式中，癌症為早期乳腺癌。在一些實施方式中，癌症為局部晚期乳腺癌。在一些實施方式中，癌症為局部晚期和/或轉移性乳腺癌。在一些實施方式中，癌症為轉移性乳腺癌。在一些實施方式中，癌症為浸潤性乳腺癌。在一些實施方式中，癌症為他莫昔芬(tamoxifen)耐受性乳腺癌。在一些實施方式中，癌症為HR陽性、HER2陰性晚期或轉移性乳腺癌。在一些實施方式中，癌症為子宮癌。在一些實施方式中，癌症為轉移性乳腺癌/子宮癌。 如本文所用，術語“治療(treatment)”、“治療(treat)”和“治療(treating)”是指逆轉、減輕如本文所述的疾病或病症或其一或多種症狀，延遲其發作，或抑制其進展。在一些實施方式中，治療可在已出現一種或多種症狀之後進行。在其它實施方式中，治療可在不存在症狀的情況下進行。舉例來說，治療可在症狀發作之前對易感個體進行(例如根據症狀病史和/或根據遺傳的或其它易感性因素)。治療還可在症狀已消退之後繼續，例如以預防或延遲其復發。 如本文所提供的化合物或其藥學上可接受的鹽的治療有效量將取決於本領域中已知的各種因素，如體重、年齡、既往病史、當前藥物治療、個體的健康狀態和交叉反應、過敏、敏感和不良副作用的可能性，以及給藥途徑和疾病發展程度。如由這些和其它情況或要求所指示，本領域普通技術人員(例如醫生或獸醫)可以按比例減少或增加劑量。化合物的用途 在某些實施方式中，本發明提供本發明的化合物、其藥學上可接受的鹽或藥物組合物在製造用於治療ER介導的或依賴性疾病或病況的藥物中的用途。 在此類情形中，本發明還提供一種篩選適合於單獨使用或與其它成分(例如第二活性成分，例如抗癌劑)組合使用本發明的化合物或藥物組合物治療的患者的方法。方法包括對來自患者的腫瘤樣品測序和檢測ER的積聚。 根據本發明的另一方面，因此提供用作藥物的如上文所定義的式(I)化合物，或其藥學上可接受的鹽。 根據本發明的另一方面，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽在製造用於選擇性下調例如人類的溫血動物中的雌激素受體的藥物中的用途。 根據本發明的另一方面，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽在製造用於治療例如人類的溫血動物中的ER介導的或依賴性疾病或病況的藥物中的用途。 根據本發明的這一方面，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽在製造用於在例如人類的溫血動物中產生抗癌效應的藥物中的用途。 根據本發明的另一特徵，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽在製造用於治療乳腺癌、卵巢癌、子宮內膜癌、子宮癌、肺癌、肝細胞癌、腎上腺皮質癌、胰腺癌、膀胱癌或胃癌的藥物中的用途。 根據本發明的另一特徵，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽在製造用於治療乳腺癌的藥物中的用途。 根據本發明的這一方面的另一個特徵，提供一種選擇性下調需要此類治療的例如人類的溫血動物中的雌激素受體的方法，其包含向所述動物施用有效量的如上文所定義的式(I)化合物或其藥學上可接受的鹽。 根據本發明的這一方面的另一個特徵，提供一種治療需要此類治療的例如人類的溫血動物中的ER介導的或依賴性疾病或病況的方法，其包含向所述動物施用有效量的如上文所定義的式(I)化合物或其藥學上可接受的鹽。 根據本發明的這一方面的另一個特徵，提供一種在需要此類治療的例如人類的溫血動物中產生抗癌效應的方法，其包含向所述動物施用有效量的如上文所定義的式(I)化合物或其藥學上可接受的鹽。 根據本發明的這一方面的另一個特徵，提供一種在需要此類治療的例如人類的溫血動物中產生抗癌效應的方法，其包含(1)確定所述溫血動物是否患有ER陽性癌症，和(2)如果是的話，則向所述動物施用有效量的如上文所定義的式(I)化合物或其藥學上可接受的鹽。 根據本發明的這一方面的另一個特徵，提供一種治療需要此類治療的例如人類的溫血動物中的乳腺癌、卵巢癌、子宮內膜癌、子宮癌、肺癌、肝細胞癌、腎上腺皮質癌、胰腺癌、膀胱癌或胃癌的方法，其包含向所述動物施用有效量的如上文所定義的式(I)化合物或其藥學上可接受的鹽。 根據本發明的這一方面的另一個特徵，提供一種治療需要此類治療的例如人類的溫血動物中的乳腺癌的方法，其包含向所述動物施用有效量的如上文所定義的式(I)化合物或其藥學上可接受的鹽。 根據本發明的另一方面，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽，用於在例如人類的溫血動物中產生選擇性ER降解效應。 根據本發明的另一方面，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽，用於治療例如人類的溫血動物中的ER介導的或依賴性疾病或病況。 根據本發明的這一方面，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽，用於在例如人類的溫血動物中產生抗癌效應。 根據本發明的另一特徵，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽，用於治療乳腺癌、卵巢癌、子宮內膜癌、子宮癌、肺癌、肝細胞癌、腎上腺皮質癌、胰腺癌、膀胱癌或胃癌。 根據本發明的另一特徵，提供如上文所定義的式(I)化合物或其藥學上可接受的鹽，用於治療乳腺癌。 在本發明的另一方面中，提供一種藥物組合物，其包含如上文所定義的式(I)化合物或其藥學上可接受的鹽以及藥學上可接受的稀釋劑或載體，用於在例如人類的溫血動物中產生選擇性ER降解效應。 在本發明的另一方面中，提供一種藥物組合物，其包含如上文所定義的式(I)化合物或其藥學上可接受的鹽以及藥學上可接受的稀釋劑或載體，用於治療例如人類的溫血動物中的ER介導的或依賴性疾病或病況。 在本發明的另一方面中，提供一種藥物組合物，其包含如上文所定義的式(I)化合物或其藥學上可接受的鹽以及藥學上可接受的稀釋劑或載體，用於在例如人類的溫血動物中產生抗癌效應。 在本發明的另一方面中，提供一種藥物組合物，其包含如上文所定義的式(I)化合物或其藥學上可接受的鹽以及藥學上可接受的稀釋劑或載體，用於治療例如人類的溫血動物的乳腺癌、卵巢癌、子宮內膜癌、子宮癌、肺癌、肝細胞癌、腎上腺皮質癌、胰腺癌、膀胱癌或胃癌。 在本發明的另一方面中，提供一種藥物組合物，其包含如上文所定義的式(I)化合物或其藥學上可接受的鹽以及藥學上可接受的稀釋劑或載體，用於治療例如人類的溫血動物的乳腺癌。實施例 以下進一步闡明本發明的一般性方法。本發明的化合物可以通過本領域中已知的方法製備。以下說明本發明的優選化合物的具體製備方法。但是，這些決不限制本發明的化合物的製備方法。實施例 1 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1- 甲基 -1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image032
用於製備1A 的程式：
Figure 02_image034
在-70℃下向咪唑(108.78 g，1.6 mol)和三乙胺(120 mL，878.87 mmol)於二氯甲烷(1.3 L)中的溶液中逐滴添加SOCl2 (32 mL，439.43 mmol)。接著將1A_1 (70 g，399.49 mmol)於二氯甲烷(650 mL)中的溶液在-70℃下在3小時內逐滴添加至反應混合物。將所得反應混合物在氮氣下在-70℃下攪拌2小時然後在20℃下攪拌16小時。接著用鹽水(300 mL×2)洗滌反應混合物。有機層經無水硫酸鈉乾燥且過濾。在減壓下濃縮濾液，得到粗產物。以相同方式進行另外兩個批次的此反應(60 g和70 g規模的化合物1A_1 )。將三個批次的粗產物(總共200 g化合物1A_1 )合併且通過矽膠柱層析(石油醚/乙酸乙酯=10:1至9:1至8:1)純化，獲得呈黃色油狀的1A_2 (190 g，67.7%產率，90%純度)。 1 H NMR (400MHz, CDCl3 ): δ=4.78 (dd,J =7.2 Hz, 9.2 Hz, 1H), 4.67 (t,J =9.2 Hz, 1H), 4.09-3.98 (m, 1H), 1.55-1.45 (m, 12H)。
Figure 02_image036
在室溫(11-19℃)下向1A_2 (90 g，406.7 mmol)於乙腈(900 mL)和水(420 mL)中的溶液中逐份添加RuCl3 ·H2 O(917 mg，2.51 mmol)，接著添加NaIO4 (104.4 g，488.08 mmol)。將所得混合物在氮氣下在20℃下攪拌16小時。反應混合物經過濾且用乙酸乙酯(300 mL×3)萃取濾液。將合併的有機層用鹽水(300 mL)洗滌，經無水硫酸鈉乾燥且過濾。在減壓下濃縮濾液，得到粗產物。以相同方式處理另一批具有100 g規模的化合物1A_2 。將兩個批次的粗產物組合且自石油醚/乙酸乙酯(7：1，800 mL)再結晶然後過濾。將濾餅真空乾燥，獲得呈白色固體狀的1A (82.4 g純產物)。在減壓下濃縮濾液然後再次自石油醚/乙酸乙酯(15：1，640 mL)再結晶。在減壓下乾燥濾餅，獲得17.5 g呈白色固體狀的產物(約90%純度)。產率總共為約48%。 1 H NMR (400MHz, CDCl3 ): δ=4.67 (dd,J =5.6, 9.2 Hz, 1H), 4.51-4.36 (m, 1H), 4.20 (dd,J =3.2, 9.2 Hz, 1H), 1.56 (s, 9H), 1.51 (d,J =6.4 Hz, 3H)。 用於製備1F 的程式：
Figure 02_image038
向化合物1F_1 (10 g，47.9 mmol，1.0當量)於THF(100 mL)中的溶液中添加NaOH水溶液(28.7 mL，143.7 mmol，5 M)。將反應混合物在17℃下攪拌一小時。將含化合物1F_1a (9.9 g，52.7 mmol，1.1當量)的THF(50 mL)逐滴添加至以上反應物。此後，將反應物在17℃下攪拌12小時。將反應物在真空中濃縮，用水(80 mL)稀釋，用二氯甲烷(80 mL×3)萃取且用鹽水(100 mL)洗滌。有機層經無水硫酸鈉乾燥，過濾，濃縮且通過柱層析(含2%甲醇的CH2 Cl2 )純化，獲得呈白色固體狀的產物1F_2 (8.85 g，79.6%產率)。 1 H NMR (400MHz, CDCl3 ) δ=4.95 (br s, 1H), 4.46 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.34-4.22 (m, 1H), 3.64-3.60 (m, 2H), 2.88-2.70 (m, 2H), 2.52 (t,J =7.2 Hz, 2H), 1.78-1.64 (m, 2H), 1.42 (s, 9H)。
Figure 02_image040
向化合物1F_2 (8.85 g，38.09 mmol，1.0當量)於二氯甲烷(100 mL)中的溶液中逐滴添加TFA(34 mL)。將反應物在16℃下攪拌3小時。TLC顯示反應完成。將反應物在真空中濃縮且與二氯甲烷共蒸發，獲得呈淡黃色油狀的產物1F (18.32 g TFA鹽，純度：67.8%)。 1 H NMR (400MHz, CDCl3 ) δ=4.47 (t,J =5.6 Hz, 1H), 4.44-4.32 (m, 3H), 4.30-4.18 (m, 3H), 3.34 (t,J =7.4 Hz, 2H), 1.96-1.81 (m, 2H)。 用於製備化合物 1 的程式：
Figure 02_image042
在-65℃下在30分鐘內向化合物1a (10 g，38.17 mmol)於THF(100 mL)中的溶液中逐滴添加n-BuLi(20 mL，45.8 mmol，2.5 M於己烷中)。在攪拌一小時之後，將化合物1A (9.05 g，38.17 mmol)於THF(50 mL)中的溶液逐滴添加至以上反應混合物中且將溫度保持於-65℃。接著將反應混合物在-70℃下再攪拌2小時然後緩慢升溫至3-12℃後維持5小時。接著將反應物用1 N檸檬酸(30 mL)淬滅然後將混合物在20℃下攪拌30分鐘。所得混合物用乙酸乙酯(300 mL×3)萃取。將合併的有機層用鹽水(100 mL×2)洗滌，經無水硫酸鈉乾燥然後過濾。於真空中蒸發濾液以得到粗產物，其通過矽膠柱層析(0-10%乙酸乙酯於石油醚中)純化，得到呈白色固體狀的化合物1b (5.6 g，43%產率)。LCMS: tR =4.153 min，於10-80AB_7min_220&254_Shimadzu.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z 285.9 [M-55+H]+ 。 1 H NMR (CDCl3 400MHz): δ=7.47-7.43 (m, 2H), 7.40 (t,J =7.2 Hz, 2H), 7.36-7.31 (m, 1H), 7.22 (t,J =7.8 Hz, 1H), 6.89-6.77 (m, 3H), 5.06 (s, 2H), 4.39 (br s, 1H), 3.92 (br s, 1H), 2.84 (dd,J =5.2, 13.2 Hz, 1H), 2.63 (dd,J =7.2, 13.0 Hz, 1H), 1.44 (s, 9H), 1.08 (d,J =6.4 Hz, 3H)。
Figure 02_image044
將化合物1b (5.6 g，16.4 mmol)於4 M HCl/1,4-二噁烷(100 mL)中的溶液在-1至8℃下攪拌16小時。接著濃縮反應混合物且將殘餘物用NaHCO3 飽和水溶液鹼化至pH=8。水層用乙酸乙酯(300 mL×4)萃取。合併的有機層經無水硫酸鈉乾燥然後過濾。於真空中濃縮濾液，得到呈黃色油狀的化合物1c (3.9 g，98%產率)。LCMS: tR =0.801 min，於5-95AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=242.0 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.47-7.30 (m, 5H), 7.23 (t,J =7.6 Hz, 1H), 6.87-6.78 (m, 3H), 5.07 (s, 2H), 3.22-3.13 (m, 1H), 2.70 (dd,J =5.2, 13.2 Hz, 1H), 2.50 (dd,J =8.0, 13.2 Hz, 1H), 1.13 (d,J =6.4 Hz, 3H)。
Figure 02_image046
向化合物1c (3.9 g，16.18 mmol)和DIEA(6.3 g，48.54 mmol)於1,4-二噁烷(80 mL)中的溶液中添加CF3 CH2 OTf(3.8 g，16.18 mmol)。在將反應混合物在80℃下攪拌16小時之後，在真空中濃縮混合物且將殘餘物溶解於乙酸乙酯(100 mL)中。將所得混合物用鹽水(50 mL×2)洗滌，經無水硫酸鈉乾燥然後過濾。於真空中濃縮濾液以獲得粗產物，其通過矽膠柱層析(0-10%乙酸乙酯於石油醚中)純化，獲得呈油狀的化合物1d (4.7 g，89%產率)。LCMS: tR =1.070 min，於10-80AB_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=324.0 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ 7.47-7.31 (m, 5H), 7.23 (t,J =8 Hz, 1H), 6.88-6.78 (m, 3H), 5.07 (s, 2H), 3.15 (q,J =9.6 Hz, 2H), 3.07-2.99 (m, 1H), 2.73-2.58 (m, 2H), 1.08 (d,J =6.4 Hz, 3H)。
Figure 02_image048
在室溫(4-9℃)下向化合物1d (4.70 g，14.54 mmol)於乙酸乙酯(150 mL)中的混合物中添加10% Pd/C(1.0 g，50%水)。接著將反應混合物在50℃下在H2 氣氛(15 psi，H2 氣球)下攪拌6小時。接著將反應混合物通過矽藻土過濾且用乙酸乙酯(15 mL×3)洗滌。在真空中濃縮合併的濾液，獲得呈淺褐色膠狀的化合物1e (3.40 g，100%)。LCMS: tR =0.254 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 234.0 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.18 (t,J= 7.6 Hz, 1H), 6.76 (d,J= 7.6 Hz, 1H), 6.71 (dd,J= 2.0, 8.0 Hz, 1H), 6.67 (s, 1H), 3.18 (q,J= 9.2 Hz, 2H), 3.12-2.99 (m, 1H), 2.73-2.55 (m, 2H), 1.11 (d,J= 6.4 Hz, 3H)。
Figure 02_image050
在室溫(4-9℃)下向化合物1e (3.40 g，14.58 mmol)於1,2-二氯乙烷(300 mL)中的溶液中添加化合物1E (4.07 g，21.87 mmol)，接著添加TFA(3.26 mL，43.73 mmol)。接著將反應混合物在室溫(4-9℃)下在氮氣下攪拌16小時。接著將反應混合物在攪拌下倒入NaHCO3 飽和水溶液(200 mL)中。分離所得混合物。水層用二氯甲烷(40 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥然後過濾。於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-20%乙酸乙酯於石油醚中)純化，獲得呈淡黃色固體狀的不可分離的4:1非對映異構體(4.3 g，74%)。主要異構體化合物1f 表徵如下。LCMS: tR =2.202 min，於30-90AB_7min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z 402.9 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.56 (d,J= 2.0 Hz, 1H), 7.77 (dd,J= 2.4, 8.4 Hz, 1H), 7.38 (d,J= 8.4 Hz, 1H), 6.72 (d,J= 8.8 Hz, 1H), 6.55 (s, 1H), 6.52 (dd,J= 2.4, 8.4 Hz, 1H), 5.70 (s, 1H), 4.93 (s, 1H), 3.48-3.35 (m, 1H), 3.30-3.16 (m, 1H), 3.08 (dd,J= 4.8, 16.4 Hz, 1H), 3.00-2.85 (m, 1H), 2.54 (dd,J= 6.4, 16.8 Hz, 1H), 1.07 (d,J= 6.4 Hz, 3H)。
Figure 02_image052
在氮氣下向化合物1f (3.80 g，9.47 mmol)、Brettphos Pd-G3(1.29 g，1.42 mmol)和t- BuONa(9.10 g，94.71 mmol)於1,4-二噁烷(130 mL)中的混合物中添加1F (6.82 g，12.84 mmol)於1,4-二噁烷(20 mL)中的溶液。接著將反應混合物在80℃下在氮氣下攪拌2小時。接著將反應混合物與先導反應批料(0.5 g規模的化合物1f )組合，用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(200 mL)洗滌，經無水硫酸鈉乾燥然後過濾，於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-10%甲醇於二氯甲烷中)純化，獲得呈黃色固體狀的化合物1g (總計4.25 g，平均產率為78.8%，90%純度)。LCMS: tR =0.761 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 453.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.79 (d,J= 2.8 Hz, 1H), 7.19 (d,J= 8.4 Hz, 1H), 6.79 (dd,J= 2.8, 8.4 Hz, 1H), 6.64 (d,J= 8.4 Hz, 1H), 6.50 (d,J= 2.4 Hz, 1H), 6.44 (dd,J= 2.4, 8.4 Hz, 1H), 4.85 (s, 1H), 4.49 (td,J= 6.0, 47.2 Hz, 2H), 4.14-4.00 (m, 2H), 3.78-3.69 (m, 2H), 3.50-3.40 (m, 1H), 3.23-3.13 (m, 1H), 3.06 (dd,J= 4.8, 11.6 Hz, 1H), 3.01-2.91 (m, 3H), 2.64 (t,J= 7.2 Hz, 2H), 2.49 (dd,J= 6.0, 16.4 Hz, 1H), 1.86-1.68 (m, 2H), 1.04 (d,J= 6.4 Hz, 3H)。
Figure 02_image054
在室溫(4-14℃)下向化合物1g (4.25 g，9.39 mmol，90%純度)於二氯甲烷(190 mL)中的混合物中添加三乙胺(4.0 mL，28.17 mmol)，接著添加PhNTf2 (6.71 g，18.78 mmol)。接著將反應混合物在25℃下攪拌5小時。接著於真空中濃縮反應混合物。將殘餘物用乙酸乙酯(50 mL)和水(50 mL)稀釋然後分離。水層用乙酸乙酯(20 mL×2)萃取。將合併的有機層用鹽水(150 mL×3)洗滌，經無水硫酸鈉乾燥然後過濾。於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-5%甲醇於二氯甲烷中)純化，獲得呈淡黃色膠狀的化合物1h (4.00 g，72.8%)。LCMS: tR =0.854 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 585.0 [M+H]+ 。 1 H NMR (CDCl3 400MHz): δ=7.83 (d,J= 2.4 Hz, 1H), 7.15 (d,J= 8.8 Hz, 1H), 7.03 (s, 1H), 6.98-6.92 (m, 2H), 6.80 (dd,J= 2.8, 8.4 Hz, 1H), 4.93 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.17-4.07 (m, 2H), 3.83-3.73 (m, 2H), 3.59-3.48 (m, 1H), 3.30-3.12 (m, 2H), 3.04-2.96 (m, 3H), 2.70-2.57 (m, 3H), 1.86-1.69 (m, 2H), 1.08 (d,J= 6.4 Hz, 3H)。
Figure 02_image056
將化合物1h (500 mg，0.870 mmol)、硼酸1H (199 mg，0.957 mmol)、Pd(dppf)Cl2 ·CH2 Cl2 (71 mg，0.087 mmol)和K2 CO3 (296 mg，2.138 mmol)的混合物用氮氣吹掃。接著在氮氣下向混合物中添加1,4-二噁烷和H2 O的混合溶液(v/v=10:1)(25 mL)。將所得混合物在100℃下在氮氣下攪拌16小時。接著將反應混合物用水(40 mL)稀釋且用乙酸乙酯(20 mL×3)萃取。合併的有機層經無水硫酸鈉乾燥且過濾。於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-5%甲醇於二氯甲烷中)純化，獲得化學純產物(250 mg)。以相同方式進行具有相同規模的另一個批次的此反應且獲得200 mg化學純產物。將這兩個批次的化學純產物組合並且通過手性SFC[柱：DAIRALCEL OJ-H(250 mm×30 mm，5 μm)；條件：30% EtOH(0.1% NH3 H2 O)於CO2 中；流動速率：60 mL/min]進一步純化，獲得呈白色固體狀的化合物 1 (總計330.5 mg，100%化學純度；100%光學純度，41%平均產率)。LCMS: tR =1.837 min，於10-80AB_7min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z 517.3 [M+H]+ 。HPLC: tR =2.29 min，於10-80_CD_1.2ml.met.層析(Ultimate C18 3.0μm 3.0×50mm)中。SFC: tR =2.330 min；100%光學純度。方法：柱：Chiralcel OJ-3 100×4.6 mm I.D.，3 μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 0.5 min，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。 1 H NMR (400MHz, CDCl3 ): δ=7.85 (d,J= 2.8 Hz, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 7.22 (s, 1H), 7.20-7.11 (m, 2H), 6.85 (d,J= 8.0 Hz, 1H), 6.80 (dd,J= 2.8, 8.4 Hz, 1H), 4.91 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.17-4.07 (m, 1H), 4.05-3.98 (m, 1H), 3.93 (s, 3H), 3.81-3.70 (m, 2H), 3.60-3.48 (m, 1H), 3.27-3.14 (m, 2H), 3.07-2.96 (m, 1H), 2.96-2.90 (m, 2H), 2.66-2.57 (m, 3H), 1.84-1.69 (m, 2H), 1.09 (d,J= 6.8 Hz, 3H)。實施例 2 2,2- 二氟 -3-((1S,3R)-1-(5-((1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 胺基 ) 吡啶 -2- 基 )-3- 甲基 -6-(1- 甲基 -1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 ) 丙 -1- 醇
Figure 02_image058
用於製備中間物2D 的程式：
Figure 02_image060
在0℃下向化合物2D_1 (4.20 g，37.47 mmol)於THF(85 mL)中的溶液中緩慢地逐份添加NaH(1.50 g，37.47 mmol，60%純度)。在0℃下攪拌反應混合物30分鐘之後，添加TBDPSCl(10.3 g，37.47 mmol)。在添加TBDPSCl期間，反應混合物變為膠狀然後向混合物中添加THF(100 mL)。使反應混合物升溫到20℃然後在20℃下在氮氣下攪拌3小時。接著將反應混合物在攪拌下倒入水(150 mL)中。所得混合物用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(200 mL)洗滌，經無水硫酸鈉乾燥然後過濾。於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-4%乙酸乙酯於石油醚中)純化，獲得呈無色油狀的2D_2 (10.9 g，83 %純度)。 1 H NMR (400MHz, CDCl3 ): δ=7.71-7.63 (m, 4H), 7.48-7.39 (m, 6H), 4.02-3.84 (m, 4H), 1.83 (t,J =7.2 Hz, 1H), 1.08 (s, 9H)。
Figure 02_image062
在0℃下在氮氣下向化合物2D_2 (10.9 g，31.10 mmol)和2,6-二甲基吡啶(10.0 g，93.30 mmol)於CH2 Cl2 (220 mL)中的溶液中逐滴添加Tf2 O(10.4 mL，62.20 mmol)。接著將反應混合物在20℃下在氮氣下攪拌3小時。接著將反應混合物用HCl(1 M)(150 mL×2)、NaHCO3 飽和水溶液(150 mL)和鹽水(150 mL)洗滌。所得有機層經無水硫酸鈉乾燥然後過濾。於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-2%乙酸乙酯於石油醚中)純化，獲得呈無色油狀的2D (14.4 g，96%純度)。 1 H NMR (400MHz, CDCl3 ): δ=7.76-7.56 (m, 4H), 7.54-7.35 (m, 6H), 4.76 (t,J =11.2 Hz, 2H), 3.89 (t,J =11.6 Hz, 2H), 1.09 (s, 9H)。 用於製備化合物 2 的程式：
Figure 02_image064
在-70℃下在氮氣下在5分鐘內向化合物2a (5.0 g，17.7 mmol)於THF(60 mL)的混合物中添加n-BuLi溶液(7.8 mL，19.5 mmol)。將反應混合物在此溫度下攪拌5分鐘，此時觀測到白色懸浮液，接著在-70℃下再攪拌30分鐘。在-70℃下在氮氣下在5分鐘內逐滴添加化合物1A (4.2 g，17.7 mmol)於THF(20 mL)中的溶液。將所得混合物在-70℃下攪拌3.5小時。反應物用檸檬酸(100 mL，1 M)淬滅且用乙酸乙酯(300 mL×2)萃取。將合併的有機層用鹽水(200 mL)洗滌，經無水硫酸鈉乾燥且在真空中濃縮以得到粗殘餘物，其通過矽膠快速柱層析(乙酸乙酯於石油醚中，0至10%)純化，獲得呈白色固體狀的標題產物2b (2.1 g，38%產率)。LCMS : tR =0.984 min，於5-95AB_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=259.8 [M-56]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=7.40-7.30 (m, 2H), 7.19-7.14 (m, 1H), 7.14-7.10 (m, 1H), 4.36 (br s, 1H), 3.89 (br s, 1H), 2.90-2.77 (m, 1H), 2.64 (dd,J= 7.6, 12.0 Hz, 1H), 1.44 (s, 9H), 1.10 (d,J= 6.0 Hz, 3H)。
Figure 02_image066
在12-21℃下向化合物2b (1.5 g，4.77 mmol)、K2 CO3 (1.06 g，7.64 mmol)和Pd(dppf)Cl2 ·CH2 Cl2 (1.4 g，2.385 mmol))於1,4-二噁烷/H2 O(20 mL/2 mL)中的溶液中添加化合物1H (1.09 g，5.25 mmol)。將混合物在100℃下在氮氣氣氛下攪拌15小時。將反應物與先導批料合併且用乙酸乙酯(100 mL×3)萃取。合併的有機層用鹽水(100 mL)洗滌，經無水硫酸鈉乾燥然後在真空中濃縮以得到粗殘餘物，其通過矽膠快速柱層析(乙酸乙酯/石油醚=0-20%)純化，獲得呈黃色油狀的標題產物2c (1.0 g，60%產率)。LCMS : tR =0.858 min，在5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=316.1 [M+H]+ 。 1 H NMR : (400MHz, CDCl3 ) δ=7.76 (s, 1H), 7.62 (s, 1H), 7.35-7.31 (m, 1H), 7.31-7.28 (m, 2H), 7.05 (d,J= 7.6 Hz, 1H), 4.41 (br s, 1H), 4.00-3.90 (m, 1H), 3.95 (s, 3H), 2.88 (br d,J= 7.6 Hz, 1H), 2.67 (dd,J= 7.6, 13.2 Hz, 1H), 1.43 (s, 9H), 1.11 (d,J= 6.4 Hz, 3H)。
Figure 02_image068
向化合物2c (1.0 g，3.17 mmol)於MeOH(3 mL)中的混合物中添加HCl/乙酸乙酯(4 M，6 mL)，接著在14-19℃下攪拌3小時。在真空中濃縮混合物以去除大部分溶劑且將殘餘物用NaHCO3 飽和水溶液處理至pH=8且再次在真空中濃縮，以得到粗物質，其通過矽膠快速柱層析(甲醇/二氯甲烷=0-10%)純化，獲得呈黃色油狀的標題產物2d (600 mg，85%產率)。LCMS: tR =0.589 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=215.7 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=7.78 (s, 1H), 7.63 (s, 1H), 7.38-7.29 (m, 3H), 7.06 (d,J= 7.6 Hz, 1H), 3.92 (s, 3H), 3.46-3.39 (m, 1H), 2.95 (dd,J= 6.8, 13.2 Hz, 1H), 2.81 (dd,J= 7.6, 13.2 Hz, 1H), 1.30 (d,J= 6.4 Hz, 3H)。
Figure 02_image070
在7-21℃下向化合物2d (600 mg，2.79 mmol)、DIEA (1.08 g，8.37 mmol)於1,4-二噁烷(10 mL)中的溶液中添加化合物2D (1.34 g，2.79 mmol)。在80℃下攪拌混合物15小時。在真空中濃縮反應物以獲得殘餘物，其通過矽膠快速柱層析(乙酸乙酯/石油醚=0-30%)純化，得到呈黃色油狀的標題產物2e (970 mg，60%產率)。LCMS: tR = 0.891 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=548.4 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=7.75 (s, 1H), 7.70-7.65 (m, 4H), 7.58 (s, 1H), 7.48-7.42 (m, 2H), 7.42-7.37 (m, 4H), 7.34-7.31 (m, 1H), 7.30-7.27 (m, 2H), 7.04 (d,J =7.2 Hz, 1H), 3.94 (s, 3H), 3.87-3.80 (m, 2H), 3.26-3.09 (m, 2H), 3.08-2.97 (m, 1H), 2.79 (dd,J= 6.4, 13.2 Hz, 1H), 2.60 (dd,J= 6.4, 13.2 Hz, 1H), 1.08 (d,J= 6.4 Hz, 3H), 1.05 (s, 9H)。
Figure 02_image072
向化合物2e (100 mg，0.182 mmol)於DCE和THF(2 mL，4/1)中的混合物中添加化合物1E (41 mg，0.220 mmol)、TMSCl(21 mg，0.182 mmol)和Yb(OTf)3 (12 mg，0.018 mmol)，接著將混合物在70℃下攪拌48小時。在真空中濃縮反應物以獲得殘餘物，其通過快速柱層析(乙酸乙酯/石油醚=0-50%)純化，獲得呈黃色固體狀的標題產物2f (80 mg，50%產率，未通過1 H NMR觀測到其它非對映異構體)。LCMS: tR =1.101 min，於5-95AB_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=717.3 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=8.54 (d,J= 2.0 Hz, 1H), 7.74 (s, 1H), 7.64 (t,J= 6.4 Hz, 4H), 7.59-7.55 (m, 2H), 7.48-7.43 (m, 2H), 7.39 (q,J= 7.2 Hz, 4H), 7.24 (s, 1H), 7.18 (d,J= 8.4 Hz, 2H), 6.89 (d,J= 8.0 Hz, 1H), 5.05 (s, 1H), 3.95 (s, 3H), 3.88-3.71 (m, 2H), 3.53-3.45 (m, 1H), 3.22 (q,J= 14.4 Hz, 1H), 3.01 (dd,J= 4.8, 16.4 Hz, 1H), 2.87 (q,J= 15.2 Hz, 1H), 2.63 (dd,J= 6.4, 16.0 Hz, 1H), 1.09 (d,J= 6.4 Hz, 3H), 1.03 (m, 9H)。
Figure 02_image074
向化合物2f (100 mg，0.139 mmol)於1,4-二噁烷(3 mL)中的混合物中添加化合物1F (66 mg，0.182 mmol)、Brettphos Pd-G3(32 mg，0.035 mmol)和t-BuONa(40 mg，0.417 mmol)，接著將混合物在80℃下在氮氣氣氛下攪拌3小時。在真空中濃縮反應物以得到粗物質，其通過矽膠快速柱層析(MeOH/CH2 Cl2 =0-10%)純化，得到呈淺黃色油狀的標題產物2g (60 mg，56%產率)。LCMS: tR =0.903 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=767.5 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=7.81 (d,J= 2.6 Hz, 1H), 7.73 (s, 1H), 7.67-7.63 (m, 4H), 7.57 (s, 1H), 7.45-7.37 (m, 6H), 7.21 (s, 1H), 7.16 (d,J= 8.0 Hz, 1H), 6.98 (d,J= 8.4 Hz, 1H), 6.85 (d,J= 8.0 Hz, 1H), 6.61 (dd,J= 2.8, 8.4 Hz, 1H), 4.96 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.05 (br d,J= 6.0 Hz, 1H), 3.94 (s, 3H), 3.90-3.83 (m, 1H), 3.80-3.67 (m, 4H), 3.55-3.47 (m, 1H), 3.22-3.11 (m, 1H), 3.03-2.85 (m, 4H), 2.62-2.55 (m, 2H), 1.75-1.72 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H), 1.03 (s, 9H)。
Figure 02_image076
向化合物2g (60 mg，0.078 mmol)於THF(3 mL)中的混合物中添加TBAF(85 mg，0.234 mmol)，將混合物在12-21℃下攪拌16小時。在真空中濃縮反應物以得到粗殘餘物，其通過製備型TLC(甲醇/二氯甲烷=1/10)，接著通過酸性製備型HPLC在TFA系統[Waters Xbridge 150×25 5u，條件：13-43% B(A：水(0.1% TFA)，B：CH3 CN)；流動速率：25 ml/min]中純化，得到呈褐色固體狀的標題產物化合物 2 (7.0 mg TFA鹽，16%產率)。LCMS: tR =1.129 min，於10-80AB_3min_220&254層析(A: Xtimate C18, 2.1×30mm, 3μm)中，MS (ESI) m/z=529.3 [M+H]+ 。HPLC: tR =3.14 min，於10-80_CD_1.2ml. met, XBridge Shield RP 18 2.1×50mm 5μm中。手性 SFC: 93%純度。柱：Chiralcel OJ-3 100×4.6 mm I.D.，3 μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min；流動速率：2.8mL/min；柱溫：40℃。 1 H NMR: (400MHz, MeOD) δ=7.96 (s, 2H), 7.81 (s, 1H), 7.65 (d,J= 8.8 Hz, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.37 (d,J= 8.4 Hz, 1H), 6.91 (d,J= 7.6 Hz, 1H), 5.26 (s, 1H), 4.63 (t,J= 5.6 Hz, 4H), 4.51 (t,J= 5.6 Hz, 2H), 4.39-3.99 (m, 2H), 3.92 (s, 3H), 3.74 (td,J= 9.6, 15.6Hz, 2H), 3.54 (d,J= 5.6 Hz, 1H), 3.48-3.36 (m, 3H), 2.97-2.71 (m, 2H), 2.12-1.95 (m, 2H), 1.17 (d,J= 6.4 Hz, 3H)。實施例 3 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1H- 吡唑 -1- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image078
用於製備化合物 3 的程式：
Figure 02_image080
在-78℃下向化合物3a (2.8 g，12.6 mmol)於THF(25 mL)中的溶液中添加n-BuLi溶液(6 mL，15.1 mmol，2.5 M於己烷中)，將混合物在-78℃下攪拌30分鐘。在-78℃下將化合物1A (2.98 g，12.6 mmol)於THF(5 mL)中的溶液添加至以上溶液。在-78℃下攪拌反應混合物4小時。將反應混合物用乙酸乙酯(50 mL)和飽和氯化銨水溶液(50 mL)稀釋，接著分離。水層用乙酸乙酯(50 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且濃縮，通過快速柱(石油醚：乙酸乙酯：30/1至10/1)純化，得到呈黃色油狀的化合物3b (1.4 g，37%產率)。 1 H NMR (400MHz, CDCl3 ) δ=7.62 (d,J= 1.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.35-7.44 (m, 3H), 6.30 (d,J= 1.6 Hz, 1H), 4.31 (br s, 1H), 3.93 (br s, 1H), 2.75-2.93 (m, 2H), 1.42 (s, 9H), 1.03 (d,J =6.4 Hz, 3H)。
Figure 02_image082
將化合物3b (1.4 g，4.65 mmol)於4 M HCl/1,4-二噁烷(20 mL)和二氯甲烷(20 mL)中的溶液在6-10℃下攪拌15小時。在減壓下濃縮反應混合物。將殘餘物溶解於水(45 mL)中，用NaHCO3 水溶液鹼化直到pH=8且用二氯甲烷/甲醇(v/v：3/1，50 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到呈黃色油狀的化合物3c (760 mg，81%產率)。LCMS: tR= 0.195 min，於5-95AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=202.1 [M+H]+ 。
Figure 02_image084
向化合物3c (750 mg，3.73 mmol)和DIEA(1.4 g，11.2 mmol)於1,4-二噁烷(20 mL)中的溶液中添加CF3 CH2 OTf (952 mg，4.1 mmol)，將所得混合物在80℃下攪拌15小時。將反應混合物用乙酸乙酯(20 mL)和水(20 mL)稀釋，接著分離。水層用乙酸乙酯(20 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且濃縮，通過快速柱(石油醚：乙酸乙酯：30/1至15/1)純化，得到呈黃色油狀的化合物3d (810 mg，77%產率)。LCMS: tR =0.544 min，於10-80AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=284.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ 7.62 (d,J= 1.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.39-7.45 (m, 3H), 6.28 (d,J= 1.6 Hz, 1H), 3.04 (q,J =9.2 Hz, 2H), 2.91-2.99 (m, 1H), 2.81 (dd,J =6.8 Hz, 14.8 Hz, 1H), 2.71 (dd,J =6.8 Hz, 14.8 Hz, 1H), 1.02 (d,J =6.0 Hz, 3H)。
Figure 02_image086
向化合物3d (810 mg，2.85 mmol)於DCE(40 mL)中的溶液中添加化合物1E (796 mg，4.3 mmol)和TFA(830 mg，7.28 mmol)。在3-9℃下攪拌所得混合物2小時。將反應混合物用二氯甲烷(20 mL)和水(20 mL)稀釋，用Na2 CO3 水溶液調節至pH=8，分離。水層用二氯甲烷(20 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且濃縮，通過快速柱(0-30%乙酸乙酯於石油醚中)純化，得到呈黃色油狀的化合物3e (1.1 g，86%產率，未通過1 H NMR觀測到其它非對映異構體)。注意：未通過 2D NMR 確認結構。 LCMS: tR =0.896 min，於10-80AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=451.1和453.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ 8.62 (d,J= 2.0 Hz, 1H), 7.80 (dd,J= 8.0 Hz, 2.0 Hz, 1H), 7.44-7.58 (m, 6H), 7.34 (t,J =7.6 Hz, 1H), 4.97 (s, 1H), 3.44-3.35 (m, 1H), 3.32-3.21 (m, 1H), 3.11-3.01 (m, 2H), 2.64 (dd,J= 16.0, 6.4 Hz, 1H), 1.19 (d,J= 6.8 Hz, 3H)。
Figure 02_image088
將氮氣下的化合物3e (200 mg，0.44 mmol)、t-BuONa (348 mg，3.5 mmol)、Brettphos Pd G3(40 mg，0.044 mmol)和化合物1F (289 mg，0.54 mmol，67.8%純度)於1,4-二噁烷(6 mL)中的混合物在80℃下攪拌15小時。將反應混合物用乙酸乙酯(20 mL)和水(20 mL)稀釋，分離。水層用乙酸乙酯(20 mL×2)萃取。將合併的有機層用鹽水(10 mL)洗滌，經無水硫酸鈉乾燥，過濾且濃縮，通過快速柱(二氯甲烷:甲醇=30/1至20/1)純化，得到呈黃色固體狀的化合物 3 (24.5 mg)，產率11%。LCMS: tR =2.849 min，於0-60AB_7min_220&254_Shimadzu.lcm (Xtimate C18 2.1×30mm)中，MS (ESI) m/z=503.2 [M+H]+ 。HPLC : tR =3.46 min，於0-60_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CDCl3 ) δ 7.89 (d,J= 2.8 Hz, 1H), 7.54 (d,J =7.6 Hz, 2H), 7.47 (t,J =8.0 Hz, 2H), 7.37 (s, 1H), 7.29-7.36 (m, 2H), 6.84 (dd,J= 8.4, 2.4 Hz, 1H), 4.87 (s, 1H), 4.51 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.19-4.06 (m, 2H), 3.84-3.74 (m, 2H), 3.53-3.44 (m, 1H), 3.21-2.92 (m, 5H), 2.69-2.56 (m, 3H), 1.86-1.71 (m, 2H), 1.14 (d,J= 6.4 Hz, 3H)。實施例 4 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1H- 吡唑 -3- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image090
向化合物1h (製備於實施例 1 中，150 mg，0.256 mmol)和硼酸酯4A (55 mg，0.28 mmol)於1,4-二噁烷/H2 O(5 mL/0.5 mL)中的混合物中添加K2 CO3 (89 mg，0.64 mmol，2.5當量)和Pd(dppf)Cl2· DCM (21 mg，0.0256 mmol)。將所得混合物在氮氣下在100℃下攪拌16小時。將混合物與另一批次的45 mg化合物1h 組合且通過矽膠快速柱層析(0-10 %甲醇於二氯甲烷中)純化以獲得50 mg純產物，其另外通過手性SFC[柱：Phenomenex-Amylose-1(250mm×30mm，5 μm)，條件：40% ETOH(0.1% NH3 H2 O)於CO2 中，流動速率(ml/min)：50]分離，獲得呈褐色固體狀的化合物 4 (35.3 mg，20.6%產率)。LCMS: tR =0.698 min，於5-95AB_1.5min_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=503.1 [M+H]+ 。HPLC : tR =3.871 min，於10-80_CD_1.2ml層析(XBridge Shield RP 18 2.1×50mm 5μm)中。 1 H NMR (400MHz, CDCl3 ) δ 10.74 (br s, 1H), 7.84 (d,J =2 Hz, 1H), 7.59 (d,J =1.6 Hz, 1H), 7.55-7.36 (m, 2H), 7.14 (d,J =8.8 Hz, 1H), 6.91 (d,J =8.0 Hz, 1H), 6.79 (dd,J =2 Hz, 8.4 Hz, 1H), 6.56 (s, 1H), 4.94 (s, 1H), 4.50 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.22 (d,J =6.8 Hz, 1H), 4.16-4.07 (m, 1H), 3.73 (q,J =6 Hz, 2H), 3.59-3.50 (m, 1H), 3.29-3.14 (m, 2H), 3.05-2.91 (m, 3H), 2.69-2.59 (m, 3H), 1.82-1.72 (m, 2H), 1.08 (d,J =6.4 Hz, 3H)。SFC : tR =4.303 min；方法：柱：Chiralcel OD-3 100×4.6 mm I.D.，3 μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min 流動速率：2.8 mL/min；柱溫：40℃。實施例 5 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-6-( 異噁唑 -4- 基 )-3- 甲基 -2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image092
用於製備化合物 5 的程式：
Figure 02_image094
向化合物1h (製備於實施例 1 中，150 mg，0.25 mmol)和二硼酸酯5A (195 mg，0.77 mmol)於1,4-二噁烷(3 mL)中的混合物中添加三乙胺(152 mg，1.5 mmol)和Pd(dppf)Cl2· DCM (20 mg，0.025 mmol)。將所得混合物在氮氣下在95℃下攪拌1.5小時。將混合物與另一批次的30 mg化合物1h 組合，濃縮且通過矽膠快速柱層析(0-8%甲醇於二氯甲烷中)純化，獲得呈褐色油狀的化合物5a (100 mg，57%產率)。LCMS: tR =0.909 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=562.9 [M+H]+ 。
Figure 02_image096
向化合物5a (80 mg，0.14 mmol)和化合物5B (23 mg，0.11 mmol)於THF/H2 O(1 mL/1 mL)中的混合物中添加Na2 CO3 (44 mg，0.42 mmol)、Pd2 (dba)3 (4 mg，0.007 mmol)和P(t-Bu)3 .HBF4 (2 mg，0.015 mmol)。將所得混合物在氮氣下在8-10℃下攪拌一小時。將混合物與另一批次的20 mg化合物5a 組合。在真空中濃縮混合物且通過矽膠快速柱層析(0-6%甲醇於二氯甲烷中)純化，以獲得25 mg產物，其另外通過手性SFC[YMC CHIRAL Amylose-C(250 mm×30 mm，10 μm，條件：30% EtOH(0.1% NH3 .H2 O)於CO2 中，流動速率(ml/min)：70]分離，獲得呈粉紅色固體狀的化合物5(10.3 mg，11.5%產率)。LCMS: tR =0.685 min，於5-95AB_1.5min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=504.2 [M+H]+ 。HPLC : tR =4.04 min，於10-80_cd_1.2ML.MET層析(XBridge Shield RP 18 2.1×50mm 5μm)中。 1 H NMR (400MHz, CDCl3 ) δ 8.63 (s, 1H), 8.52 (s, 1H), 7.85 (d,J =2.8 Hz, 1H), 7.23 (s, 1H), 7.18 (t,J =8.4 Hz, 2H), 6.93 (d,J =8 Hz, 1H), 6.82 (dd,J =2.8 Hz, 8.4 Hz, 1H), 4.94 (s, 1H), 4.51 (dt,J =47.2 Hz, 6 Hz, 2H), 4.24-4.13 (m, 2H), 3.83 (brs, 2H), 3.58-3.51 (m, 1H), 3.27-3.18 (m, 2H), 3.09 (brs, 2H), 3.03-2.92 (m, 1H), 2.71 (t,J =7.2 Hz, 2H), 2.64 (dd,J =5.2 Hz, 16 Hz, 1H), 1.86-1.79 (m, 2H), 1.10 (d,J =6.4 Hz, 3H)。SFC : tR =1.526 min；柱：Chiralpak AD-3 50×3mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B經0.15min從40%至5%；流動速率：2.5 mL/min；柱溫：40℃。實施例 6 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image098
向化合物1h (製備於實施例 1 中，200 mg，0.34 mmol)和硼酸酯6A (73 mg，0.37 mmol)於1,4-二噁烷/H2 O(5 mL/0.5 mL)中的混合物中添加K2 CO3 (118 mg，0.85 mmol)和Pd(dppf)Cl2 ·DCM(28 mg，0.034 mmol)。將所得混合物在氮氣下在95℃下攪拌6小時。將混合物濃縮且通過矽膠快速柱層析(0-10%甲醇於二氯甲烷中)純化以獲得80 mg產物，其與另一批次的20 mg產物組合且另外通過手性SFC[DAICEL CHIRALPAK AD-H(250 mm×30 mm，5 μm)，條件：35% IPA(0.1% NH3 H2 O)於CO2 中，流動速率(ml/min)：50]分離，獲得呈白色固體狀的化合物 6 (44.7 mg，7.1%產率)。LCMS: tR =0.829 min，於5-95AB_1.5min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=503.3 [M+H]+ 。HPLC : tR =4.79 min，於10-80_1.5ML_LONG.MET層析(YMC-C18 4.6×150mm 5μm_長柱)中。 1 H NMR (400MHz, CDCl3 ) δ 7.85 (d,J =2.4 Hz, 1H), 7.76 (s, 2H), 7.25-7.16 (m, 3H), 6.88 (d,J =8.4 Hz, 1H), 6.81 (dd,J =2.8 Hz, 8.8 Hz, 1H), 4.93 (s, 1H), 4.50 (dt,J =47.2 Hz, 6 Hz, 2H), 4.17-4.07 (m, 2H), 3.78-3.71 (m, 2H), 3.58-3.49 (m, 1H), 3.28-3.15 (m, 2H), 3.06-2.92 (m, 3H), 2.66-2.58 (m, 3H), 1.85-1.70 (m, 2H), 1.10 (d,J =6.8 Hz, 3H)。SFC : tR =1.880 min；柱：Chiralpak AD-3 50×3mm I.D.，3μm；流動相：A：CO2 ；B：異丙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B經0.15 min從40%至5%；流動速率：2.5 mL/min；柱溫：40℃。實施例 7 6-((1S,3R)-6-(1- 乙基 -1H- 吡唑 -4- 基 )-3- 甲基 -2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺
Figure 02_image100
在11-21℃下向化合物1h (製備於實施例 1 中，100 mg，0.171 mmol)、K2 CO3 (36 mg，0.256 mmol)和Pd(dppf)Cl2 ·CH2 Cl2 (50 mg，0.0855 mmol)於1,4-二噁烷/H2 O(3 mL/0.3 mL)中的溶液中添加硼酸酯7A (45 mg，0.205 mmol)。在100℃下攪拌所得混合物2小時。接著將反應混合物用水稀釋然後用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥然後過濾，於真空中濃縮濾液以得到粗殘餘物，其通過矽膠柱層析(0-20%乙酸乙酯於石油醚中)純化，獲得呈黃色固體狀的標題產物實施例 7 (36.3 mg，97%純度，39%產率)。LCMS: tR =1.283 min，於10-80AB_3min_220&254層析(A：Xtimate C18, 2.1×30mm, 3μm；B：XBrige Shield RP18 2.1×50mm)中，MS (ESI) m/z=531.3 [M+H]+ 。HPLC : tR =3.95 min，於10-80_CD_1.2ml. met XBridge Shield RP 18 2.1×50mm 5μm中。SFC 法 : tR =1.707 min；100%光學純度；柱：Chiralpak AD-3 50×3mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B經0.15 min從40%至5%；流動速率：2.5 mL/min；柱溫：40℃。 1 H NMR (400MHz, CDCl3 ) δ=7.84 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.22 (s, 1H), 7.16 (d,J= 8.0 Hz, 2H), 6.83 (d,J= 7.6 Hz, 1H), 6.79 (d,J= 8.4 Hz, 1H), 4.90 (s, 1H), 4.49 (dt,J= 46.8 Hz, 6.0 Hz, 2H), 4.18 (q,J= 7.2 Hz, 2H), 4.14-4.04 (m, 2H), 3.79-3.70 (m, 2H), 3.57-3.47 (m, 1H), 3.27-3.13 (m, 2H), 3.05-2.89 (m, 3H), 2.68-2.56 (m, 3H), 1.83-1.70 (m, 2H), 1.50 (t,J= 7.2 Hz, 3H), 1.07 (d,J= 6.4 Hz, 3H)。實施例 8 6-((1S,3R)-6-(1- 環丙基 -1H- 吡唑 -4- 基 )-3- 甲基 -2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺
Figure 02_image102
在11-21℃下向化合物1h (製備於實施例 1 中，100 mg，0.171 mmol)、K2 CO3 (36 mg，0.256 mmol)和Pd(dppf)Cl2 ·CH2 Cl2 (50 mg，0.0855 mmol)於1,4-二噁烷/H2 O(3 mL/0.3 mL)中的溶液中添加硼酸酯8A (45 mg，0.205 mmol)。在100℃下攪拌所得混合物2小時。接著將反應混合物用水稀釋然後用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥然後過濾，於真空中濃縮濾液以得到粗殘餘物，其通過矽膠柱層析(0-20%乙酸乙酯於石油醚中)純化，獲得呈灰白色固體狀的標題產物化合物 8 (29.2 mg，97.3%純度，30.6%產率)。LCMS: tR =1.736min，於10-80AB_4min_220&254.lcm層析(A：Xtimate C18,2.1×30mm,3μm B：XBrige Shield RP18 2.1×50mm)中，MS (ESI) m/z=543.3 [M+H]+ 。HPLC: tR =2.59 min，於10-80_AB_1.2ml.met. HPLC-AUltimate C18 3×50mm 3μm中。SFC 法 : tR =1.928 min；柱：Chiralpak AD-3 50×3mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B經0.15 min從40%至5%；流動速率：2.5 mL/min；柱溫：40℃。 1 H NMR (400 MHz, CD3 OD) δ=7.98 (s, 1H), 7.78 (d,J= 2.8 Hz, 1H), 7.76 (s, 1H), 7.33 (s, 1H), 7.23-7.18 (m, 1H), 7.12 (d,J= 8.4 Hz, 1H), 6.94 (dd,J= 2.4, 8.4 Hz, 1H), 6.70 (d,J= 8.0 Hz, 1H), 4.85 (s, 1H), 4.48 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.23-4.11 (m, 1H), 3.94 (br s, 2H), 3.72-3.60 (m, 1H), 3.57-3.46 (m, 1H), 3.39-3.32 (m, 1H), 3.29-3.23 (m, 1H), 3.18 (br s, 2H), 2.97-2.91 (m, 1H), 2.80 (t,J =7.2 Hz, 2H), 2.68 (dd,J= 4.4, 16.0 Hz, 1H), 1.91-1.66 (m, 2H), 1.13-1.03 (m, 7H)。實施例 9 6-((1S,3R)-6-(1-( 二氟甲基 )-1H- 吡唑 -4- 基 )-3- 甲基 -2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺
Figure 02_image104
在11-21℃下向化合物1h (製備於實施例 1 中，100 mg，0.171 mmol)、K2 CO3 (36 mg，0.256 mmol)和Pd(dppf)Cl2 ·CH2 Cl2 (50 mg，0.0855 mmol)於1,4-二噁烷/H2 O(3 mL/0.3 mL)中的溶液中添加硼酸酯9A (45 mg，0.205 mmol)。在100℃下攪拌所得混合物2小時。接著將反應混合物用水稀釋然後用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(30 mL)洗滌，經Na2 SO4 乾燥然後過濾，於真空中濃縮濾液以得到粗殘餘物，其通過矽膠柱層析(0-20%乙酸乙酯於石油醚中)純化，獲得呈灰色固體狀的標題產物化合物 9 (36.5 mg，96%純度，38.61%產率)。LCMS: tR =1.569 min，於10-80AB_3min_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=553.2 [M+H]+ 。HPLC: tR =3.32 min，於10-80_AB_1.2ml層析(Ultimate C18 3×50mm 3μm)中。SFC 法 ： tR =1.736 min；柱：Chiralcel OJ-3 100×4.6 mm I.D.，3 μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min，流動速率：2.8 mL/min；柱溫：40℃ 1 H NMR (400 MHz, CD3 OD) δ=8.36 (s, 1H), 8.05 (s, 1H), 7.78 (d,J =2.8 Hz, 1H), 7.47 (t,J =59.6 Hz, 1H), 7.42 (s, 1H), 7.29 (dd,J =2.0 Hz, 8.0 Hz, 1H), 7.13 (d,J =8.8 Hz, 1H), 6.95 (dd,J =2.8, 8.8 Hz, 1H), 6.76 (d,J =8.0 Hz, 1H), 4.82 (s, 1H), 4.47 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.18-4.08 (m, 1H), 3.93-3.85 (m, 2H), 3.60-3.50 (m, 1H), 3.40-3.33 (m, 1H), 3.30-3.26 (m, 1H), 3.14-3.07 (m, 2H), 3.00-2.89 (m, 1H), 2.78-2.66 (m, 3H), 1.86-1.73 (m, 2H), 1.09 (d,J =6.4 Hz, 3H)。實施例 10 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1- 甲基 -1H- 吡唑 -3- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺 方法一：
Figure 02_image106
用於製備化合物 10 的程式：
Figure 02_image108
向化合物1d (1.9 g，5.87 mmol)於甲苯(50 mL)和乙酸(0.8 mL)中的溶液中添加化合物1E (1.09 g，5.87 mmol)。在80℃下攪拌混合物2天。混合物經濃縮且將殘餘物溶解於二氯甲烷(30 mL)中且用飽和碳酸氫鈉水溶液(30 mL)洗滌，用二氯甲烷(30 mL×3)萃取水層。合併的有機層經無水硫酸鈉乾燥，過濾且濃縮以獲得粗產物，其通過快速柱(0-30%乙酸乙酯於石油醚中)純化，獲得呈油狀的化合物10a (1.7 g，含有1.5當量化合物1E )且將0.8 g化合物1d 再迴圈。含有10a 的混合物不經進一步純化即直接使用。僅通過H NMR觀測到一種主要異構體且表徵如下。LCMS: tR =1.033 min，於5-95AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=491.0 and 493.0 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=8.55 (d,J =2 Hz, 1H), 7.72 (dd,J =2.4 Hz, 8.8 Hz, 1H), 7.43-7.32 (m, 6H), 6.80 (d,J =8.4 Hz, 1H), 6.74-6.71 (m, 2H), 5.02 (s, 2H), 4.93 (s, 1H), 3.50-3.42 (m, 1H), 3.29-3.18 (m, 1H), 3.15 (dd,J =4.4 Hz, 16.4 Hz, 1H), 3.00-2.88 (m, 1H), 2.58 (dd,J =5.6 Hz, 16 Hz, 1H), 1.08 (d,J =6.8 Hz, 3H)。
Figure 02_image110
向化合物10a (1.7 g，3.46 mmol)和化合物1F (2.25 g，4.64 mmol，67%純度)於1,4-二噁烷(60 mL)中的混合物中添加t-BuONa(2.7 g，27.68 mmol)和Brettphos Pd G3(313 mg，0.34 mmol)。將所得混合物在氮氣下在80℃下攪拌16小時。混合物經濃縮。添加水(30 mL)且用乙酸乙酯(30 mL×4)萃取。將合併的有機層用鹽水(50 mL×3)洗滌，經無水硫酸鈉乾燥，過濾且濃縮以獲得粗產物，其通過製備型TLC(石油醚/乙酸乙酯=25/1 4次，和石油醚/乙酸乙酯= 20/1 4次)，接著通過柱層析(0-50%乙酸乙酯於石油醚中至0-10%甲醇於二氯甲烷中)純化，獲得呈黃色油狀的產物10b (700 mg，21.9%產率(兩步))。LCMS: tR =0.761 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=543.2 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.84 (d,J =2.8 Hz, 1H), 7.44-7.30 (m, 5H), 7.15 (d,J =8.4 Hz, 1H), 6.81-6.76 (m, 2H), 6.74-6.69 (m, 2H), 5.01 (s, 2H), 4.87 (s, 1H), 4.50 (dt,J =47.2 Hz, 6.0 Hz, 2H), 3.97 (brs, 1H), 3.78-3.71 (m, 2H), 3.53-3.47 (m, 1H), 3.23-3.12 (m, 2H), 3.04-2.87 (m, 3H), 2.63-2.57 (m, 3H), 1.83-1.69 (m, 2H), 1.07 (d,J =6.8 Hz, 3H)。
Figure 02_image112
向化合物10b (0.7 g，1.29 mmol)於甲醇(30 mL)中的混合物中添加10% Pd/C(100 mg)。將所得混合物在50℃下在氫氣氣氛(50 psi)下攪拌16小時。通過矽藻土墊過濾混合物且濃縮濾液以獲得粗產物，其通過柱層析(0-10%甲醇於二氯甲烷中)純化，獲得呈油狀的化合物1g (380 mg，65%產率)。 1 H NMR (400MHz, CDCl3 ) δ=7.81 (d,J =2.8 Hz, 1H), 7.18 (d,J =8.8 Hz, 1H), 6.79 (dd,J =2.4 Hz, 8.4 Hz, 1H), 6.68 (d,J =8.4 Hz, 1H), 6.54 (d,J =2.4 Hz, 1H), 6.48 (dd,J =2.4 Hz, 8.4 Hz, 1H), 4.85 (s, 1H), 4.50 (dt,J =47.2 Hz, 5.6 Hz, 2H), 4.13-4.02 (m, 2H), 3.78-3.74 (m, 2H), 3.51-3.41 (m, 1H), 3.22-3.05 (m, 2H), 3.02-2.94 (m, 3H), 2.65 (t,J =7.2 Hz, 2H), 2.51 (dd,J =6 Hz, 16.4 Hz, 1H), 1.86-1.71 (m, 3H), 1.06 (d,J =6.8 Hz, 3H)。
Figure 02_image114
向化合物1g (335 mg，0.74 mmol)、三乙胺(224 mg，2.22 mmol)於二氯甲烷(15 mL)中的混合物中添加化合物10A (555 mg，1.48 mmol)。將所得混合物在25℃下攪拌5小時。將混合物用水(20 mL)淬滅，用二氯甲烷(30 mL×4)萃取。水層也含有產物，因此分別濃縮有機層和水層。有機層通過柱層析(0-10%甲醇於二氯甲烷中)純化，獲得呈黃色固體狀的化合物1h (198 mg)。水層通過柱層析(0-10%甲醇於二氯甲烷中)純化，獲得呈黃色固體狀的化合物1h (100 mg)，60.7%總產率。LCMS: tR =0.761 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=585.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=11.30 (brs, 1H), 8.05-7.90 (m, 1H), 7.51 (brs, 2H), 7.38 (s, 1H), 7.31-7.22 (m, 1H), 7.10-7.04 (m, 1H), 5.36 (brs, 1H), 4.65-4.43 (m, 5H), 4.28 (brs, 1H), 4.09 (brs, 1H), 3.96-3.87 (m, 2H), 3.60 (dd,J =9.6 Hz, 15.6 Hz, 1H), 3.45-3.38 (m, 1H), 3.24-3.16 (m, 1H), 3.07-3.01 (m, 2H), 2.75 (dd,J =4.4 Hz, 16.4 Hz, 1H), 2.00-1.90 (m, 2H), 1.01 (d,J =6.4 Hz, 3H)。
Figure 02_image116
向化合物1h (140 mg，0.24 mmol)和化合物10B (55 mg，0.26 mmol)於1,4-二噁烷/水(10 mL/1 mL)中的混合物中添加碳酸鉀(83 mg，0.60 mmol)和Pd(dppf)Cl2· CH2 Cl2 (20 mg，0.024 mmol)。將所得混合物在氮氣下在100℃下攪拌16小時。混合物經濃縮且通過柱層析(0-10%甲醇於二氯甲烷中)，接著通過製備型TLC(二氯甲烷/甲醇=15/1 2次)純化，獲得52 mg產物，其與18 mg1h 規模的試驗性反應物組合。手性HPLC譜顯示光學純度為85%。產物另外通過手性SFC[柱：DAICEL CHIRALCEL OJ-H(250 mm×30 mm，5 μm)，條件：40% ETOH(0.1% NH3. H2 O)，流動速率(mL/min)：70]分離，獲得呈黃色固體狀的化合物 10 (46.7 mg，26.7%產率)。通過2D NMR確認最終化合物的立體化學。LCMS: tR =0.710 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=517.1 [M+H]+ 。LCMS: tR =0.700 min，於5-95AB_1.5min_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=517.1 [M+H]+ 。HPLC : tR =4.04 min，於10-80_CD_1.2ml層析(Ultimate C18 2.1×50mm 5μm)中 1 H NMR (400MHz, CDCl3 ) δ 7.85 (d,J =2.8 Hz, 1H), 7.58 (s, 1H), 7.43 (dd,J =1.2 Hz, 8 Hz, 1H), 7.35 (d,J =2.4 Hz, 1H), 7.13 (d,J =8.8 Hz, 1H), 6.87 (d,J =8 Hz, 1H), 6.78 (dd,J =2.8 Hz, 8.4 Hz, 1H), 6.48 (d,J =2.4 Hz, 1H), 4.92 (s, 1H), 4.50 (dt,J =47.2 Hz, 6 Hz, 2H), 4.16-4.07 (m, 1H), 4.01 (brd,J =7.6 Hz, 1H), 3.94 (s, 3H), 3.75 (q,J =6 Hz, 2H), 3.57-3.50 (m, 1H), 3.30-3.14 (m, 2H), 3.07-2.97 (m, 1H), 2.95-2.89 (m, 2H), 2.70-2.59 (m, 3H), 1.83-1.70 (m, 2H), 1.08 (d,J =6.4 Hz, 3H)。SFC : tR =1.853 min；方法：柱：Chiralpak AD-3 50×3 mm I.D.，3μm；流動相：A：CO2 ；B：IPA(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B於0.15 min內從40%至5%；流動速率：2.5mL/min；柱溫：40℃。 方法二：
Figure 02_image118
用於製備化合物 10 的程式：
Figure 02_image120
在-65℃至-70℃下在氮氣下向化合物10c (14.0 g，49.38 mmol)於THF(160 mL)中的溶液中逐滴添加n-BuLi溶液(921.7 ml，54.32 mmol，2.5 M於己烷中)。出現黃色溶液。在添加之後，在-65℃至-70℃下逐滴添加化合物1A (10 g，42.15 mmol)於THF(50 mL)中的溶液。在此溫度下攪拌反應混合物2小時。接著在-65℃至-70℃下向此上述混合物中添加1 M檸檬酸溶液(100 mL)，出現白色懸浮液。使混合物升溫到室溫，用水(200 mL)稀釋且用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(300 mL)洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮。殘餘物通過矽膠柱層析(0-5%乙酸乙酯於石油醚中)純化，獲得呈白色固體狀的純化合物10d (8.10 g)和不純產物(1.90 g，50%純度)。產率：68%。 1 H NMR (400MHz, CDCl3 ): δ=7.40-7.32 (m, 2H), 7.17 (t,J= 7.6 Hz, 1H), 7.12 (d,J= 7.6 Hz, 1H), 4.37 (br s, 1H), 3.89 (br s, 1H), 2.91-2.77 (m, 1H), 2.64 (dd,J= 7.2, 13.2 Hz, 1H), 1.43 (s, 9H), 1.09 (d,J= 6.4 Hz, 3H)。
Figure 02_image122
將化合物10d (4.2 g，13.4 mmol)、化合物10B (3.07 g，14.7 mmol)、Pd(dppf)Cl2 ·CH2 Cl2 (1.1 g，1.34 mmol)和碳酸鉀(4.6 g，33.5 mmol)於1,4-二噁烷/水(60/6 mL)中的混合物在100℃下在氮氣氣氛下攪拌15小時。將反應物用水(50 mL)淬滅且用乙酸乙酯(300 mL×2)萃取。將合併的有機層用鹽水(200 mL)洗滌經無水硫酸鈉乾燥然後在真空中濃縮，以得到粗殘餘物，其通過矽膠柱層析(乙酸乙酯/石油醚=0-20%)純化，獲得呈褐色油狀的標題產物10e (3.3 g，78%產率)。LCMS : tR =0.856 min，於5-95AB_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z= 338.0 [M+Na]+ 。 1 H NMR : (400MHz, CDCl3 ) δ=7.64 (d,J =7.6 Hz, 1H), 7.62 (s, 1H), 7.38 (d,J= 2.0 Hz, 1H), 7.32 (t,J= 8.0 Hz, 1H), 7.13 (d,J= 7.6 Hz, 1H), 6.54 (d,J= 2.0 Hz, 1H), 4.41 (brs, 1H), 4.01-3.91 (m, 1H), 3.96 (s, 3H), 2.90 (dd,J= 5.6 Hz和12.8 Hz, 1H), 2.70 (dd,J =7.2和13.6 Hz, 1H), 1.43 (s, 9H), 1.11 (d,J= 6.4 Hz, 3H)。
Figure 02_image124
將10e (3.0 g，9.5 mmol)和HCl/甲醇(40 mL，4 M)於甲醇(20 mL)中的混合物在10℃下攪拌2小時。在真空中濃縮反應物以去除大部分溶劑且將殘餘物用氫氧化鈉溶液(1.0 mL，15%)、乙酸乙酯(50 mL)和甲醇(4 mL)處理。將混合物攪拌10分鐘且過濾。在真空中濃縮濾液以獲得粗產物。將粗物質和濾餅分別通過矽膠快速柱層析純化(用A/B=5%-20%洗提，A：2% NH3 .H2 O/MeOH的混合物溶劑，B：CH2 Cl2 )且與洗提組合，獲得呈黃色固體狀的產物10f (1.7 g，83%產率)。LCMS: tR =0.724 min，於5-95AB_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=216.0 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=7.68-7.63 (m, 2H), 7.62 (d,J= 2.0 Hz, 1H), 7.37 (t,J= 8.0 Hz, 1H), 7.18 (d,J= 7.6 Hz, 1H), 6.63 (d,J= 2.8 Hz, 1H), 3.95 (s, 3H), 3.37-3.33 (m, 1H), 2.86-2.71 (m, 2H), 1.18 (d,J= 6.4 Hz, 3H)。
Figure 02_image126
將4f (1.4 g，6.5 mmol)和CF3 CH2 OTf(1.82 g，7.8 mmol)和DIEA(1.67 g，13.0 mmol於1,4-二噁烷(20 mL)中的混合物在80℃下攪拌5小時。在真空中濃縮反應混合物以得到粗物質，其通過柱層析純化(用0-20%乙酸乙酯/石油醚洗提)，獲得呈無色油狀的產物10g (1.7 g，88%產率)。LCMS: tR = 0.674 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=298.0 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=7.69-7.61 (m, 2H), 7.39 (d,J= 2.4 Hz, 1H), 7.34 (t,J =8.0 Hz, 1H), 7.12 (d,J= 7.6 Hz, 1H), 6.55 (d,J= 2.4 Hz, 1H), 3.97 (s, 3H), 3.18 (q,J= 9.6 Hz, 2H), 3.13-3.04 (m, 1H), 2.78 (dd,J =6.8 Hz和13.6 Hz, 1H), 2.67 (dd,J =6.4 Hz和13.6 Hz, 1H), 1.10 (d,J= 6.0 Hz, 3H)。
Figure 02_image128
向化合物10g (400 mg，1.35 mmol)和化合物1E (300 mg，1.61 mmol)於二氯乙烷(6 mL)中的混合物中添加三氟乙酸(462 mg，4.05 mmol)且將混合物在100℃下在氮氣下攪拌10小時。將反應混合物與具有相同規模的其它三個平行批次合併(總共1.6 g化合物10g )。向合併的混合物中添加碳酸氫鈉飽和水溶液(50 mL)且用乙酸乙酯(100 ml×3)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且在真空中濃縮。殘餘物通過矽膠快速柱層析純化(用0-20%乙酸乙酯/石油醚洗提)，獲得呈褐色油狀的產物10h (1.4 g，56%產率)，且再迴圈以獲得呈褐色油狀的起始物質10g (400 mg)。獲得的化合物10h 為不可分離的混合物且根據H NMR譜，比率為約8.3:1。主要異構體表徵如下。LCMS: tR =1.101 min，於5-95AB_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=464.8 and 466.8 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ) δ=8.58 (d,J= 2.4 Hz, 1H), 7.73 (dd,J= 2.4, 8.4 Hz, 1H), 7.61 (s, 1H), 7.46 (dd,J= 1.6 Hz和8.4 Hz, 1H), 7.36 (d,J= 2.0 Hz, 1H), 7.32 (d,J= 8.4 Hz, 1H), 6.90 (d,J= 8.0 Hz, 1H), 6.49 (d,J= 2.0 Hz, 1H), 5.00 (s, 1H), 3.95 (s, 3H), 3.57-3.48 (m, 1H), 3.32-3.20 (m, 2H), 3.03-2.93 (m, 1H), 2.69 (dd,J= 5.2, 16.0 Hz, 1H), 1.09 (d,J= 6.4 Hz, 3H)。
Figure 02_image130
將化合物10h (400 mg，0.86 mmol)、化合物1F (148 mg，1.12 mmol)、Brettphos Pd G3 (195 mg，0.215 mmol)和t-BuONa(232 mg，2.4 mmol)於1,4-二噁烷(5 mL)中的混合物在氮氣下在60℃下攪拌15小時。將反應物與其它三個平行批次組合(總共1.6 g化合物10h )且在真空中濃縮組合的混合物。將殘餘物懸浮於70 mL混合物溶劑(二氯甲烷/甲醇=55 mL/15 mL)中。將混合物攪拌30分鐘且過濾，在真空中濃縮以得到粗物質，且通過柱層析直接純化(用0-5%甲醇/二氯甲烷洗提)，獲得呈褐色油狀的產物化合物 10 (1.4 g，89%光學純度，78%產率)。主要異構體表徵如下。LCMS: tR =0.723 min，於5-95AB_1.5min_shimadzu.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=517.1 [M+H]+ 。手性 SFC ： 89%光學純度。柱：Chiralpak AD-3 50 ×3 mm I. D.，3μm OJ-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：異丙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B於0.15 min內從40%至5%；流動速率：2.5mL/min；柱溫：40℃。 1 H NMR: (400MHz, CDCl3 ) δ=7.85 (d,J= 2.4 Hz, 1H), 7.58 (s, 1H), 7.43 (dd,J= 1.6 Hz和8.0 Hz, 1H), 7.35 (d,J= 2.4 Hz, 1H), 7.13 (d,J= 8.8 Hz, 1H), 6.87 (d,J= 8.0 Hz, 1H), 6.78 (dd,J= 2.8, 8.8 Hz, 1H), 6.48 (d,J= 2.4 Hz, 1H), 4.92 (s, 1H), 4.50 (dt,J= 47.2 Hz和6.0 Hz, 2H), 4.11-4.07 (m, 1H), 3.94 (s, 3H), 4.00-3.90 (m, 1H), 3.74 (q,J= 5.6 Hz, 2H), 3.57-3.51 (m, 1H), 3.31-3.18 (m, 2H), 3.07-2.95 (m, 1H), 2.92-2.87 (m, 2H), 2.66 (dd,J= 4.8, 16.0 Hz, 1H), 2.60 (t,J= 7.2 Hz, 2H), 1.82-1.77 (m, 1H), 1.76-1.71 (m, 1H), 1.08 (d,J= 6.8 Hz, 3H)。實施例 11 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(4H-1,2,4- 三唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image132
用於製備11F 的程式：
Figure 02_image134
向化合物11F_1 (13.7 g，157.4 mmol)於DMF(150 mL)中的溶液中添加亞硫醯氯(46.4 g，393.6 mmol)。接著將混合物在12℃下攪拌48小時。將沉澱物過濾且用DMF(10 mL)，接著用甲基叔丁基醚(10 mL)洗滌。在真空乾燥之後，獲得呈白色固體狀的產物(29 g，86.1%產率)。LCMS: tR =0.123 min，於5-95AB_220&254 _Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=142.8 [M+H]+ 。 1 H NMR (400MHz, D2 O): δ=8.33 (s, 2H), 3.21 (br s, 12H)。 用於製備化合物 11 的程式：
Figure 02_image136
向化合物10d (製備於實施例 10 中，5.60 g，17.82 mmol)於二氯甲烷(90 mL)中的溶液中添加三氟乙酸(30 mL)，將反應混合物在12-26℃下攪拌0.5小時。將混合物在攪拌下倒入碳酸氫鈉飽和水溶液(400 mL)中且用碳酸鉀固體鹼化至pH=8-9。混合物用乙酸乙酯(200 mL×3)萃取，經無水硫酸鈉乾燥，過濾且在真空中濃縮，得到呈無色油狀的粗化合物11a (4.20 g，90%純度，100%產率)。LCMS: tR =0.555 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 213.9 and 215.9 [M+H]+ 。 1 H NMR (400MHz, CD3 OD): δ=7.46-7.34 (m, 2H), 7.22 (t,J= 7.6 Hz, 1H), 7.18 (d,J= 7.6 Hz, 1H), 3.20-3.04 (m, 1H), 2.71-2.57 (m, 2H), 1.09 (d,J= 6.4 Hz, 3H)。
Figure 02_image138
向化合物11a (4.20 g，17.65 mmol，90%純度)於1,4-二噁烷(80 mL)中的溶液中添加N,N-二異丙基乙胺(6.2 mL，35.30 mmol)，接著添加化合物1C (4.10 g，17.65 mmol)。將反應混合物在80℃下在氮氣下攪拌16小時。將混合物用水(100 mL)稀釋且用乙酸乙酯(20 mL×3)萃取。將合併的有機層用鹽水(150 mL)洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮。殘餘物通過矽膠柱層析(0-5%乙酸乙酯/石油醚)純化，獲得呈無色油狀的化合物11b (3.70 g，70.8%產率)。LCMS: tR =0.656 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 295.9 and 297.9 [M+H]+ 。 1 H NMR (CD3 OD 400MHz): δ=7.39 (s, 1H), 7.35 (dt,J= 7.2, 2.0 Hz, 1H), 7.23-7.15 (m, 2H), 3.29-3.15 (m, 2H), 3.03-2.90 (m, 1H), 2.81 (dd,J= 5.6, 13.2 Hz, 1H), 2.50 (dd,J= 7.6, 13.2 Hz, 1H), 1.01 (d,J= 6.4 Hz, 3H)。
Figure 02_image140
在氮氣下向Pd(OAc)2 (561 mg，2.498 mmol)、BINAP (3.19 g，4.996 mmol)和碳酸銫(12.21 g，37.47 mmol)的混合物中添加化合物11b (3.70 g，12.49 mmol)於甲苯(60 mL)中的溶液和化合物11B (3.75 g，20.69 mmol)於甲苯(10 mL)中的溶液。將反應混合物在氮氣下在100℃下攪拌16小時。將混合物用水(150 mL)稀釋且用乙酸乙酯(30 mL×3)萃取。將合併的有機層用鹽水(200 mL)洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮。殘餘物通過矽膠快速層析(0-5%乙酸乙酯/石油醚)純化，獲得呈黃色油狀的化合物11c (3.70 g，80%純度，59.8%產率)。LCMS: tR =0.788 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 397.2 [M+H]+ 。
Figure 02_image142
將化合物11c (3.70 g，80%純度，7.47 mmol)、羥胺鹽酸鹽(1.04 g，14.94 mmol)和乙酸鈉(1.59 g，19.42 mmol)於甲醇(370 mL)中的混合物在16-24℃下攪拌一小時。在真空中濃縮混合物，將殘餘物用碳酸氫鈉飽和水溶液(100 mL)和乙酸乙酯(30 mL)處理然後分離。水層用乙酸乙酯(20 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且在真空中濃縮。殘餘物通過矽膠快速層析(0-10%乙酸乙酯/石油醚)純化，獲得呈黃色膠狀的化合物11d (1.90 g，90%純度，97.7%產率)。LCMS: tR =0.126 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 233.0 [M+H]+ 。 1 H NMR (400MHz, CD3 OD): δ=7.07-6.96 (m, 1H), 6.63-6.56 (m, 2H), 6.54 (d,J= 7.2 Hz, 1H), 3.22 (q,J= 9.6 Hz, 2H), 3.01-2.89 (m, 1H), 2.69 (dd,J= 6.4, 13.2 Hz, 1H), 2.44 (dd,J= 7.6, 13.2 Hz, 1H), 1.03 (d,J= 6.4 Hz, 3H)。
Figure 02_image144
將化合物11d (1.90 g，7.36 mmol，90%純度)、1E (1.37 g，7.36 mmol)和水(662 mg，36.8 mmol)於乙酸(20 ml)中的混合物在80℃下在氮氣下攪拌一小時。將混合物在攪拌條件下倒入碳酸氫鈉飽和水溶液(300 mL)中，用碳酸鉀固體鹼化至pH=8-9且用乙酸乙酯(50 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且在真空中濃縮。通過矽膠快速層析(0-10%乙酸乙酯/石油醚)純化殘餘物，獲得呈橙色膠狀的化合物11e (2.87 g，90%純度，87.8%產率)。產物為不可分離的非對映異構體且根據H NMR譜，比率為約4：1。主要異構體表徵如下：LCMS: tR =0.745 min，於5-95AB_1.5min_220&254.lcm層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z 400.1 and 402.1 [M+H]+ 。 1 H NMR (400MHz, CD3 OD): δ=8.51 (d,J= 2.4 Hz, 1H), 7.86 (dd,J= 2.8, 8.8 Hz, 1H), 7.30 (d,J= 8.8 Hz, 1H), 6.57-6.49 (m, 2H), 6.46 (dd,J= 2.4, 8.4 Hz, 1H), 4.85 (s, 1H), 3.48-3.33 (m, 2H), 3.11 (dd,J= 4.8, 16.0 Hz, 1H), 3.00-2.83 (m, 1H), 2.55 (dd,J= 4.8, 16.0 Hz, 1H), 1.06 (d,J= 6.4 Hz, 3H)。
Figure 02_image146
在12℃下向化合物11e (200 mg，0.5 mmol)於吡啶(5 mL)中的溶液中添加化合物11F (362.5 mg，1.5 mmol)。接著將混合物在130℃下攪拌2小時。在減壓下濃縮反應混合物以得到粗產物，其通過快速柱(0-15%甲醇/乙酸乙酯)純化，得到呈無色油狀的11f (200 mg，88%產率)。LCMS: tR =0.885 min，於5-95AB_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=452.0 and 454.0 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.57 (d,J =2.4 Hz, 1H), 8.45 (s, 2H), 7.79 (dd,J= 2.4, 8.4 Hz, 1H), 7.41 (d,J= 8.4 Hz, 1H), 7.17 (s, 1H), 7.14-7.10 (m, 2H), 5.06 (s, 1H), 3.55-3.49 (m, 1H), 3.35-3.19 (m, 2H), 3.02-2.89 (m, 1H), 2.69 (dd,J= 6.0, 16.8 Hz, 1H), 1.12 (d,J= 6.8 Hz, 3H)。
Figure 02_image148
在氮氣下向11f (150 mg，0.33 mmol)、1F (231.0 mg，0.43 mmol，67%純度)和t-BuONa(319.6 mg，3.3 mmol))於1,4-二噁烷(3 mL)中的混合物中添加Brettphos-Pd G3 (45.9 mg，0.05 mmol)。接著將反應物加熱至80℃且在80℃下攪拌16小時。用乙酸乙酯(100 mL)和水(30 mL)稀釋混合物。在分離之後，用乙酸乙酯(300 mL×2)萃取水層。將合併的有機層用鹽水(30 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且濃縮以得到粗產物，其通過快速柱(0-5%乙酸乙酯/石油醚)，接著通過手性SFC(柱：DAICEL CHIRALPAK IC(250 mm×30 mm，10 μm)；條件：55% B(A：CO2 ，B：EtOH (0.1% NH3. H2 O))；流動速率：70 ml/min)純化，獲得呈白色固體狀的化合物 11 (27.8 mg，16.6%產率，tR ：2.647 min)且通過2D NMR確認立體化學。還獲得呈白色固體狀的另一異構體化合物 11a (8.2 mg，4.9%產率)。手性 SFC 分析方法 ：tR =2.153 min，85.81%光學純度；方法：柱：Chiralpak IC100×4.6 mm I.D., 3 μm；流動相：40%甲醇(0.05% DEA)於CO2 中；流動速率：3 mL/min；柱溫：40℃。化合物 11 ：LCMS: tR =0.676 min，於5-95AB_220&254 _Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=504.3 [M+H]+ 。HPLC: tR =2.31 min，於10-80_AB_1.2ml.met (Ultimate C18 3×50mm 3μm)中。SFC: tR =2.647 min，於IC_3_40_3ML_8min_10CM.M中(柱：Chiralpak IC 100×4.6mm I.D., 3μm；流動相：40%甲醇(0.05% DEA)於CO2 中；流動速率：3 mL/min；柱溫：40℃)。 1 H NMR (400MHz, CDCl3 ): δ=8.44 (s, 2H), 7.85 (d,J= 2.8 Hz, 1H), 7.23 (d,J= 8.4 Hz, 1H), 7.14 (s, 1H), 7.10-7.05 (m, 2H), 6.85 (dd,J= 2.8, 8.4 Hz, 1H), 4.99 (s, 1H), 4.51 (dt,J= 47.2 Hz和6.0 Hz, 2H), 4.34 (br s, 1H), 4.22-4.13 (m, 1H), 3.85 (t,J =7.2 Hz, 2H), 3.61-3.51 (m, 1H), 3.31-3.18 (m, 2H), 3.18-3.08 (m, 2H), 3.05-2.91 (m, 1H), 2.74 (t,J =7.2 Hz, 2H), 2.67 (dd,J =5.6 Hz和16.8 Hz, 1H), 1.81-1.73 (m, 2H), 1.11 (d,J= 6.4 Hz, 3H)。化合物 11a ：LCMS: tR =0.712 min，於5-95AB_220&254 _Shimadzu.lcm (Xtimate C18 2.1×30mm)中，MS (ESI) m/z=504.3 [M+H]+ 。HPLC: tR =2.33 min，於10-80_AB_1.2ml.met (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CDCl3 ): δ=8.43 (s, 2H), 7.91 (s, 1H), 7.31 (d,J= 8.4 Hz, 1H), 7.12-7.07 (m, 3H), 6.91 (d,J= 7.2 Hz, 1H), 5.21 (s, 1H), 4.92 (br s, 1H), 4.53 (dt,J= 46.8 Hz和5.6 Hz, 2H), 4.36-4.26 (m, 1H), 4.09-3.99 (m, 2H), 3.61-3.39 (m, 3H), 3.34-3.18 (m, 2H), 3.01-2.92 (m, 2H), 2.83 (d,J= 6.4 Hz, 2H), 2.07-1.88 (m, 2H), 1.35 (d,J= 6.0 Hz, 3H)。實施例 12 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(2H-1,2,3- 三唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image150
用於製備化合物 12 的程式：
Figure 02_image152
向化合物1h (製備於實施例 1 中，500 mg，0.855 mmol)、CuI(16 mg，0.0856 mmol)和[1,1'-雙(二苯膦基)二茂鐵]二氯化鈀(ii)(31 mg，0.0428 mmol)於N,N-二甲基甲醯胺(5 mL)中的混合物中添加二異丙胺(173 mg，1.71 mmol)，接著添加化合物12A (168 mg，1.71 mmol)然後將混合物在氮氣下在80℃下攪拌2小時。將混合物用水(50 mL)稀釋且用乙酸乙酯(30 mL×3)萃取。在減壓下濃縮合併的有機層以得到粗產物，其通過矽膠柱層析純化，用0-3%甲醇/二氯甲烷洗提，獲得呈褐色膠狀的化合物12a (300 mg，61.2%產率，90%純度)。LCMS: tR =0.795 min，於5-95AB_220&254_Shimadzu.lcm (Merck RP18 2.5-2mm)中，MS (ESI) m/z=533.4 [M+H]+ 。
Figure 02_image154
在室溫(4-20℃)下向化合物12a (300 mg，0.507 mmol，90%純度)於四氫呋喃(3 mL)中的溶液中添加四丁基氟化銨(1.0 mL，1.014 mmol，1 M於四氫呋喃中)。接著在室溫(4-20℃)下攪拌反應混合物1小時。將所得反應混合物用飽和碳酸氫鈉(30 mL)稀釋然後用乙酸乙酯(10 mL×3)萃取。合併的有機層用飽和碳酸氫鈉(40 mL×2)洗滌，經無水硫酸鈉乾燥然後過濾。於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，獲得呈紫色固體狀的化合物12b (150 mg，64.3%產率)。LCMS: tR =0.760 min，於5-95AB_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=461.3 [M+H]+ 。 1 H NMR (400 MHz, CD3 OD): δ=7.77 (d,J= 2.4 Hz, 1H), 7.26 (s, 1H), 7.17-7.06 (m, 2H), 6.94 (dd,J= 2.8, 8.8 Hz, 1H), 6.71 (d,J= 8.4 Hz, 1H), 4.86 (s, 1H), 4.46 (dt,J= 47.6, 5.6 Hz, 2H), 4.17-1.04 (m, 1H), 3.82 (t,J= 7.2 Hz, 2H), 3.58 - 3.46 (m, 1H), 3.41 (s, 1H), 3.36-3.32 (m, 1H), 3.28-3.17 (m, 1H), 3.01 (br s, 2H), 2.97-2.86 (m, 1H), 2.73-2.56 (m, 3H), 1.87-1.69 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H)。
Figure 02_image156
將化合物12b (120 mg，0.261 mmol)、疊氮基三甲基矽烷(285 mg，2.476 mmol)和碘化銅(I)(12.4 mg，0.0653 mmol)於N,N-二甲基甲醯胺(9.6 mL)中的混合物在100℃下攪拌2小時。接著於真空中濃縮反應混合物以得到粗產物，其通過逆相矽膠柱層析(0-100%甲醇/水(0.1%氫氧化銨))純化然後另外通過製備型TLC(二氯甲烷/甲醇=6:1 (0.1%氫氧化銨))純化，獲得呈無色膠狀的化學純產物(25 mg)。接著通過手性SFC[柱：Phenomenex-Amylose-1(250 mm×30 mm，5 μm)；條件：35%乙醇(0.1%氫氧化銨)於二氧化碳中；流動速率：50 mL/min]純化化學純產物，獲得呈白色固體狀的化合物 12 (12.8 mg，94.90%化學純度，99.48%光學純度，9.8%產率)。LCMS: tR =3.134 min，於10-80CD_7min_220&254.lcm層析(A:Xtimate C18, 2.1×30mm, 3μm B: XBrige Shield RP18 2.1×50mm)中，MS (ESI) m/z 504.3[M+H]+ 。HPLC: tR =2.92 min，於10-80_CD_1.2ml.met.層析(XBridge Shield RP 18 2.1×50mm 5μm)中。SFC: tR =3.577 min；柱：Chiralcel OD-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：甲醇(0.05% DEA)；梯度B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。 1 H NMR (400MHz, CD3 OD): δ=8.10 (s, 1H), 7.78 (d,J= 2.8 Hz, 1H), 7.63 (s, 1H), 7.49 (d,J= 8.0 Hz, 1H), 7.14 (d,J= 8.8 Hz, 1H), 6.95 (dd,J= 2.8, 8.4 Hz, 1H), 6.81 (d,J= 8.0 Hz, 1H), 4.91 (s, 1H), 4.47 (dt,J= 47.2, 6.0 Hz, 2H), 4.19-4.05 (m, 1H), 3.92-3.78 (m, 2H), 3.61-3.49 (m, 1H), 3.41-3.33 (m, 1H), 3.30-3.26 (m, 1H), 3.12-3.02 (m, 2H), 3.02-2.87 (m, 1H), 2.78-2.65 (m, 3H), 1.88-1.70 (m, 2H), 1.10 (d,J= 6.4 Hz, 3H)。實施例 13 5- 氟 -N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image158
用於製備實施例 13 的程式：
Figure 02_image160
向化合物13a (400 mg，1.72 mmol)和化合物13A (526.3 mg，2.58 mmol)於i- PrOH(20 mL)中的溶液中添加TFA(0.4 mL，5.16 mmol)。將混合物在氮氣下在25℃下攪拌16小時。將反應物倒入NaHCO3 水溶液(10 mL)和鹽水(50 mL)的混合溶液中且用乙酸乙酯(150 mL×3)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥，過濾，濃縮。粗物質通過矽膠柱層析(0-10%乙酸乙酯/石油醚)純化為呈黃色固體狀的不可分離的13：1非對映異構體(550 mg，76.6%產率)。通過2D NMR(NOE)確認主要反式異構體13b 。LCMS: tR =0.917 min，於5-95AB_ 1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=419.0 [M+H]+ 。SFC( 方法 1): tR =3.326 min；90.35%純度。方法：柱：Chiralpak AD-3 150×4.6mm I.D., 3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 2.5 min；流動速率：2.5 mL/min；柱溫：35℃。SFC( 方法 2): tR =3.255 min；90.38%純度。方法：柱：Chiralcel OD-3 150×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA) 梯度：B於5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 2.5 min；流動速率：2.5 mL/min；柱溫：35℃。 1 H NMR (400MHz, CDCl3 ) δ=8.30 (d,J= 1.6 Hz, 1H), 7.49 (dd,J= 8.8, 1.6 Hz, 1H), 6.57 (d,J= 8.8 Hz, 1H), 6.53 (d,J= 2.0 Hz, 1H), 6.45 (dd,J= 8.0, 2.4 Hz, 1H), 5.15 (s, 1H), 3.53-3.45 (m, 1H), 3.20-3.10 (m, 1H), 2.97 (dd,J= 16.4, 4.8 Hz, 1H), 2.93-2.86 (m, 1H), 2.47 (dd,J= 16.8, 7.2 Hz, 1H), 0.99 (d,J= 6.4 Hz, 3H)。
Figure 02_image162
在24-31℃下在氮氣下向化合物13b (500 mg，1.2 mmol)和化合物13B (857 mg，1.8 mmol)於1,4-二噁烷(20 mL)中的溶液中添加t-BuONa(634 mg，6.6 mmol)，接著添加Brettphos-Pd-G3(54 mg，0.06 mmol)。將反應混合物在80℃下在氮氣下攪拌16小時。接著將混合物用H2 O(100 mL)稀釋且用乙酸乙酯(100 mL×3)萃取，用鹽水(30 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且蒸發，以得到粗產物。粗物質通過矽膠柱層析(0-5%甲醇/二氯甲烷)純化，獲得呈黃色固體狀的化合物13c (500 mg，89.1%產率)。LCMS: tR =0.739 min，於5-95AB_ 1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=471.2 [M+H]+ 。
Figure 02_image164
在28℃下向化合物13c (450 mg，0.96 mmol)和PhNTf2 (985.9 mg，1.92 mmol)於二氯甲烷(20 mL)中的溶液中添加三乙胺(291.4 mg，2.88 mmol)。將反應混合物在80℃下在氮氣下攪拌5小時。接著將混合物用水(100 mL)稀釋且用二氯甲烷(100 mL×3)萃取，用鹽水(30 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且蒸發，以得到粗產物。粗物質通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，獲得呈黃色固體狀的化合物13d (550 mg，95.5%產率)，其含有一些Et3 N。LCMS: tR =0.860 min，於5-95AB_1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=603.3 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.69 (d,J= 2.0 Hz, 1H), 7.05 (d,J= 2.4 Hz, 1H), 6.97 (dd,J= 8.4, 2.4 Hz, 1H), 6.87 (d,J= 8.4 Hz, 1H), 6.57 (dd,J= 11.6, 2.0 Hz, 1H), 5.21 (s, 1H), 5.05 (d,J= 6.4 Hz, 1H), 4.51 (dt,J= 46.8, 5.6 Hz, 2H), 4.34-4.28 (m, 1H), 4.11 (br s, 2H), 3.68-3.63 (m, 1H), 3.53 (br s, 2H), 3.03-2.99 (m, 3H), 2.61 (br dd,J= 16.8, 6.8 Hz, 1H), 1.94-1.82 (m, 2H), 1.08 (d,J= 6.8 Hz, 3H)。
Figure 02_image166
在氮氣下向13d (150 mg，0.25 mmol)、6A (97 mg，0.50 mmol)、碳酸鉀(103.4 mg，0.75 mmol))於1,4-二噁烷(3 mL)和水(0.3 mL)中的混合物中添加Pd(dppf)Cl2 ∙CH2 Cl2 (40.8 mg，0.05 mmol)。接著將反應物加熱至100℃且在氮氣下在100℃下攪拌16小時。接著將混合物用水(50 mL)稀釋且用二氯甲烷(150 mL×3)萃取，用鹽水(50 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且蒸發以得到粗產物，其通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，以獲得粗產物。通過手性SFC(92.59%純度，柱：DAICEL CHIRALCEL OJ-H (250mm×30mm，5μm))；條件：35% B(A：CO2 ，B：0.1% NH3 H2 O/EtOH)；流動速率：60 mL/min)分離粗產物，得到呈黃色固體狀的實施例 13 (11.3 mg，8.7%產率)。LCMS: tR =0.743 min，於5-95AB_1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=521.4 [M+H]+ 。HPLC: tR =3.44 min，於10-80_AB_1.2ml.met.層析(Ultimate C18 3.0μm 3.0×50mm)中。SFC: tR =2.289 min；100%純度。方法：柱：Chiralcel OJ-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.1%乙醇胺)；梯度：B於4.5 min內從5%至40%，接著保持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。 1 H NMR (400MHz, CD3 OD) δ=7.89 (br s, 2H), 7.63 (d,J= 2.0 Hz, 1H), 7.34 (s, 1H), 7.24 (dd,J= 8.0, 1.6 Hz, 1H), 6.70 (s, 1H), 6.69-6.66 (m, 1H), 5.11 (s, 1H), 4.46 (dt,J= 47.2, 5.6 Hz, 2H), 4.15-4.11 (m, 1H), 3.91 (br t,J= 6.8 Hz, 2H), 3.61-3.54 (m, 1H), 3.31-3.30 (m, 1H), 3.24-3.08 (m, 3H), 3.00-2.87 (m, 1H), 2.77 (t,J= 7.6 Hz, 2H), 2.65 (dd,J= 16.0, 5.2 Hz, 1H), 1.87-1.71 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H)。 用於合成中間物13B 的程式：
Figure 02_image168
向化合物1F_2 (23 g，99.01 mmol)於甲苯(150 mL)中的溶液中添加TsOH∙H2 O(37.7 g，198.02 mmol)和TfOH(575 mg，3.83 mmol)。在50℃下攪拌所得混合物2小時。將反應混合物用乙酸乙酯(150 mL)稀釋且通過過濾快速地收集固體。將濾餅用乙酸乙酯(150 mL)洗滌且在高真空下乾燥，得到呈白色固體狀的化合物13B (47 g TsOH鹽，99%產率)。LCMS : tR =0.099 min，於0-60AB_2min_E_50_Agilent.M層析(Xtimate C18, 2.1×30mm, 3μm)中，MS (ESI) m/z= 133.1 [M+H]+ 。 1 H NMR (400MHz, MeOD): δ=7.73 (d,J= 8.0 Hz, 4H), 7.27 (d,J= 8.0 Hz, 4H), 4.70-4.20 (m, 7H), 3.50 (br t,J= 6.8 Hz, 2H), 2.39 (s, 6H), 2.09-2.01 (m, 1H), 2.00-1.92 (m, 1H)。實施例 14 3-((1S,3R)-1-(2,6- 二氟 -4-((1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 胺基 ) 苯基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 )-2,2- 二氟丙 -1- 醇
Figure 02_image170
用於製備實施例 14 的程式：
Figure 02_image172
在室溫(0-6℃)下向化合物2D (1.60 g，6.63 mmol)於1,4-二噁烷(30 mL)中的混合物中添加DIEA(3.5 mL，19.89 mmol)，接著添加含化合物1c (3.20 g，6.63 mmol)的1,4-二噁烷(2 mL)。接著將反應混合物在80℃下在氮氣下攪拌24小時。接著將反應混合物用水(40 mL)稀釋且用乙酸乙酯(10 mL×3)萃取。將合併的有機層用鹽水(80 mL×3)洗滌，經無水硫酸鈉乾燥，過濾然後在真空中濃縮，以得到粗產物，其通過矽膠柱層析(0-5%乙酸乙酯/石油醚)純化，獲得呈無色膠狀的化合物14a (1.9 g，50%產率)。LCMS: tR =0.996 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=574.1 [M+H]+ 。 1 H NMR (400 MHz, CDCl3 ):δ =7.73-7.63 (m, 4H), 7.48-7.30 (m, 11H), 7.20 (t,J= 8.0 Hz, 1H), 6.87-6.81 (m, 2H), 6.79 (d,J= 7.6 Hz, 1H), 5.05 (s, 2H), 3.94-3.74 (m, 2H), 3.26-3.04 (m, 2H), 3.04-2.93 (m, 1H), 2.75 (dd,J= 13.2, 6.4 Hz, 1H), 2.57 (dd,J= 13.6, 7.2 Hz, 1H), 1.10-1.03 (m, 9H)。
Figure 02_image174
向化合物14a (400 mg，0.697 mmol)於乙酸乙酯(30 mL)中的溶液中添加10% Pd/C(80 mg，50 w%水)。接著將反應混合物在40℃下在氫氣氣氛(15 psi，H2 氣球)下攪拌16小時。接著通過矽藻土過濾反應混合物。向濾液中添加10% Pd/C(80 mg，50 w%水)。將所得混合物在50℃下在H2 氣氛(15 psi，H2 氣球)下攪拌5小時。接著通過矽藻土過濾反應混合物。於真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-10%乙酸乙酯/石油醚)純化，獲得呈無色膠狀的化合物14b (300 mg，89%產率)。LCMS: tR =0.936 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=484.1 [M+H]+ 。 1 H NMR (400 MHz, CDCl3 ):δ =7.76-7.63 (m, 4H), 7.52-7.36 (m, 6H), 7.14 (t,J= 8.0 Hz, 1H), 6.74 (d,J= 7.2 Hz, 1H), 6.68 (dd,J= 8.4, 2.4Hz, 1H), 6.64 (s, 1H), 3.91-3.72 (m, 2H), 3.25-3.05 (m, 2H), 3.05-2.97 (m, 1H), 2.71 (dd,J= 13.6, 6.8Hz, 1H), 2.57 (dd,J= 13.6, 6.4Hz, 1H), 1.09 (d,J= 6.4 Hz, 3H), 1.07 (s, 9H)。
Figure 02_image176
在室溫(15-23℃)下向化合物14b (600 mg，1.24 mmol))於甲苯(27 mL)中的溶液中添加乙酸(3 mL)和14A (300 mg，1.36 mmol)。接著將反應混合物在80℃下攪拌20小時。接著於真空中濃縮反應混合物。將殘餘物用乙酸乙酯(20 mL)和水(20 mL)處理，接著分離。用乙酸乙酯(20 mL×3)萃取水層。將合併的有機層用飽和NaHCO3 溶液(20 mL×3)洗滌，經無水硫酸鈉乾燥且過濾。於真空中濃縮濾液且通過矽膠柱層析(0-20%乙酸乙酯/石油醚)純化，獲得呈黃色油狀的9:1不可分離的非對映異構體(400 mg，46.7%)。化合物14c 為主要非對映異構體。LCMS: tR =1.120 min，於5-95AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=688.3 [M+2+H]+ 。
Figure 02_image178
在室溫(13-25℃)下向Brettphos Pd G3(69.7 mg，0.077 mmol)和t-BuONa(440.6 mg，4.59 mmol)的混合物中添加14c (350 mg，0.510 mmol)和1F (367.4 mg，1.02 mmol)於1,4-二噁烷(9 mL)中的溶液。接著將反應混合物在80℃下攪拌3小時。接著過濾反應混合物且於真空中濃縮濾液。將殘餘物用乙酸乙酯(20 mL)和水(20 mL)處理，然後分離。用乙酸乙酯(20 mL×3)萃取水層。將合併的有機層用鹽水(20 mL×3)洗滌，經無水硫酸鈉乾燥且過濾。於真空中濃縮濾液且通過矽膠柱(0-10% MeOH/CH2 Cl2 )純化，獲得呈黃色油狀的5 (230 mg，61.1%)。LCMS: tR =0.887 min，於5-95AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=738.4 [M+H]+ 。 1 H NMR (400 MHz, MeOD):δ =7.63-7.57 (m, 4H), 7.50-7.33 (m, 6H), 6.52-6.39 (m, 3H), 5.89 (d,J= 11.6 Hz, 2H), 4.96 (s, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 4.01-3.82 (m, 2H), 3.78-3.67 (m, 2H), 3.59-3.35 (m, 2H), 3.06 (br dd,J= 15.2, 4.8 Hz, 2H), 2.90 (t,J= 7.2 Hz, 2H), 2.64 (br t,J= 7.2 Hz, 3H), 2.40 (dd,J= 15.2, 2.4 Hz, 1H), 1.85-1.65 (m, 2H), 1.07-0.95 (m, 12H)。
Figure 02_image180
在室溫(16-28℃)下向化合物14d (230 mg，0.312 mmol)於二氯甲烷(7 mL)中的溶液中添加Et3 N(94.7 mg，0.936 mmol)，接著添加PhNTf2 (223 mg，0.624 mmol)。接著在室溫(16-28℃)下攪拌反應混合物16小時。接著於真空中濃縮反應混合物。將殘餘物用乙酸乙酯(20 mL)和水(20 mL)處理，然後分離。用乙酸乙酯(20 mL×3)萃取水層。將合併的有機層用鹽水(20 mL×3)洗滌，經無水硫酸鈉乾燥且過濾。於真空中濃縮濾液且通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，獲得呈灰藍色固體狀的化合物14e (220 mg，76.9%)。LCMS: tR =1.018 min，於5-95AB_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=870.5 [M+H]+ 。 1 H NMR (400 MHz, MeOD):δ =7.65-7.56 (m, 4H), 7.50-7.36 (m, 6H), 7.09 (d,J= 2.4 Hz, 1H), 7.00 (dd,J= 8.4, 2.4Hz, 1H), 6.85 (d,J= 8.4 Hz, 1H), 5.94 (br d,J= 11.6 Hz, 2H), 5.10 (s, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.96-3.86 (m, 2H), 3.79 (br s, 2H), 3.57 (br s, 1H), 3.50-3.39 (m, 1H), 3.20-3.05 (m, 2H), 3.04-2.92 (m, 2H), 2.80-2.65 (m, 3H), 2.60 (dd,J= 16.0, 3.2 Hz, 1H), 1.85-1.68 (m, 2H), 1.06-0.94 (m, 12H)。
Figure 02_image182
在室溫(8-17℃)下向化合物14B (25 mg，0.086 mmol)、Pd(dppf)Cl2 .CH2 Cl2 (9.3 mg，0.015 mmol)和K2 CO3 (23.6 mg，0.171 mmol)的混合物中添加化合物14e (50 mg，0.057 mmol)於1,4-二噁烷/H2 O(5 mL (v/v=10:1))中的溶液。接著將反應混合物在100℃下攪拌20小時。接著將反應混合物與以相同方式進行的前述先導批料(10 mg化合物14e )組合。過濾反應混合物且於真空中濃縮濾液。將殘餘物用乙酸乙酯(10 mL)和水(10 mL)處理，然後分離。接著用乙酸乙酯(10 mL×3)萃取水層且將合併的有機層用鹽水(10 mL×3)洗滌，經無水硫酸鈉乾燥且過濾。於真空中濃縮濾液且通過矽膠柱層析(0-10%甲醇/CH2 Cl2 )純化，獲得呈灰藍色固體狀的化合物14f (60 mg，65.5%)。LCMS: tR =1.046 min，於5-95AB_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=788.6 [M+H]+ 。 1 H NMR (400 MHz, MeOD):δ =7.88 (s, 2H), 7.67-7.55 (m, 4H), 7.50-7.33 (m, 6H), 7.27 (s, 1H), 7.20 (br d,J= 8.0 Hz, 1H), 6.67 (d,J= 8.0 Hz, 1H), 5.92 (d,J= 11.6 Hz, 2H), 5.04 (s, 1H), 4.45 (dt,J= 47.2, 6.0 Hz, 2H), 4.03-3.85 (m, 2H), 3.76 (br t,J= 7.2 Hz, 2H), 3.59 (br d,J= 7.2 Hz, 1H), 3.49-3.35 (m, 1H), 3.22-3.05 (m, 2H), 2.96 (br t,J= 6.8 Hz, 2H), 2.86-2.71 (m, 1H), 2.67 (t,J= 7.2 Hz, 2H), 2.55 (br dd,J= 2.8, 15.6 Hz, 1H), 1.86-1.66 (m, 2H), 1.04-0.96 (m, 12H)。
Figure 02_image184
在室溫(8-24℃)下向化合物14f (40 mg，0.063 mmol)於THF(5 mL)中的溶液中添加TBAF(0.189 mL，0.189 mmol，1 M於THF中)。接著在室溫(8-24℃)下攪拌反應混合物3小時。將反應混合物用飽和NaHCO3 溶液(10 mL)稀釋且用乙酸乙酯(10 mL×3)萃取水層。將合併的有機層用鹽水(10 mL×3)洗滌，經無水硫酸鈉乾燥且過濾。於真空中濃縮濾液且通過製備型TLC(CH2 Cl2 /甲醇=9:1)純化，獲得粗產物。接著將粗產物另外通過手性SFC(柱：Lux Cellulose-2 150×4.6mm I.D.，3μm；梯度：40%甲醇(0.05% DEA)於CO2 中；流動速率：2.5 mL/min；柱溫：40℃)純化，得到呈灰白色固體狀的實施例 14 (13.6 mg，38.2%)。LCMS: tR= 1.623 min，於10-80AB_4min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=550.1H]+ 。HPLC: tR= 1.91min，於10-80_AB_1.2ml.met. HPLC-A Ultimate C18 3×50mm 3μm中。SFC: tR= 2.788 min，純度：100%，柱：Lux Cellulose-2 150×4.6mm I.D.，3μm；梯度：40%甲醇(0.05% DEA)於CO2 中；流動速率：2.5 mL/min；柱溫：40℃。 1 H NMR (400 MHz, MeOD):δ =7.91 (br s, 2H), 7.30 (s, 1H), 7.23 (d,J= 8.0 Hz, 1H), 6.71 (d,J= 8.0 Hz, 1H), 6.10 (d,J= 11.2 Hz, 2H), 5.07 (s, 1H), 4.45 (dt,J= 47.2, 6.0 Hz, 2H), 4.11 (br t,J= 6.4 Hz, 1H), 3.91 (br d,J= 4.8 Hz, 2H), 3.82-3.66 (m, 1H), 3.59 (br s, 1H), 3.43-3.32 (m, 1H), 3.24 (br d,J= 4.4 Hz, 1H), 3.20-3.04 (m, 3H), 2.82-2.75 (m, 2H), 2.75-2.67 (m, 1H), 2.64 (dd,J= 3.2, 15.6 Hz, 1H), 1.89-1.70 (m, 2H), 1.05 (d,J= 6.4 Hz, 3H)。實施例 15 2,2- 二氟 -3-((1S,3R)-1-(3- 氟 -5-((1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 胺基 ) 吡啶 -2- 基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 ) 丙 -1- 醇
Figure 02_image186
用於製備實施例 15 的程式：
Figure 02_image188
向化合物14b (200 mg，0.414 mmol)、化合物13A (101.4 mg，0.497 mmol)和Yb(OTf)3 (10.3 mg，0.0166 mmol)於MeCN(6 mL)中的溶液中添加水(37.3 μL，2.07 mmol)。此後，將反應物在氮氣下在70℃下攪拌12小時。濃縮混合物以得到粗產物，其通過矽膠柱層析(0-18%乙酸乙酯/石油醚)純化，獲得呈黃色油狀的10:1不可分離的非對映異構體(215.8 mg，78.0%產率)。化合物15a 為主要非對映異構體。LCMS: tR =1.133 min，於5-95AB_1.5min_220&254.lcm層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=671.4 [M+H+2]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.33 (d,J= 1.2 Hz, 1H), 7.66-7.61 (m, 4H), 7.49-7.36 (m, 7H), 6.65-6.60 (m, 2H), 6.57-6.53 (m, 1H), 4.86 (s, 1H), 3.99-3.87 (m, 1H), 3.77-3.69 (m, 1H),3.63-3.55 (m, 1H), 3.32-3.19 (m, 1H), 2.99 (dd,J= 16.0, 4.0 Hz, 1H), 2.87-2.77(m, 1H), 2.53 (dd,J= 16.4, 6.8 Hz, 1H), 1.07-1.03 (m, 12H)。
Figure 02_image190
在氮氣下向化合物15a (195.8 mg，0.293 mmol)、13B (209.0 mg，0.439 mmol)於1,4-二噁烷(8 mL)中的混合物中添加Brettphos Pd-G3 (26.5 mg，0.0293 mmol)和t-BuONa (154.7 mg，1.612 mmol)。接著將反應混合物在80℃下在氮氣下攪拌12小時。將混合物與以相同方式進行的平行批料(90 mg化合物14b )合併。在真空中濃縮反應混合物且通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，獲得呈黃色油狀的化合物15b (201.6 mg，65.3%平均產率)。LCMS: tR =0.862 min，於5-95AB_1.5min_220&254.lcm層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z= 721.6 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.67-7.59 (m, 5H), 7.45-7.35 (m, 6H), 6.59-6.52 (m, 2H), 6.44-6.34 (m, 2H), 5.17 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.46 (s, 1H), 4.05-3.92 (m, 2H), 3.73-3.66 (m, 3H), 3.59-3.53 (m, 1H), 3.18 (q,J= 14.8 Hz, 1H), 3.06-2.98 (m, 2H), 2.92 (dd,J= 16.4, 4.4 Hz, 1H), 2.78 (q,J= 14.8 Hz, 1H), 2.66 (t,J= 7.2 Hz, 2H), 2.49 (dd,J= 16.4, 7.6 Hz, 1H), 1.83-1.72 (m, 2H), 1.07-1.01 (m, 12H)。
Figure 02_image192
向化合物15b (201.6 mg，0.280 mmol)於二氯甲烷(5 mL)中的混合物中添加三乙胺(188.5 μL，1.12 mmol)，接著添加PhNTf2 (150.0 mg，0.420 mmol)。接著在室溫(24-35℃)下攪拌反應混合物12小時。將混合物與另一批料(48.3 mg化合物15b )合併。接著在真空中濃縮混合物以得到粗產物，其通過矽膠柱層析(0-8%甲醇/二氯甲烷)純化，獲得呈黃色油狀的化合物15c (227.1 mg，76.8%產率)。LCMS: tR =1.035 min，於5-95AB_1.5min_220&254.lcm層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z= 853.6 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.67-7.60 (m, 5H), 7.49-7.35 (m, 6H), 7.04 (d,J= 2.4 Hz, 1H), 6.95 (dd,J =8.4, 2.0 Hz, 1H), 6.84 (d,J= 8.8 Hz, 1H), 6.39 (dd,J= 12.0, 2.0 Hz, 1H), 5.24 (s, 1H), 4.59-4.52 (br s, 1H), 4.50 (dt,J= 47.2, 5.6 Hz, 2H), 4.16-4.05 (m, 1H), 4.00-3.90 (m, 1H), 3.90-3.82 (m, 2H), 3.73-3.61 (m, 2H), 3.25-3.17 (m, 3H), 3.02 (dd,J= 16.4, 4.4 Hz, 1H), 2.87-2.76 (m, 3H), 2.59 (dd,J= 16.4, 6.4 Hz, 1H), 1.87-1.76 (m, 2H), 1.10-1.00 (m, 12H)。
Figure 02_image194
將化合物15c (227.1 mg，0.267 mmol)、化合物6A (117.9 mg，0.401 mmol)、Pd(dppf)Cl2 .二氯甲烷(43.6 mg，0.0534 mmol)和K2 CO3 (92.3 mg，0.668 mmol)的混合物用氮氣吹掃。接著在氮氣下向混合物中添加1,4-二噁烷和H2 O的混合溶液(v/v=4:1)(7.5 mL)。將所得混合物在100℃下在氮氣下攪拌3小時。將混合物過濾且在真空下濃縮以得到粗產物，其通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，獲得呈褐色固體狀的化合物15d (總共182.7 mg，88.8%產率)。LCMS: tR =0.918 min，於5-95AB_1.5min_220&254.lcm層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=771.3 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.76 (s, 2H), 7.64-7.57 (m, 5H), 7.45-7.34 (m, 6H), 7.23 (s, 1H), 7.15 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 7.6 Hz, 1H), 6.38 (d,J= 11.6 Hz, 1H), 5.23 (s, 1H), 4.74-4.58 (br s, 1H), 4.46 (dt,J= 46.8, 5.2 Hz, 2H), 4.12-4.04 (m, 1H), 4.00-3.84 (m, 3H), 3.74-3.60 (m, 2H), 3.25-3.12 (m, 3H), 3.01 (d,J= 13.2 Hz, 1H), 2.86-2.73 (m, 3H), 2.58 (dd,J= 16.4, 7.2 Hz, 1H), 1.85-1.71 (m, 2H), 1.08-1.00 (m, 12H)。
Figure 02_image196
向化合物15d (182.7 mg，0.237 mmol)於四氫呋喃(5 mL)的混合物中添加TBAF溶液(356 μL，0.356 mmol，1 M於THF中)。將所得混合物在60℃下在氮氣下攪拌12小時。將混合物用飽和NaHCO3 溶液調節至pH約8。將混合物用乙酸乙酯(20 mL×3)萃取，用鹽水(20 mL×2)洗滌，經無水Na2 SO4 乾燥，過濾且在減壓下濃縮，獲得粗物質。通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化混合物，獲得80.9 mg 10:1不可分離的非對映異構體，其另外通過手性SFC(柱：DAICEL CHIRALCEL OJ-H(250mm×30 mm，5 μm)；條件：(0.1% NH3 H2 O)MeOH；流動速率：60 mL/min)純化，獲得呈白色固體狀的化合物實施例 15 (43.5 mg，34.5%產率)。HPLC: tR =3.29 min，於0-60_AB_1.2ml.met.層析(Ultimate C18 3×50mm 3μm)中。SFC: tR =2.479 min；99.84%純度。方法：柱：Chiralcel OJ-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：甲醇(0.1%乙醇胺)；梯度：B於4.5 min內從5%至40%，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。 1 H NMR (400MHz, CDCl3 ): δ=7.80 (s, 2H), 7.75 (d,J= 1.6 Hz, 1H), 7.27-7.25 (m, 1H), 7.19 (d,J= 8.0 Hz, 1H), 6.74 (d,J= 8.4 Hz, 1H), 6.55 (dd,J= 11.6, 2.4 Hz, 1H), 5.18 (s, 1H), 4.50 (dt,J= 46.8, 5.6 Hz, 2H), 4.38 (d,J= 6.8 Hz, 1H), 4.11-4.03 (m, 1H), 3.95-3.79 (m, 1H), 3.72 (q,J= 6.0 Hz, 2H), 3.76-3.67 (m, 1H), 3.62-3.51 (m, 1H), 3.29 (dd,J= 16.0, 4.8 Hz, 1H), 3.23-3.13 (m, 1H), 3.00-2.91 (m, 2H), 2.90-2.76 (m, 1H), 2.69-2.58 (m, 3H), 1.82-1.77 (m, 2H),1.12 (d,J= 6.4 Hz, 3H)。實施例 16 2,2- 二氟 -3-((1S,3R)-1-(5-((1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 胺基 ) 吡啶 -2- 基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 ) 丙 -1- 醇
Figure 02_image198
用於製備實施例 16 的程式：
Figure 02_image200
向化合物14b (1.2 g，2.48 mmol)於DCE(10 mL)中的的混合物中添加化合物1E (560 mg，2.98 mmol)和TFA(0.554 mL，7.44 mmol)，將所得混合物在12-18℃下攪拌16小時。將反應物用NaHCO3 飽和水溶液鹼化以調節至pH=8，接著用乙酸乙酯(200 mL×3)萃取。將合併的有機層用鹽水(100 mL)洗滌，經無水硫酸鈉乾燥且過濾，於真空中濃縮濾液以得到粗產物，其通過製備型HPLC[Boston Green ODS，40×150 mm，10 μm，120A 條件：90-100% B(A：水(0.1% TFA) B：CH3 CN)；流動速率：25 mL/min]純化。將含有所需化合物的洗提份用NaHCO3 飽和水溶液鹼化以調節至pH=8且用乙酸乙酯(200 mL×3)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液，獲得呈黃色固體狀的化合物16a (1.0 g，61%產率)。LCMS: tR =1.116 min，於5-95AB_220&254.lcm層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=653.3 [M+H+2]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.51 (d,J= 2.0 Hz, 1H), 7.62 (br t,J= 6.4 Hz, 4H), 7.56 (dd,J= 8.4, 2.4 Hz, 1H), 7.47-7.42 (m, 2H), 7.38 (t,J= 7.6 Hz, 4H), 7.15 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 8.4 Hz, 1H), 6.60-6.52 (m, 2H), 4.98 (s, 1H), 4.82 (br s, 1H), 3.91-3.69 (m, 2H), 3.45-3.37 (m, 1H), 3.25-3.10 (m, 1H), 2.97-2.75 (m, 2H), 2.54 (dd,J=16.4 , 6.4 Hz, 1H), 1.05 (d,J= 6.4 Hz, 3H), 1.01 (s, 9H)。
Figure 02_image202
在氮氣下向化合物16a (0.9 g，1.38 mmol)於1,4-二噁烷(10 mL)中的的混合物中添加化合物1F (0.995 g，2.76 mmol)、Brettphos Pd G3(313 mg，0.345 mmol)、t-BuONa (1.19 g，12.42 mmol)。將所得混合物在氮氣下在80℃下攪拌4小時。將反應混合物與平行批次的反應物(100 mg化合物16a )組合且過濾，在真空中濃縮濾液以得到殘餘物，其用乙酸乙酯(200 mL)和水(150 mL)稀釋，有機層用乙酸乙酯(200 mL×3)萃取，將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(甲醇/二氯甲烷=0-10%)純化，獲得呈褐色固體狀的化合物16b (450 mg，42%產率)。LCMS: tR =0.837 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=703.5 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.77 (d,J= 2.8 Hz, 1H), 7.66-7.60 (m, 4H), 7.47-7.40 (m, 2H), 7.40-7.33 (m, 4H), 6.98 (d,J= 8.4 Hz, 1H), 6.66 (d,J= 8.4 Hz, 1H), 6.61 (dd,J= 8.4, 2.8 Hz, 1H), 6.53 (d,J= 2.4 Hz, 1H), 6.44 (dd,J= 8.4, 2.4 Hz, 1H), 4.90 (s, 1H), 4.48 (dt,J= 47.2 , 6.0 Hz, 2H), 4.06-3.97 (m, 1H), 3.94-3.82 (m, 2H), 3.77-3.66 (m, 3H), 3.46-3.38 (m, 1H), 3.13 (q,J= 14.4 Hz, 1H), 2.91-2.83 (m, 3H), 2.60 (t,J =7.2 Hz, 2H), 2.49 (dd,J= 16.4, 7.6 Hz, 1H), 1.82-169 (m, 2H), 1.05-1.01 (m, 12H)。
Figure 02_image204
向化合物16b (380 mg，0.54 mmol)於二氯甲烷(6 mL)中的混合物中添加Et3 N(0.194 mL，1.32 mmol)，接著添加PhNTf2 (387 mg，1.08 mmol)。將所得混合物在13-23℃下攪拌16小時。將反應混合物與平行批次的反應物(70 mg化合物16b )組合且在真空中濃縮以得到殘餘物，其用二氯甲烷(200 mL)和水(150 mL)稀釋。將有機層用二氯甲烷(200 mL×3)萃取，且將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾。在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(甲醇/二氯甲烷=0-10%)純化並且在高真空中進一步濃縮，得到呈黃色固體狀的化合物16c (450 mg，75%產率)。LCMS: tR =0.949 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=835.5 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.76 (d,J= 2.4 Hz, 1H), 7.64-7.60 (m, 4H), 7.49-7.33 (m, 6H), 7.24-7.18 (m, 2H), 7.02 (s, 1H), 6.94 (s, 1H), 6.64 (dd,J= 8.4, 2.4 Hz, 1H), 4.97 (s, 1H),  4.45 (dt,J= 47.2, 6.0 Hz, 2H), 4.11 (br s, 2H), 3.91-3.80 (m, 3H), 3.71 (q,J= 12.0 Hz, 1H), 3.54-3.44 (m, 1H), 3.14-3.12 (m, 3H), 2.97 (br dd,J= 16.4, 4.0 Hz, 1H), 2.87-2.77 (m, 1H), 2.72 (t,J= 7.2 Hz, 2H), 2.58 (br dd,J= 16.4, 6.8 Hz, 1H), 1.84-1.70 (m, 2H), 1.07-0.96 (m, 12H)。
Figure 02_image206
在氮氣下在16-25℃下向化合物16c (150 mg，0.179 mmol)、K2 CO3 (75 mg，0.539 mmol)和Brettphos Pd G3(25 mg，0.0239 mmol)於1,4-二噁烷/H2 O(5.5 mL，10/1 v/v)中的溶液中添加化合物14B (106 mg，0.359 mmol)。將混合物在氮氣下在100℃下攪拌16小時。在真空中濃縮反應物以得到殘餘物，用乙酸乙酯(100 mL)和水(80 mL)稀釋，且分離。水層用乙酸乙酯(100 mL×3)萃取，合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮以獲得粗物質，其通過製備型TLC(甲醇/二氯甲烷=1/10)純化，獲得呈黃色固體狀的化合物16d (65 mg，48%產率)。LCMS: tR= 0.861 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=753.6 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.82-7.77 (m, 3H), 7.67-7.61 (m, 4H), 7.48-7.41 (m, 2H), 7.40-7.35 (m, 4H), 7.24 (s, 1H), 7.18 (br d,J= 8.0 Hz, 1H), 6.99 (d,J= 8.4 Hz, 1H), 6.86 (d,J= 8.0 Hz, 1H), 6.60 (dd,J= 8.4, 3.2 Hz, 1H), 4.97 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.05-3.98 (m, 1H), 3.97-3.82 (m, 2H), 3.73 (s, 1H), 3.72-3.68 (m, 2H), 3.55-3.45 (m, 1H), 3.17 (q,J= 14.0 Hz, 1H), 3.00 (br dd,J= 16.0, 4.0 Hz, 1H), 2.92-2.83 (m, 3H), 2.64-2.56 (m, 3H), 1.78-1.72 (m, 2H), 1.07 (d,J= 6.8 Hz, 3H), 1.02 (s, 9H)。
Figure 02_image208
向化合物16d (60 mg，0.079 mmol)於THF(3 mL)中的混合物中添加TBAF溶液(0.24 mL，0.237 mmol，1 M於THF中)，將混合物在室溫(12-21℃)下攪拌4小時。將反應物用NaHCO3 飽和水溶液鹼化以調節至pH=8且用乙酸乙酯(100 mL×3)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾。在真空中濃縮濾液以獲得粗物質，其通過製備型TLC(甲醇/二氯甲烷=1/10)純化以得到呈淺黃色油狀的產物，然後凍幹以獲得呈黃色固體狀的所需產物實施例 16 (18.0 mg，43%產率)。LCMS: tR =0.988 min，於10-80AB_3min_220&254_Agilent, XBrige Shield RP18 2.1×50mm中，MS (ESI) m/z=515.3 [M+H]+ 。 1 H NMR (400MHz, CD3 OD): δ=7.91 (br s, 2H), 7.79 (d,J= 2.4 Hz, 1H), 7.37 (s, 1H), 7.26 (br d,J= 8.0 Hz, 1H), 7.05 (d,J= 8.4 Hz, 1H), 6.92 (dd,J= 8.4, 2.8 Hz, 1H), 6.74 (d,J= 8.0 Hz, 1H), 4.83 (s, 1H), 4.47 (dt,J= 47.2, 6.0 Hz, 2H), 4.16-4.07 (m, 1H), 3.86 (br t,J= 7.2 Hz, 2H), 3.71 (q,J= 13.2 Hz, 1H), 3.59-3.48 (m, 2H), 3.20-3.12 (m, 2H), 3.07 (br s, 2H), 2.82-2.64 (m, 4H), 1.85-1.71 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H)。HPLC: tR =3.02 min，於10-80_CD_1.2ml.met，層析(XBridge Shield RP 18 2.1×50mm 5μm)中。SFC: tR =4.451 min。方法：柱：Chiralcel OD-3 100×4.6 mm I.D., 3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。實 施 例 17 6-((1S,3R)-8- 氟 -3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺
Figure 02_image210
用於製備實施例 17 的程式：
Figure 02_image212
在-70℃下在10分鐘內向化合物17a (4.0 g，14 mmol)於THF(20 mL)中的溶液中逐滴添加n-BuLi(6.8 mL，17 mmol，2.5 M於己烷中)。在攪拌30分鐘之後，在-70℃下逐滴添加化合物1A (3.3 g，14 mmol)於THF(20 mL)中的溶液。在-70℃下攪拌所得混合物2小時。接著將反應物用1 N檸檬酸(30 mL)淬滅且用乙酸乙酯(30 mL×3)萃取。將合併的有機層用鹽水洗滌，經無水硫酸鈉乾燥然後過濾。於真空中蒸發濾液且將殘餘物通過C18-快速層析，洗提梯度40%至90% MeCN/水(0.02% FA)純化。將純洗提份蒸發至乾燥，獲得呈白色固體狀的化合物17b (480 mg，9.4%產率)。LCMS: tR =1.95 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA)，Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 360.4 [M+H]+ 。
Figure 02_image214
將化合物17b (460 mg，1.3 mmol)於TFA( 2mL)中的溶液在20℃下攪拌1小時。接著濃縮反應混合物且將殘餘物通過C18-快速層析，洗提梯度5%至40% MeCN/水(0.02% FA)純化。將純洗提份蒸發至乾燥，獲得呈白色固體狀的化合物17c (380 mg，97%產率)。LCMS: tR =1.32 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 260.2 [M+H]+ 。
Figure 02_image216
向化合物17c (350 mg，1.1 mmol)和DIEA(290 mg，2.2 mmol)於1,4-二噁烷(5 mL)中的溶液中添加CF3CH2OTf(520 mg，2.2 mmol)。將所得混合物在80℃下攪拌5小時。在真空中濃縮混合物且將殘餘物通過C18-快速層析，洗提梯度5%至60% MeCN/水(0.02% FA)純化。將純洗提份蒸發至乾燥，獲得呈白色固體狀的化合物17d (320 mg，82%產率)。LCMS: tR =1.44 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 342.4 [M+H]+ 。
Figure 02_image218
向化合物17d (320 mg，0.94 mmol)於甲醇(5 mL)中的溶液中添加Pd/C(64 mg，10重量%)。將所得混合物在20℃下攪拌16小時。接著過濾混合物且於真空中濃縮濾液。將殘餘物通過C18-快速層析，洗提梯度5%至60% MeCN/水(0.02% FA)純化。將純洗提份蒸發至乾燥，獲得呈白色固體狀的化合物17e (180 mg，76%)。LCMS: tR =0.96 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 252.2 [M+H]+ 。
Figure 02_image220
向化合物17e (180 mg，0.72 mmol)於異丙醇(5 mL)中的溶液中添加化合物1E (270 mg，2.2 mmol)和TFA(245 mg，2.2 mmol)。將所得混合物在20℃下攪拌2小時，接著在真空中濃縮混合物且將殘餘物通過C18-快速層析，洗提梯度5%至70% MeCN/水(0.02% FA)純化。將純洗提份蒸發至乾燥，以獲得呈白色固體狀的化合物17f (110 mg，37%)。LCMS: tR =1.81 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA), Warters Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 419.2, 421.2 [M+H]+ 。 1 H NMR (500 MHz, DMSO-d6): δ 9.88 - 9.59 (s, 1H), 8.54 - 8.53 (d, J=2.4 Hz, 1H), 8.06 - 8.03 (dd, J=2.4, 8.4 Hz, 1H), 7.42 - 7.37 (d, J=8.5 Hz, 1H), 6.42 - 6.41 (d, J=2.2 Hz, 1H), 6.37 - 6.33 (dd, J=2.3, 11.3 Hz, 1H), 5.04 - 5.02 (s, 1H), 3.60 - 3.51 (m, 1H), 3.09 - 3.01 (m, 2H), 2.59 - 2.55 (m, 2H), 1.02 - 0.99 (d, J=6.6 Hz, 3H)。
Figure 02_image222
向化合物17f (187 mg，0.39 mmol)和Brettphos-Pd-G3 (24 mg，0.026 mmol)於1,4-二噁烷(4 mL)中的混合物中添加叔丁醇鈉(150 mg，1.6 mmol)。將所得混合物在氮氣下在70℃下攪拌1小時。接著將混合物通過C18-快速層析，洗提梯度5%至60% MeCN/水(0.02% TFA)直接純化。將純洗提份蒸發至乾燥，獲得呈黃色固體狀的化合物17g (120 mg，87%產率)。LCMS: tR =1.14 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA), Warters Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 471.5 [M+H]+ 。
Figure 02_image224
向化合物17g (120 mg，0.21 mmol)和三乙胺(62 mg，0.62 mmol)於DCM(5 mL)中的溶液中添加PhNTf2 (147 mg，0.41 mmol)。將所得混合物在25℃下攪拌16小時。接著在真空中濃縮混合物且將殘餘物通過C18-快速層析，洗提梯度5%至80% MeCN/水(0.02% FA)純化。將純洗提份蒸發至乾燥，獲得呈白色固體狀的化合物17h (90 mg，59%產率)。LCMS: tR =1.49 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA), Warters Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 603.5 [M+H]+ 。
Figure 02_image226
向化合物17h (90 mg，0.15 mmol)、化合物14B (88 mg，0.30 mmol)、Pd2(dba)3(7 mg，0.0075 mmol)、1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷雜金剛烷(4 mg，0.015 mmol)於1,4-二噁烷(3 mL)和水(1 mL)中的混合物中添加碳酸鉀(62 mg，0.45 mmol)。將所得混合物在120℃下在微波中加熱15分鐘。接著將混合物通過C18-快速層析，洗提梯度5%至60% MeCN/水(0.02% TFA)直接純化。將純洗提份蒸發至乾燥，獲得呈黃色固體狀的化合物實施例 17 (52 mg，67%產率)。LCMS: tR =1.14 min，於3 min層析(3 min-5-95% MeCN/水(0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃)中，MS (ESI) m/z 521.5 [M+H]+ 。 1 H NMR (500 MHz, DMSO-d6) : δ10.23 - 9.95 (d, J=58.8 Hz, 1H), 8.16 - 8.01 (s, 2H), 7.84 - 7.71 (dd, J=2.8, 23.6 Hz, 1H), 7.32 - 7.28 (d, J=8.6 Hz, 1H), 7.28 - 7.26 (s, 1H), 7.24 - 7.18 (d, J=10.9 Hz, 1H), 7.16 - 7.05 (m, 1H), 6.98 - 6.58 (s, 1H), 5.11 - 5.08 (s, 1H), 4.59 - 4.55 (m, 2H), 4.49 - 4.46 (m, 1H), 4.35 - 4.30 (m, 2H), 4.09 - 4.07 (m, 1H), 3.90 - 3.87 (m, 1H), 3.63 - 3.56 (m, 1H), 3.37 - 3.28 (m, 2H), 3.23 - 3.15 (m, 1H), 3.10 - 3.01 (m, 1H), 2.79 - 2.60 (m, 2H), 1.96 - 1.84 (m, 2H), 1.06 - 0.98 (d, J=6.7 Hz, 3H)。實施例 18 6-((1S,3R)-7- 氟 -3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺
Figure 02_image228
製備實施例 18 的程式類似於製備實施例 17 的程式。關鍵步驟如下：
Figure 02_image230
向化合物18a (240 mg，0.955 mmol)於DCE(5 mL)中的混合物中添加化合物1E (213 mg，1.15 mmol)，接著添加TFA(327 mg，2.87 mmol)，將所得混合物在90℃下在氮氣下攪拌12小時。將反應物用NaHCO3 飽和水溶液鹼化以調節至pH=8，接著用乙酸乙酯(100 mL×3)萃取。將合併的有機層用鹽水(100 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(乙酸乙酯/石油醚=0-20%)純化，得到呈黃色固體狀的化合物18b (240 mg，57%產率)。LCMS: tR =2.395 min，於10-80AB_3min_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=418.9 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.58-8.55 (m, 1H), 7.79 (dd,J= 8.4, 2.4 Hz, 1H), 7.40 (d,J= 8.4 Hz, 1H), 6.74-6.71 (m, 1H), 6.63 (d,J= 11.6 Hz, 1H), 4.91 (s, 1H), 3.45-3.36 (m, 1H), 3.31-3.12 (m, 2H), 3.08-2.97 (m, 1H), 2.52 (dd,J= 16.4, 6.4 Hz, 1H), 1.08 (d,J= 6.8 Hz, 3H)。
Figure 02_image232
向化合物18b (240 mg，0.572 mmol)於1,4-二噁烷(5 mL)中的混合物中添加化合物13B (545 mg，1.144 mmol)、Brettphos-Pd-G3(52 mg，0.0572 mmol)和t-BuONa(495 mg，5.148 mmol)，將所得混合物在80℃下在氮氣下攪拌4小時。將反應混合物與平行批次的反應物(300 mg化合物18b )組合且過濾，在真空中濃縮濾液以得到殘餘物，其用二氯甲烷(100 mL)和水(50 mL)稀釋，有機層用二氯甲烷(50 mL×3)萃取，將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(甲醇/二氯甲烷=0-10%)純化，獲得呈淡黃色油狀的化合物18c (510 mg，84%產率)。基於H NMR，反式/順式的比為約3/1。LCMS: tR =0.797 min，於10-80AB_2.0min_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=471.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.79 (d,J= 2.8 Hz, 1H), 7.21 (d,J= 8.4 Hz, 1H), 6.81 (dd,J =8.8, 2.8 Hz, 1H), 6.61 (d,J= 8.8 Hz, 1H), 6.51 (d,J =12.0 Hz, 1H), 4.80 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H), 4.16-4.11 (m, 2H), 3.81-3.68 (m, 2H), 3.47-3.38 (m, 1H), 3.19-3.13 (m, 1H), 3.05-2.87 (m, 4H), 2.70-2.59 (m, 2H), 2.45 (dd,J= 16.0, 6.4 Hz, 1H), 1.83-1.72 (m, 2H), 1.04 (d,J= 6.4 Hz, 3H)。
Figure 02_image234
向化合物18c (300 mg，0.637 mmol)於二氯甲烷(5 mL)中的混合物中添加Et3 N(195 mg，1.911 mmol)，接著添加PhNTf2 (456 mg，1.28 mmol)，將混合物在26-33℃下攪拌4小時。在真空中濃縮反應物以得到殘餘物，其用二氯甲烷(100 mL)和水(50 mL)稀釋，有機層用二氯甲烷(30 mL×3)萃取，合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(甲醇/二氯甲烷=0-10%)純化，得到呈黃色油狀的化合物18d (370 mg，96%產率)。LCMS: tR =1.066 min，於10-80AB_2min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=603.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) : δ=7.83 (d,J= 2.8 Hz, 1H), 7.18 (d,J =8.4 Hz, 1H), 7.07 (d,J= 7.2 Hz, 1H), 6.83-6.79 (m, 2H), 4.89 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H), 4.24-4.08 (m, 2H), 3.83-3.73 (m, 2H), 3.56-3.47 (m, 1H), 3.30-3.09 (m, 2H), 3.02-2.90 (m, 3H), 2.65 (t,J= 7.2 Hz, 2H), 2.58 (br dd,J= 16.4, 5.6 Hz, 1H), 1.86-1.67 (m, 2H), 1.08 (d,J= 6.8 Hz, 3H)。
Figure 02_image236
在27-36℃下向化合物18d (300 mg，0.498 mmol)、K2 CO3 (207 mg，1.49 mmol)和Brettphos-Pd-G3(45 mg，0.0498 mmol))於二噁烷-EtOH-H2 O(5 mL，5/2/1 v/v/v)中的溶液中添加化合物14B (193 mg，0.995 mmol)。將混合物在氮氣下在100℃下攪拌12小時。在真空中濃縮反應物以得到殘餘物，其用乙酸乙酯(100 mL)和水(50 mL)溶解，水層經分離且用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃縮以獲得粗物質，其通過矽膠柱層析(甲醇/二氯甲烷=0-10%)純化，得到呈黃色固體狀的粗產物(200 mg，77%產率)。粗產物通過手性SFC[柱：DAICEL CHIRALPAK AD-H (250 mm×30 mm，5 μm)，條件：(0.1% NH3 ·H2 O)EtOH；開始B：30%，結束B：30%；流動速率：50 mL/min]分離並且另外通過酸性製備型HPLC在TFA系統[Boston Green ODS 150×30 5u；條件：24-54% B(A：水(0.075% TFA)B：CH3 CN)；流動速率：25 mL/min]中純化，得到呈黃色固體狀的實 施 例 18 的標題產物(51.8 mg TFA鹽，72%產率)。LCMS : tR =0.858 min，於10-80AB_2min_220&254層析(Xtimate C18, 2.1×30mm, 3μm中), MS (ESI) m/z=521.1 [M+H]+ 。 1 H NMR (400MHz, D2 O): δ=8.11 (s, 2H), 7.97-7.87 (m, 1H), 7.70-7.60 (m, 2H), 7.56 (br d,J= 7.6 Hz, 1H), 6.88 (br d,J= 11.2 Hz, 1H), 5.30 (s, 1H), 4.70-4.59 (m, 3H), 4.55 (br t,J= 5.6 Hz, 1H), 4.52-4.44 (m, 1H), 4.41-4.26 (m, 1H), 4.12-4.04 (m, 1H), 3.64-3.45 (m, 3H), 3.27 (br d,J= 5.2 Hz, 1H), 3.15-2.97 (m, 2H), 2.68 (dd,J= 16.4, 7.6 Hz, 1H), 2.16-1.97 (m, 2H), 1.13 (d,J= 6.0 Hz, 3H)。HPLC: tR =3.64 min，於10-80_CD_1.2ml. met, XBridge Shield RP 18 2.1×50mm 5μm中。SFC: tR =4.710 min。方法：柱：Chiralcel AD-3 150×4.6 mm I.D.，3 μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5.5 min內從5%至40%，接著維持5% B 1.5 min；流動速率：2.5 mL/min。實施例 19 6-((1S,3R)-5- 氟 -3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺 實 施 例 19 的製備類似於實 施 例 18 的製備。實 施 例 19 的分析資料展示於下文：LCMS : tR =1.593 min，於10-80AB_4min_220&254_Shimadzu層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=521.2 [M+H]+ 。HPLC : tR =2.85 min，於10-80_AB_1.2ml.met.層析(Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CDCl3 ): δ=7.97- 7.73 (m, 3H), 7.27- 7.16 (m, 2H), 6.83 (dd,J =8.8, 2.8 Hz, 1H), 6.71 (d,J =8.4 Hz, 1H), 4.97 (s, 1H), 4.49 (dt,J =47.2, 6.0 Hz, 2H), 4.32 (d,J =7.2 Hz, 1H), 4.16- 4.04 (m, 1H), 3.71 (t,J =7.2 Hz, 2H), 3.55- 3.43 (m, 1H), 3.29- 3.14 (m, 1H), 3.05- 2.88 (m, 4H), 2.68- 2.57 (m, 3H), 1.85- 1.66 (m, 2H), 1.11 (d,J =6.8 Hz, 3H)。SFC : tR =1.434 min；100%純度。方法：柱：Chiralpak IC-3 150×4.6 mm I.D.，3 μm；流動相：40%乙醇(0.05% DEA)於CO2 中；流動速率：2.5 mL/min；柱溫：35℃；ABPR：1500 psi。實 施 例 20 6-((1S,3R)-6-(3- 氟 -1H- 吡唑 -4- 基 )-3- 甲基 -2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺
Figure 02_image238
用於製備實施例 20 的程式： 將化合物5a (102.5 mg，0.18 mmol)和化合物20A (45.0 mg，0.28 mmol)與Cs2 CO3 (176 mg，0.54 mmol)於1,4-二噁烷/EtOH/H2 O的混合溶劑(5.0 mL/2.0 mL/1.0 mL，5/2/1 v/v/v)中的攪拌混合物脫氣且用氮氣吹掃三次，快速添加Pd-118(11.7 mg，0.018 mmol)，將所得混合物再次脫氣且用氮氣吹掃，接著在100℃下在氮氣氣氛下攪拌12小時。過濾反應混合物，且在真空中濃縮濾液以得到呈褐色油狀的粗產物(120 mg)，其通過製備型TLC(二氯甲烷：甲醇=8：1)純化，得到不純的產物(50 mg)。將不純的產物另外通過製備型HPLC[柱：Boston Prime C18 150×30 mm 5 μm，條件：50-80%(A：水/0.05% NH3 .H2 O，B：CH3 CN)，流動速率：25 mL/min]純化。將含有所需化合物的洗提份凍幹，獲得呈白色固體狀的實施例 20 (3.0 mg，3%產率)。LCMS: tR =1.616 min，於10-80AB_4min_220&254_Shimadzu (Xtimate C18 2.1×30 mm)中，MS (ESI) m/z=521.2 [M +H]+ 。HPLC: tR =2.94 min，於10-80AB_1.2ml.met; 層析(Ultimate C18 3×50mm 3μm)中。 1 H NMR: (400MHz, CDCl3 ) δ=10.58 (br s, 1H), 7.83 (d,J= 2.4 Hz, 1H), 7.34 (d,J= 2.0 Hz, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.18 (d,J= 8.0 Hz, 1H), 6.89 (d,J= 8.8 Hz, 1H), 6.84 (dd,J= 8.8, 3.2 Hz, 1H), 4.96 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.18-4.08 (m, 2H), 3.78-3.73 (m, 2H), 3.55-3.45 (m, 1H), 3.30-3.07 (m, 2H), 3.03-2.89 (m, 3H), 2.66-2.56 (m, 3H), 1.85-1.74 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H)。實施例 21 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(5- 甲基 -1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image240
用於製備實施例 21 的程式： 在N2 下向化合物1h (200 mg，0.34 mmol)、碳酸鉀(140 mg，1.02 mmol)、Pd(dppf)Cl2 .CH2 Cl2 (27.7 mg，0.034 mmol)和化合物21A (107 mg，0.51 mmol)的混合物中添加1,4-二噁烷(10 mL)和水(1 mL)的混合溶劑。將所得混合物在100℃下攪拌5小時。在減壓下濃縮反應混合物以得到粗殘餘物，其用CH2 Cl2 (30 mL)和水(30 mL)稀釋，分離有機層，用CH2 Cl2 (20 mL×2)萃取水層。合併的有機層經無水硫酸鈉乾燥，過濾且在真空中濃縮以得到粗產物，其通過矽膠柱層析(0-5%甲醇/二氯甲烷)純化以得到80 mg不純的產物，其另外通過手性SFC(柱：DAICEL CHIRALCEL OJ-H (250 mm×30 mm，5 μm)，條件：35% EtOH(0.1% NH3. H2 O)，流動速率：50 mL/min)純化，獲得呈黃色固體狀的實 施 例 21 (21.2 mg，12%產率)。LCMS: tR =2.800 min, 於0-60AB_7min_220&254_1500_Shimadzu.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=517.3 [M+H]+ 。HPLC : tR =2.03 min，於10-80_AB_1.2ml.方法(Ultimate C18 3×50mm 3μm)中。SFC: tR =1.812 min，99.69%純度。柱：Chiralpak AD-3 50×3 mm I.D.，3 μm；流動相：A：CO2 ；B：異丙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B於0.15 min內從40%至5%；流動速率：2.5 mL/min；柱溫：40℃。 1 H NMR (400MHz, CDCl3 ) δ=7.86 (d,J= 2.4 Hz, 1H), 7.67 (br s, 1H), 7.20 (d,J= 8.8 Hz, 1H), 7.15 (s, 1H), 7.11 ( d,J= 8.0 Hz, 1H), 6.89 (d,J= 8.4 Hz, 1H), 6.82 (dd,J= 8.4, 2.8 Hz, 1H), 4.94 (s, 1H), 4.51 (dt,J= 47.2, 6.0 Hz, 2H), 4.12 (br s, 2H), 3.78 (br s, 2H), 3.59-3.50 (m, 1H), 3.29-3.14 (m, 2H), 3.08-2.94 (m, 3H), 2.72-2.59 (m, 3H), 2.43 (s, 3H), 1.84-1.77 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H)。實施例 22 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(2H- 四唑 -5- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image242
用於製備實 施 例 22 的程式：
Figure 02_image244
在室溫(14-23℃)下向化合物11e (1.80 g，4.498 mmol)和CuI(1.03 g，5.397 mmol)於乙腈(27 mL)中的混合物中緩慢地逐滴添加t-BuONO(809 μL，6.747 mmol)。接著將反應混合物在50℃下在氮氣下攪拌16小時。使反應混合物冷卻到室溫且用水(50 mL)稀釋。所得混合物用乙酸乙酯(10 mL×3)萃取。合併的有機層經無水硫酸鈉乾燥，過濾然後在真空中濃縮以得到粗產物，其通過矽膠柱層析(0-5%乙酸乙酯/石油醚)純化，獲得呈褐色膠狀的化合物22a (570 mg，根據LCMS的80%純度，19.8%產率)。LCMS : tR =1.101 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=512.9 [M+2+H]+ 。 1 H NMR (400 MHz, 甲醇-d 4):δ =8.52 (d,J =2.0 Hz, 1H), 7.90 (dd,J =8.4, 2.4 Hz, 1H), 7.54 (s, 1H), 7.43-7.34 (m, 2H), 6.63 (d,J =8.0 Hz, 1H), 4.97 (s, 1H), 3.50-3.35 (m, 2H), 3.09 (dd,J =16.4, 4.8 Hz, 1H), 3.02-2.89 (m, 1H), 2.64 (dd,J =16.8, 6.0 Hz, 1H), 1.08 (d,J =6.8 Hz, 3H)。
Figure 02_image246
將化合物22a (570 mg，0.892 mmol，80%純度)、Zn(CN)2 (79 mg，0.669 mmol)和Pd(PPh3 )4 (129 mg，0.112 mmol)於DMF(14 mL)中的混合物在80℃下在氮氣氣氛下攪拌2小時。將反應混合物用水(30 mL)稀釋然後用乙酸乙酯(10 mL×3)萃取。合併的有機層用鹽水(50 mL×2)洗滌，經無水硫酸鈉乾燥，過濾然後在真空中濃縮以得到粗產物，其通過矽膠柱層析(0-5%乙酸乙酯/石油醚)純化，獲得呈無色膠狀的化合物22b (200 mg，54.6%產率)。LCMS: tR =0.988 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2mm)中，MS (ESI) m/z=410.1 [M+H]+ 。 1 H NMR (400 MHz，甲醇-d4 ):δ =8.53 (d,J= 2.4 Hz, 1H), 7.94 (dd,J= 8.4, 2.4 Hz, 1H), 7.56 (s, 1H), 7.47-7.38 (m, 2H), 7.09 (d,J= 8.4 Hz, 1H), 5.13 (s, 1H), 3.54-3.40 (m, 2H), 3.13 (dd,J= 16.8, 4.4 Hz, 1H), 3.06-2.92 (m, 1H), 2.75 (dd,J= 16.8, 6.8 Hz, 1H), 1.10 (d,J= 6.4 Hz, 3H)。
Figure 02_image248
將ZnBr2 於真空中和加熱下預乾燥。接著將化合物22b (200 mg，0.488 mmol)、NaN3 (200 mg，0.488 mmol)和ZnBr2 (220 mg，0.976 mmol)於DMF(4 mL)中的混合物在130℃下在氮氣下攪拌16小時。於真空中濃縮反應混合物。通過矽膠柱層析(0-20% MeOH(0.1%氫氧化銨)於CH2 Cl2 (0.1%氫氧化銨)中)純化殘餘物，獲得呈黃色固體狀的化合物22c (240 mg，根據1 H NMR的80%純度，86.8%產率)。LCMS: tR =0.898 min，於5-95AB_1.5 min_220&254層析(Merck RP18 2.5-2 mm)中，MS (ESI) m/z=455.0 [M+2+H]+ 。 1 H NMR (400 MHz，甲醇-d4 ):δ =8.55 (d,J= 2.4 Hz, 1H), 7.94 (dd,J= 8.4, 2.4 Hz, 1H), 7.86 (s, 1H), 7.73 (d,J= 8.4 Hz, 1H), 7.44 (d,J= 8.4 Hz, 1H), 7.09 (d,J= 8.0 Hz, 1H), 5.13 (s, 1H), 3.57-3.41 (m, 2H), 3.24 (dd,J= 16.4, 4.4 Hz, 1H), 3.08-3.00 (m, 1H), 2.81 (dd,J= 16.4, 6.0 Hz, 1H), 1.13 (d,J= 6.4 Hz, 3H)。
Figure 02_image250
在室溫(16-21℃)下向氫化鈉(17 mg，0.424 mmol，60%純度)於DMF(1.2 mL)中的混合物中逐滴添加化合物22c (120 mg，0.212 mmol，80%純度)於DMF(1.2 mL)中的溶液。在室溫(16-21℃)下在氮氣下攪拌反應混合物0.5小時之後，在室溫(16-21℃)下在氮氣下逐滴添加SEMCl(53 mg，0.318 mmol)於DMF(0.5 mL)中的溶液。接著將反應混合物在50℃下在氮氣下攪拌2小時，得到黃色懸浮液。將反應混合物在攪拌下倒入水(20 mL)中。將所得混合物與先導反應物(50 mg化合物22c )合併。合併的混合物用乙酸乙酯(10 mL×3)萃取。將合併的有機層用鹽水(50 mL×2)洗滌，經無水硫酸鈉乾燥，過濾然後在真空中濃縮以得到粗產物，其通過製備型TLC(石油醚/乙酸乙酯=4：1)純化，獲得全部呈無色膠狀的化合物22d 和22d' 的混合物產物(60 mg)。平均產率為約34%。LCMS: tR =1.100 & 1.146 min，於5-95AB_1.5 min_220 &254層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=583.3 [M+H]+ 。
Figure 02_image252
在氮氣下向化合物22d 和22d' (70 mg，0.120 mmol)、Brettphos Pd G3(16.3 mg，0.018 mmol)和t- BuONa(115 mg，1.20 mmol)的混合物中添加化合物1F (86 mg，0.144 mmol，60%純度)於1,4-二噁烷(3.5 mL)中的溶液。接著將反應混合物在80℃下在氮氣下攪拌2小時。將反應混合物與試驗性反應物(10 mg化合物22d 和22d' )合併。合併的有機層經無水硫酸鈉乾燥，過濾且在真空下濃縮以得到粗產物，其通過製備型TLC(CH2 Cl2 /MeOH=10:1)純化，獲得全部呈淡黃色膠狀的化合物22e 和22e' 的混合物產物(40 mg)。平均產率為約46%。LCMS: tR =0.868 min，於5-95AB_1.5 min_220&254層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z= 635.4 [M+H]+ 。
Figure 02_image254
在室溫(22-29℃)下向化合物22e 和22e' (35 mg，0.055 mmol)於THF(2.1 mL)中的溶液中添加TBAF(1.4 mL，1 M於THF中)。接著將反應混合物在40℃下在氮氣下攪拌2小時。接著將反應混合物與先導反應物(5 mg化合物22e 和22e' )合併。將合併的混合物用飽和NaHCO3 (30 mL)稀釋然後用乙酸乙酯(10 mL×4)萃取。合併的有機層經無水硫酸鈉乾燥，過濾然後在真空中濃縮以得到粗產物，其通過製備型TLC(CH2 Cl2 /MeOH=5:1，(0.1%氫氧化銨))純化，得到15 mg不純的產物。接著將產物另外通過手性SFC[柱：DAICEL CHIRALPAK AS-H(250 mm×30 mm，5 μm)；條件：30% EtOH(0.1%氫氧化銨)於CO2 中；流動速率：65 mL/min]純化，獲得呈淺黃色固體狀的實施例 22 (7.6 mg，23.9%產率)LCMS: tR =2.585 min，於0-60AB_7 min_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=505.1 [M+H]+ 。HPLC: tR =3.69 min，於0-60AB_1.2ml. met中；柱: Ultimate C18 3×50 mm 3 μm。SFC 法 : tR =3.003 min；99.004%純度；柱：Chiralpak AS-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.1%乙醇胺)，梯度：B於4.5 min內從5%至40%且保持於40% 0.5 min，接著維持5% B 1 min，流動速率：2.8 mL/min；柱溫：40℃。 1 H NMR (400 MHz, 甲醇-d4 ):δ =7.88-7.80 (m, 2H), 7.68 (d,J= 8.0 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 7.00 (dd,J= 8.4, 2.4 Hz, 1H), 6.81 (d,J= 8.0 Hz, 1H), 4.93 (s, 1H), 4.64-4.42 (m, 5H), 4.02-3.88 (m, 2H), 3.63-3.50 (m, 1H), 3.43-3.32 (m, 4H), 3.04-2.87 (m, 1H), 2.76 (dd,J= 16.4, 4.4 Hz, 1H), 2.09-1.91 (m, 2H), 1.11 (d,J= 6.4 Hz, 3H)。實施例 23 5-((1S,3R)-1-(5-((1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 胺基 ) 吡啶 -2- 基 )-3- 甲基 -2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -6- 基 ) 吡啶 -2(1H)- 酮
Figure 02_image256
用於製備實施例 23 的程式： 將化合物1h (180 mg，0.308 mmol)、化合物23A (51 mg，0.369 mmol)、Pd(dppf)Cl2 .CH2 Cl2 (25 mg，0.0308 mmol)和碳酸鉀(107 mg，0.77 mmol)的混合物用氮氣吹掃，接著在氮氣下添加1,4-二噁烷和水的混合溶劑(5.5 mL，v/v =10：1)。將所得混合物在95℃下在氮氣下攪拌2小時。將混合物與以相同方式進行的先導批料(30 mg化合物1 )合併且在真空下濃縮以得到粗產物，其通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，獲得100 mg粗產物。其另外通過手性SFC(柱：DAICEL CHIRALPAK AD-H(250 mm×30 mm，5 μm)；條件：35% IPA(0.1%氨)於CO2 中；流動速率：50 mL/min)純化，獲得呈白色固體狀的實施例 23 (峰1，27.4 mg，100%化學純度；99.07%光學純度，6.9%產率)，連同呈黃色固體狀的實施例 23 的順式異構體(峰2，5 mg，100%化學純度)。實施例 23( 峰 1) 的譜 ： LCMS: tR =2.644 min，於0-60AB_7min_220&254_Shimadzu.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=530.2 [M+H]+ 。HPLC: tR =3.80 min，於0-60_AB_1.2ml.met，層析(Ultimate C18 3.0μm 3.0×50mm)中。SFC: tR =2.108 min；99.07%純度。方法：柱：Chiralpak AD-3 50×3 mm I.D.，3 μm；流動相：A：CO2 ；B：異丙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B於0.15 min內從40%至5%；流動速率：2.5 mL/min；柱溫：40℃。 1 H NMR (400MHz, CDCl3 ): δ=7.85 (d,J= 2.4 Hz, 1H), 7.75 (dd,J= 9.6, 2.8 Hz, 1H), 7.54 (d,J= 2.0 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 7.16 (s, 1H), 7.11 (d,J= 8.0 Hz, 1H), 6.93 (d,J= 8 Hz, 1H), 6.81 (dd,J= 8.4, 2.8 Hz, 1H), 6.66 (d,J= 9.6 Hz, 1H), 4.95 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H), 4.16-4.10 (m, 2H), 3.78-3.71 (m, 2H), 3.59-3.50 (m, 1H), 3.27-3.15 (m, 2H), 3.06-2.92 (m, 3H), 2.67-2.59 (m, 3H), 1.82-1.69 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H)。實施例 23 的順式異構體 ( 峰 2) 的異構體的譜 LCMS: tR =2.653 min，於0-60AB_7.0min_220 &254_Shimadzu.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=530.1 [M+H]+ 。HPLC: tR =3.83 min，於0-60_AB_1.2ml.met.層析(Ultimate C18 3.0μm 3.0×50mm)中。 1 H NMR (400MHz, MeOD): δ=7.91 (dd,J= 9.2, 2.4 Hz, 1H), 7.84 (d,J= 2.4 Hz, 1H), 7.65 (d,J= 2.8 Hz, 1H), 7.36 (d,J= 8.8 Hz, 1H), 7.29 (d,J= 1.2 Hz, 1H), 7.20 (dd,J= 8, 1.2 Hz, 1H), 7.04 (dd,J= 8.4, 2.8 Hz, 1H), 6.84 (d,J= 8.4 Hz, 1H), 6.62 (d,J= 9.6 Hz, 1H), 5.10 (s, 1H), 4.65-4.45 (m, 6H), 4.00 (brs, 2H), 3.46-3.37 (m, 3H), 3.23-3.18 (m, 1H), 2.92-2.78 (m, 2H), 2.09-2.03 (m, 1H), 2.00-1.94 (m, 1H), 1.31 (d,J= 6.0 Hz, 3H)。實施例 24 4-((1S,3R)-1-(5-((1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 胺基 ) 吡啶 -2- 基 )-3- 甲基 -2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -6- 基 ) 吡啶 -2(1H)- 酮
Figure 02_image258
製備實施例 24 的程式類似於製備實施例 23 的程式。實施例 24( 峰 1) 的譜 LCMS: tR =2.717 min，於0-60AB_7min_220& 254_Shimadzu.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=530.1 [M+H]+ 。HPLC: tR =3.77 min，於0-60_AB_1.2ml.met，層析(Ultimate C18 3.0μm 3.0×50mm)中。SFC: tR =2.083 min；100%純度。方法：柱：Chiralpak AD-3 50×3 mm I.D.，3 μm；流動相：A：CO2 ；B：異丙醇(0.05% DEA)；梯度：B於2.5 min內從5%至40%且保持於40% 0.35 min，接著B於0.15 min內從40%至5%；流動速率：2.5 mL/min；柱溫：40℃。 1 H NMR (400MHz, CDCl3 ): δ=7.85 (d,J= 2.8 Hz, 1H), 7.39 (d,J= 7.2 Hz, 1H), 7.35 (s, 1H), 7.31-7.28 (m, 1H), 7.20 (d,J= 8.8 Hz, 1H), 6.98 (d,J= 8.0 Hz, 1H), 6.82 (dd,J= 8.4, 2.8 Hz, 1H), 6.76 (d,J= 1.2 Hz, 1H), 6.53 (dd,J= 6.8, 1.6 Hz, 1H), 4.97 (s, 1H), 4.50 (dt,J= 46.8, 5.6 Hz, 2H), 4.18-4.08 (m, 2H), 3.79-3.72 (m, 2H), 3.60-3.53 (m, 1H), 3.29-3.18 (m, 2H), 3.05-2.94 (m, 3H), 2.71-2.60 (m, 3H), 1.84-1.70 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H)。實施例 24 的順式異構體 ( 峰 2) 的異構體的譜 LCMS: tR =2.757 min，於0-60AB_7.0min_220& 254_Shimadzu.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=530.1 [M+H]+ 。HPLC: tR =3.78 min，於0-60_AB_1.2ml.met.層析(Ultimate C18 3.0μm 3.0×50mm)中。 1 H NMR (400MHz, MeOD): δ=7.81 (d,J= 2.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.37 (d,J= 10 Hz, 1H), 7.30 (d,J= 8.8 Hz, 1H), 6.99 (dd,J= 8.8, 2.8 Hz, 1H), 6.90 (d,J= 8 Hz, 1H), 6.75-6.70 (m, 2H), 5.12 (s, 1H), 4.62 (brs, 3H), 4.48 (dt,J= 46.8, 5.6 Hz, 2H), 4.18-4.11 (m, 1H), 3.92-3.84 (m, 2H), 3.50-3.41 (m, 1H), 3.12-3.03 (m, 2H), 2.97-2.85 (m, 2H), 2.73 (brt,J= 7.2 Hz, 2H), 1.86-1.72 (m, 2H), 1.33 (d,J= 6.0 Hz, 3H)。實施例 25 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1H-1,2,4- 三唑 -3- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image260
用於製備實施例 25 的程式：
Figure 02_image262
在0℃下向化合物22b (240 mg，0.585 mmol)於DMSO(6 mL)中的混合物中添加H2 O2 水溶液(0.88 mL，8.78 mmol，30%)，接著在0℃下逐滴添加NaOH水溶液(2.94 mL，2.93 mmol，1 M)。將所得混合物在0℃下攪拌1小時，得到無色溶液。在0-10℃下將混合物用Na2 SO3 飽和水溶液(50 mL)淬滅，用乙酸乙酯(50 ml×3)萃取。將合併的有機層用鹽水(30 mL)洗滌，經無水硫酸鈉乾燥且在真空中濃縮以得到粗產物，其通過矽膠柱層析(0-60%乙酸乙酯/石油醚)純化，獲得呈黃色油狀的化合物25a (270 mg，93%純度，100%產率)。LCMS: tR =0.862 min，於5-95AB_220&254層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=430.0 [M+2+H]+ 。 1 H NMR (400MHz, CD3 OD) δ=8.54 (d,J= 2.4 Hz, 1H), 7.93 (dd,J= 8.4, 2.0 Hz, 1H), 7.70 (d,J= 1.6 Hz, 1H), 7.57 (dd,J= 8.4, 2.0 Hz, 1H), 7.39 (d,J= 8.4 Hz, 1H), 6.96 (d,J= 8.0 Hz, 1H), 5.09 (s, 1H), 3.56-3.40 (m, 2H), 3.22 (dd,J= 16.4, 4.8 Hz, 1H), 3.00-2.92 (m, 1H), 2.76 (dd,J= 16.4, 6.0 Hz, 1H), 1.10 (d,J= 6.8 Hz, 3H)。
Figure 02_image264
在20-32℃下向化合物25a (230 mg，0.497 mmol，92.6%純度)於甲苯(5.8 mL)中的混合物中添加DMF-DMA (330 μL，2.49 mmol)。將混合物脫氣且用氮氣吹掃3次，接著在110℃下在氮氣下攪拌1小時，得到黃色溶液。在真空中直接濃縮混合物，得到化合物25b (240.3 mg，100%產率)，其不經進一步純化即直接用於下一步驟中。LCMS: tR =0.811 min，於5-95AB_220&254層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=483.1 [M+H]+ 。
Figure 02_image266
在20-32℃下向化合物25b (240.3 mg，0.497 mmol)於乙醇(5.8 mL)中的混合物中添加NH2 NH2 .H2 O(173 μL，3.48 mmol，98%)。將混合物脫氣且用氮氣吹掃3次，接著在20-32℃下在氮氣下攪拌1小時，得到黃色溶液。將反應物與以相同方式進行的先導批料(41.8 mg化合物25b )合併且用乙酸乙酯(100 mL)稀釋。將有機相用鹽水(30 mL×3)洗滌且經無水硫酸鈉乾燥，過濾且在真空中濃縮以得到殘餘物，其通過製備型TLC(二氯甲烷：甲醇=20：1)純化兩次，得到呈黃色固體狀的化合物25c (95 mg，36.0%平均產率)。LCMS: tR =0.870 min，於5-95AB_220&254層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=454.1 [M+2+H]+ 。
Figure 02_image268
向化合物25c (70 mg，0.155 mmol)、化合物1F (119.5 mg，0.232 mmol，70%純度)和t- BuONa(148.7 mg，1.55 mmol)於二噁烷(3.5 mL)中的混合物中添加Brettphos-Pd-G3 (28.1 mg，0.031 mmol)。將混合物用N2 吹掃，密封且在80℃下在氮氣下攪拌2小時，得到黑褐色溶液。將混合物過濾且在真空中濃縮以得到殘餘物，其通過製備型TLC(二氯甲烷：甲醇=12：1，具有1%氨)純化以得到產物(45 mg)，其另外通過手性SFC(柱：DAICEL CHIRALCEL OD-H(250 mm×30 mm，5 μm)；條件：30% EtOH(0.1%氨)於CO2 中；流動速率：60 mL/min)分離，得到呈白色固體狀的實施例 25 的標題產物(峰2，25.1 mg，98.81%純度，32%產率)，連同呈黃色固體狀的實施例 25 的異構體(峰1，2.5 mg，98.88%化學純度)。實施例 25( 峰 2) 的 譜 ： LCMS: tR =1.714 min，於0-60AB_3min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=504.2 [M+H]+ 。HPLC: tR =2.40 min，於10-80_AB_1.2ml.met.層析(Ultimate C18 3.0μm 3.0×50mm)中。SFC: tR =4.565 min；98.81%純度。方法：柱：ChiralCel OD-3 150×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5.5 min內從5%至40%且保持於40% 3 min，接著維持5% B 1.5 min；流動速率：2.5 mL/min；柱溫：40℃。 1 H NMR (400MHz, CDCl3 ): δ=8.04 (s, 1H), 7.78 (d,J= 2.4 Hz, 1H), 7.68 (s, 1H), 7.46 (br d,J= 7.2 Hz, 1H), 7.29 (s, 1H), 6.90 (d,J= 8.0 Hz, 1H), 6.85 (dd,J= 8.8, 2.8 Hz, 1H), 4.98 (s, 1H), 4.54 (t,J= 6.0 Hz, 1H), 4.48-4.36 (m, 2H), 4.20-4.05 (m, 1H), 3.74 (q,J= 6.0 Hz, 2H), 3.61-3.45 (m, 1H), 3.30-3.13 (m, 1H), 3.08-2.88 (m, 4H), 2.66 (t,J= 7.2 Hz, 2H), 2.56 (dd,J= 16.8, 7.2 Hz, 1H), 1.87-1.68 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H)。實施例 25 的異構體 ( 峰 1) 的 譜 ： LCMS: tR =1.984 min，於0-60AB_220&254層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=504.3 [M+H]+ 。HPLC: tR =2.43 min，於10-80_AB_1.2ml.met (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CDCl3 ): δ=8.15 (s, 1H), 7.89 (d,J= 2.4 Hz, 1H), 7.76 (s, 1H), 7.68-7.64 (m, 1H), 7.26 (s, 1H), 6.96 (d,J= 8.0 Hz, 1H), 6.82 (dd,J= 8.8, 2.4 Hz, 1H), 5.18 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.19-4.06 (m, 2H), 3.79-3.71 (m, 2H), 3.48-3.36 (m, 1H), 3.31-3.21 (m, 2H), 3.01-2.93 (m, 2H), 2.84-2.79 (m, 2H), 2.63 (t,J= 7.2 Hz, 2H), 1.85-1.71 (m, 2H), 1.31 (d,J= 6.0 Hz, 3H)。實施例 26 6-(2-( 雙環 [1.1.1] 戊 -1- 基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-1,2,3,4- 四氫異喹啉 -1- 基 )-N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 吡啶 -3- 胺
Figure 02_image270
用於製備實施例 26 反式異構體 1 和實施例 26 反式異構體 2 的程式：
Figure 02_image272
將化合物26A (1.146，9.6 mmol)和Et3 N(0.970 g，9.6 mmol)於甲醇(26 mL)中的混合物在50℃下攪拌30分鐘，接著添加化合物26a (2.0 g，8.0 mmol)於甲醇(4 mL)中的溶液且用AcOH調節至pH=6。在50℃下攪拌所得混合物2小時。在0℃下向混合物中添加NaBH3 CN(0.992 g，16 mmol)，且將混合物在50℃下攪拌2.5小時(呈白色懸浮液狀)。將反應物冷卻至20℃且用NaHCO3 飽和水溶液(50 mL)淬滅且用乙酸乙酯(200 mL×3)萃取，將合併的有機層用鹽水(100 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(乙酸乙酯/石油醚=0-30 %)純化，獲得呈白色固體狀的化合物26b (2.5 g，98%產率)。LCMS: tR =0.737 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=317.6 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.26-7.19 (m, 2H), 7.16 (s, 1H), 6.86 (d,J= 7.2 Hz, 1H), 6.45 (br s, 1H), 3.06-3.02 (m, 1H), 2.73 (dd,J= 13.2, 6.4 Hz, 1H), 2.53 (dd,J= 13.2, 7.2 Hz, 1H), 2.37 (s, 1H), 1.85-1.75 (m, 6H), 1.53 (s, 9H), 1.05 (d,J= 6.4 Hz, 3H)。
Figure 02_image274
在14-24℃下向含化合物26b (2.5 g，7.9 mmol)的二氯甲烷(30 mL)中添加TFA(6 mL)且將混合物在14-24℃下攪拌4小時。將反應混合物用NaHCO3 飽和水溶液(50 mL)淬滅且用乙酸乙酯(100 mL×2)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(用0-50%乙酸乙酯/石油醚洗提)純化，獲得呈褐色油狀的產物26c (1.3 g，76%)。LCMS: tR =1.673 min，於10-80CD_220&254.lcm層析(A：Xtimate C18, 2.1 × 30 mm, 3 μm，B：XBrige Shield RP18 2.1 × 50 mm)中，MS (ESI) m/z=217.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.08 (t,J= 7.6 Hz, 1H), 6.61-6.54 (m, 2H), 6.52 (s, 1H), 3.63 (br s, 2H), 3.01 (m, 1H), 2.66 (dd,J= 13.2, 6.8 Hz, 1H), 2.48 (dd,J= 13.2, 6.8 Hz, 1H), 2.37 (s, 1H), 1.81 (dq,J= 9.6, 1.6 Hz, 6H), 1.06 (d,J= 6.0 Hz, 3H)。
Figure 02_image276
在15-23℃下用密封管向化合物26c (300 mg，1.39 mmol)、化合物1E (284 mg，1.53 mmol)於CH3 CN(9 mL)和水(125.1 mg，6.95 mmol)中的混合物中添加Yb(OTf)3 (17.5 mg，0.0278 mmol)。將混合物在70℃下攪拌2小時(呈褐色溶液狀)。將反應混合物與四個平行批次的反應物(各為300 mg化合物26c )合併且用水(50 mL)淬滅。用乙酸乙酯(100 mL×3)萃取水層。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠快速柱層析(用0-10%乙酸乙酯/石油醚洗提)純化，獲得呈褐色固體狀的化合物26d (1.9 g，基於H NMR的反式/順式=3.5/1，73%平均產率)。LCMS: tR =1.146 min，於10-80AB_220&254.lcm層析(Xtimate C18 2.1 × 30 mm)中，MS (ESI) m/z=383.9 [M+H]+ 。 1 H NMR: (400MHz, CDCl3 ): δ=8.56 (d,J= 2.0 Hz, 1H), 7.62 (dd,J= 2.4, 8.4 Hz, 1H), 7.31 (d,J= 8.4 Hz, 1H), 6.72 (d,J= 8.4 Hz, 1H), 6.41 (s, 1H), 6.40-6.35 (m, 1H), 4.95 (s, 1H), 3.65-3.59 (m, 1H), 3.53 (br s, 2H), 3.29 (dd,J= 15.2, 4.8 Hz, 1H), 2.47 (d,J= 17.2 Hz, 1H), 2.23 (s, 1H), 1.76 (dd,J= 9.6, 1.2 Hz, 3H), 1.48 (dd,J=9.2, 1.6 Hz, 3H), 1.03 (d,J= 6.4 Hz, 3H)。
Figure 02_image278
在5℃下在氮氣下向化合物26d (700 mg，1.82 mmol)於二氯甲烷(8.4 mL)和水(7.0 mL)中的攪拌混合物中先後添加CH2 I2 (976 mg，3.6 mmol)、NaNO2 (628 mg，9.1 mmol)於水(1.4 mL)中的溶液和AcOH(2184 mg，36.4 mmol)。將所得混合物在20-25℃下攪拌5分鐘，此時從淺褐色溶液變為黑色溶液。在20-25℃下再攪拌1小時之後，將反應物與平行批次的反應物(700 mg化合物26d )合併且用乙酸乙酯(20 mL)稀釋，接著用NaHCO3 飽和水溶液處理以調節至pH= 9。過濾混合物且用乙酸乙酯(100 mL×2)萃取濾液。將合併的有機層用鹽水(100 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中在30℃下濃縮濾液以得到粗產物，其通過製備型TLC(石油醚/乙酸乙酯=4/1)純化，獲得呈褐色固體狀的化合物26e (540 mg，30%)。LCMS: tR =0.880 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=495.1 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.57 (d,J= 2.0 Hz, 1H), 7.64 (dd,J= 8.4, 2.4 Hz, 1H), 7.45 (s, 1H), 7.33 (br d,J= 8.4 Hz, 1H), 7.29 (d,J= 8.4 Hz, 1H), 6.72 (d,J= 8.4 Hz, 1H), 4.99 (s, 1H), 3.69-3.60 (m, 1H), 3.32 (dd,J= 15.6, 4.4 Hz, 1H), 2.54 (dd,J= 15.6, 2.0 Hz, 1H), 2.24 (s, 1H), 1.75 (dd,J= 9.6, 1.6 Hz, 3H), 1.48 (dd,J= 9.2, 1.6 Hz, 3H), 1.02 (d,J= 6.4 Hz, 3H)。
Figure 02_image280
將化合物26e (270 mg，0.545 mmol)、化合物26B (211 mg，0.708 mmol)、Pd(PPh3 )4 (63 mg，0.0545 mmol)、Cs2 CO3 (357 mg，1.09 mmol)和Et3 N(110 mg，1.09 mmol)於EtOH(5 mL)和水(1.1 mL)中的混合物在40℃下在氮氣下攪拌15小時(呈褐色溶液狀)。用乙酸乙酯(10 mL)和水(5 mL)稀釋反應物。在真空中濃縮混合物且用乙酸乙酯(50 mL×3)萃取殘餘物。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠快速柱層析(用0-15%乙酸乙酯/石油醚洗提)純化，獲得呈棕色油狀的產物26f (200 mg，64%產率)。LCMS: tR =0.901 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=567.2 [M+H+2]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.62 (d,J= 2.4 Hz, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 7.67 (dd,J= 8.4, 2.4 Hz, 1H), 7.36 (d,J= 8.4 Hz, 1H), 7.26 (s, 1H), 7.19 (d,J= 8.0 Hz, 1H), 7.00 (d,J= 8.0 Hz, 1H), 5.46 (s, 2H), 5.09 (s, 1H), 3.73-3.68 (m, 1H), 3.56 (t,J= 8.0 Hz, 2H), 3.42 (dd,J= 15.2, 4.8 Hz, 1H), 2.65 (d,J= 15.2 Hz, 1H), 2.28 (s, 1H), 1.81 (dd,J= 9.2, 1.2 Hz, 3H), 1.53 (dd,J= 9.2, 1.2 Hz, 3H), 1.08 (d,J= 6.4 Hz, 3H), 0.91 (t,J= 8.0 Hz, 2H), 0.00 (s, 9H)。
Figure 02_image282
將化合物26f (200 mg，0.355 mmol)、化合物13B (253 mg，0.53 mmol)、BrettPhos-Pd-G3 (64 mg，0.071 mmol)、t-BuONa(187mg，1.95 mmol)於1,4-二噁烷(5 mL)中的混合物在100℃下在氮氣下攪拌4小時(呈黑色溶液狀)。將反應物用NH4 Cl飽和水溶液(15 mL)稀釋且用乙酸乙酯(50 mL×3)萃取，將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液願意得到粗產物，其通過矽膠柱層析(用0-15%甲醇/二氯甲烷洗提)純化，獲得呈褐色固體狀的產物26g (136 mg，62%產率)。LCMS: tR =1.747 min，於10-80AB_220&254.lcm層析(Xtimate C18 2.1×30 mm)中，MS (ESI) m/z=617.4 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.8 Hz, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.21 (s, 1H), 7.14 (d,J= 8.4 Hz, 2H), 6.95 (d,J= 8.0 Hz, 1H), 6.73 (dd,J= 8.4, 2.8 Hz, 1H), 5.43 (s, 2H), 4.98 (s, 1H), 4.50 (dt,J= 46.8, 6.0 Hz, 2H), 4.12-4.06 (m, 1H), 3.97-3.93 (m, 1H), 3.78-3.71 (m, 2H), 3.68-3.65 (m, 1H), 3.55 (t,J= 8.0 Hz, 2H), 3.39 (dd,J= 4.8, 15.2 Hz, 1H), 2.95-2.88 (m, 2H), 2.66-2.54 (m, 3H), 2.22 (s, 1H), 1.83-1.71 (m, 5H), 1.50 (d,J= 8.8 Hz, 3H), 1.06 (d,J= 6.4 Hz, 3H), 0.90 (t,J= 8.0 Hz, 2H), -0.02 (s, 9H)。
Figure 02_image284
將化合物26g (116 mg，0.188 mmol)和TFA(2.0 mL)於二氯甲烷(5.0 mL)中的混合物在21-25℃下攪拌2.5小時。將反應物與以相同方式進行的先導批料(10 mg化合物26g )合併且用NaHCO3 飽和水溶液調節至pH=9，用二氯甲烷(50 mL×3)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥且過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(用0-15%甲醇/二氯甲烷洗提)純化，獲得呈褐色固體狀的實施例 26 反式異構體 1 和實施例 26 反式異構體 2 的1:1混合物(70 mg，70%產率)。LCMS: tR =0.640 min，於5-95AB_220&254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=487.3 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.4 Hz, 1H), 7.79 (s, 2H), 7.22 (s, 1H), 7.18-7.13 (m, 2H), 6.94 (d,J= 8.0 Hz, 1H), 6.76 (dd,J= 8.4, 2.8 Hz, 1H), 4.99 (s, 1H), 4.50 (dt,J= 47.2, 5.6 Hz, 2H), 4.38-4.23 (m, 1H), 4.21-4.15 (m, 1H), 3.88-3.80 (m, 2H), 3.70-3.63 (m, 1H), 3.38 (dd,J= 15.8, 4.8 Hz, 1H), 3.26-3.15 (m, 2H), 2.74 (t,J= 7.2 Hz, 2H), 2.60 (d,J= 15.2 Hz, 1H), 2.22 (s, 1H), 1.89-1.83 (m, 2H), 1.80-1.77 (m, 3H), 1.50 (dd,J= 9.2, 1.2 Hz, 3H), 1.07 (d,J= 6.4 Hz, 3H)。針對混合物的 SFC: tR =4.115 min和5.539 min。方法：柱：Chiralcel OD-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。 將獲得的混合物(70 mg，0.14 mmol)通過手性SFC [Phenomenex-Amylose(250 mm×30 mm，5 μm)；條件：EtOH(0.1% NH3 H2 O)於CO2 中；流動速率：50 mL/min]分離，獲得呈黃色固體狀的實施例 26 反式異構體 1 (19.2 mg，27%產率，峰1)和呈黃色固體狀的實施例 26 反式異構體 2 (19.4 mg，27%產率，峰2)。實施例 26 反式異構體 1 的 譜 ： LCMS: tR =1.796 min，於0-60AB_4min_220&254.lcm層析(Xtimate C18 2.1×30 mm)中，MS (ESI) m/z=487.2 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.4 Hz, 1H), 7.78 (s, 2H), 7.21 (s, 1H), 7.15 (d,J= 8.4 Hz, 2H), 6.94 (d,J= 8.0 Hz, 1H), 6.73 (dd,J= 8.4, 2.4 Hz, 1H), 4.98 (s, 1H), 4.49 (dt,J= 47.2, 6.0 Hz, 2H), 4.17-3.98 (m, 2H), 3.73 (q,J= 6.8 Hz, 2H), 3.69-3.63 (m, 1H), 3.44-3.32 (m, 1H), 2.95-2.88 (m, 2H), 2.63-2.57 (m, 3H), 2.22 (s, 1H), 1.80-1.72 (m, 5H), 1.50 (d,J= 9.2 Hz, 3H), 1.06 (d,J= 6.8 Hz, 3H)。HPLC: tR =3.43 min，於0-60_AB_1.2ml.met，層析(Ultimate C18 3 × 50 mm 3μm)中。SFC: tR =4.111 min。方法：柱：Chiralcel OD-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05 % DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。實施例 26 反式異構體 2 的 譜 ： LCMS: tR =1.798 min，於0-60AB_4min_220&254.lcm層析(Xtimate C18 2.1×30 mm)中，MS (ESI) m/z=487.2 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.4 Hz, 1H), 7.79 (s, 2H), 7.22 (s, 1H), 7.15 (d,J= 8.8 Hz, 2H), 6.95 (d,J= 8.4 Hz, 1H), 6.74 (dd,J= 8.4, 2.4 Hz, 1H), 4.99 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.15-4.09 (m, 1H), 4.05-3.99 (m, 1H), 3.79-3.71 (m, 2H), 3.70-6.65 (m, 1H), 3.42-3.33 (m, 1H), 2.99-2.92 (m, 2H), 2.65-2.57 (m, 3H), 2.22 (s, 1H), 1.78-1.75 (m, 5H), 1.50 (d,J= 9.5 Hz, 3H), 1.07 (d,J= 6.4 Hz, 3H)。HPLC: tR =3.44 min，於0-60_AB_1.2ml.met，層析(Ultimate C18 3×50 mm 3μm)中。SFC: tR =5.500 min。方法：柱：Chiralcel OD-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。實施例 27 N-(1-(3- 氟丙基 ) 氮雜環丁 -3- 基 )-6-(3- 甲基 -2-(3- 甲基雙環 [1.1.1] 戊 -1- 基 )-6-(1H- 吡唑 -4- 基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image286
製備實施例 27 反式異構體 1 和實施例 27 反式異構體 2 的程式類似於製備實施例 26 的程式： 將實施例 27 的反式混合物(100 mg，0.199 mmol)通過手性SFC[柱：DAICEL CHIRALCEL OD(250 mm×30 mm，5 μm)；條件：(0.1% NH3 .H2 O)IPA於CO2 中；流動速率：50 mL/min]分離，獲得呈黃色固體狀的實施例 27 反式異構體 1 (30.9 mg，30%，峰1)和實施例 27 反式異構體 2 (32.8 mg，峰2)。實施例 27 反式異構體 1 的 譜 ： LCMS: tR =1.960 min，於0-60AB_4min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=501.2 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.89 (d,J= 2.8 Hz, 1H), 7.79 (s, 2H), 7.21 (s, 1H), 7.14 (d,J= 8.4 Hz, 2H), 6.94 (d,J= 8.4 Hz, 1H), 6.73 (dd,J= 8.4, 2.8 Hz, 1H), 4.95 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.16-4.07 (m, 1H), 4.03-4.00 (m, 1H), 3.75 (q,J= 6.4 Hz, 2H), 3.67-3.63 (m, 1H), 3.38 (dd,J =15.2, 4.8 Hz, 1H), 2.99-2.91 (m, 2H), 2.66-2.56 (m, 3H), 1.81-1.73 (m, 2H), 1.63 (d,J= 9.6 Hz, 3H), 1.35 (d,J= 9.2 Hz, 3H), 1.09 (s, 3H), 1.05 (d,J= 6.4 Hz, 3H)。HPLC: tR =3.67 min，於0-60_AB_1.2ml.met，層析(Ultimate C18 38 50 mm 3μm)中。SFC: tR =2.494 min。方法：柱：ChiralPak IC-3 150× 4.6mm I.D.，3μm；流動相：A：CO2 ；B：IPA(0.1%乙醇胺)；等度：40% B；流動速率：2.5 mL/min；柱溫：40℃。實施例 27 反式異構體 2 的 譜 ： LCMS: tR= 1.871 min，於10-80CDAB_3.0min_220& 254.lcm層析(A：Xtimate C18，2.1×30 mm, 3μm，B：XBrige Shield RP18 2.1×50mm)中，MS (ESI) m/z=501.3 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.89 (d,J= 2.4 Hz, 1H), 7.79 (s, 2H), 7.21 (s, 1H), 7.15 (d,J= 8.4 Hz, 2H), 6.94 (d,J= 8.0 Hz, 1H), 6.73 (dd,J= 8.4, 2.4 Hz, 1H), 4.95 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.18-4.08 (m, 1H), 4.06-4.00 (m, 1H), 3.77 (q,J= 6.8 Hz, 2H), 3.65-3.63 (m, 1H), 3.39 (dd,J= 15.2, 4.4 Hz, 1H), 2.98-2.97 (m, 2H), 2.68-2.55 (m, 3H), 1.82-1.73 (m, 2H), 1.64 (d,J= 9.6 Hz, 3H), 1.35 (d,J= 9.2 Hz, 3H), 1.09 (s, 3H), 1.05 (d,J= 6.4 Hz, 3H)。HPLC: tR =3.67 min，於0-60_AB_1.2ml.met，層析(Ultimate C18 38 50 mm 3μm)中。SFC: tR =3.609 min。方法：柱：ChiralPak IC-3 150×4.6mm I.D.，3μm；流動相：A：CO2 ；B：IPA(0.1%乙醇胺)；等度：40% B；流動速率：2.5 mL/min；柱溫：40℃。實施例 28 N-((S)-1-(3- 氟丙基 ) 吡咯烷 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺
Figure 02_image288
用於製備28A 的程式： 向化合物28A_1 (0.3 g，1.6 mmol)於THF(5 mL)中的溶液中添加NaOH水溶液(0.64 mL，3.2 mmol，5 M)，接著添加含化合物1F_1a (184 μL，1.7 mmol)的THF(1 mL)。將所得混合物在20-28℃下攪拌16小時。將混合物用乙酸乙酯(15 mL)稀釋，用NH4 Cl飽和水溶液(15 mL)洗滌，用乙酸乙酯(15 mL×2)萃取水層。有機層經無水硫酸鈉乾燥，過濾且在真空中濃縮以得到粗產物，其通過矽膠柱層析(二氯甲烷/甲醇=97/3)純化，獲得呈黃色油狀的產物28A_2 (0.27 g，68%產率)。 1 H NMR (400MHz, CDCl3 ) δ=4.90 (br s, 1H), 4.52 (dt,J= 47.2, 5.6 Hz, 2H), 4.19 (br s, 1H), 2.90 (brs, 1H), 2.68-2.57 (m, 4H), 2.41-2.21 (m, 2H), 2.00-1.82 (m, 3H), 1.44 (s, 9H)。 向化合物28A_2 (0.27 g，1.09 mmol)於二氯甲烷(4 mL)中的溶液中逐滴添加TFA(1 mL)。將反應混合物在21-28℃下攪拌1小時。在真空中濃縮反應物，獲得呈黃色油狀的產物28A (0.66 g TFA鹽，純度：61.7%)，其不經進一步純化即直接用於下一步驟中。 1 H NMR (400MHz, MeOD) δ=4.58 (dt,J =47.2, 5.2 Hz, 2H), 4.21-4.07 (m, 1H), 3.93-3.40 (m, 6H), 2.69-2.56 (m, 1H), 2.28-2.09 (m, 3H)。 用於製備實施例 28 的程式：
Figure 02_image290
在氮氣下向化合物1f (350 mg，0.87 mmol)、28A (593 mg，0.97 mmol，61.7%純度)於1,4-二噁烷(13 mL)中的混合物中添加Brettphos-Pd-G3 (80 mg，0.087 mmol)和t-BuONa(835 mg，8.7 mmol)。將所得混合物在氮氣下在80℃下攪拌2小時。將混合物與以相同方式進行的先導批料(40 mg化合物1f )合併且通過矽藻土墊過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-6%甲醇/二氯甲烷)純化，獲得呈黃色油狀的化合物28a (370 mg，81%產率)。LCMS: tR =0.647 min，於5-95AB_1.5min_220& 254.lcm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=467.4 [M+H]+。 1 H NMR (400MHz, CDCl3 ): δ=7.82 (d,J= 2.4 Hz, 1H), 7.15 (d,J= 8.4 Hz, 1H), 6.79 (dd,J= 8.8, 2.8 Hz, 1H), 6.68 (d,J= 8.4 Hz, 1H), 6.51 (d,J =2.0 Hz, 1H), 6.47 (dd,J =8.0, 2.0 Hz, 1H), 4.85 (s, 1H), 4.52 (dt,J= 47.2, 5.6 Hz, 2H), 4.05 (brs, 1H), 3.49-3.42 (m, 1H), 3.23-2.90 (m, 4H), 2.84-2.66 (m, 4H), 2.55-2.44 (m, 2H), 2.41-2.32 (m, 1H), 2.03-1.88 (m, 2H), 1.82-1.73 (m, 1H),  1.05 (d,J= 6.8 Hz, 3H)。
Figure 02_image292
在室溫(21-27℃)下向化合物28a (320 mg，0.687 mmol)於二氯甲烷(9 mL)中的混合物中添加三乙胺(277 mg，2.75 mmol)，接著添加PhNTf2 (368 mg，1.03 mmol)。接著將反應混合物在21-27℃下攪拌16小時。將混合物與以相同方式進行的先導批料(50 mg化合物28a )合併且用二氯甲烷(10 mL)稀釋，將有機層用鹽水(15 mL×2)洗滌，經無水硫酸鈉乾燥然後過濾，在真空中濃縮濾液以得到粗產物，其通過矽膠柱層析(0-5%甲醇/二氯甲烷)純化，獲得呈黃色油狀的化合物28b (0.4 g，84%產率，基於NMR含有少量Et3 N)。LCMS: tR =0.848 min，於5-95AB_1.5min_220& 254.l cm層析(Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=599.4 [M+H]+。 1 H NMR (400MHz, CDCl3 ): δ=7.87 (d,J= 2.8 Hz, 1H), 7.14 (d,J= 8.4 Hz, 1H), 7.03 (s, 1H), 6.98-6.95 (m, 2H), 6.86 (dd,J= 8.4, 2.8 Hz, 1H), 4.93 (s, 1H), 4.53 (dt,J= 47.2, 5.6 Hz, 2H), 4.09-4.00 (m, 1H), 3.58-3.50 (m, 1H), 3.26-3.18 (m, 2H), 3.05-2.92 (m, 2H), 2.85-2.49 (m, 6H), 2.43-2.32 (m, 1H), 2.02-1.88 (m, 2H), 1.81-1.74 (m, 1H), 1.08 (d,J= 6.8 Hz, 3H)。
Figure 02_image294
將化合物28b (170 mg，0.283 mmol)、化合物14B (125 mg，0.426 mmol)、Pd(dppf)Cl2 .CH2 Cl2 (23 mg，0.0283 mmol)和碳酸鉀(98 mg，0.707 mmol)的混合物用氮氣吹掃，接著在氮氣下添加1,4-二噁烷和H2 O的混合溶劑(5 mL，v/v=4：1)。將所得混合物在95℃下在氮氣下攪拌4小時。將混合物與以相同方式進行的先導批料(30 mg 化合物28b )合併且在真空下濃縮以得到粗產物，其通過矽膠柱層析(0-7%甲醇/二氯甲烷)純化，獲得100 mg化學純產物。其另外通過手性SFC(DAICEL CHIRALCEL OD-H(250 mm×30 mm，5 μm)；條件：30% EtOH(0.1%氨)於CO2 中；流動速率：60 mL/min]純化，獲得呈白色固體狀的實施例 28 (53.9 mg，31%平均產率)。LCMS: tR =2.698 min，於0-60AB_7min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=517.1 [M+H]+。HPLC: tR =3.91 min，於0-60_AB_1.2ml.met.層析(Ultimate C18 3×50mm 3μm)中。SFC ( 方法 1): tR =3.494 min；98.58%純度。方法：柱：Chiralpak AS-3 150×4.6mm I.D., 3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5 min內從5%至40%並於0.5 min內從40%至5% ，維持B 5% 1.5 min；流動速率：2.5 mL/min；柱溫：35℃。SFC ( 方法 2): tR =3.073 min；97.51%純度。方法：柱：Chiralcel OJ-3 150×4.6mm I.D., 3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5 min內從5%至40 %並於0.5 min內從40%至5% B，維持B 5% 1.5 min；流動速率：2.5 mL/min；柱溫：35℃。 1 H NMR (400MHz, CDCl3 ): δ=7.89 (d,J= 2.8 Hz, 1H), 7.78 (s, 2H), 7.24 (s, 1H), 7.19 (d,J= 8.8 Hz, 2H), 6.89 (d,J= 8.0 Hz, 1H), 6.85 (dd,J= 8.8, 2.8 Hz, 1H), 4.93 (s, 1H), 4.52 (dt,J= 46.8, 5.6 Hz, 2H), 4.11-3.95 (m, 2H), 3.59-3.49 (m, 1H), 3.28-3.14 (m, 2H), 3.08-2.87 (m, 2H), 2.76-2.55 (m, 5H), 2.49-2.41 (m, 1H), 2.40-2.29 (m, 1H), 2.00-1.85 (m, 2H), 1.77-1.68 (m, 1H), 1.10 (d,J= 6.8 Hz, 3H)。實施例 29 N-((R)-1-(3- 氟丙基 ) 吡咯烷 -3- 基 )-6-((1S,3R)-3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 胺 實施例 29 的合成類似於實施例 28 的合成。實施例 29 的譜為：LCMS: tR =2.687 min，於0-60AB_7min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=517.2 [M+H]+ 。HPLC: tR =3.90 min，於0-60_AB_1.2ml.met.層析(Ultimate C18 3×50mm 3μm)中。SFC: tR =3.408 min；93.26%純度。方法：柱：Chiralpak AS-3 150×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5 min內從5%至40%並於0.5 min內從40%至5%，維持B 5% 1.5 min；流動速率：2.5 mL/min；柱溫：35℃。 1 H NMR (400MHz, CDCl3 ): δ=7.89 (d,J= 2.8 Hz, 1H), 7.78 (s, 2H), 7.25 (s, 1H), 7.22-7.16 (m, 2H), 6.89 (d,J= 8.0 Hz, 1H), 6.85 (dd,J= 8.4, 2.8 Hz, 1H), 4.93 (s, 1H), 4.53 (dt,J= 47.6, 6.0 Hz, 2H), 4.11-3.95 (m, 2H), 3.59-3.49 (m, 1H), 3.28-3.14 (m, 2H), 3.08-2.97 (m, 2H), 2.95-2.86 (m, 1H), 2.76-2.58 (m, 5H), 2.47-2.40 (m, 1H), 2.40-2.29 (m, 1H), 2.00-1.85 (m, 2H), 1.77-1.68 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H)。實施例 30 3-((1S,3R)-1-(2,6- 二氟 -4-(((S)-1-(3- 氟丙基 ) 吡咯烷 -3- 基 ) 胺基 ) 苯基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 )-2,2- 二氟丙 -1- 醇 實施例 30 的合成類似於實施例 28 的合成。實施例 30 的譜為：LCMS: tR =1.831 min，於10-80CD_3min_220& 254_Agilent.lcm層析(A：Xtimate C18 2.1×30mm, 3μm；B：XBrige Shield RP18 2.1×50mm)中，MS (ESI) m/z=564.3 [M+H]+ 。HPLC: tR =4.49 min，於10-80_AB_15MIN.met.層析(YMCpack-ODS AQ 150×4.6MM 5μm)中。SFC: tR =2.920 min；100%純度。方法：柱：Chiralcel OJ-3 100×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於4.5 min內從5%至40%且保持於40 % 2.5 min，接著維持5% B 1 min；流動速率：2.8 mL/min；柱溫：40℃。 1 H NMR (400MHz, CD3 OD): δ=7.89 (s, 2H), 7.35-7.26 (m, 1H), 7.23 (d,J =8.0 Hz, 1H), 6.73 (d,J =8.0 Hz, 1H), 6.13 (d,J =12.4 Hz, 2H), 5.07 (s, 1H), 4.48 (dt,J =47.2, 6.0 Hz, 2H), 3.99-3.88 (m, 1H), 3.84-3.67 (m, 1H), 3.66-3.54 (m, 1H), 3.43-3.32 (m, 1H), 3.30-3.21 (1H), 3.19-3.04 (m, 1H), 2.92 (dd,J =10.0, 7.2 Hz, 1H), 2.82-2.68 (m, 2H), 2.68-2.54 (m, 4H), 2.49 (dd,J = 9.6, 4.4 Hz, 1H), 2.37-2.23 (m, 1H), 1.99-1.81 (m, 2H), 1.75-1.62 (m, 1H), 1.05 (d,J =6.4 Hz, 3H)。實施例 31 3- 氟 -N-(3-(6-((1S,3R)-3- 甲基 -6-(1H- 吡唑 -4- 基 )-2-(2,2,2- 三氟乙基 )-1,2,3,4- 四氫異喹啉 -1- 基 ) 吡啶 -3- 基 ) 丙基 ) 丙 -1- 胺
Figure 02_image296
用於製備31A 的程式： 向化合物31A_1 (5 g，26.9 mmol)於EtOH(60 mL)和THF(20 mL)的混合物溶劑中的溶液中添加NaBH4 (406 mg，10.7 mmol)。將反應混合物在1-7℃下攪拌45分鐘且添加2.5 mL水。TLC顯示觀測到所需產物。將反應混合物用DCM(50 mL)和水(50 mL)稀釋，分離。水層用DCM(50 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾，在真空中濃縮且通過矽膠柱層析(0-10%乙酸乙酯/石油醚)純化，得到呈白色固體狀的化合物31A_2 (5 g，99%產率)。 1 H NMR (400MHz, CDCl3 ) : δ=8.63 (d,J= 2.0 Hz, 1H), 7.82 (dd,J= 8.4, 2.4 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 4.74 (d,J= 3.6 Hz, 2H), 3.34 (br s,J= 5.2 Hz, 1H)。 在0℃下向化合物31A_2 (5 g，26.6 mmol)於THF(90 mL)中的溶液中添加氫化鈉(1.6 g，39.9 mmol)。在2-9℃下攪拌混合物30分鐘。接著添加DPTBSCl(8 g，29.3 mmol)且將所得混合物在2-9℃下攪拌2小時。TLC顯示觀測到所需產物。將反應物用乙酸乙酯(80 mL)和水(50 mL)稀釋，分離。水層用乙酸乙酯(80 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾，在真空中濃縮且通過矽膠柱層析(0-10%乙酸乙酯/石油醚)純化，得到呈無色油狀的化合物31A_3 (9 g，81%產率)。 1 H NMR (400MHz, CDCl3 ) : δ=8.54 (d,J= 2.0 Hz, 1H), 7.87 (dd,J= 8.4, 2.4 Hz, 1H), 7.69 (d,J= 7.6 Hz, 4H), 7.60 (d,J= 8.4 Hz, 1H), 7.46-7.37 (m, 6H), 4.83 (s, 2H), 1.14 (s, 9H)。 向化合物31A_3 (1.66 g，10.5 mmol)於THF(70 mL)中的溶液中添加9-BBN(21 ml，10.5 mmol，0.5 M於THF中)，將所得混合物在室溫(21-25℃)下攪拌2小時。向混合物中添加0.6 mL水。在氮氣下向裝備有機械攪拌器的250 mL三頸圓底燒瓶中添加含烯丙基胺基甲酸叔丁酯(3 g，7.0 mmol)、Cs2 CO3 (6.9 g，21.0 mmol)、Pd(dppf)Cl2 (258 mg，0.35 mmol)和Ph3 As(117 mg，0.35 mmol)的DMF(70 mL)。添加以上反應溶液且在60℃下攪拌15小時。將反應物用乙酸乙酯(100 mL)和水(100 mL)稀釋，接著分離。水層用乙酸乙酯(50 mL×2)萃取。將合併的有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥，過濾，在真空中濃縮且通過矽膠柱層析(0-65%乙酸乙酯/石油醚)純化，得到呈黃色油狀的化合物31A_4 (3.1 g，88%產率)。LCMS: tR =0.938 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=505.8 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ): δ=8.31 (d,J= 1.6 Hz, 1H), 7.69 (dd,J= 8.0, 1.6 Hz, 4H), 7.63-7.53 (m, 2H), 7.47-7.33 (m, 6H), 4.86 (s, 2H), 3.20-3.10 (m, 2H), 2.64 (t,J =8.0 Hz, 2H), 1.83-1.76 (m, 2H), 1.46 (s, 9H), 1.13 (s, 9H)。 向化合物31A_4 (3.1 g，6.15 mmol)於THF(30 mL)中的溶液中添加TBAF溶液(12.3 mL，12.3 mmol，1 M於THF中)。將反應混合物在19-26℃下攪拌15小時。將反應物用乙酸乙酯(20 mL)和水(20 mL)稀釋，然後分離。將水層用乙酸乙酯(20 mL×2)萃取，經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-30%乙酸乙酯/石油醚)純化，得到呈黃色油狀的化合物31A_5 (1 g，62%產率)。LCMS: tR =0.608 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=267.2 [M+H]+ 。 向化合物31A_5 (1 g，3.76 mmol)於DCM(20 mL)中的溶液中添加MnO2 (3.9 g，45.12 mmol)。將混合物在18-28℃下攪拌4小時。過濾反應物，將濾液濃縮，且通過矽膠柱層析(0-50%乙酸乙酯。石油醚)純化，得到呈黃色油狀的化合物31A (700 mg，70%產率)。LCMS: tR =0.753 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=265.2 [M+H]+ 。 1 H NMR (400MHz, CDCl3) : δ=10.06 (s, 1H), 8.63 (d,J =1.6 Hz, 1H), 7.91 (d,J =7.6 Hz, 1H), 7.70 (dd,J =7.6, 1.6 Hz, 1H), 3.20 (q,J= 6.4 Hz, 2H), 2.76 (t,J =7.6 Hz, 2H), 1.91-1.83 (m, 2H), 1.45 (s, 9H)。 用於製備31A 的程式：
Figure 02_image298
向化合物31A (626 mg，2.68 mmol)於i- PrOH(31 mL)中的溶液中添加化合物1e (780 mg，2.95 mmol)和TFA(916 mg，8.04 mmol)。將所得混合物在21-28℃下攪拌3小時。將反應物用DCM(30 mL)和飽和NaHCO3 溶液(30 mL)稀釋，分離。水層用DCM(30 mL×2)萃取。將合併的有機層經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-50%乙酸乙酯/石油醚)純化，得到呈黃色油狀的化合物31a (850 mg，66%產率)。LCMS: tR =0.823 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=480.7 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=8.30 (s, 1H), 7.47 (dd,J= 8.0, 1.6 Hz, 1H), 7.38 (d,J= 8.0 Hz, 1H), 6.67 (d,J= 8.4 Hz, 1H), 6.52 (s, 1H), 6.49-6.43 (m, 1H), 4.94 (s, 1H), 4.61 (s, 1H), 3.50-3.34 (m, 1H), 3.27-3.11 (m, 3H), 3.06 (dd,J= 16.4, 4.4 Hz, 1H), 3.01-2.85 (m, 1H), 2.61 (t,J= 7.6 Hz, 2H), 2.51 (dd,J= 16.4, 6.4 Hz, 1H), 1.87-1.77 (m, 2H), 1.45 (s, 10H), 1.05 (d,J= 6.4 Hz, 3H)。
Figure 02_image300
向化合物31a (550 mg，1.15 mmol)於DCM(11 mL)中的溶液中添加Et3 N(232 mg，2.3 mmol)和PhNTf2 (492 mg，1.38 mmol)。將所得混合物在22-29℃下攪拌15小時。將反應物用DCM(30 mL)和水(25 mL)稀釋，分離。水層用DCM (30 mL×2)萃取。將合併的有機層經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-20%乙酸乙酯/石油醚)純化，得到呈黃色油狀的化合物31b (560 mg，79%產率)。LCMS: tR =0.933 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=612.4 [M+H]+ 。
Figure 02_image302
將化合物31b (560 mg，0.9 mmoL)、碳酸鉀(397 mg，1.35 mmol)、Pd(dppf)Cl2 .CH2 Cl2 (73 mg，0.09 mmol)和化合物14B (397 mg，1.35 mmol)於1,4-二噁烷(12 mL)和水(1.2 mL)中的溶液在氮氣下在100℃下攪拌15小時。將反應物用DCM(30 mL)和水(20 mL)稀釋，分離。水層用DCM(30 mL×2)萃取。將合併的有機層經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-50%乙酸乙酯/石油醚)純化，得到呈黃色油狀的化合物31c (380 mg，79%產率)。LCMS: tR =0.803 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=530.4 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=8.27 (d,J= 1.6 Hz, 1H), 7.71 (s, 2H), 7.42-7.38 (m, 1H), 7.30 (d,J= 8.4 Hz, 1H), 7.18 (s, 1H), 7.12 (d,J= 7.6 Hz, 1H), 6.83 (d,J= 8.0 Hz, 1H), 4.95 (s, 1H), 4.52 (s, 1H), 3.54-3.40 (m, 1H), 3.25-3.15 (m, 1H), 3.20-3.13 (m, 3H), 2.99-2.85 (m, 1H), 2.62-2.52 (m, 3H), 1.77-1.69 (m , 2H), 1.37 (s, 9H), 1.03 (d,J= 6.4 Hz, 3H)
Figure 02_image304
向31c (380 mg，0.718 mmol)於DCM(4 mL)中的溶液中添加HCl/MeOH(4 mL，4 M)，接著將混合物在室溫(22-24℃)下攪拌2小時。將混合物用飽和Na2 CO3 溶液調節至pH =9，接著將混合物用DCM(5 mL×3)萃取。將合併的有機層用鹽水(5 mL)洗滌，經無水硫酸鈉乾燥且過濾。在減壓下濃縮濾液，得到呈棕色油狀的化合物31d (290 mg，94%產率)。LCMS: tR =0.658 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=430.3 [M+H]+ 。 1 H NMR (400MHz, MeOD) δ=8.31 (d,J= 1.6 Hz, 1H), 7.91 (s, 2H), 7.63 (dd,J = 8.0, 2.0 Hz, 1H), 7.39 (s, 1H), 7.33 (d,J= 8.0 Hz, 1H), 7.25 (dd,J= 8.0, 1.2 Hz, 1H), 6.74 (d,J= 8.4 Hz, 1H), 4.97 (s, 1H), 3.58-3.50 (m, 1H), 3.44-3.35 (m, 1H), 3.30-3.26 (m, 1H), 3.01-2.88 (m, 1H), 2.74-2.62 (m, 5H), 1.82-1.74 (m , 2H), 1.10 (d,J= 6.8 Hz, 3H)
Figure 02_image306
向化合物31d (320 mg，0.745 mmol)於DMF(10 mL)中的溶液中添加DIEA(192 mg，1.488 mmol)和化合物1F_1a (140 mg，0.745 mmol)。將所得混合物在20-28℃下攪拌15小時。將反應物用DCM(20 mL)和水(20 mL)稀釋，分離。水層用DCM(10 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，得到120 mg不純的產物，其另外通過SFC(柱：Phenomenex-Amylose-1(250 mm×30 mm，5 μm)，條件：40 % EtOH(0.1% NH3 H2 O)，流動速率：50 mL/min)純化，獲得呈黃色固體狀的實施例 31 (4.67 min，38.6 mg)和呈黃色固體狀的實施例 31 的順式異構體 (5.17 min，4.2 mg)。實施例 31 的譜 ： LCMS: tR =0.688 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=490.4 [M+H]+ 。SFC: tR =4.679 min；97.34%純度。方法：柱：Chiralpak AD-3 150×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 2.5 min；流動速率：2.5 mL/min；柱溫：35℃。HPLC : tR =2.77 min，於10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, MEOD) δ=8.32 (d,J= 1.2 Hz, 1H), 7.91 (s, 2H), 7.64 (dd,J= 8.4, 2.0 Hz, 1H), 7.39 (s, 1H), 7.34 (d,J= 8.4 Hz, 1H), 7.26 (d,J= 9.2 Hz, 1H), 6.75 (d,J= 8.0 Hz, 1H), 4.97 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 3.64-3.49 (m, 1H), 3.48-3.35 (m, 1H), 3.30-3.24 (m, 1H), 2.87-3.07 (m, 1H), 2.74-2.61 (m, 7H), 1.96-1.88 (m, 1H), 1.88-1.78 (m, 3H), 1.10 (d,J= 6.8 Hz, 3H)。實施例 31 的順式異構體的譜 ： LCMS: tR =0.683 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=490.4 [M+H]+ 。S FC: tR =5.179 min；90.59%純度。方法：柱：Chiralpak AD-3 150×4.6mm I.D.，3μm，流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5 min內從5%至40%且保持於40% 2.5 min，接著維持5% B 2.5 min；流動速率：2.5 mL/min；柱溫：35℃。HPLC : tR =2.69 min，於10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, MeOD) δ=8.33 (d,J= 2.0 Hz, 1H), 7.90 (s, 2H), 7.68 (dd,J =8.0, 2.4 Hz, 1H), 7.54 (d,J= 8.0 Hz, 1H), 7.35 (s, 1H), 7.27 (dd,J= 8.0, 1.6 Hz, 1H), 6.84 (d,J= 8.0 Hz, 1H), 5.15 (s, 1H), 4.51 (dt,J =47.6, 6.0 Hz, 2H), 3.48-3.36 (m, 2H), 3.25-5.17 (m, 1H), 2.89-2.70 (m, 8H), 2.01-1.84 (m, 4H), 1.33 (d,J= 6.0 Hz, 3H)。實施例 32 3-((1S,3R)-1-(2,6- 二氟 -4-(3-((3- 氟丙基 ) 胺基 )-1- 羥丙基 ) 苯基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 )-2,2- 二氟丙 -1- 醇
Figure 02_image308
用於製備32A 的程式： 向化合物32A_1 (10 g，133 mmol)於DMF(70 mL)中的溶液中添加DIEA(34.3 g，266 mmol)和化合物1F_1a (27.6 g，146 mmol)。在室溫(24-32℃)下攪拌混合物15小時。接著將DIEA(17.1 g，133 mmol)和Boc2 O(29 g，133 mmol)添加至以上混合物中且再在室溫(24-32℃)下攪拌15小時。將反應物用乙酸乙酯(100 mL)和水(100 mL)稀釋，分離。水層用乙酸乙酯(100 mL×2)萃取。將合併的有機層用鹽水(100 mL)洗滌，經無水硫酸鈉乾燥，過濾，在真空中濃縮且通過矽膠柱層析(0-10%乙酸乙酯/石油醚)純化，得到呈黃色油狀的化合物32A_2 (10.5 g，33%產率)。 1 H NMR (400MHz, CDCl3 ) δ=4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.81 (s, 1H), 3.53 (br s, 2H), 3.40-3.30 (m, 4H), 3.26 (t,J= 6.0 Hz, 1H), 1.98-1.77 (m, 2H), 1.73-1.60 (m, 2H), 1.43 (s, 9H)。 在0℃下向化合物32A_2 (10.5 g，44.6 mmol)於二氯甲烷(100 mL)中的溶液中添加戴斯-馬丁試劑(28.4 g，67.0 mmol)。在室溫(24-29℃)下攪拌混合物2小時。將反應物用二氯甲烷(50 mL)以及NaHCO3 和Na2 SO3 的混合物飽和溶液(v/v：3/1，100 mL)稀釋，分離。水層用二氯甲烷(100 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾，在真空中濃縮且通過矽膠柱層析(0-10%乙酸乙酯/石油醚)純化，得到呈無色油狀的化合物32A_3 (7 g，67%產率)。 1 H NMR (400MHz, CDCl3 ) δ=9.78 (t,J= 1.6 Hz, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.52 (d,J= 6.4 Hz, 2H), 3.32 (t,J= 6.8 Hz, 2H), 2.70 (t,J= 6.0 Hz, 2H), 2.01-1.79 (m, 2H), 1.43 (s, 9H)。 在0℃下在氮氣下向化合物32A_4 (3.58 g，12.1 mmol)於THF(20 mL)中的溶液中逐滴添加i- PrMgCl溶液(7.3 mL，14.5 mmol，2 M於THF中)。在室溫(27-32℃)下攪拌反應物1小時。接著在0℃下將化合物32A_3 (3.39 g，14.5 mmol)逐滴添加至以上反應物中。此後，將反應物在室溫(27-32℃)下在氮氣下攪拌2小時。將混合物用NH4 Cl飽和水溶液淬滅至pH=7。將所得混合物用乙酸乙酯(100 mL×3)萃取。將合併的有機層用鹽水(50 mL)洗滌且經無水硫酸鈉乾燥，過濾，在真空中濃縮且通過矽膠柱層析(10-30%乙酸乙酯/石油醚)純化，得到呈無色油狀的化合物32A_5 (2.88 g，53%產率)。 1 H NMR (400MHz, CDCl3 ): δ=6.91 (d,J= 9.2 Hz, 2H), 5.71 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H)，4.52-4.45 (m, 1H), 3.82-3.70 (m, 2H), 3.66-3.55 (m, 2H), 3.50-3.26 (m, 4H), 2.03-1.88 (m, 4H), 1.48 (s, 9H), 1.25 (t,J= 6.8 Hz, 6H)。 將化合物32A_5 (3.5 g，7.79 mmol)和PPTS(783 mg，3.89 mmol)於丙酮(90 mL)和水(9 mL)中的溶液在60℃下在氮氣下加熱16小時。在真空中濃縮反應混合物，以得到殘餘物。將殘餘物用水(90 mL)和乙酸乙酯(100 mL)稀釋。在分離之後，將水層用乙酸乙酯(100 mL×2)萃取。將合併的有機層用鹽水(100 mL)洗滌。有機層經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(10-20%乙酸乙酯/石油醚)純化，得到呈褐色固體狀的化合物32A (2.26 g，77%產率)。LCMS: tR =0.863 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=276.1 [M+H-100]+ 。 1 H NMR (400MHz, CDCl3 ): δ=10.31 (s, 1H), 7.03 (d,J= 10.0 Hz, 2H), 4.67-4.36 (m, 4H), 3.57-3.02 (m, 4H), 2.03-1.86 (m, 4H), 1.48 (s, 9H)。 用於製備實施例 32 異構體 1 和實 施 例 32 異構體 2 的程式：
Figure 02_image310
向化合物32a (800 mg，1.66 mmol)和化合物32A (624 mg，1.66 mmol)於AcOH(6 mL)中的溶液中添加水(149 mg，8.29 mmol)，將所得混合物在80℃下在氮氣下攪拌一小時。將反應物倒入NaHCO3 (20 mL)和鹽水(25 mL)的飽和水溶液混合物中，用乙酸乙酯(50 mL×3)萃取。將合併的有機層用鹽水(30 mL)洗滌，經無水硫酸鈉乾燥，過濾，濃縮，通過矽膠柱層析(10-50%乙酸乙酯/石油醚)純化，得到呈黃色油狀的化合物32b (900 mg，64%產率)。LCMS: tR =1.043 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=840.7 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.66-7.59 (m, 4H), 7.45-7.38 (m, 6H), 6.75-6.65 (m, 2H), 6.49 (dd,J= 7.6, 0.8 Hz, 1H), 6.43 (d,J= 2.0 Hz, 1H), 6.38-6.35 (m, 1H), 5.14 (s, 1H), 4.48 (dt,J= 47.2, 5.6 Hz 2H), 4.46-4.42 (m, 1H), 4.00-3.86 (m, 1H), 3.84-3.80 (m, 1H), 3.56-3.36 (m, 4H), 3.19-3.06 (m, 3H), 2.77-2.65 (m, 1H), 2.42 (dd,J= 15.6, 3.6 Hz, 1H), 2.01-1.75 (m, 4H), 1.47 (s, 9H), 1.03 (s, 9H), 1.02 (d,J =6.0 Hz, 3H)。
Figure 02_image312
在0℃下向化合物32b (1.7 g，2.02 mmol)、TsOH(1.04 g，6.06 mmol)於CH3 CN(50 mL)中的攪拌混合物中添加NaNO2 (279 mg，4.04 mmol)和KI(838 mg，5.05 mmol)於水(10 mL)中的溶液。將混合物在室溫(27-36℃)下在氮氣下攪拌3小時，得到褐色溶液。將混合物用NaHCO3 飽和水溶液(30 mL)淬滅且用乙酸乙酯(30 ml×3)萃取。將合併的有機層用鹽水(35 mL)洗滌，經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-20%乙酸乙酯/石油醚)純化，得到呈黃色固體狀的化合物32c (860 mg，45%產率)。 1 H NMR (400MHz, CDCl3 ) δ=7.65-7.57 (m, 4H), 7.48-7.34 (m, 8H), 6.80-6.65 (m, 2H), 6.46 (d,J= 8.0 Hz, 1H), 5.17 (s, 1H),4.48 (dt,J= 47.2, 5.6 Hz, 2H), 4.47-4.42 (m, 1H),3.98-3.74 (m, 2H), 3.65-3.34 (m, 3H), 3.27-2.97 (m, 4H), 2.86-2.59 (m, 1H), 2.48 (dd,J= 14.0,4.0 Hz, 1H), 2.05-1.64 (m, 4H), 1.47 (s, 9H), 1.04-0.99 (m, 12H)。
Figure 02_image314
在室溫(27-37℃)下向化合物32c (360 mg，0.053 mmol)和化合物14B (223 mg，0.758 mmol)於1,4-二噁烷(3.5 mL)中的溶液中添加K2 CO3 (209 mg，1.516 mmol)，接著添加水(0.7 mL)和EtOH(1.4 mL)，接著快速添加Pd(dppf)Cl2 .CH2 Cl2 (46 mg，0.057 mmol)。在脫氣且用氮氣吹掃三次之後，將所得混合物在70℃下在氮氣下攪拌16小時。將反應混合物用水(20 mL)稀釋且用CH2 Cl2 (30 mL×2)萃取。將合併的有機層用鹽水(25 mL)洗滌，經無水硫酸鈉乾燥，過濾，濃縮，通過矽膠柱層析(0-50%乙酸乙酯/石油醚)純化，得到呈黃色固體狀的化合物32d (220 mg，65%產率)。LCMS: tR =1.153 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=891.8 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.82 (s, 2H), 7.68-7.58 (m, 4H), 7.48-7.35 (m, 6H), 7.24 (d,J= 0.8 Hz 1H), 7.16 (d,J= 8.4 Hz, 1H), 6.80-6.70 (m, 3H), 5.25 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.48-4.42 (m, 1H), 4.03-3.78 (m, 2H), 3.67-3.39 (m, 3H), 3.32-2.96 (m, 4H), 2.83-2.66 (m, 1H), 2.57 (dd,J= 16.0, 4.0 Hz, 1H), 2.02-1.79 (m, 4H), 1.47 (s, 9H), 1.09-0.99 (m, 12H)。
Figure 02_image316
將化合物32d (220 mg，0.247 mmol)於TFA(1 mL)和二氯甲烷(3 mL)中的溶液在室溫(26-34℃)下在氮氣下攪拌一小時。將混合物用Na2 CO3 飽和水溶液(20 mL)中和且用二氯甲烷(30 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且濃縮，得到呈黃色固體狀的化合物32e (170 mg，87%產率)。LCMS: tR =0.968 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=791.6 [M+H]+ 。
Figure 02_image318
在氮氣下向化合物32e (150 mg，0.189 mmol)於THF(3 mL)中的溶液中添加TBAF(0.38 mL，0.379 mmol，1 M於THF中)，將所得混合物在室溫(27-34℃)下攪拌2小時。將反應物用二氯甲烷(20 mL)和水(20 mL)稀釋，分離。水層用二氯甲烷(10 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-10%甲醇/二氯甲烷)純化，得到100 mg粗產物，其另外通過手性SFC(柱：Phenomenex-Amylose-1(250 mm×30 mm，5 μm)，條件：30% EtOH(0.1% NH3. H2 O)，流動速率：50 mL/min)純化，獲得呈白色固體狀的實施例 32 異構體 1 (15.5 mg)和呈黃色固體狀的實施例 32 異構體 2 (22.4 mg)。總產率為39%。實施例 32 異構體 1 的 譜 ： LCMS: tR =0.733 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=553.4 [M+H]+ 。SFC: tR =4.752 min；92.42%純度。方法：柱：Chiralpak AD-3 150×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.1%乙醇胺)；梯度：B於5.5 min內從5%至40%，接著維持5% B 1.5 min；流動速率：2.5 mL/min；柱溫：35℃。HPLC : tR =3.02 min，於10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CD3 OD) δ=7.90 (s, 2H), 7.34 (s, 1H), 7.23 (d,J= 8.0 Hz, 1H), 6.95 (d,J= 10.0 Hz, 2H), 6.69 (d,J= 8.0 Hz, 1H), 5.25 (s, 1H), 4.75 (d,J =4.8 Hz, 1h), 4.59-4.56 (m, 1H), 4.45 (t,J= 5.6 Hz, 1H), 3.80-3.56 (m, 2H), 3.45-3.35 (m, 2H), 3.24-3.08 (m, 1H), 2.84-2.74 (m, 4H), 2.68 (dd,J= 15.6, 4.0 Hz, 2H), 2.02-1.81 (m, 4H), 1.40-1.28 (m, 1H), 1.07 (d,J= 6.4 Hz, 3H)。實施例 32 異構體 2 的 譜 ： LCMS: tR =0.738 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=553.4 [M+H]+ 。SFC: tR =4.941 min；83.59%純度。方法：柱：Chiralpak AD-3 150×4.6mm I.D.，3μm，流動相：A：CO2 ；B：乙醇(0.1%乙醇胺)；梯度：B於5.5 min內從5%至40%，接著維持5% B 1.5 min；流動速率：2.5 mL/min；柱溫：35℃。HPLC : tR =3.02 min，於10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CD3 OD) δ=7.89 (s, 2H), 7.34 (s, 1H), 7.23 (d,J= 6.8 Hz, 1H), 6.98 (d,J= 10.0 Hz, 2H), 6.68 (d,J= 8.0 Hz, 1H), 5.26 (s, 1H), 4.90 (s, 1H), 4.58 (dt,J= 47.2, 5.6 Hz, 2H), 3.78-3.56 (m, 2H), 3.47-3.32 (m, 2H), 3.22-3.06 (m, 5H), 2.78-2.62 (m, 2H), 2.17-1.93 (m, 4H), 1.07 (d,J= 6.4 Hz, 3H)。實施例 33 3-((1S,3R)-1-(2,6- 二氟 -4-(1- 氟 -3-((3- 氟丙基 ) 胺基 ) 丙基 ) 苯基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 )-2,2- 二氟丙 -1- 醇
Figure 02_image320
用於製備實施例 33 異構體 1 和實施例 33 異構體 2 的程式：
Figure 02_image322
在0℃下向化合物32c (500 mg，0.526 mmol)於二氯甲烷(15 mL)中的溶液中添加DAST(593 mg，3.682 mmol)。在室溫(26-31℃)下攪拌混合物2小時。將反應混合物用NaHCO3 飽和水溶液(20 mL)和二氯甲烷(20 mL×2)稀釋，然後分離。將合併的有機層用鹽水(25 mL)洗滌，經無水硫酸鈉乾燥，過濾，在真空中濃縮且通過矽膠柱層析(10-50 %乙酸乙酯/石油醚)純化，得到呈黃色固體狀的化合物33a (110 mg，22%產率)。LCMS: tR =1.357 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=953.6 [M+H]+ 。 1 H NMR (400MHz, CDCl3 ) δ=7.65-7.57 (m, 4H), 7.51-7.31 (m, 8H), 6.69 (t,J= 9.2 Hz, 2H), 6.46 (d,J= 8.0 Hz, 1H), 5.45-5.30 (m, 1H), 5.20 (s, 1H), 4.46(dt,J= 47.6, 5.6 Hz, 2H), 3.99-3.80 (m, 1H), 3.65-3.43 (m, 2H), 3.40-3.11 (m, 6H), 2.80-2.62 (m, 1H), 2.48 (dd,J= 16.4, 4.0 Hz, 1H), 2.05-1.80 (m, 4H), 1.45 (s, 9H), 1.08-0.98 (m, 12H)。
Figure 02_image324
在室溫(23-31℃)下向化合物33a (220 mg，0.231 mmol)和化合物14B (136 mg，0.46 mmol)於1,4-二噁烷(3 mL)中的攪拌溶液中添加K2 CO3 (127 mg，1.0 mmol)，接著添加水(0.6 mL)和EtOH(1.2 mL)，接著快速添加Pd(dppf)Cl2 .CH2 Cl2 (28 mg，0.0345 mmol)。在脫氣且用氮氣吹掃三次之後，將所得混合物在70℃下在氮氣下攪拌16小時。將反應混合物用水(20 mL)稀釋且用二氯甲烷(30 mL×2)萃取。將合併的有機層用鹽水(25 mL)洗滌，經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-50%乙酸乙酯/石油醚)純化，得到呈黃色固體狀的化合物33b (110 mg，53%產率)。LCMS: tR =1.194 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=893.7 [M+H]+ 。
Figure 02_image326
在室溫(24-31℃)下向化合物33b (110 mg，0.123 mmol)於二氯甲烷(1.5 mL)中的溶液中添加TFA(0.5 mL)。在室溫(24-31℃)下攪拌混合物2小時。將混合物用Na2 CO3 飽和水溶液(20 mL)淬滅至pH ＞7且用二氯甲烷(30 mL×2)萃取。合併的有機層經無水硫酸鈉乾燥，過濾且濃縮，得到呈黃色固體狀的化合物33c (90 mg，92%產率)。LCMS: tR =1.000 min，於5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm)中，MS (ESI) m/z=793.3 [M+H]+ 。
Figure 02_image328
在氮氣下在室溫(24-31℃)下向化合物33c (90 mg，0.113 mmol)於THF(2 mL)中的溶液中添加TBAF(0.23 mL，0.227 mmol)。在室溫(24-31℃)下攪拌所得混合物2小時。將反應物用二氯甲烷(20 mL)和水(20 mL)稀釋，分離。水層用二氯甲烷(20 mL×2)萃取。將合併的有機層經無水硫酸鈉乾燥，過濾，濃縮且通過矽膠柱層析(0-10%甲烷/二氯甲烷)純化，得到120 mg產物，其另外通過手性SFC (柱：DAICEL CHIRALPAK AD-H(250 mm×30 mm，5 μm)，條件：20% EtOH(0.1% NH3 .H2 O)於CO2 中，流動速率：50 mL/min)，接著通過製備型HPLC(柱：Venusil ASB Phenyl 250×50 mm 10 μm，條件：38-68% B(A：水0.05% HCl)，B：CH3 CN)，流動速率：25 mL/min)分離，得到呈白色固體狀的實施例 33 異構體 1 (7.8 mg)和呈黃色固體狀的實施例 33 異構體 2 (8.1 mg)。總產率為25%。實施例 33 異構體 1 的 譜 ： LCMS: tR =0.771 min，於5-95AB_220&254 Shimadzu (Merck RP18e 25×3.0mm)中，MS (ESI) m/z=555.5 [M+H]+ 。SFC: tR =4.696 min；95.10%純度。方法：柱：Chiralpak AD-3 150×4.6mm I.D.，3μm；流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5.5 min內從5%至40%且保持於40% 3 min，接著維持5% B 1.5 min；流動速率：2.5 mL/min；柱溫：40℃。HPLC : tR =3.49 min，於10-80_AB_1.2mL METHOD (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CD3 OD) δ=8.12 (s, 2H), 7.50 (s, 1H), 7.40 (d,J= 8.0 Hz, 1H), 7.10 (d,J= 10.0 Hz, 2H), 6.90 (d,J= 7.6 Hz, 1H), 5.88-5.62 (m, 2H), 4.58 (dt,J= 47.2, 5.6 Hz, 2H), 3.88 (br s, 1H), 3.82-3.70 (m, 1H), 3.68-3.52 (m, 2H), 3.50-3.35 (m, 2H), 3.26-3.16 (m, 4H), 2.92 (d,J= 13.6 Hz, 1H), 2.45-2.23 (m, 2H), 2.19-1.98 (m, 2H), 1.30 (d,J= 6.4 Hz, 3H)。實施例 33 異構體 2 的 譜 ： LCMS: tR =0.767 min，於5-95AB_220&254 Shimadzu (Merck RP18e 25×3.0mm)中，MS (ESI) m/z=577.4 [M+Na]+ 。SFC: tR =4.995 min；94.43%純度。方法：柱：Chiralpak AD-3 150×4.6mm I.D.，3μm，流動相：A：CO2 ；B：乙醇(0.05% DEA)；梯度：B於5.5 min內從5%至40%且保持於40% 3 min，接著維持5% B 1.5 min；流動速率：2.5 mL/min；柱溫：40℃。HPLC : tR =3.49 min，於10-80_AB_1.2mL METHOD (Ultimate C18 3×50mm 3μm)中。 1 H NMR (400MHz, CD3 OD) δ=8.11 (s, 2H), 7.59 (s, 1H), 7.49 (d,J= 8.0 Hz, 1H), 7.19 (d,J= 10.0 Hz, 2H), 7.06 (d,J= 8.4 Hz, 1H), 6.13 (s, 1H), 5.89-5.68 (m, 1H), 4.62 (dt,J= 46.8, 5.2 Hz, 2H), 4.21-4.06 (m, 1H), 4.03-3.77 (m, 3H), 3.63-3.39 (m, 2H), 3.30-3.17 (m, 4H), 3.15-3.03 (m, 1H), 2.43-2.24 (m, 2H), 2.22-2.04 (m, 2H), 1.46 (d,J= 6.4 Hz, 3H)。實施例 34 3-((1S,3R)-1-(2,6- 二氟 -4-( 氟 (1-(3- 氟丙基 ) 氮雜環丁 -3- 基 ) 甲基 ) 苯基 )-3- 甲基 -6-(1H- 吡唑 -4- 基 )-3,4- 二氫異喹啉 -2(1H)- 基 )-2,2- 二氟丙 -1- 醇
Figure 02_image330
用於製備實施例 34 異構體 1 和實施例 34 異構體 2 的程式：
Figure 02_image332
在0℃下向化合物34a (430.0 mg，0.476 mmol)於二氯甲烷(13 mL)中的溶液中添加DAST(537 mg，3.33 mmol)。將混合物在室溫(26-34℃)下攪拌2小時，得到紅色溶液。將混合物與以相同方式進行的先導批料(100 mg化合物34a )合併，用NaHCO3 飽和水溶液(60 mL)淬滅至pH=8然後用二氯甲烷(100 mL×3)萃取。將有機相合併且用鹽水(50 mL)洗滌且經無水硫酸鈉乾燥，過濾且在真空中濃縮以得到殘餘物，其通過矽膠柱層析(0-10%乙酸乙酯/石油醚)純化，獲得呈黃色油狀的化合物34b (430 mg，81%平均產率)。LCMS: tR =1.322 min，於5-95AB_1.5min_220& 254.l cm層析(Agilent pursult5 C18 20×2 mm)中，MS (ESI) m/z=927.5 [M+Na]+。 1 H NMR (CDCl3 400MHz): δ=7.66-7.59 (m, 4H), 7.50-7.33 (m, 8H), 6.71-6.64 (m, 2H), 6.46 (d,J= 8.4 Hz, 1H), 5.46-5.28 (m, 1H), 5.21 (s, 1H), 3.95-3.81 (m, 4H), 3.78-3.71 (m, 1H), 3.62-3.43 (m, 2H), 3.30-3.12 (m, 2H), 2.90-2.61 (m, 2H), 2.49 (dd,J= 16.0, 3.6 Hz, 1H), 1.46-1.42 (m, 9H), 1.06-0.99 (m, 12H)。
Figure 02_image334
在0℃下向化合物34b (430 mg，0.475 mmol)於二氯甲烷(6.5 mL)中的混合物中逐滴添加三氟乙酸(2.2 mL)。將混合物在0℃下攪拌1小時，得到黃色溶液。通過在0℃下添加NaHCO3 飽和水溶液(50 mL)將混合物調節至pH=8，且用二氯甲烷(80 ml×3)萃取。將有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥。將有機層過濾且在真空中濃縮，得到呈黃色固體狀的化合物34c (378 mg，99%產率)。LCMS: tR =1.080 min，於5-95AB_1.5min_220& 254.l cm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=805.1 [M+H]+ 。
Figure 02_image336
將化合物34c (378 mg，0.470 mmol)、化合物1F_1a (102 mg，0.540 mmol)和K2 CO3 (325 mg，2.35 mmol)於乙腈(7 mL)中的混合物在室溫(26-34℃)下攪拌16小時，得到黃色懸浮液。將混合物用乙酸乙酯(100 mL)稀釋。將合併的有機層用鹽水(30 mL)洗滌，經無水硫酸鈉乾燥。將有機層過濾且在真空中濃縮以得到殘餘物，其通過矽膠柱層析(0-1%甲醇(0.1%氨)/二氯甲烷)純化，獲得呈黃色油狀的化合物34d (235 mg，58%產率)。LCMS: tR =1.104 min，於5-95AB_1.5min_220& 254.l cm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=865.5 [M+H]+。
Figure 02_image338
將化合物34d (185 mg，0.214 mmol)、化合物14B (126 mg，0.428 mmol)和K2 CO3 (118 mg，0.856 mmol)於1,4-二噁烷(1.9 mL)、乙醇(0.7 mL)和水(0.4 mL)中的混合物脫氣且用氮氣吹掃3次。接著添加Pd(dppf)Cl2 .DCM(26 mg，0.032 mmol)且脫氣且用氮氣吹掃3次。將混合物在70℃下在氮氣下攪拌16小時，得到褐色溶液。將混合物與以相同方式進行的先導批料(50 mg化合物34d )合併，用乙酸乙酯(200 mL)稀釋。將合併的有機層用鹽水(30 mL)洗滌，經無水硫酸鈉乾燥。將有機層過濾且在真空中濃縮以得到殘餘物，其通過矽膠柱層析(0-1%甲醇(0.1%氨)/二氯甲烷)純化，獲得呈非對映異構體的混合物形式的化合物34e (145 mg，66%平均產率)，其可基於SFC分離。SFC: tR =3.114 min和4.135 min(方法：柱：Lux Cellulose-2 150×4.6mm I.D., 3μm；流動相：40%甲醇(0.05% DEA)於CO2 中，流動速率：2.5 mL/min；柱溫：40℃)。 方法：柱：Lux Cellulose-2 150×4.6mm I.D.，3μm；流動相：40%甲醇(0.05% DEA)於CO2 中，流動速率：2.5 mL/min；柱溫：40℃。LCMS: tR =1.024 min，於5-95AB_1.5min_220& 254.l cm層析(Agilent pursult5 C18 20×2mm)中，MS (ESI) m/z=805.3 [M+H]+ 。 1 H NMR (CDCl3 400MHz): δ=7.83 (s, 2H), 7.68-7.59 (m, 4H), 7.48-7.36 (m, 6H), 7.26-7.24 (m, 1H), 7.18 (d,J= 8.0 Hz, 1H), 6.76-6.63 (m, 3H), 5.45-5.32 (m, 1H), 5.28 (br s, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.99-3.85 (m, 1H), 3.68-3.59 (m, 1H), 3.57-3.45 (m, 1H), 3.33-3.20 (m, 4H), 3.17-3.10 (m, 1H), 2.98-2.91 (m, 1H), 2.88-2.65 (m, 2H), 2.62-2.50 (m, 3H), 1.79-1.65 (m, 2H), 1.10-1.00 (m, 12H)。
Figure 02_image340
向化合物34e (125.0 mg，0.155 mmol)於四氫呋喃(3 mL)中的溶液中添加TBAF(0.233 mL，0.233 mmol，1 M於THF中)。將混合物在室溫(26-35℃)下攪拌2小時，得到黃色溶液。將混合物用乙酸乙酯(100 mL)稀釋。將合併的有機層用鹽水(30 mL)洗滌，經無水硫酸鈉乾燥。將有機層過濾且在真空中濃縮以得到殘餘物，其通過製備型TLC(二氯甲烷：甲醇=20：1)純化，獲得呈黃色油狀的產物(86 mg)。總共100 mg此化合物通過手性SFC(柱：Phenomenex-Cellulose-2(250 mm×30 mm，5 μm)，條件：(0.1% NH3. H2 O) 甲醇於CO2 中，開始B 45%，結束B 45%，流動速率：50 mL/min)分離，得到呈黃色固體狀的實施例 34 異構體 1 (29.9 mg，tR =2.579 min，峰1，100%純度，29%產率)和呈黃色固體狀的實施例 34 異構體 2 (32.9 mg，tR =3.476 min，峰2，100%純度，32%產率)。針對外消旋的 SFC ： tR =2.473 min和3.274 min。方法：柱：Lux Cellulose-2 150×4.6mm I.D., 3μm；流動相：40%甲醇(0.05% DEA)於CO2 中；流動速率：2.5 mL/min；柱溫：40℃。實施例 34 異構體 1 的 譜 ： LCMS: tR =1.919 min，於10-80AB_4min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=567.2 [M+H]+ 。HPLC: tR =3.29 min，於10-80_AB_1.2ml.met.層析(Ultimate C18 3.0μm 3.0×50mm)中。SFC: tR =2.579 min；99.71%純度。方法：柱：Lux Cellulose-2 150×4.6 mm I.D.，3μm；流動相：40%甲醇(0.05% DEA)於CO2 中，流動速率：2.5 mL/min，柱溫：40℃。 1 H NMR (400MHz, CDCl3 ): δ=7.83 (s, 2H), 7.28 (s, 1H), 7.20 (dd,J= 8.0, 2.0 Hz, 1H), 6.88-6.82 (m, 2H), 6.72 (d,J= 8.0 Hz, 2H), 5.52 (dd,J= 47.6, 6.0 Hz, 1H), 5.22 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 3.74-3.52 (m, 3H), 3.50-3.40 (m, 2H), 3.36 (dd,J= 16.0, 4.4 Hz, 1H), 3.30-3.21 (m, 2H), 3.20-3.12 (m, 1H), 3.03-2.91 (m, 1H), 2.87-2.75 (m, 1H), 2.72-2.61 (m, 3H), 1.84-1.71 (m, 2H), 1.10 (d,J= 6.4 Hz, 3H)。實施例 34 異構體 2 的 譜 ： LCMS: tR =1.898 min，於10-80AB_4min_220&254.lcm層析(Xtimate C18 2.1×30mm)中，MS (ESI) m/z=567.2 [M+H]+。HPLC: tR =3.32 min，於10-80_AB_1.2ml.met.層析(Ultimate C18 3.0μm 3.0×50mm)中。SFC: tR =3.476min；98.65%純度。 1 H NMR (400MHz, CDCl3 ): δ=7.83 (s, 2H), 7.28 (s, 1H), 7.21 (dd,J= 7.6, 1.2 Hz, 1H), 6.87-6.81 (m, 2H), 6.72 (d,J= 8.0 Hz, 1H), 5.52 (dd,J= 48.0, 6.4 Hz, 1H), 5.23 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 3.74-3.51 (m, 3H), 3.50-3.41 (m, 2H), 3.36 (dd,J= 15.6, 4.8 Hz, 1H), 3.30-3.13 (m, 3H), 3.04-2.91 (m, 1H), 2.88-2.75 (m, 1H), 2.72-2.60 (m, 3H), 1.84-1.71 (m, 2H), 1.10 (d,J= 6.4 Hz, 3H)。實 施 例 35 TR-FRET ER-α 配體結合域結合分析 此實施 例涉及受試化合物與ER-α配體結合域的結合分析。 受試化合物在DMSO中以10 μM製備且以2倍滴定連續稀釋，以在低體積非結合聚苯乙烯黑色384孔板(Geiner目錄號784900)中獲得總共22個點。 ER-α配體結合域/Tb-抗GST Ab複合體篩選緩衝液在實驗當天通過混合以下各者新鮮地製備：10 ml核受體緩衝液、50 μl 1 M DTT至終濃度5 mM、10 μl 20000 nM ER-α配體結合域重組蛋白至終濃度20 nM和22.8 μl Tb-抗GST抗體(Lantha篩選TR-FRET雌激素α受體競爭性結合試劑盒，Thermofisher，目錄號A15887)至終濃度4 nM。通過倒置將複合體篩選緩衝液平緩地混合若干次，然後在使用之前在冰上培育30分鐘。 通過在指定孔中首先分配100 nl每種製備的化合物稀釋液(通常至少十二種不同濃度用於每種化合物以獲得劑量反應曲線)，以及空白(DMSO)和陽性對照樣品(例如氟維司群或含有氟維司群的藥物)來製備反應板。還將5 μl複合體篩選緩衝液分配至樣品/對照/空白孔中的每一個中，且將反應板覆蓋且在冰上培育30分鐘。 同時，Fluoromone ES2篩選緩衝液通過混合以下各者製備：3 ml核受體緩衝液、15 μl的1 M DTT至終濃度5 mM、12 μl的10% Tween-20至終濃度0.02%和40 μl的1800 nM Fluoromone ES2至終濃度24 nM，渦旋製備的緩衝液。在培育受試化合物和複合體篩選緩衝液進行30分鐘後，接著將5 μl Fluoromone ES2篩選緩衝液分配至各個樣品/對照/空白孔中，且將反應板覆蓋且在冰上再培育60分鐘。 使用Tecan Spark 20M在Ex337nm和Em490nm/520nm處進行每個孔的螢光發射信號測量。相對於空白和氟維司群對照計算抑制百分比值。使用GraphPad Prism 7軟體進行曲線擬合和IC50 計算。實 施 例 36 乳腺癌細胞 ER-α 降解分析 此實施 例涉及受試化合物對在例如MCF7細胞的乳腺癌細胞的細胞表面上表達的ER-α受體的降解分析。此分析方法識別具有ER α降解特性的化合物。 第1天-MCF7乳腺癌細胞在96孔聚賴胺酸塗布的組織培養板(Greiner編號T-3101-4)中在100 µl含有RPMI (Gibco，目錄號11835-030)與10%活性炭處理的FBS (BioSun，目錄號BS-004-500)的無酚L-穀胺醯胺中以每孔12,000個細胞的密度接種且培育過夜。將培養板在37℃、5% CO2 下培育過夜。 第2天-在DMSO中順次製備化合物儲備溶液(33 μΜ、11 μΜ、3.3 μΜ、1.1 μΜ、0.3 μΜ、0.1 μΜ、0.03 μΜ、0.01 μΜ、0.001 μΜ)，接著使用Freedom Evo液體處理工作站(liquid Handling Workstation)(TECAN)在細胞培養基中1:33稀釋以獲得9種工作濃度(1 μΜ、333 nM、100 nM、33 nM、10 nM、3.3 nM、1 nM、0.3 nM、0.03 nM)。 使用Freedom Evo液體處理工作站(TECAN)將11 μl的每種化合物稀釋液、對照化合物(通過細胞培養基稀釋的1 µM氟維司群工作溶液)和空白對照(DMSO)分配至細胞培養板的預先指定的孔中，獲得如下最終濃度：針對每種化合物100 nM、33.3 nM、10 nM、3 nM、1 nM、0.3 nM、0.1 nM、0.03 nM、0.003 nM，作為最小對照的100 nM氟維司群和作為最大對照的0.3% DMSO。將細胞培養板在37℃下培育過夜。 第3天-進行固定和滲透，如下： 1)在化合物處理24小時之後，去除組織培養生長培養基。 2)通過添加100 μL 1×PBS至每個孔來洗滌細胞。平緩地渦流或輕拍約20秒，接著通過抽吸徹底去除所有流體。 3)通過添加100 μL細胞固定緩衝液至每個樣品孔來固定細胞。在室溫下培育至少7分鐘。通過平緩地渦旋或輕拍來混合。 4)去除固定溶液且丟棄。 5)用250 μL 1× PBS洗滌每個樣品孔3次，如上文所述。 6)添加100 μL細胞滲透緩衝液至每個樣品孔且通過平緩地渦旋或輕拍來混合。在室溫下培育8分鐘。 7)去除細胞滲透溶液且丟棄。 8)用250 μL 1× PBS洗滌每個孔3次，如上文所述。 9)添加100 μL阻斷緩衝液至每個樣品孔且在室溫下培育1小時。阻斷緩衝液製備為具有3% BSA的1× PBST(0.05 % Tween-20)。 10)去除阻斷緩衝液且添加100 μL稀釋的第一抗體(在抗體1號稀釋劑(Antibody #1 Dilute)中1:10000稀釋)至每個樣品孔，通過平緩地渦旋或輕拍來混合且在4℃下培育過夜。 第4天-如下進行第二抗體培育和ELISA讀取： 1)去除第一抗體且用250 μL 1×洗滌緩衝液洗滌樣品孔3次。在最後一次洗滌之後，將板倒置且在紙巾上輕拍以去除殘餘流體。(立即進行下一步驟。不要讓板在步驟之間風乾)。 2)製備1× HRP結合的抗兔IgG抗體2號(在抗體2號稀釋劑中1:100稀釋)，通過平緩地渦旋或輕拍添加100 μL第二抗體混合物且在室溫下培育1小時。 3)用250 μL 1×洗滌溶液洗滌板3次。在最後一次洗滌之後，將板倒置且在紙巾上輕拍以去除殘餘流體。(立即進行下一步驟。不要讓板在添加TMB底物之前乾燥)。 4)添加100 μL TMB底物且覆蓋反應板。緊接在添加TMB底物之後開始對反應計時。手動搖動板1分鐘以徹底混合反應物。 5)在室溫下培育5-45分鐘，然後添加100 μL終止緩衝液以終止酶反應。 6)在添加終止緩衝液之後盡可能快地在設定為450 nm波長的Multiscan Spectrum讀取器上讀板(程式“OD450-OD540”)。 使用GraphPad Prism 7軟體進行曲線擬合和IC50 計算。 ER降解%=1-(經過化合物處理的-經過100 nM氟維司群處理的)/(經過0.3% DMSO處理的-經過100 nM氟維司群處理的)×100實 施 例 37 PR 拮抗劑分析 此實施 例涉及拮抗劑分析，其通過測量對在ER α下游的孕酮受體的效應來間接識別雌二醇刺激的ER α的拮抗劑。 第1天-MCF7乳腺癌細胞在96孔聚賴胺酸塗布的組織培養板(Greiner編號T-3101-4)中在100 µl含有RPMI (Gibco，目錄號11835-030)與10%活性炭處理的FBS (BioSun，目錄號BS-004-500)的無酚L-穀胺醯胺中以每孔12,000個細胞的密度接種且培育過夜。將培養板在37℃、5% CO2 下培育過夜。 第2天-在DMSO中順次製備化合物儲備溶液(33 μΜ、11 μΜ、3.3 μΜ、1.1 μΜ、0.3 μΜ、0.1 μΜ、0.03 μΜ、0.01 μΜ、0.001 μΜ)然後使用Freedom Evo液體處理工作站(TECAN)在細胞培養基中1:33稀釋以獲得9種工作濃度(1 μΜ、333 nM、100 nM、33 nM、10 nM、3.3 nM、1 nM、0.3 nM、0.03 nM)。 給藥前，將11 μl的1 nM E2工作儲備液(在細胞培養基中稀釋)分配於每個孔中以獲得0.1 nM的終濃度且在CO2 培育箱中培育30分鐘。接著使用Freedom Evo液體處理工作站(TECAN)將11 μl的每種化合物稀釋液和空白對照(DMSO)分配至細胞培養板的預先指定的孔中，獲得如下終濃度：針對每種化合物的100 nM、33.3 nM、10 nM、3 nM、1 nM、0.3 nM、0.1 nM、0.03 nM、0.003 nM，作為最大對照的0.1 nM E2和作為最小對照的0.3% DMSO。將細胞培養板在37℃下培育過夜。 第3天-進行固定和滲透，如下： 1)在24小時化合物處理之後，去除組織培養生長培養基。 2)通過添加100 μL 1×PBS至每個孔來洗滌細胞。平緩地渦流或輕拍約20秒，接著通過抽吸徹底去除所有流體。 3)通過添加100 μL細胞固定緩衝液至每個樣品孔來固定細胞。在室溫下培育至少7分鐘。通過平緩地渦旋或輕拍來混合。 4)去除固定溶液且丟棄。 5)用250 μL 1× PBS洗滌每個樣品孔3次，如上文所述。 6)添加100 μL細胞滲透緩衝液至每個樣品孔且通過平緩地渦旋或輕拍來混合。在室溫下培育8分鐘。 7)去除細胞滲透溶液且丟棄。 8)用250 μL 1× PBS洗滌每個孔3次，如上文所述。 9)添加100 μL稀釋的第一抗體(在抗體1號稀釋劑中1：10000稀釋)至每個樣品孔，通過平緩地渦旋或輕拍來混合且在4℃下培育過夜。 第4天-進行第二抗體培育和ELISA讀取如下： 1)去除第一抗體且用250 μL 1×洗滌緩衝液洗滌樣品孔3次。在最後一次洗滌之後，將板倒置且在紙巾上平緩地輕拍以去除殘餘流體。(立即進行下一步驟。不要讓板在步驟之間風乾)。 2)製備1× HRP結合的抗小鼠IgG抗體2號(在抗體2號稀釋劑中1:100稀釋)，通過平緩地渦旋或輕拍板添加100 μL第二抗體混合物且在室溫下培育1小時。 3)用250 μL 1×洗滌溶液洗滌板3次。在最後一次洗滌之後，將板倒置且在紙巾上平緩地輕拍以去除殘餘流體。(立即進行下一步驟。不要讓板在添加TMB底物之前乾燥)。 4)添加100 μL TMB底物且覆蓋反應板。緊接在添加TMB底物之後開始對反應計時。平緩地手動搖動板1分鐘以徹底混合反應物。 5)在室溫下培育5-45分鐘，然後添加100 μL終止緩衝液以終止酶反應。 6)在添加終止緩衝液之後盡可能快地在設定為450 nm波長的Multiscan Spectrum讀取器上讀板(程式“OD450-OD540”)。 使用GraphPad Prism 7軟體進行曲線擬合和IC50 計算。 PR拮抗作用%=1-(經過化合物加0.1 nM E2處理的-經過0.3% DMSO處理的)/(經過0.1 nM E2處理的-經過0.3% DMSO處理的)×100 示例性化合物1-12的ER-α配體結合域結合、乳腺癌細胞ER-α降解和PR拮抗劑分析的結果在下表2中列出。
Figure 02_image342
實 施 例 38 體外大鼠 / 人類肝細胞清除率分析 採用大鼠/人肝細胞代謝穩定性分析方案測定本發明化合物在體外的清除率。 雄性大鼠肝細胞和混合性別的人類肝細胞獲自商業供應商(例如BioreclamationIVT)且在使用前儲存於-150℃下。在DMSO中製備測試化合物的10 mM儲備溶液。在使用前將解凍培養基和補充培育培養基(無血清)置於37℃水浴中，持續至少15分鐘。通過組合198 μL乙腈和2 μL的10 mM儲備溶液將儲備溶液稀釋至100 μM。 從儲存中取出冷凍保存的肝細胞的小瓶，確保所述小瓶保持於低溫溫度。將小瓶在平緩振盪下在37℃水浴中解凍。將小瓶保持在水浴中，直至所有冰晶都溶解並且不再可見。將小瓶用70%乙醇噴灑，隨後將其轉移至生物安全櫃中。然後將內含物倒入50 mL解凍培養基錐形管中。將小瓶在室溫下在100 g下離心10分鐘。抽吸出解凍培養基且將肝細胞再懸浮於無血清培育培養基中，得到約1.5×106 個細胞/毫升。 使用台盼藍拒染法(Trypan Blue exclusion)對細胞活力和密度進行計數，然後用無血清培育培養基稀釋細胞以達到1×106 個活細胞/毫升的工作細胞密度。將一部分1×106 個活細胞/毫升的肝細胞煮沸10分鐘，隨後添加至板中作為陰性對照，這樣可以消除酶活性以使得只有極少量或沒有底物轉換可以觀察到。使用失活的肝細胞製備陰性樣品，其用於排除由化學物質本身的不穩定性引起的誤導因素。 將247.5 μL肝細胞的等分試樣分配至96孔未塗布板的各個孔中。在軌道振盪器上將板置於培育箱中，保持約10分鐘。將2.5 μL的100 μM測試化合物的等分試樣添加至未塗布96孔板的對應孔中以起始反應。此分析進行兩個重複實驗。將板在培育箱中置於軌道振盪器上培育，持續設計的時間點。在5、15、30、45、60、80和100分鐘時間點處，轉移20 μL內含物且與6倍體積(120 μL)含內標的冷乙腈混合以終止反應。將樣品在4000 g下離心20分鐘且將100 μL上清液的等分試樣用於LC-MS/MS分析以測量受試化合物。 基於測定的化合物自初始濃度消失的消除半衰期(T1/2 )來估計體外肝細胞清除率。計算每種化合物(測試或對照)與IS的峰面積比。標繪Ln(對照%)相對於培育時間(分鐘)的曲線，並計算線性擬合線的斜率。藥物消除速率常數k(min-1)、T1/2 (分鐘)和體外固有清除率CLint (μL/min/E6)根據以下等式計算： k=-斜率 T1/2 =0.693/k CLint =k/Chep 其中Chep (細胞×μL-1 )是培育系統中的細胞濃度。實施例 39 用於測定 Log D 的 程式 將10 μL的每個盒的工作溶液依序置於對應的96孔擱架位置(Log D板)中。將500 μL飽和辛醇添加至以上無蓋Log D板的每個小瓶中，接著添加500 μL飽和磷酸鹽緩衝液。用模制的PTDE/SIL 96孔板蓋密封。 將Log D板轉移至Eppendorf Thermomixer Comfort板振盪儀且在25℃、2,000 rpm下振盪2小時。 將樣品在4,000 rpm下在25℃下離心30分鐘以分離各相。吸液管和注射器用於分別從辛醇和緩衝液相吸取約100 μL至新96孔板。 將5 μL辛醇樣品轉移至新96孔板，接著添加495 μL H2 O和含內標的乙腈(1:1)的混合物作為100倍辛醇樣品。在1,000 rpm下渦旋5分鐘。 將50 μL的100倍樣品轉移至新96孔板，接著添加450 μL H2 O和含內標的乙腈(1:1)的混合物作為1,000倍辛醇樣品。在1,000 rpm下渦旋5分鐘。 用H2 O和含內標的乙腈(1:1)的混合物將1,000倍辛醇樣品連續稀釋為10,000、100,000和1,000,000倍。 將50 μL的緩衝液樣品轉移至新96孔板，接著添加450 μL H2 O和含內標的乙腈(1:1)的混合物作為10倍緩衝液樣品。在1,000 rpm下渦旋5分鐘。 用H2 O和含內標的乙腈(1:1)的混合物將10倍緩衝液樣品連續稀釋為100、1,000和10,000倍。通過LC/MS/MS分析評估樣品。所有化合物進行單次測試。 所有計算使用Microsoft Excel進行。通過LC/MS/MS評估受試化合物於辛醇/緩衝溶液中的濃度。如下計算測試化合物的Log D值：
Figure 02_image344
DF意指稀釋係數。實 施 例 40 通過使用平衡透析在人類血漿中進行蛋白質結合測量的程式 將597 μL空白血漿添加至新塑膠板的每個小孔或獨立塑膠管中並添加各自分配的3 μL的工作溶液，在1,000 rpm下渦旋5分鐘。有機溶劑的最終體積百分數為0.5%且受試化合物的終濃度為5 μM。緊接著將50 μL加標血漿懸浮液轉移至96孔板以充當T=0對照樣品。與培育之後的樣品相同地處理所述樣品。將所有剩餘的加標血漿在研究的持續時間內置於培育箱中。 將插入物開口端朝上地置於底板的孔中。將500 μL磷酸鹽緩衝液(pH 7.4)添加至緩衝室中，其由白色圓圈指示。將300 μL加標血漿樣品添加至樣品室中，其由紅色圓圈指示。用透氣蓋覆蓋所述單元且在CO2 培育箱中的軌道振盪器以5% CO2 、300rpm在37℃培育18小時。在培育結束時，去除蓋且分別將50 μL透析後樣品從緩衝液室和血漿室吸取至獨立的96孔板中用於分析。 同時，將塑膠板或獨立塑膠管中剩餘的加標血漿樣品在CO2 培育箱中以5% CO2 在37℃下培育18小時。在T=18小時處，將50 μL原始加標血漿懸浮液轉移至96孔板用於分析。 將50 μL人類血漿添加至緩衝液樣品，且將相等體積的PBS添加至收集的血漿樣品。將板在1,000 rpm下渦旋2分鐘且添加400 μL含有適當內標(IS)的乙腈以使蛋白質沉澱和釋放化合物。在1,000 rpm下渦旋10分鐘。在4,000 rpm下離心30分鐘。將250 μL上清液轉移至新的96孔板且再次離心(4,000 rpm，30分鐘)。接著將100 μL上清液轉移至新的96孔板用於分析。添加100 μL蒸餾水至每一樣品且在1,000 rpm下渦旋5分鐘以通過LC-MS/MS進行分析。所有化合物在人類血漿中以5 μM一式一份地測試。 所有計算使用Microsoft Excel進行。 如下計算測試化合物的非結合百分比、結合和回收百分比：
Figure 02_image346
示例性資料顯示於下表3中。
Figure 02_image348
實 施 例 41 未成熟子宮濕重分析 未成熟子宮濕重分析 該研究在年齡在17-19天之間的未性成熟的雌性SD大鼠中進行。大鼠按照體重分別隨機分成以下匹配組：媒劑(花生油)、17-β-雌二醇、單獨的氟維司群或加上17-β-雌二醇、單獨的他莫昔芬或加上17-β-雌二醇、單獨的受試化合物或加上17-β-雌二醇。花生油媒劑、每只大鼠1 μg的17-β-雌二醇、0.2 mg/kg氟維司群和所有受試化合物均經由皮下途徑以每次注射0.2 ml的總體積每天施用，而他莫昔芬通過經口管飼每天一次地以1 mg/kg給藥。受試化合物以10 µg和100 µg的兩個劑量給藥。 向所有動物每天給藥，持續三天。在最後一次給藥之後24小時，收集血漿用於藥代動力學分析，且緊接在血漿收集之後，對動物進行安樂死且取出子宮且稱重。 子宮增重和抗子宮增重活性用子宮重量計算為
Figure 02_image350
Figure 02_image352
。
Figure 02_image354
In one aspect, the invention provides compounds of formula (I):
Figure 02_image001
Formula (I) Or a pharmaceutically acceptable salt thereof, wherein: A1 , A2 And A3 Each independently -C(R6 )= or -N=; Ring Q is a 6-membered aromatic ring, wherein the ring atoms are independently selected from carbon or nitrogen; Ring B is a 5-membered or 6-membered unsaturated ring, which may be carbon-linked or nitrogen-linked; wherein if the 5-membered or 6-membered unsaturated ring contains a -NH- moiety, the nitrogen may be optionally substituted From R7 Group substitution; X is -O-, -NR8 -、-C(R9 )(R10 )-Or-S-; R1 And R3 Is a substituent on carbon and is independently selected from hydroxyl, halogen, nitro, cyano, carboxyl, amine, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, fluoromethyl, difluoro Methyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino; or on adjacent atoms Of two R1 The group forms a five-membered or six-membered fused carbocyclic group or a fused heterocyclic group ring; wherein the five-membered or six-membered fused carbocyclic group or fused heterocyclic group ring may optionally be substituted on the carbon by R11 Substitution; and wherein if the five- or six-membered fused heterocyclyl ring contains a -NH- moiety, then the nitrogen may optionally be selected from R12 Group substitution; R2 And R5 Independently selected from C1-12 Alkyl, 3-10 membered saturated or unsaturated carbocyclic group, or 3-10 membered saturated or unsaturated heterocyclic group; wherein R2 And R5 Optionally on carbon via R13 Substitution; and wherein if the 3-10 membered saturated or unsaturated heterocyclic group contains a -NH- moiety, then the nitrogen may optionally be selected from R14 Group substitution; R4 For C1-3 Alkyl or C3-4 Cycloalkyl; where R4 May be optionally substituted with one or more hydroxyl, halogen or methoxy; R8 Is hydrogen or C optionally substituted with one or more halo or hydroxy groups1-12 alkyl; R6 , R9 And R10 Each independently is hydrogen, hydroxyl, halogen, nitro, cyano, carboxyl, amine, carbamoyl, mercapto, sulfamoyl, C1-12 Alkyl or C1-12 Alkoxy; wherein the C1-12 Alkyl or C1-12 The alkoxy group may be independently optionally substituted with one or more halo or hydroxy groups; R11 And R13 Is a substituent on carbon and is independently selected from the group consisting of hydroxy, halogen, nitro, cyano, carboxy, trifluoromethoxy, amine, carbamoyl, mercapto, sulfamoyl, C1-12 Alkyl, C1-12 Alkoxy, C1-12 Alkyl, C1-12 Alkyloxy, N-(C1-12 Alkyl)amine, N,N-(C1-12 alkyl)2 Amino group, C1-12 Alkylamide, N-(C1-12 Alkyl)amine formamide, N,N-(C1-12 alkyl)2 Carboxamide, C1-12 Alkyl S(O)a , Where a is 0 to 2, C1-12 Alkoxycarbonyl, N-(C1-12 Alkyl) sulfamoyl, N, N-(C1-12 alkyl)2 Sulfasulfamide, C1-12 Alkyl sulfonamide, C1-12 Alkyl-OH, C1-12 Haloalkyl, -Si(Ra Rb Rc ), 3-10 membered saturated or unsaturated carbocyclic group, or 3-10 membered saturated or unsaturated heterocyclic group; wherein R11 And R13 Each independently can optionally pass one or more R on carbon15 Substitution; and wherein if the 3-10 membered saturated or unsaturated heterocyclic group contains a -NH- moiety, then the nitrogen may optionally be selected from R16 Group substitution; R7 , R12 , R14 And R16 Independently selected from C1-12 Alkyl, C1-12 Alkyl, C1-12 Alkylsulfonyl, C1-12 Alkoxycarbonyl, carbamoyl, N-(C1-12 Alkyl)amine formamide, N,N-(C1-12 alkyl)2 Carboxamide, 3-10 membered saturated or unsaturated carbocyclic group, 3-10 membered saturated or unsaturated heterocyclic group, 3-10 membered saturated or unsaturated carbocyclic group C1-12 Alkyl, 3-10 membered saturated or unsaturated heterocyclic group C1-12 Alkyl, benzyl, benzyloxycarbonyl, benzyl or phenylsulfonyl; where R7 , R12 , R14 And R16 R can be independently17 replace; R15 And R17 Each is independently selected from the group consisting of hydroxyl, halogen, nitro, cyano, carboxyl, trifluoromethoxy, amine, carbamoyl, mercapto, sulfamoyl, C1-12 Alkyl, C1-12 Alkoxy, C1-12 Haloalkyl, N-(C1-12 Alkyl)amine, N-(C1-12 Haloalkyl) amine or C1-12 Alkyl-OH; Ra , Rb And Rc Independently selected from hydroxyl group, C1-12 Alkyl or C1-12 Alkyl-OH; and m is 0, 1, 2, 3 or 4; n is 0, 1, or 2. In one aspect of the invention, A1 , A2 And A3 Each is -C(R6 )= or -N=; where R6 Each is independently hydrogen or halogen. In one aspect of the invention, A1 , A2 And A3 Each is -C(R6 )= or -N=; where R6 Each is independently hydrogen or fluorine. In one aspect of the invention, A1 , A2 And A3 Each is -C(R6 )=. In one aspect of the invention, A1 , A2 And A3 Each is -C(R6 )=; where R6 For hydrogen. In one aspect of the invention, A1 Is -N= and A2 And A3 Each independently -C(R6 )=. In one aspect of the invention, A2 Is -N= and A1 And A3 Each independently -C(R6 )=. In one aspect of the invention, A3 Is -N= and A1 And A2 Each independently -C(R6 )=. In one aspect of the invention, ring Q is phenyl or pyridyl. In one aspect of the invention, ring Q is pyridyl. In one aspect of the invention, ring Q is phenyl. In one aspect of the invention, Ring B is a 5-membered or 6-membered unsaturated ring, which may be carbon-linked or nitrogen-linked; wherein if the 5-membered or 6-membered unsaturated ring contains a -NH- moiety, then The nitrogen can optionally be selected from R7 Group substitution; where R7 From C1-12 Alkyl or cyclopropyl; where R7 One or more R can be optionally17 Replace; and R17 Each is independently selected from halogen. In one aspect of the invention, ring B is pyrazolyl, oxazolyl, 1,2,4-triazol-4-yl, 1,2,3-triazol-4-yl, 2,5-di Hydrothiophen-4-yl 1,1-dioxide, pyrimidinyl, pyridazinyl, pyridyl, pyrrolyl, tetrazolyl or imidazolyl; wherein if the pyrazolyl, 1,2,3-triazole Group, pyrrolyl, tetrazolyl, 1,2,4-triazolyl and imidazolyl contain -NH- moieties, then the nitrogen may optionally be selected from R7 Group substitution; where R7 Selected from methyl, ethyl or cyclopropyl; where R7 One or more R can be optionally17 Replace; and R17 Each is independently selected from fluorine. In one aspect of the invention, Ring B is 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-4-yl, 4H-1,2 ,4-triazol-4-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-3-yl, 2,5-dihydrothiophen-4- 1,1-dioxide, pyrimidin-5-yl, pyridazin-4-yl, pyridin-3-yl, pyridin-4-yl, 1H-pyrrol-3-yl, 2H-tetrazol-5-yl Or 1H-imidazol-2-yl; wherein the 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 2H-1,2,3-triazol-4-yl, 1H-pyrrole-3 -Yl, 2H-tetrazol-5-yl, 1H-1,2,4-triazol-3-yl and 1H-imidazol-2-yl can optionally be selected from R on the -NH- moiety7 Group substitution; where R7 It is selected from methyl, difluoromethyl, ethyl or cyclopropyl. In one aspect of the invention, ring B is pyrazolyl, oxazolyl, 1,2,4-triazol-4-yl, 1,2,3-triazol-4-yl, 2,5-di Hydrothiophen-4-yl 1,1-dioxide, pyrimidinyl, pyridazinyl, pyridyl, pyrrolyl, tetrazolyl or imidazolyl; wherein if the pyrazolyl, 1,2,3-triazole Group, pyrrolyl, tetrazolyl, 1,2,4-triazolyl and imidazolyl contain -NH- moieties, then the nitrogen may optionally be selected from R7 Group substitution. In one aspect of the invention, Ring B is 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-4-yl, 4H-1,2 ,4-triazol-4-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-3-yl, 2,5-dihydrothiophen-4- 1,1-dioxide, pyrimidin-5-yl, pyridazin-4-yl, pyridin-3-yl, pyridin-4-yl, 1H-pyrrol-3-yl, 2H-tetrazol-5-yl Or 1H-imidazol-2-yl; wherein the 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 2H-1,2,3-triazol-4-yl, 1H-pyrrole-3 -Yl, 2H-tetrazol-5-yl, 1H-1,2,4-triazol-3-yl and 1H-imidazol-2-yl can optionally be selected from R on the -NH- moiety7 Group substitution. In one aspect of the invention, X is -O-. In one aspect of the invention, X is -NR8 -. In one aspect of the invention, X is -NR8 -; where R8 For hydrogen. In one aspect of the invention, X is -C(R9 )(R10 )-. In one aspect of the invention, X is -C(R9 )(R10 )-; where R9 And R10 Each is independently hydrogen, hydroxyl or halogen. In one aspect of the invention, X is -S-. In one aspect of the invention, X is -O-, -NR8 -Or-C(R9 )(R10 )-;among them R8 Is hydrogen; and R9 And R10 Each is independently hydrogen, hydroxyl or halogen. In one aspect of the invention, X is -O-, -NH-, -CH2 -, -CH(OH)- or -CH(F)-. In one aspect of the invention, R1 Not hydroxyl. In one aspect of the invention, R1 Is a substituent on carbon and is independently selected from hydroxyl, halogen or methyl. In one aspect of the invention, R1 Is a substituent on carbon and is independently selected from halogen or methyl. In one aspect of the invention, R1 Is a substituent on carbon and is independently selected from hydroxyl, fluorine or methyl. In one aspect of the invention, R1 Is a substituent on carbon and is independently selected from fluorine or methyl. In one aspect of the invention, R2 From C1-12 Alkyl or 5-membered saturated carbocyclic group; where R2 Optionally one or more R on carbon13 Replace R13 Is a substituent on carbon and is independently selected from hydroxyl, halogen or C1-12 alkyl. In one aspect of the invention, R2 Selected from ethyl, propyl or bicyclo[1.1.1]pent-1-yl; where R2 Optionally one or more R on carbon13 Replace R13 Is a substituent on carbon and is each independently selected from hydroxyl, fluorine, or methyl. In one aspect of the invention, R2 From C1-12 Alkyl or 5-membered saturated carbocyclic group. In one aspect of the invention, R2 Selected from ethyl, propyl or bicyclo[1.1.1]pent-1-yl; where R2 Optionally one or more R on carbon13 replace. In one aspect of the invention, R3 Is a substituent on carbon and is independently selected from halogen or methoxy. In one aspect of the invention, R3 Is a substituent on carbon and is independently selected from fluorine or methoxy. In one aspect of the invention, R4 For C1-3 Alkyl or C3-4 Cycloalkyl; where R4 It may be optionally substituted with one or more halogens. In one aspect of the invention, R4 Is methyl, ethyl or cyclopropyl; where R4 It may be optionally substituted with one or more fluorine. In one aspect of the invention, R4 It is methyl, difluoromethyl, ethyl, 2,2-difluoroethyl-2-yl or cyclopropyl. In one aspect of the invention, R4 It is methyl. In one aspect of the invention, R5 From C1-12 Alkyl or 4- or 5-membered saturated heterocyclic group; where R5 Optionally one or more R on carbon13 Substitution; and wherein if the 4- or 5-membered saturated heterocyclic group contains a -NH- moiety, then the nitrogen may be optionally selected from R14 Group substitution; where R13 Is a substituent on carbon and is independently selected from N-(C1-12 Alkyl) amine; where R13 Each independently may optionally pass one or more R on carbon15 replace; R14 Independently selected from C1-12 Alkyl; where R14 One or more R can be optionally17 Replace; and R15 And R17 Each is independently selected from halogen. In one aspect of the invention, R5 Selected from ethyl, azetidine-3-yl or pyrrolidin-3-yl; where R5 Optionally one or more R on carbon13 Substituted; and wherein the azetidine-3-yl or pyrrolidin-3-yl may optionally be selected from R on the -NH- moiety14 Group substitution; where R13 Is a substituent on carbon and is independently selected from propylamine; where R13 Each independently may optionally pass one or more R on carbon15 replace; R14 Independently selected from propyl; where R14 One or more R can be optionally17 Replace; and R15 And R17 Each is independently selected from fluorine. In one aspect of the invention, R5 From C1-12 Alkyl or 4- or 5-membered saturated heterocyclic group; where R5 Optionally one or more R on carbon13 Substitution; and wherein if the 4- or 5-membered saturated heterocyclic group contains a -NH- moiety, then the nitrogen may be optionally selected from R14 Group substitution. In one aspect of the invention, R5 Selected from ethyl, azetidine-3-yl or pyrrolidin-3-yl; where R5 Optionally one or more R on carbon13 Substituted; and wherein the azetidine-3-yl or pyrrolidin-3-yl may optionally be selected from R on the -NH- moiety14 Group substitution. In one aspect of the invention, R5 It is 1-(3-fluoropropyl)azetidin-3-yl. In one aspect of the invention, -X-R5 It is [1-(3-fluoropropyl)azetidin-3-yl]amine. In one aspect of the invention, R6 Each is independently hydrogen or halogen. In one aspect of the invention, R6 Each is independently hydrogen or fluorine. In one aspect of the invention, R7 It is selected from methyl, difluoromethyl, ethyl or cyclopropyl. In one aspect of the invention, R8 For hydrogen. In one aspect of the invention, R9 And R10 Each is independently hydrogen, hydroxyl or halogen. In one aspect of the invention, R13 Is a substituent on carbon and is independently selected from hydroxyl, halogen or C1-12 alkyl. In one aspect of the invention, R13 Is a substituent on carbon and is each independently selected from hydroxyl, fluorine, or methyl. In one aspect of the invention, R13 Is a substituent on carbon and is independently selected from N-(C1-12 Alkyl) amine; where R13 Each independently may optionally pass one or more R on carbon15 replace. In one aspect of the invention, R14 Independently selected from C1-12 Alkyl; where R14 One or more R can be optionally17 replace. In one aspect of the invention, R15 And R17 Each is independently selected from halogen. m is 0. m is 1. m is 2. m is 3. m is 4. m is 0 or 1. n is 0. n is 1. n is 2. In one aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A1 , A2 And A3 Each independently -C(R6 )= or -N=; where R6 Each independently hydrogen or halogen; Ring Q is phenyl or pyridyl; Ring B is a 5-membered or 6-membered unsaturated ring, which may be carbon or nitrogen-linked; wherein if the 5-membered or 6-membered unsaturated ring contains a -NH- moiety, the nitrogen may optionally be selected from R7 Substituted by the group; where R7 From C1-12 Alkyl or cyclopropyl; where R7 One or more R can be optionally17 Replace; and R17 Independently selected from halogen; X is -O-, -NR8 -Or-C(R9 )(R10 )-; where R8 Is hydrogen; and R9 And R10 Each is independently hydrogen, hydroxyl or halogen; R1 Is a substituent on carbon and is independently selected from hydroxyl, halogen or methyl; R2 From C1-12 Alkyl or 5-membered saturated carbocyclic group; where R2 Optionally one or more R on carbon13 Replace; where R13 Is a substituent on carbon and is independently selected from hydroxyl, halogen or C1-12 alkyl; R3 Is a substituent on carbon and is independently selected from halogen or methoxy; R4 For C1-3 Alkyl or C3-4 Cycloalkyl; where R4 May be optionally substituted with one or more halogens; R5 From C1-12 Alkyl or 4- or 5-membered saturated heterocyclic group; where R5 Optionally one or more R on carbon13 Substitution; and wherein if the 4- or 5-membered saturated heterocyclic group contains a -NH- moiety, then the nitrogen may be optionally selected from R14 Substituted by the group; where R13 Is a substituent on carbon and is independently selected from N-(C1-12 Alkyl) amine; where R13 Each independently may optionally pass one or more R on carbon15 Replace; R14 Independently selected from C1-12 Alkyl; where R14 One or more R can be optionally17 Replace; and R15 And R17 Independently selected from halogen; m is 0 or 1; and n is 0, 1, or 2. In one aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A1 , A2 And A3 Each independently -C(R6 )= or -N=; where R6 Each is independently hydrogen or fluorine; Ring Q is phenyl or pyridyl; Ring B is pyrazolyl, oxazolyl, 1,2,4-triazol-4-yl, 1,2,3-triazol-4-yl, 2,5-dihydrothiophen-4-yl 1, 1-dioxide, pyrimidinyl, pyridazinyl, pyridyl, pyrrolyl, tetrazolyl or imidazolyl; wherein if the pyrazolyl, 1,2,3-triazolyl, pyrrolyl, tetrazolyl , 1,2,4-triazolyl and imidazolyl contain -NH- moiety, then the nitrogen can optionally be selected from R7 Substituted by the group; where R7 Selected from methyl, ethyl or cyclopropyl; where R7 One or more R can be optionally17 Replace; and R17 Independently selected from fluorine; X is -O-, -NH-, -CH2 -, -CH(OH)- or -CH(F)-; R1 Is a substituent on carbon and is independently selected from hydroxyl, fluorine or methyl; R2 Selected from ethyl, propyl or bicyclo[1.1.1]pent-1-yl; where R2 Optionally one or more R on carbon13 Replace; where R13 Is a substituent on carbon and is independently selected from hydroxyl, fluorine or methyl; R3 Is a substituent on carbon and is independently selected from fluorine or methoxy; R4 Is methyl, ethyl or cyclopropyl; where R4 May be optionally substituted with one or more fluorine; R5 Selected from ethyl, azetidine-3-yl or pyrrolidin-3-yl; where R5 Optionally one or more R on carbon13 Substituted; and wherein the azetidine-3-yl or pyrrolidin-3-yl may optionally be selected from R on the -NH- moiety14 Substituted by the group; where R13 Is a substituent on carbon and is independently selected from propylamine; where R13 Each independently may optionally pass one or more R on carbon15 Replace; R14 Independently selected from propyl; where R14 One or more R can be optionally17 Replace; and R15 And R17 Independently selected from fluorine; m is 0 or 1; and n is 0, 1, or 2. In another aspect of the invention, there is provided a compound of formula (I), which is a compound of formula (Ia):
Figure 02_image004
(Ia) Or a pharmaceutically acceptable salt thereof, wherein R1 , R2 , R3 , R4 , R5 , X, A1 , A2 , A3 , Ring B, ring Q, m and n are as defined herein. In another aspect of the present invention, there is provided a compound of formula (I), which is a compound of formula (Ib):
Figure 02_image006
(Ib) Or a pharmaceutically acceptable salt thereof, wherein R1 , R2 , R3 , R4 , R5 , X, A1 , A2 , A3 , Ring B, ring Q, m and n are as defined herein. In another aspect of the invention, there is provided a compound of formula (I), which is a compound of formula (Ic):
Figure 02_image008
(Ic) Or a pharmaceutically acceptable salt thereof, wherein R1 , R2 , R3 , R4 , R5 , X, A1 , A2 , A3 , Ring B, ring Q, m and n are as defined herein. In another aspect of the invention, there is provided a compound of formula (I), which is a compound of formula (Id):
Figure 02_image010
(Id) Or a pharmaceutically acceptable salt thereof, wherein R1 , R2 , R3 , R4 , R5 , X, A1 , A2 , A3 , Ring B, ring Q, m and n are as defined herein. In another aspect of the invention, there is provided a compound of formula (I), which is a compound of formula (Ie):
Figure 02_image012
Formula (Ie) Or a pharmaceutically acceptable salt thereof, wherein R1 , R2 , R3 , R4 , R5 , X, A1 , A2 , A3 , Ring B, m and n are as defined herein. In another aspect of the invention, there is provided a compound of formula (I), which is a compound of formula (If):
Figure 02_image014
(If) Or a pharmaceutically acceptable salt thereof, wherein R1 , R2 , R3 , R4 , R5 , X, A1 , A2 , A3 , Ring B, m and n are as defined herein. In one aspect of the present invention, there is provided a compound of formula (I) selected from the following or a pharmaceutically acceptable salt thereof: N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1-methyl-1H-pyrazole-4 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 2,2-difluoro-3-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl) -3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-1-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-3-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-6-(isoxazol-4-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-4-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-((1S,3R)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 , 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1, 2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3R)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1-methyl-1H-pyrazole-3 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(4H-1,2,4-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; and N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(2H-1,2,3-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine. In one aspect of the present invention, there is provided a compound of formula (I) selected from the following or a pharmaceutically acceptable salt thereof: N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 2,2-difluoro-3-(1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl- 6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-6-(1H-pyrazol-1-yl)-2-(2,2, 2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-6-(1H-pyrazol-3-yl)-2-(2,2, 2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(6-(isoxazol-4-yl)-3-methyl-2-(2,2,2 -Trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-6-(1H-pyrazol-4-yl)-2-(2,2, 2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-(6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetra Hydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4- Tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3 ,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-6-(1-methyl-1H-pyrazol-3-yl)-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-6-(4H-1,2,4-triazol-4-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; and N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-6-(2H-1,2,3-triazol-4-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine. In one aspect of the present invention, there is provided a compound of formula (I) selected from the following or a pharmaceutically acceptable salt thereof: N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-3-methyl-6-(1-methyl-1H-pyrazole-4 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 2,2-difluoro-3-((1R,3S)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl) -3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-3-methyl-6-(1H-pyrazol-1-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-3-methyl-6-(1H-pyrazol-3-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-6-(isoxazol-4-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-3-methyl-6-(1H-pyrazol-4-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-((1R,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 , 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1R,3S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1, 2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1R,3S)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-3-methyl-6-(1-methyl-1H-pyrazole-3 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-3-methyl-6-(4H-1,2,4-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; and N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3S)-3-methyl-6-(2H-1,2,3-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine. In one aspect of the present invention, there is provided a compound of formula (I) selected from the following or a pharmaceutically acceptable salt thereof: N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-3-methyl-6-(1-methyl-1H-pyrazole-4 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 2,2-difluoro-3-((1R,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl) -3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-3-methyl-6-(1H-pyrazol-1-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-3-methyl-6-(1H-pyrazol-3-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-6-(isoxazol-4-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-3-methyl-6-(1H-pyrazol-4-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-((1R,3R)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 , 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1R,3R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1, 2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1R,3R)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-3-methyl-6-(1-methyl-1H-pyrazole-3 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-3-methyl-6-(4H-1,2,4-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; and N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1R,3R)-3-methyl-6-(2H-1,2,3-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine. In one aspect of the present invention, there is provided a compound of formula (I) selected from the following or a pharmaceutically acceptable salt thereof: N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-3-methyl-6-(1-methyl-1H-pyrazole-4 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 2,2-difluoro-3-((1S,3S)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl) -3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-3-methyl-6-(1H-pyrazol-1-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-3-methyl-6-(1H-pyrazol-3-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-6-(isoxazol-4-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-3-methyl-6-(1H-pyrazol-4-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-((1S,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 , 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1, 2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3S)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-3-methyl-6-(1-methyl-1H-pyrazole-3 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-3-methyl-6-(4H-1,2,4-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; and N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3S)-3-methyl-6-(2H-1,2,3-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine. Exemplary compounds of formula (I) 1-54 are set forth in Table 1 below.
Figure 02_image016
Figure 02_image018
Figure 02_image020
Figure 02_image022
Figure 02_image024
Figure 02_image026
Figure 02_image028
It should be understood that certain features of the invention described in the context of separate embodiments for clarity may also be combined in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for simplicity can also be provided separately or in any suitable sub-combination. In several places in this document, linking substituents are described. In the case where the structure clearly requires a linking group, the markush variable listed with respect to the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush definition of the variable enumerates "alkyl", it should be understood that the "alkyl" represents a linear alkylene group. As used herein, when referring to a chemical group, the term "substituted" means that the chemical group has one or more hydrogen atoms removed and replaced with a substituent. As used herein, the term "substituent" has the ordinary meaning known in the art and refers to a chemical moiety that is covalently attached to, or where appropriate, fused to the parent group. As used herein, the term "optionally substituted" or "optionally... substituted" means that the chemical group may have no substituents (ie, unsubstituted) or may have one or more substituents (ie, substituted) replace). It should be understood that the substitution at a given atom is limited by the valence state. As used herein, the term "Cij "Indicates a range of carbon atoms, where i and j are integers and the range of carbon atoms includes endpoints (ie, i and j) and every integer point in between, and where j is greater than i. For example, C1-6 Indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C1-12 "Indicates 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms. As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated or unsaturated hydrocarbon chain, and the latter can be further subdivided into hydrocarbon chains having at least one double or triple bond (ene Group or alkynyl group). The above-mentioned hydrocarbon chain may be linear or branched. The term "Cij "Alkyl" refers to an alkyl group having i to j carbon atoms. Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl , Sec-butyl; higher homologues, such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylbutyl, etc. Examples include but are not limited to vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, ethynyl, propyn-1-yl, propyn-2-yl and the like. "C1-12 Examples of "alkyl" are methyl, ethyl, propyl and butyl. "C1-3 Examples of "alkyl" are methyl, ethyl, propyl and isopropyl. As used herein, the terms "halo" and "halogen" refer to atoms selected from fluorine, chlorine, bromine, and iodine. As used herein, the term "alkoxy", whether used as part of another term or independently, refers to a group of formula -O-alkyl. The term "Cij "Alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropyl Oxygen), tert-butoxy, etc. "C1-12 Examples of "alkoxy" are methoxy, ethoxy and propoxy. As used herein, the term "Cij Alkyl-OH" refers to the formula "-C1-12 An alkyl-OH" group, wherein the alkyl portion of the group has i to j carbon atoms, and one or more hydroxyl groups can be attached to any carbon atom in the alkyl portion. "C1-12 Examples of "alkyl-OH" are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxyisopropyl. As used herein, the term "Cij "Haloalkyl" means halogen-substituted (mono- or poly-substituted) Cij alkyl. "C1-12 Examples of "haloalkyl" are fluoromethyl, trifluoromethyl, 2-chloroethyl and 1-bromoisopropyl. "N-(C1-12 Examples of "haloalkyl)amino" are fluoromethylamino, trifluoromethylamino, 2-chloroethylamino and 1-bromoisopropylamino. "C1-12 Examples of "alkyl acetyl" are propyl and acetyl. "C1-12 Examples of "alkyl amide groups" are methyl amide groups, acetyl amide groups, and propyl amide groups. "C1-12 An example of "alkyloxy" is acetyloxy. "C1-12 Examples of "alkoxycarbonyl" are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl. "C1-12 Alkyl (O)a Examples where a is 0 to 2" are methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesylate and ethylsulfonyl. "C1-12 Examples of "alkylsulfonyl" are mesyl, ethylsulfonyl and isopropylsulfonyl. "C1-12 Examples of "alkylsulfonamide" are mesyl, ethylsulfonamide and isopropylsulfonamide. "N-(C1-12 Examples of "alkyl)amino" are methylamino and ethylamino. "N-(C1-12 Examples of "alkyl)aminecarboxamide" are methylaminocarbonyl and ethylaminocarbonyl. "N-(C1-12 Examples of "alkyl) sulfamoyl" are N-(methyl) sulfamoyl and N-(ethyl) sulfamoyl. "N,N-(C1-12 alkyl)2 Examples of "amino groups" are di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. "N,N-(C1-12 alkyl)2 Examples of "aminomethylamino" are dimethylaminocarbonyl and methylethylaminocarbonyl. "N,N-(C1-12 alkyl)2 Examples of "sulfamidyl" are N,N-(dimethyl)sulfamoyl and N-(methyl)-N(ethyl)-sulfamoyl. Examples of "trifluoroethoxy" are 2,2,2-trifluoroethoxy and 1,2,2-trifluoroethoxy. Examples of "trifluoroethyl" are 2,2,2-trifluoroethyl and 1,2,2- Trifluoroethyl. As used herein, the term "carbocyclyl", whether used as part of another term or independently, refers to any ring, including monocyclic or polycyclic (eg, having 2 or 3 fused rings, bridged rings, or spiro rings), All ring atoms are carbon and contain at least three ring-forming carbon atoms. In some embodiments, the carbocyclyl group may contain 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, or 4 to 8 ring-forming carbon atoms. Carbocyclic groups can be saturated, partially unsaturated, or completely unsaturated. In some embodiments, the carbocyclic group may be a saturated cyclic alkyl group. In some embodiments, the carbocyclic group may be an unsaturated cyclic alkyl group containing at least one double bond in the ring system. In some embodiments, the unsaturated carbocyclic group may contain one or more aromatic rings. In some embodiments, ring-CH2 -The group can be replaced by a ring-C(O)- group. Examples of monocyclic carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene Base etc. As used herein, the term "spiro ring" refers to a ring system where two rings are connected by a single common atom; the term "fused ring" refers to a ring system where two rings share two adjacent atoms; and the term "bridge ring" is Refers to a ring system in which two rings share three or more atoms. Examples of spirocarbocyclyl include, but are not limited to spiro[5.5]undecyl, spiropentadienyl, spiro[3.6]decyl and the like. Examples of fused carbocyclic groups include, but are not limited to, naphthyl, benzopyrene, anthracenyl, acenaphthyl, stilbendyl, and the like. Examples of bridged carbocyclic groups include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2] Octyl, bicyclic [3.3.1] nonyl, bicyclic [3.3.3] undecyl, etc. "3-10 membered saturated or unsaturated carbocyclic group" is a saturated, partially unsaturated or completely unsaturated monocyclic or polycyclic system having 3 to 10 ring carbon atoms, wherein -CH2 -The group may optionally be replaced by -C(O)-. "5-membered saturated carbocyclic group" is a saturated monocyclic system having 5 ring carbon atoms, where -CH2 -The group may optionally be replaced by -C(O)-. When "the two Rs on the adjacent atom1 When the group forms a five-membered or six-membered fused carbocyclic group", the carbocyclic group is a saturated, partially unsaturated, or fully unsaturated monocyclic system having 5 or 6 ring carbon atoms, wherein -CH2 -The group may optionally be replaced by -C(O)-. Examples of "3-10 membered saturated or unsaturated carbocyclic group" are cyclopropyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl and bicyclo[1.1.1]pent-1-yl. An example of "5-membered saturated carbocyclyl" is cyclopentyl. "3-10 member saturated or unsaturated carbocyclic group C1-12 Examples of "alkyl" are cyclopropylmethyl, cyclohexylethyl, 1-cyclohexenylprop-2-yl, benzyl, 1-naphthylethyl and bicyclo[1.1.1]pent-1-yl methyl. "C3-4 Examples of "cycloalkyl" are cyclopropyl and cyclobutyl. "Two Rs on adjacent atoms1 An example of the group forming a five-membered or six-membered fused carbocyclic group" is a fused cyclohexenyl group, and a fused phenyl group is a fused cyclopentyl group. As used herein, the term "heterocyclyl" refers to a carbocyclic group in which one or more (eg, 1, 2, or 3) ring atoms are replaced with heteroatoms including, but not limited to, oxygen, sulfur, nitrogen, phosphorus, and the like. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is an unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group. In some embodiments, the heterocyclic group is a fully unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the unsaturated heterocyclic group may contain one or more aromatic rings. In some embodiments, the episulfide atoms can be optionally oxidized to form S-oxides. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. Exemplary monocyclic heterocyclic groups include, but are not limited to, pyridinyl, pyrrolidinyl, tetrahydrofuranyl, pyridinyl, pyrazinyl, morpholinyl, and the like. Examples of spiroheterocyclic groups include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of fused heterocyclic groups include, but are not limited to, quinolinyl, isoquinolinyl, quinazinyl, quinazolinyl, pyridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, Indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, oxazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, etc. . Examples of bridged heterocyclic groups include, but are not limited to, morphanyl, hexamethylenetetramine, 8-azabicyclo[3.2.1]octane, 1-azabicyclo[2.2 .2] Octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), etc. "3-10 membered saturated or unsaturated heterocyclic group" is a saturated, partially unsaturated, or fully unsaturated monocyclic or polycyclic ring having 3 to 10 ring atoms (at least one of which is selected from nitrogen, sulfur, or oxygen) Unless otherwise stated, the system can be carbon or nitrogen linked, where -CH2 -The group may optionally be replaced by -C(O)- and the episulfide atom may optionally be oxidized to form an S-oxide. "4- or 5-membered saturated heterocyclic group" is a saturated monocyclic system having 4 or 5 ring atoms (at least one of which is selected from nitrogen, sulfur, or oxygen), which may be carbon or nitrogen-linked unless otherwise specified Of which -CH2 -The group may optionally be replaced by -C(O)- and the episulfide atom may optionally be oxidized to form an S-oxide. "A 5- or 6-membered unsaturated ring that may be carbon or nitrogen-linked" is a partially unsaturated or fully unsaturated monocyclic system having 5 or 6 ring atoms (where the ring atoms are selected from carbon, nitrogen, sulfur, or oxygen) Unless otherwise stated, it may be carbon or nitrogen linked, where -CH2 -The group may optionally be replaced by -C(O)- and the episulfide atom may optionally be oxidized to form an S-oxide. When two R on adjacent atoms1 When the group forms a five-membered or six-membered fused heterocyclic ring, the heterocyclic ring is saturated, partially unsaturated or has 5 or 6 ring atoms (at least one of which is selected from nitrogen, sulfur, or oxygen) Fully unsaturated single ring system, where -CH2 -The group may optionally be replaced by -C(O)- and the episulfide atom may optionally be oxidized to form an S-oxide. Examples of "3-10 membered saturated or unsaturated heterocyclic group" are pyrrolyl, pyrazolyl, oxathiolanyl, isoxazolyl, pyrimidinyl and pyridazinyl. "3-10 membered saturated or unsaturated heterocyclic group C1-12 Examples of "alkyl" are pyrrolylmethyl, 1-pyrazolylethyl, oxathiolanylmethyl, 1-isoxazolylpropan-2-yl, pyrimidinylmethyl and pyridazinylbutyrate base. Examples of "4-membered or 5-membered saturated heterocyclic group" are azetidinyl and 1,3-dioxolyl. Examples of "a 5-membered or 6-membered unsaturated ring which may be carbon or nitrogen linkage" are phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 2-pyrrolinyl, and 2-pyrazolinyl. Two Rs on adjacent atoms1 Examples of groups forming a five-membered or six-membered fused heterocyclic ring are fused pyrimidinyl, fused pyridazinyl, fused furanyl, fused isothiazolyl and fused triazolyl. "6-membered aromatic ring in which ring atoms are independently selected from carbon or nitrogen" refers to a monocyclic carbocyclic or heterocyclic group moiety having alternating double and single bonds between ring-forming atoms. Exemplary "6-membered aromatic rings in which ring atoms are independently selected from carbon or nitrogen" are phenyl, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. Unless otherwise stated, the "compound" of the present invention is intended to cover all stereoisomers, geometric isomers and tautomers of the depicted structure. The term "stereoisomer" refers to various stereoisomeric configurations (eg, enantiomers, non-symmetrical compounds) of asymmetric compounds (eg, compounds having one or more asymmetrically substituted carbon atoms or "asymmetric centers") Any of enantiomers and racemates). Compounds of the invention containing asymmetric centers can be separated into optically active (enantiomers or diastereomers) or non-optically active (racemic) forms. The term "enantiomer" includes a pair of stereoisomers that are not mirror images that can overlap each other. A 1:1 mixture of a pair of enantiomers is a "racemic mixture". The term "diastereomer (diastereomer or diastereoisomer)" includes stereoisomers having at least two asymmetric atoms but not mirror images of each other. Certain compounds containing one or more asymmetric centers can produce enantiomers, diastereomers or other stereoisomeric forms, which can be based on the Cahn-Ingold-Prelog RS system at each asymmetric center According to the absolute configuration, it is defined as (R)- or (S)-. The term "or" can be used at the asymmetric center to identify resolved compounds whose absolute configuration is unknown. Methods for preparing optically active forms from racemic mixtures are known in the art, such as resolution by HPLC or stereoselective synthesis. The terms "geometric isomers" or "cis and trans isomers" refer to compounds that have the same formula but whose functional groups rotate to different orientations in three-dimensional space. The term "tautomer" includes proton transfer tautomers in an isomeric protonated state of compounds having the same formula and total charge. Examples of proton transfer tautomers include, but are not limited to, keto-enol pairs, amide-imide pairs, endo-amide-endo-imide pairs, enamine-imine pairs, and cyclic forms, where protons Can occupy two or more positions of the heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2 , 4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomers can be in equilibrium or sterically locked into a form by appropriate substitution. Unless otherwise stated, compounds of the present invention identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms. The "compound" of the present invention is also intended to cover all isotopes of atoms in the compound. Atomic isotopes include atoms with the same atomic number but different mass numbers. For example, unless otherwise stated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the "compound" of the present invention are also intended to include their isotopes, such as but not limited to1 H,2 H,3 H,11 C,12 C,13 C,14 C,14 N,15 N,16 O,17 O,18 O,31 P,32 P,32 S,33 S,34 S,36 S,17 F,19 F,35 Cl,37 Cl,79 Br,81 Br,127 I and131 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, the term "deuterium substituted" or "deuterium substituted" refers to another isotope (eg, protium) that replaces hydrogen in a chemical group with deuterium. In some embodiments, carbon includes12 C and13 C. It should also be understood that the "compounds" of the present invention may exist in solvated forms as well as unsolvated forms, such as hydrated forms, solid forms, and the present invention is intended to cover all such solvated forms and unsolvated forms. It should also be understood that the "compounds" of the present invention may exist in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable" means that within the scope of reasonable medical judgment, it is suitable for contact with tissues of humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications. The benefit/risk ratio is commensurate with the compound, material, composition and/or dosage form. In some embodiments, pharmaceutically acceptable compounds, materials, compositions and/or dosage forms refer to regulated institutions (such as the US Food and Drug Administration (US Food and Drug Administration), China National Food and Drug Administration ( Approved by China Food and Drug Administration or European Medicines Agency or listed in recognized pharmacopoeia (e.g. US Pharmacopoeia, China Pharmacopoeia or European Pharmacopoeia) Used in animals, and more precisely those used in the human body. As used herein, "pharmaceutically acceptable salt" refers to a derivative of a compound of the present invention, wherein the parent compound is converted to its salt by converting an existing acidic moiety (eg, carboxyl group, etc.) or basic moiety (eg, amine, alkali metal, etc.) Form. In many cases, the compounds of the present invention can form acid and/or base salts by virtue of the presence of amine and/or carboxyl groups or similar groups. And pharmaceutically acceptable salts are acid salts and/or alkali salts that retain the biological effectiveness and properties of the parent compound, which generally do not adversely affect biologically or otherwise. Suitable pharmaceutically acceptable salts of the compounds of the invention include, for example, acid addition salts, which can be derived from, for example, inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (such as formic acid, acetic acid, Propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, trimesic acid, citric acid, lactic acid, phenylacetic acid, benzoic acid, mandelic acid, methanesulfonic acid Acid, naphthalene disulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, salicylic acid, sulfosalicylic acid, etc.). In some embodiments, the pharmaceutically acceptable salt of the compound of the invention is a formate salt. In some embodiments, the pharmaceutically acceptable salt of the compound of the invention is a TFA salt. Suitable pharmaceutically acceptable salts of the compounds of the invention also include, for example, base addition salts, which can be derived from, for example, inorganic bases (eg, metals in columns I to XII of the periodic table, such as calcium, magnesium, iron, silver, zinc , Copper, sodium, potassium, ammonium salts and hydroxides, carbonates, bicarbonates) or organic bases (such as primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, Alkaline ion exchange resin, etc.). Certain organic amines include, but are not limited to, isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, xylazine, and tromethamine. Those skilled in the art will understand that other acids or bases than those shown in the examples can also be added for the formation of acid/base addition salts. A list of other suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties" , Selection and Application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) (Wiley-VCH, Weinheim, Germany, 2002). The invention also includes active intermediates, active metabolites and prodrugs of the compounds of the invention. As used herein, "active intermediate" refers to an intermediate compound in a synthetic method that exhibits the same or substantially the same biological activity as the final synthesized compound. As used herein, "active metabolite" refers to the decomposition or final product of a compound of the present invention or a salt or prodrug thereof produced by metabolism or biotransformation in an animal or human body, which exhibits the same or substantially the same organism as the specified compound active. Such metabolites can be produced, for example, by the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. As used herein, "prodrug" refers to any compound or conjugate that releases the active parent drug when administered to an animal or human subject. Prodrugs can be prepared by modifying the functional groups present in the compound in such a way that the modification is sheared during routine operations or in vivo to release the parent compound. Prodrugs include compounds in which a hydroxyl group, an amine group, a sulfhydryl group, or a carboxyl group is bonded to any group so that when administered to a mammalian individual, they are cleaved to form a free hydroxyl group, an amine group, a sulfhydryl group, or a carboxyl group, respectively compound of. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. The preparation and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", "ACS Symposium Series", Article 14 Volume, and "Bioreversible Carriers in Drug Design", edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.resolve resolution The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, therefore, these schemes are merely illustrative and are not intended to limit other possibilities that can be used to prepare the compounds provided herein Methods. In addition, the steps in the scheme are for better explanation and can be changed as appropriate. Examples of compounds in the examples were synthesized for research and possible submission to regulatory agencies. The reaction for preparing the compound of the present invention can be carried out in a suitable solvent, which can be easily selected by a person skilled in the art of organic synthesis. A suitable solvent may not substantially react with the starting material (reactant), intermediate, or product at a temperature at which the reaction proceeds, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, suitable solvents for the specific reaction step can be selected by the skilled person. The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the choice of appropriate protecting groups, can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found in, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Edition, Wiley & Sons, Inc., New York (1999), the full text of which The way cited is incorporated herein. The reaction can be monitored according to any suitable method known in the art. For example, it can be done by spectral means, such as nuclear magnetic resonance spectroscopy (NMR, for example1 H or13 C), infrared spectroscopy (IR), spectrophotometry (eg, ultraviolet-visible light), mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer Analysis (TLC) to monitor product formation. A person skilled in the art can adopt various methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization") , Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem., 2004, 6(6), 874-883, which is incorporated by reference in its entirety In this article) and normal phase silica chromatography to purify the compound. The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift (δ ) Is 10-6 (ppm) is given in units.1 H-NMR spectrum is used on Bruker AVANCE NMR (400 MHz) spectrometer using ICON-NMR (under the control of TopSpin program), or on Varian 400MR NMR or Varian VNMR400 NMR (400 MHz) spectrometer (under VnmrJ program control) ), in dimethyl sulfoxide-d 6 (DMSO-d 6 ) Or CDCl3 Or CD3 OD or D2 O or acetone_d6 Or CD3 Recorded in CN (from Aldrich or Cambridge Isotope Lab., Inc.), with tetramethylsilane as internal standard. The MS measurement was performed using a Shimadzu 2010 mass spectrometer or an Agilent 6110A MSD or 1969A TOF mass spectrometer using a series of instruments using electrospray, chemical, and electron impact ionization methods. High performance liquid chromatography (HPLC) measurement is performed on the Shimadzu LC-20A system or the Shimadzu LC-2010HT series, or the Agilent 1200 LC or Agilent 1100 series, using the Ultimate XB-C18 column (3.0×50 mm, 3 μm or 3.0× 150 mm, 3 μm), or Xbridge shieldRP18 column (5 μm, 50 mm×2.1 mm), or Xtimate C18 column (3 μm, 2.1×30 mm), or MERCK RP18 2.5-2 mm, etc. TLC was performed using Yantai Huanghai HSGF254 silicone gel or Anhui Liang Chen Gui Yuan plate. Silicone plates for thin layer chromatography (TLC) are 0.15 mm-0.2 mm. The silica gel plate used to separate and purify the product by TLC is 0.4 mm-0.5 mm. Purification chromatography column uses silica gel as carrier (100-200, 200-300 or 300-400 mesh, manufactured by Yantai Huanghai co. or Anhui Liang Chen Gui Yuan co., etc.), or Teledyne ISCO combi-flash or Biotage flash chromatography Flash column in the system (silica-CS flash column manufactured by Agela Technologies 40-60 μm, or reverse phase C18 column 20-35 μm, etc.) or flash column silica-CS manufactured by Agela Technologies (40- 60 μm) or C18 column (20-40 μm). The size of the chromatography column is adjusted according to the amount of compound. The known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Alfa Aesar, TCI, Aldrich, Bepharm, and Scochem (or PharmaBlock, Bide, Amatek, Stru Chem, Firster Pharmaceutical, Titan (Adamas), etc.). Unless otherwise stated, the reactions are all carried out under argon or nitrogen atmosphere. An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L. The hydrogenation is usually carried out under pressure. Unless otherwise stated, the reaction temperature in the examples is ambient temperature, which is 10°C-30°C. The reaction progress was monitored by TLC or/and LC-MS. The eluent system used for the reaction includes a dichloromethane-methanol system and a petroleum ether-ethyl acetate system. The volume ratio of the solvent is adjusted according to the different polarities of the compounds. The elution system for column chromatography for purification of compounds and the elution system for TLC include a dichloromethane-methanol system and a petroleum ether-ethyl acetate system. The volume ratio of the solvent is adjusted according to the different polarities of the compounds. A small amount of alkaline or acidic reagent (0.1%-1%), such as formic acid, or acetic acid, or TFA, or ammonia water can be added for adjustment. The abbreviations of chemical reagents used in the synthesis of the compounds provided herein are listed below:
Figure 02_image030
Pharmaceutical composition The present invention provides a pharmaceutical composition comprising at least one compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains more than one compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Generally speaking, a pharmaceutically acceptable carrier is a conventional pharmaceutical carrier in the art, which can be prepared in a manner well known in the pharmaceutical field. In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof can be blended with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition. The form of the pharmaceutical composition depends on various criteria, including but not limited to the route of administration, the degree of disease, or the dose to be administered. The pharmaceutical composition may be formulated for oral, nasal, rectal, transdermal, intravenous, or intramuscular administration. Depending on the desired route of administration, the pharmaceutical composition can be formulated into tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, air Aerosol (in solid form or in liquid medium), spray, ointment, paste, cream, lotion, gel, patch, inhaler or suppository. In certain embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg, specifically 1 mg to about 50 mg of the compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises one or more compounds of the present invention or a pharmaceutically acceptable salt thereof as the first active ingredient, and further comprises a second active ingredient. The second active ingredient may be any antitumor agent known in the art, such as chemotherapeutic agents, cell signal transduction inhibitors, alkylating agents, topoisomerase inhibitors, immunotherapeutic agents, mitotic inhibitors, antihormones Drugs, chemotherapy drugs, EGFR inhibitors, CTLA-4 inhibitors, CDK 4/6 inhibitors, MEK inhibitors, PD-L1 inhibitors, OX40 agonists, anti-androgen inhibitors, IgG4 isotype antibodies, tyrosine Kinase inhibitor, DNA methyltransferase inhibitor, Hsp90 inhibitor, FGFR inhibitor, mTOR inhibitor, aromatase inhibitor, VEGF inhibitor, LHRH antagonist, PI3K inhibitor, AKT inhibitor, aurora kinase inhibitor, MEK inhibitor, HDAC inhibitor, BET inhibitor, PIK3CA inhibitor, proteasome inhibitor, other SERD, farnesyl transferase inhibitor, VEGF-A antibody, ErbB3 (Her3) antibody, proteasome inhibitor, protein kinase Cβ inhibitor, anti-PD-L1 antibody, anti-IGF-1R antibody, anti-HER2 antibody, SERM, IGF inhibitor, anti-IgG antibody, etc. Representative examples of anti-neoplastic agents used to treat cancer or tumors may include, but are not limited to sorafenib, neratinib, sunitinib, dasatinib , Vorinostat, temsirolimus, everolimus, pazopanib, trastuzumab, addo-trastuzumab Endo-trastuzumab emtansine, pertuzumab, bevacizumab, cetuximab, cetuximab, ranibizumab, valgatanib pegaptanib), panitumumab, tremelimumab, pembrolizumab, nivolumab, ipilimumab, atizumab ( atezolizumab), avelumab, durvalumab, crizotinib, ruxolitinib, paclitaxel, vincristine, vinblastine, cisplatin, carboplatin, Gemcitabine, tamoxifen, raloxifene, cyclophosphamide, chromabucil, carmustine, methotrexate, fluorouracil, actinic Mycocin, doxorubicin, epirubicin, anthracycline, bleomycin, mitomycin-C, irinotecan, topotecan 、Teniposide interleukin, interferon, pabociclib, abemaciclib, enzalutamide, dovitinib, lapatinib, arginine Erlotinib, CC-486, ganetespib, Debio 1347, erdafitinib, vitusertib, sapanisertib, GDC-0980, Jeddah Gedatolisib, anastrozole, sildenib, goserelin, alpelisib, BKM120, copanlisib, AZD88 35, GDC-0941, taselisib, AZD5363, MK2206, alisertib, alisumetinib, selumetinib, entinostat, GS-5829, GSK525762, G1T38, Rebocillin, MLN9708, GDC-0810, docetaxel, AFP464, tipifarnib, tipifarnib, seribantumab, bortezomib, enzastaurin, gefitinib ( gefitinib), AVE1642, xentuzumab (xentuzumab), dalotuzumab (dalotuzumab), tamoxifen, AMG 479, MCLA-128, etc. In some embodiments, the second active agent is a CDK 4/6 inhibitor, such as Papoxil or Poxacillin. According to this aspect of the invention, there is provided a combination suitable for the treatment of cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and any one of the anti-tumor agents listed above. Therefore, in another aspect of the present invention, there is provided a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an antitumor agent selected from one of the above. Herein, when the term "combination" is used, it should be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. When administered sequentially or separately, the delay in applying the second component should not cause the beneficial effects of the combination to be lost. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from one of the above, and a pharmaceutically acceptable Diluent or carrier. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from one of the above, and a pharmaceutically acceptable The diluent or carrier used to produce anti-cancer effects. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from one of the above, and a pharmaceutically acceptable Diluent or carrier for the treatment of breast cancer (among others). According to another aspect of the present invention, there is provided a kit comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumor agent selected from one of the above. According to another aspect of the present invention, there is provided a kit comprising: a) The compound of formula (I) or a pharmaceutically acceptable salt thereof in the first unit dosage form; b) an anti-neoplastic agent selected from one of the above listed in the second unit dosage form; and c) A container device for containing the first and second dosage forms. In addition to being used for therapeutic drugs, the compound of formula (I) or a pharmaceutically acceptable salt thereof is also suitable as a pharmacological tool in the development and standardization of in vitro and in vivo test systems for evaluating SERD activity in eg cats , Dogs, rabbits, monkeys, rats and mice in experimental animals as part of the search for new therapeutic agents. In the above other pharmaceutical compositions, processes, methods, uses and pharmaceutical manufacturing features, alternative and preferred embodiments of the compounds of the invention described herein also apply.treatment method The compounds of the present invention are selective estrogen receptor down-regulators (SERD). In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof has potent anticancer activity in early stage cancer, actively advanced cancer, metastatic cancer, and/or drug-resistant cancer. In addition, the compounds of the present invention or pharmaceutically acceptable salts thereof may be suitable for the treatment of other diseases and conditions, such as aging (such as menopause), metabolic diseases (such as diabetes, osteoporosis), cardiovascular diseases and other diseases, especially bone Looseness, especially aging. The present invention provides a method of treating a disease or condition by administering the selective ER down-regulating compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. Specifically, cancer includes but is not limited to breast cancer, ovarian cancer, endometrial cancer, uterine cancer, lung cancer, hepatocellular carcinoma, adrenocortical cancer, pancreatic cancer, bladder cancer, or gastric cancer. In some embodiments, the cancer is breast cancer, uterine cancer, ovarian cancer, endometrial cancer, or lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is hormone receptor positive breast cancer. In some embodiments, the cancer is hormone receptor positive breast cancer in postmenopausal women whose disease progresses after endocrine therapy. In some embodiments, the cancer is early breast cancer. In some embodiments, the cancer is locally advanced breast cancer. In some embodiments, the cancer is locally advanced and/or metastatic breast cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is invasive breast cancer. In some embodiments, the cancer is tamoxifen-resistant breast cancer. In some embodiments, the cancer is HR positive, HER2 negative advanced, or metastatic breast cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is metastatic breast/uterine cancer. As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of a disease or disorder or one or more symptoms thereof as described herein, or Suppress its progress. In some embodiments, treatment may be performed after one or more symptoms have occurred. In other embodiments, the treatment can be performed in the absence of symptoms. For example, treatment may be performed on susceptible individuals before the onset of symptoms (eg, based on the history of symptoms and/or based on genetic or other susceptibility factors). Treatment can also continue after the symptoms have resolved, for example to prevent or delay their recurrence. The therapeutically effective amount of a compound as provided herein or a pharmaceutically acceptable salt thereof will depend on various factors known in the art, such as weight, age, previous medical history, current medical treatment, individual's health status and cross-reaction, The possibility of allergies, allergies and adverse side effects, as well as the route of administration and the degree of disease development. As indicated by these and other circumstances or requirements, one of ordinary skill in the art (such as a doctor or veterinarian) can reduce or increase the dose proportionally.Use of the compound In certain embodiments, the present invention provides the use of a compound of the present invention, a pharmaceutically acceptable salt or pharmaceutical composition thereof for the manufacture of a medicament for the treatment of ER-mediated or dependent diseases or conditions. In such cases, the present invention also provides a method for screening patients suitable for use alone or in combination with other ingredients (such as a second active ingredient, such as an anticancer agent) for treatment of a compound or pharmaceutical composition of the present invention. Methods include sequencing tumor samples from patients and detecting the accumulation of ER. According to another aspect of the invention, there is thus provided a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament. According to another aspect of the present invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the selective down-regulation of estrogen receptors in, for example, human warm-blooded animals use. According to another aspect of the present invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the manufacture of an ER-mediated or dependent disease or condition in a warm-blooded animal such as a human Use in medicine. According to this aspect of the invention, there is provided the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for producing an anticancer effect in, for example, a warm-blooded animal in humans. According to another feature of the invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of breast cancer, ovarian cancer, endometrial cancer, uterine cancer, lung cancer, liver cells Use of drugs in cancer, adrenal cortical cancer, pancreatic cancer, bladder cancer, or gastric cancer. According to another feature of the invention, there is provided the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of breast cancer. According to another feature of this aspect of the invention, there is provided a method for selectively down-regulating the estrogen receptor in a warm-blooded animal such as a human in need of such treatment, which comprises administering to the animal an effective amount of the estrogen receptor as described above The compound of formula (I) as defined or a pharmaceutically acceptable salt thereof. According to another feature of this aspect of the invention, there is provided a method of treating an ER-mediated or dependent disease or condition in a warm-blooded animal such as a human in need of such treatment, which comprises administering an effective amount to the animal Of the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof. According to another feature of this aspect of the invention, there is provided a method of producing an anticancer effect in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to the animal an effective amount of a formula as defined above (I) The compound or a pharmaceutically acceptable salt thereof. According to another feature of this aspect of the invention, there is provided a method of producing an anti-cancer effect in a warm-blooded animal such as a human in need of such treatment, which comprises (1) determining whether the warm-blooded animal has a positive ER Cancer, and (2) if so, an effective amount of the compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof is administered to the animal. According to another feature of this aspect of the invention, there is provided a treatment for breast cancer, ovarian cancer, endometrial cancer, uterine cancer, lung cancer, hepatocellular carcinoma, adrenal cortex in warm-blooded animals such as humans in need of such treatment A method of cancer, pancreatic cancer, bladder cancer, or gastric cancer, which comprises administering to the animal an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. According to another feature of this aspect of the invention, there is provided a method of treating breast cancer in a warm-blooded animal such as a human in need of such treatment, which comprises administering to the animal an effective amount of the formula as defined above ( I) The compound or a pharmaceutically acceptable salt thereof. According to another aspect of the present invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in generating a selective ER degradation effect in, for example, a human warm-blooded animal. According to another aspect of the invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of ER-mediated or dependent diseases or conditions in, for example, warm-blooded animals of humans. According to this aspect of the invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in producing an anticancer effect in, for example, a warm-blooded animal in humans. According to another feature of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above is provided for the treatment of breast cancer, ovarian cancer, endometrial cancer, uterine cancer, lung cancer, hepatocellular carcinoma , Adrenal cortical cancer, pancreatic cancer, bladder cancer or gastric cancer. According to another feature of the invention, there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of breast cancer. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and a pharmaceutically acceptable diluent or carrier for use in, for example Selective ER degradation effects occur in human warm-blooded animals. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and a pharmaceutically acceptable diluent or carrier for the treatment of, for example ER-mediated or dependent diseases or conditions in human warm-blooded animals. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and a pharmaceutically acceptable diluent or carrier for use in, for example Anticancer effects are produced in human warm-blooded animals. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and a pharmaceutically acceptable diluent or carrier for the treatment of, for example Breast cancer, ovarian cancer, endometrial cancer, uterine cancer, lung cancer, hepatocellular carcinoma, adrenal cortical cancer, pancreatic cancer, bladder cancer, or gastric cancer of human warm-blooded animals. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and a pharmaceutically acceptable diluent or carrier for the treatment of, for example Breast cancer of human warm-blooded animal.Examples The general method of the present invention is further explained below. The compounds of the present invention can be prepared by methods known in the art. The specific preparation methods of the preferred compounds of the present invention are explained below. However, these in no way limit the method of preparing the compounds of the present invention.Examples 1 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(1- methyl -1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image032
For preparation1A 'S program:
Figure 02_image034
To a solution of imidazole (108.78 g, 1.6 mol) and triethylamine (120 mL, 878.87 mmol) in methylene chloride (1.3 L) was added SOCl dropwise at -70°C2 (32 mL, 439.43 mmol). Then will1A_1 (70 g, 399.49 mmol) in dichloromethane (650 mL) was added dropwise to the reaction mixture at -70°C over 3 hours. The resulting reaction mixture was stirred under nitrogen at -70°C for 2 hours and then at 20°C for 16 hours. Then the reaction mixture was washed with brine (300 mL×2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Two other batches of this reaction were carried out in the same way (60 g and 70 g scale compounds1A_1 ). Three batches of crude product (total 200 g of compound1A_1 ) Combined and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 9:1 to 8:1) to obtain a yellow oil1A_2 (190 g, 67.7% yield, 90% purity). 1 H NMR (400MHz, CDCl3 ): δ=4.78 (dd,J =7.2 Hz, 9.2 Hz, 1H), 4.67 (t,J =9.2 Hz, 1H), 4.09-3.98 (m, 1H), 1.55-1.45 (m, 12H).
Figure 02_image036
At room temperature (11-19 ℃)1A_2 (90 g, 406.7 mmol) in acetonitrile (900 mL) and water (420 mL) was added RuCl in portions3 ·H2 O (917 mg, 2.51 mmol), followed by addition of NaIO4 (104.4 g, 488.08 mmol). The resulting mixture was stirred under nitrogen at 20°C for 16 hours. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (300 mL×3). The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Process another batch of compounds with 100 g scale in the same way1A_2 . The two batches of crude product were combined and recrystallized from petroleum ether/ethyl acetate (7:1,800 mL) and then filtered. The filter cake was vacuum dried to obtain a white solid1A (82.4 g pure product). The filtrate was concentrated under reduced pressure and then recrystallized from petroleum ether/ethyl acetate (15:1, 640 mL) again. The filter cake was dried under reduced pressure to obtain 17.5 g of the product as a white solid (about 90% purity). The yield is about 48% in total. 1 H NMR (400MHz, CDCl3 ): δ=4.67 (dd,J =5.6, 9.2 Hz, 1H), 4.51-4.36 (m, 1H), 4.20 (dd,J =3.2, 9.2 Hz, 1H), 1.56 (s, 9H), 1.51 (d,J =6.4 Hz, 3H). For preparation1F 'S program:
Figure 02_image038
Compound1F_1 (10 g, 47.9 mmol, 1.0 equiv.) To a solution in THF (100 mL) was added aqueous NaOH (28.7 mL, 143.7 mmol, 5 M). The reaction mixture was stirred at 17°C for one hour. Compound1F_1a (9.9 g, 52.7 mmol, 1.1 equiv) of THF (50 mL) was added dropwise to the above reactant. Thereafter, the reaction was stirred at 17°C for 12 hours. The reaction was concentrated in vacuo, diluted with water (80 mL), extracted with dichloromethane (80 mL×3) and washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and passed through column chromatography (2% methanol in CH2 Cl2 ) Purification to obtain the product as a white solid1F_2 (8.85 g, 79.6% yield). 1 H NMR (400MHz, CDCl3 ) δ=4.95 (br s, 1H), 4.46 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.34-4.22 (m, 1H), 3.64-3.60 (m, 2H), 2.88-2.70 (m, 2H), 2.52 (t,J =7.2 Hz, 2H), 1.78-1.64 (m, 2H), 1.42 (s, 9H).
Figure 02_image040
Compound1F_2 (8.85 g, 38.09 mmol, 1.0 equiv) TFA (34 mL) was added dropwise to a solution in dichloromethane (100 mL). The reaction was stirred at 16°C for 3 hours. TLC showed the reaction was complete. The reaction was concentrated in vacuo and co-evaporated with dichloromethane to obtain the product as a light yellow oil1F (18.32 g TFA salt, purity: 67.8%). 1 H NMR (400MHz, CDCl3 ) δ=4.47 (t,J =5.6 Hz, 1H), 4.44-4.32 (m, 3H), 4.30-4.18 (m, 3H), 3.34 (t,J =7.4 Hz, 2H), 1.96-1.81 (m, 2H). For preparationChemical compound 1 'S program:
Figure 02_image042
At -65 ℃ within 30 minutes to the compound1a (10 g, 38.17 mmol) in THF (100 mL) was added n-BuLi (20 mL, 45.8 mmol, 2.5 M in hexane) dropwise. After stirring for one hour, the compound1A (9.05 g, 38.17 mmol) in THF (50 mL) was added dropwise to the above reaction mixture and the temperature was kept at -65 °C. Next, the reaction mixture was stirred at -70°C for another 2 hours and then slowly warmed up to 3-12°C for 5 hours. The reaction was then quenched with 1 N citric acid (30 mL) and the mixture was stirred at 20°C for 30 minutes. The resulting mixture was extracted with ethyl acetate (300 mL×3). The combined organic layer was washed with brine (100 mL×2), dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give the compound as a white solid1b (5.6 g, 43% yield).LCMS: tR =4.153 min, in 10-80AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z 285.9 [M-55+H]+ . 1 H NMR (CDCl3 400MHz): δ=7.47-7.43 (m, 2H), 7.40 (t,J =7.2 Hz, 2H), 7.36-7.31 (m, 1H), 7.22 (t,J =7.8 Hz, 1H), 6.89-6.77 (m, 3H), 5.06 (s, 2H), 4.39 (br s, 1H), 3.92 (br s, 1H), 2.84 (dd,J =5.2, 13.2 Hz, 1H), 2.63 (dd,J =7.2, 13.0 Hz, 1H), 1.44 (s, 9H), 1.08 (d,J =6.4 Hz, 3H).
Figure 02_image044
Compound1b A solution of (5.6 g, 16.4 mmol) in 4 M HCl/1,4-dioxane (100 mL) was stirred at -1 to 8°C for 16 hours. Then the reaction mixture was concentrated and the residue was washed with NaHCO3 The saturated aqueous solution was alkalized to pH=8. The aqueous layer was extracted with ethyl acetate (300 mL×4). The combined organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give the compound as a yellow oil1c (3.9 g, 98% yield).LCMS: tR =0.801 min, in 5-95AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=242.0 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.47-7.30 (m, 5H), 7.23 (t,J =7.6 Hz, 1H), 6.87-6.78 (m, 3H), 5.07 (s, 2H), 3.22-3.13 (m, 1H), 2.70 (dd,J =5.2, 13.2 Hz, 1H), 2.50 (dd,J =8.0, 13.2 Hz, 1H), 1.13 (d,J =6.4 Hz, 3H).
Figure 02_image046
Compound1c (3.9 g, 16.18 mmol) and DIEA (6.3 g, 48.54 mmol) in 1,4-dioxane (80 mL) were added CF3 CH2 OTf (3.8 g, 16.18 mmol). After the reaction mixture was stirred at 80°C for 16 hours, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL). The resulting mixture was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to obtain the compound as an oil1d (4.7 g, 89% yield).LCMS: tR =1.070 min, in 10-80AB_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=324.0 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ 7.47-7.31 (m, 5H), 7.23 (t,J =8 Hz, 1H), 6.88-6.78 (m, 3H), 5.07 (s, 2H), 3.15 (q,J =9.6 Hz, 2H), 3.07-2.99 (m, 1H), 2.73-2.58 (m, 2H), 1.08 (d,J =6.4 Hz, 3H).
Figure 02_image048
At room temperature (4-9 ℃) to the compound1d (4.70 g, 14.54 mmol) in ethyl acetate (150 mL) was added 10% Pd/C (1.0 g, 50% water). Then the reaction mixture was heated at 50°C in H2 Atmosphere (15 psi, H2 Balloon) and stir for 6 hours. The reaction mixture was then filtered through celite and washed with ethyl acetate (15 mL×3). The combined filtrate was concentrated in vacuo to obtain the compound as a light brown gum1e (3.40 g, 100%).LCMS: tR =0.254 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 234.0 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.18 (t,J= 7.6 Hz, 1H), 6.76 (d,J= 7.6 Hz, 1H), 6.71 (dd,J= 2.0, 8.0 Hz, 1H), 6.67 (s, 1H), 3.18 (q,J= 9.2 Hz, 2H), 3.12-2.99 (m, 1H), 2.73-2.55 (m, 2H), 1.11 (d,J= 6.4 Hz, 3H).
Figure 02_image050
At room temperature (4-9 ℃) to the compound1e (3.40 g, 14.58 mmol) in 1,2-dichloroethane (300 mL) was added compound1E (4.07 g, 21.87 mmol), followed by the addition of TFA (3.26 mL, 43.73 mmol). The reaction mixture was then stirred at room temperature (4-9°C) under nitrogen for 16 hours. Next, the reaction mixture was poured into NaHCO with stirring3 Saturated aqueous solution (200 mL). The resulting mixture was separated. The aqueous layer was extracted with dichloromethane (40 mL×2). The combined organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to obtain an inseparable 4:1 diastereomer as a light yellow solid (4.3 g, 74%). Major isomer compound1f Characterization is as follows.LCMS: tR =2.202 min, in 30-90AB_7min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z 402.9 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.56 (d,J= 2.0 Hz, 1H), 7.77 (dd,J= 2.4, 8.4 Hz, 1H), 7.38 (d,J= 8.4 Hz, 1H), 6.72 (d,J= 8.8 Hz, 1H), 6.55 (s, 1H), 6.52 (dd,J= 2.4, 8.4 Hz, 1H), 5.70 (s, 1H), 4.93 (s, 1H), 3.48-3.35 (m, 1H), 3.30-3.16 (m, 1H), 3.08 (dd,J= 4.8, 16.4 Hz, 1H), 3.00-2.85 (m, 1H), 2.54 (dd,J= 6.4, 16.8 Hz, 1H), 1.07 (d,J= 6.4 Hz, 3H).
Figure 02_image052
To the compound under nitrogen1f (3.80 g, 9.47 mmol), Brettphos Pd-G3 (1.29 g, 1.42 mmol) andt- BuONa (9.10 g, 94.71 mmol) was added to a mixture of 1,4-dioxane (130 mL)1F (6.82 g, 12.84 mmol) in 1,4-dioxane (20 mL). The reaction mixture was then stirred at 80°C under nitrogen for 2 hours. Next, the reaction mixture is combined with the pilot reaction batch (0.5 g scale compound1f ) Combine and extract with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (0-10% methanol in dichloromethane) To obtain the compound as a yellow solid1g (Total 4.25 g, average yield 78.8%, 90% purity).LCMS: tR =0.761 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 453.1 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.79 (d,J= 2.8 Hz, 1H), 7.19 (d,J= 8.4 Hz, 1H), 6.79 (dd,J= 2.8, 8.4 Hz, 1H), 6.64 (d,J= 8.4 Hz, 1H), 6.50 (d,J= 2.4 Hz, 1H), 6.44 (dd,J= 2.4, 8.4 Hz, 1H), 4.85 (s, 1H), 4.49 (td,J= 6.0, 47.2 Hz, 2H), 4.14-4.00 (m, 2H), 3.78-3.69 (m, 2H), 3.50-3.40 (m, 1H), 3.23-3.13 (m, 1H), 3.06 (dd,J= 4.8, 11.6 Hz, 1H), 3.01-2.91 (m, 3H), 2.64 (t,J= 7.2 Hz, 2H), 2.49 (dd,J= 6.0, 16.4 Hz, 1H), 1.86-1.68 (m, 2H), 1.04 (d,J= 6.4 Hz, 3H).
Figure 02_image054
At room temperature (4-14 ℃) to the compound1g (4.25 g, 9.39 mmol, 90% purity) To a mixture in dichloromethane (190 mL) was added triethylamine (4.0 mL, 28.17 mmol), followed by PhNTf2 (6.71 g, 18.78 mmol). Next, the reaction mixture was stirred at 25°C for 5 hours. Then the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and water (50 mL) and then separated. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (150 mL×3), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-5% methanol in dichloromethane) to obtain the compound as a pale yellow gum.1h (4.00 g, 72.8%).LCMS: tR =0.854 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 585.0 [M+H]+ . 1 H NMR (CDCl3 400MHz): δ=7.83 (d,J= 2.4 Hz, 1H), 7.15 (d,J= 8.8 Hz, 1H), 7.03 (s, 1H), 6.98-6.92 (m, 2H), 6.80 (dd,J= 2.8, 8.4 Hz, 1H), 4.93 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.17-4.07 (m, 2H), 3.83-3.73 (m, 2H), 3.59-3.48 (m, 1H), 3.30-3.12 (m, 2H), 3.04-2.96 (m, 3H), 2.70-2.57 (m, 3H), 1.86-1.69 (m, 2H), 1.08 (d,J= 6.4 Hz, 3H).
Figure 02_image056
Compound1h (500 mg, 0.870 mmol), boric acid1H (199 mg, 0.957 mmol), Pd(dppf)Cl2 ·CH2 Cl2 (71 mg, 0.087 mmol) and K2 CO3 (296 mg, 2.138 mmol) was purged with nitrogen. Then add 1,4-dioxane and H to the mixture under nitrogen2 O mixed solution (v/v=10:1) (25 mL). The resulting mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was then diluted with water (40 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-5% methanol in dichloromethane) to obtain a chemically pure product (250 mg). Another batch of this reaction of the same scale was carried out in the same way and 200 mg of chemically pure product was obtained. The two batches of chemically pure products were combined and passed through a chiral SFC [column: DAIRALCEL OJ-H (250 mm×30 mm, 5 μm); conditions: 30% EtOH (0.1% NH3 H2 O) to CO2 Medium; flow rate: 60 mL/min] for further purification to obtain a white solidChemical compound 1 (Total 330.5 mg, 100% chemical purity; 100% optical purity, 41% average yield).LCMS: tR =1.837 min, in 10-80AB_7min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z 517.3 [M+H]+ .HPLC: tR = 2.29 min, in 10-80_CD_1.2ml.met. chromatography (Ultimate C18 3.0μm 3.0×50mm).SFC: tR =2.330 min; 100% optical purity. Method: Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 μm; mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 0.5 min, followed by 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40℃. 1 H NMR (400MHz, CDCl3 ): δ=7.85 (d,J= 2.8 Hz, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 7.22 (s, 1H), 7.20-7.11 (m, 2H), 6.85 (d,J= 8.0 Hz, 1H), 6.80 (dd,J= 2.8, 8.4 Hz, 1H), 4.91 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.17-4.07 (m, 1H), 4.05-3.98 (m, 1H), 3.93 (s, 3H), 3.81-3.70 (m, 2H), 3.60-3.48 (m, 1H) , 3.27-3.14 (m, 2H), 3.07-2.96 (m, 1H), 2.96-2.90 (m, 2H), 2.66-2.57 (m, 3H), 1.84-1.69 (m, 2H), 1.09 (d,J= 6.8 Hz, 3H).Examples 2 2,2- Difluoro -3-((1S,3R)-1-(5-((1-(3- Fluoropropyl ) Azetidine -3- base ) Amine ) Pyridine -2- base )-3- methyl -6-(1- methyl -1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base ) C -1- alcohol
Figure 02_image058
Used to prepare intermediates2D 'S program:
Figure 02_image060
At 0 ℃ to the compound2D_1 (4.20 g, 37.47 mmol) in THF (85 mL) was slowly added NaH (1.50 g, 37.47 mmol, 60% purity) in portions. After stirring the reaction mixture at 0°C for 30 minutes, TBDPSCl (10.3 g, 37.47 mmol) was added. During the addition of TBDPSCl, the reaction mixture became gummy and then THF (100 mL) was added to the mixture. The reaction mixture was warmed to 20°C and then stirred at 20°C under nitrogen for 3 hours. Then the reaction mixture was poured into water (150 mL) with stirring. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-4% ethyl acetate in petroleum ether) to obtain a colorless oil2D_2 (10.9 g, 83% purity). 1 H NMR (400MHz, CDCl3 ): δ=7.71-7.63 (m, 4H), 7.48-7.39 (m, 6H), 4.02-3.84 (m, 4H), 1.83 (t,J =7.2 Hz, 1H), 1.08 (s, 9H).
Figure 02_image062
To the compound at 0 °C under nitrogen2D_2 (10.9 g, 31.10 mmol) and 2,6-lutidine (10.0 g, 93.30 mmol) in CH2 Cl2 (220 mL) Tf was added dropwise to the solution2 O (10.4 mL, 62.20 mmol). Next, the reaction mixture was stirred at 20°C under nitrogen for 3 hours. Next, the reaction mixture was washed with HCl (1 M) (150 mL×2), NaHCO3 Wash with saturated aqueous solution (150 mL) and brine (150 mL). The resulting organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-2% ethyl acetate in petroleum ether) to obtain a colorless oil2D (14.4 g, 96% purity). 1 H NMR (400MHz, CDCl3 ): δ=7.76-7.56 (m, 4H), 7.54-7.35 (m, 6H), 4.76 (t,J =11.2 Hz, 2H), 3.89 (t,J =11.6 Hz, 2H), 1.09 (s, 9H). For preparationChemical compound 2 'S program:
Figure 02_image064
At -70 ℃ under nitrogen in 5 minutes to the compound2a (5.0 g, 17.7 mmol) to a mixture of THF (60 mL) was added n-BuLi solution (7.8 mL, 19.5 mmol). The reaction mixture was stirred at this temperature for 5 minutes, at which time a white suspension was observed, followed by stirring at -70°C for another 30 minutes. Add compound dropwise at -70°C under nitrogen in 5 minutes1A (4.2 g, 17.7 mmol) in THF (20 mL). The resulting mixture was stirred at -70°C for 3.5 hours. The reaction was quenched with citric acid (100 mL, 1 M) and extracted with ethyl acetate (300 mL×2). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue, which was passed through silica gel flash column chromatography (ethyl acetate in petroleum ether, 0 to 10%) Purify to obtain the title product as a white solid2b (2.1 g, 38% yield).LCMS : tR =0.984 min, in 5-95AB_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=259.8 [M-56]+ . 1 H NMR: (400MHz, CDCl3 ) δ=7.40-7.30 (m, 2H), 7.19-7.14 (m, 1H), 7.14-7.10 (m, 1H), 4.36 (br s, 1H), 3.89 (br s, 1H), 2.90-2.77 ( m, 1H), 2.64 (dd,J= 7.6, 12.0 Hz, 1H), 1.44 (s, 9H), 1.10 (d,J= 6.0 Hz, 3H).
Figure 02_image066
At 12-21 ℃ to the compound2b (1.5 g, 4.77 mmol), K2 CO3 (1.06 g, 7.64 mmol) and Pd(dppf)Cl2 ·CH2 Cl2 (1.4 g, 2.385 mmol)) in 1,4-dioxane/H2 Add compound to the solution in O (20 mL/2 mL)1H (1.09 g, 5.25 mmol). The mixture was stirred at 100°C for 15 hours under a nitrogen atmosphere. The reaction was combined with the pilot batch and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to obtain a crude residue, which was purified by silica gel flash column chromatography (ethyl acetate/petroleum ether=0-20%), Obtain the title product as a yellow oil2c (1.0 g, 60% yield).LCMS : tR =0.858 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=316.1 [M+H]+ . 1 H NMR : (400MHz, CDCl3 ) δ=7.76 (s, 1H), 7.62 (s, 1H), 7.35-7.31 (m, 1H), 7.31-7.28 (m, 2H), 7.05 (d,J= 7.6 Hz, 1H), 4.41 (br s, 1H), 4.00-3.90 (m, 1H), 3.95 (s, 3H), 2.88 (br d,J= 7.6 Hz, 1H), 2.67 (dd,J= 7.6, 13.2 Hz, 1H), 1.43 (s, 9H), 1.11 (d,J= 6.4 Hz, 3H).
Figure 02_image068
Compound2c (1.0 g, 3.17 mmol) in MeOH (3 mL) was added HCl/ethyl acetate (4 M, 6 mL), followed by stirring at 14-19°C for 3 hours. The mixture was concentrated in vacuo to remove most of the solvent and the residue was washed with NaHCO3 The saturated aqueous solution was treated to pH=8 and concentrated again in vacuo to obtain the crude material, which was purified by silica gel flash column chromatography (methanol/dichloromethane=0-10%) to obtain the title product as a yellow oil2d (600 mg, 85% yield).LCMS: tR =0.589 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=215.7 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ) δ=7.78 (s, 1H), 7.63 (s, 1H), 7.38-7.29 (m, 3H), 7.06 (d,J= 7.6 Hz, 1H), 3.92 (s, 3H), 3.46-3.39 (m, 1H), 2.95 (dd,J= 6.8, 13.2 Hz, 1H), 2.81 (dd,J= 7.6, 13.2 Hz, 1H), 1.30 (d,J= 6.4 Hz, 3H).
Figure 02_image070
At 7-21 ℃ to the compound2d Compounds (600 mg, 2.79 mmol), DIEA (1.08 g, 8.37 mmol) in 1,4-dioxane (10 mL) were added2D (1.34 g, 2.79 mmol). The mixture was stirred at 80°C for 15 hours. The reaction was concentrated in vacuo to obtain a residue, which was purified by silica gel flash column chromatography (ethyl acetate/petroleum ether=0-30%) to give the title product as a yellow oil2e (970 mg, 60% yield).LCMS: tR = 0.891 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=548.4 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ) δ=7.75 (s, 1H), 7.70-7.65 (m, 4H), 7.58 (s, 1H), 7.48-7.42 (m, 2H), 7.42-7.37 (m, 4H), 7.34-7.31 (m, 1H), 7.30-7.27 (m, 2H), 7.04 (d,J =7.2 Hz, 1H), 3.94 (s, 3H), 3.87-3.80 (m, 2H), 3.26-3.09 (m, 2H), 3.08-2.97 (m, 1H), 2.79 (dd,J= 6.4, 13.2 Hz, 1H), 2.60 (dd,J= 6.4, 13.2 Hz, 1H), 1.08 (d,J= 6.4 Hz, 3H), 1.05 (s, 9H).
Figure 02_image072
Compound2e (100 mg, 0.182 mmol) was added to the mixture of DCE and THF (2 mL, 4/1)1E (41 mg, 0.220 mmol), TMSCl (21 mg, 0.182 mmol) and Yb (OTf)3 (12 mg, 0.018 mmol), then the mixture was stirred at 70 °C for 48 hours. The reaction was concentrated in vacuo to obtain a residue, which was purified by flash column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain the title product as a yellow solid2f (80 mg, 50% yield, failed1 H NMR observed other diastereomers).LCMS: tR =1.101 min in 5-95AB_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=717.3 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ) δ=8.54 (d,J= 2.0 Hz, 1H), 7.74 (s, 1H), 7.64 (t,J= 6.4 Hz, 4H), 7.59-7.55 (m, 2H), 7.48-7.43 (m, 2H), 7.39 (q,J= 7.2 Hz, 4H), 7.24 (s, 1H), 7.18 (d,J= 8.4 Hz, 2H), 6.89 (d,J= 8.0 Hz, 1H), 5.05 (s, 1H), 3.95 (s, 3H), 3.88-3.71 (m, 2H), 3.53-3.45 (m, 1H), 3.22 (q,J= 14.4 Hz, 1H), 3.01 (dd,J= 4.8, 16.4 Hz, 1H), 2.87 (q,J= 15.2 Hz, 1H), 2.63 (dd,J= 6.4, 16.0 Hz, 1H), 1.09 (d,J= 6.4 Hz, 3H), 1.03 (m, 9H).
Figure 02_image074
Compound2f (100 mg, 0.139 mmol) was added to a mixture of 1,4-dioxane (3 mL)1F (66 mg, 0.182 mmol), Brettphos Pd-G3 (32 mg, 0.035 mmol) and t-BuONa (40 mg, 0.417 mmol), and then the mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. The reaction was concentrated in vacuo to obtain crude material, which was passed through silica gel flash column chromatography (MeOH/CH2 Cl2 =0-10%) purification to give the title product as a light yellow oil2g (60 mg, 56% yield).LCMS: tR =0.903 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=767.5 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ) δ=7.81 (d,J= 2.6 Hz, 1H), 7.73 (s, 1H), 7.67-7.63 (m, 4H), 7.57 (s, 1H), 7.45-7.37 (m, 6H), 7.21 (s, 1H), 7.16 (d,J= 8.0 Hz, 1H), 6.98 (d,J= 8.4 Hz, 1H), 6.85 (d,J= 8.0 Hz, 1H), 6.61 (dd,J= 2.8, 8.4 Hz, 1H), 4.96 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.05 (br d,J= 6.0 Hz, 1H), 3.94 (s, 3H), 3.90-3.83 (m, 1H), 3.80-3.67 (m, 4H), 3.55-3.47 (m, 1H), 3.22-3.11 (m, 1H), 3.03 -2.85 (m, 4H), 2.62-2.55 (m, 2H), 1.75-1.72 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H), 1.03 (s, 9H).
Figure 02_image076
Compound2g To a mixture of (60 mg, 0.078 mmol) in THF (3 mL) was added TBAF (85 mg, 0.234 mmol), and the mixture was stirred at 12-21°C for 16 hours. The reaction was concentrated in vacuo to obtain a crude residue, which was passed through preparative TLC (methanol/dichloromethane=1/10), followed by acidic preparative HPLC on TFA system [Waters Xbridge 150×25 5u, condition: 13- 43% B(A: water (0.1% TFA), B: CH3 CN); flow rate: 25 ml/min] to obtain the title product as a brown solidChemical compound 2 (7.0 mg TFA salt, 16% yield).LCMS: tR =1.129 min, in 10-80AB_3min_220&254 chromatography (A: Xtimate C18, 2.1×30mm, 3μm), MS (ESI) m/z=529.3 [M+H]+ .HPLC: tR =3.14 min in 10-80_CD_1.2ml. met, XBridge Shield RP 18 2.1×50mm 5μm.Chiral SFC: 93% purity. Column: Chiralcel OJ-3 100×4.6 mm I.D., 3 μm; mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40℃. 1 H NMR: (400MHz, MeOD) δ=7.96 (s, 2H), 7.81 (s, 1H), 7.65 (d,J= 8.8 Hz, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.37 (d,J= 8.4 Hz, 1H), 6.91 (d,J= 7.6 Hz, 1H), 5.26 (s, 1H), 4.63 (t,J= 5.6 Hz, 4H), 4.51 (t,J= 5.6 Hz, 2H), 4.39-3.99 (m, 2H), 3.92 (s, 3H), 3.74 (td,J= 9.6, 15.6Hz, 2H), 3.54 (d,J= 5.6 Hz, 1H), 3.48-3.36 (m, 3H), 2.97-2.71 (m, 2H), 2.12-1.95 (m, 2H), 1.17 (d,J= 6.4 Hz, 3H).Examples 3 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(1H- Pyrazole -1- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image078
For preparationChemical compound 3 'S program:
Figure 02_image080
At -78 ℃ to the compound3a To a solution of (2.8 g, 12.6 mmol) in THF (25 mL) was added n-BuLi solution (6 mL, 15.1 mmol, 2.5 M in hexane), and the mixture was stirred at -78°C for 30 minutes. Compound at -78℃1A A solution of (2.98 g, 12.6 mmol) in THF (5 mL) was added to the above solution. The reaction mixture was stirred at -78°C for 4 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL), followed by separation. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by flash column (petroleum ether: ethyl acetate: 30/1 to 10/1) to give the compound as yellow oil.3b (1.4 g, 37% yield). 1 H NMR (400MHz, CDCl3 ) δ=7.62 (d,J= 1.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.35-7.44 (m, 3H), 6.30 (d,J= 1.6 Hz, 1H), 4.31 (br s, 1H), 3.93 (br s, 1H), 2.75-2.93 (m, 2H), 1.42 (s, 9H), 1.03 (d,J =6.4 Hz, 3H).
Figure 02_image082
Compound3b A solution of (1.4 g, 4.65 mmol) in 4 M HCl/1,4-dioxane (20 mL) and dichloromethane (20 mL) was stirred at 6-10°C for 15 hours. The reaction mixture was concentrated under reduced pressure. Dissolve the residue in water (45 mL) and use NaHCO3 The aqueous solution was basified until pH=8 and extracted with dichloromethane/methanol (v/v: 3/1, 50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the compound as a yellow oil3c (760 mg, 81% yield).LCMS: tR= 0.195 min, in 5-95AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=202.1 [M+H]+ .
Figure 02_image084
Compound3c Add CF to a solution of (750 mg, 3.73 mmol) and DIEA (1.4 g, 11.2 mmol) in 1,4-dioxane (20 mL)3 CH2 OTf (952 mg, 4.1 mmol), the resulting mixture was stirred at 80 °C for 15 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL), and then separated. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by flash column (petroleum ether: ethyl acetate: 30/1 to 15/1) to give the compound as yellow oil.3d (810 mg, 77% yield).LCMS: tR =0.544 min, in 10-80AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=284.1 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ 7.62 (d,J= 1.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.39-7.45 (m, 3H), 6.28 (d,J= 1.6 Hz, 1H), 3.04 (q,J =9.2 Hz, 2H), 2.91-2.99 (m, 1H), 2.81 (dd,J =6.8 Hz, 14.8 Hz, 1H), 2.71 (dd,J =6.8 Hz, 14.8 Hz, 1H), 1.02 (d,J =6.0 Hz, 3H).
Figure 02_image086
Compound3d (810 mg, 2.85 mmol) in DCE (40 mL) was added compound1E (796 mg, 4.3 mmol) and TFA (830 mg, 7.28 mmol). The resulting mixture was stirred at 3-9°C for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and water (20 mL) and washed with Na2 CO3 The aqueous solution was adjusted to pH=8 and separated. The aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by flash column (0-30% ethyl acetate in petroleum ether) to give the compound as a yellow oil3e (1.1 g, 86% yield, failed1 H NMR observed other diastereomers).Note: failed 2D NMR Confirm the structure. LCMS: tR =0.896 min, in 10-80AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=451.1 and 453.1 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ 8.62 (d,J= 2.0 Hz, 1H), 7.80 (dd,J= 8.0 Hz, 2.0 Hz, 1H), 7.44-7.58 (m, 6H), 7.34 (t,J =7.6 Hz, 1H), 4.97 (s, 1H), 3.44-3.35 (m, 1H), 3.32-3.21 (m, 1H), 3.11-3.01 (m, 2H), 2.64 (dd,J= 16.0, 6.4 Hz, 1H), 1.19 (d,J= 6.8 Hz, 3H).
Figure 02_image088
Compound under nitrogen3e (200 mg, 0.44 mmol), t-BuONa (348 mg, 3.5 mmol), Brettphos Pd G3 (40 mg, 0.044 mmol) and compounds1F A mixture of (289 mg, 0.54 mmol, 67.8% purity) in 1,4-dioxane (6 mL) was stirred at 80°C for 15 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL) and separated. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by a flash column (dichloromethane: methanol = 30/1 to 20/1) to give a yellow solidChemical compound 3 (24.5 mg), yield 11%.LCMS: tR =2.849 min, in 0-60AB_7min_220&254_Shimadzu.lcm (Xtimate C18 2.1×30mm), MS (ESI) m/z=503.2 [M+H]+ .HPLC : tR =3.46 min in 0-60_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CDCl3 ) δ 7.89 (d,J= 2.8 Hz, 1H), 7.54 (d,J =7.6 Hz, 2H), 7.47 (t,J =8.0 Hz, 2H), 7.37 (s, 1H), 7.29-7.36 (m, 2H), 6.84 (dd,J= 8.4, 2.4 Hz, 1H), 4.87 (s, 1H), 4.51 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.19-4.06 (m, 2H), 3.84-3.74 (m, 2H), 3.53-3.44 (m, 1H), 3.21-2.92 (m, 5H), 2.69-2.56 ( m, 3H), 1.86-1.71 (m, 2H), 1.14 (d,J= 6.4 Hz, 3H).Examples 4 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(1H- Pyrazole -3- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image090
Compound1h (Prepared fromExamples 1 Medium, 150 mg, 0.256 mmol) and borate4A (55 mg, 0.28 mmol) in 1,4-dioxane/H2 Add K to the mixture in O (5 mL/0.5 mL)2 CO3 (89 mg, 0.64 mmol, 2.5 equivalents) and Pd(dppf)Cl2· DCM (21 mg, 0.0256 mmol). The resulting mixture was stirred under nitrogen at 100°C for 16 hours. Mix the mixture with another batch of 45 mg of compound1h Combined and purified by silica gel flash column chromatography (0-10% methanol in dichloromethane) to obtain 50 mg of pure product, which was additionally passed through chiral SFC [column: Phenomenex-Amylose-1 (250 mm×30 mm, 5 μm) , Condition: 40% ETOH (0.1% NH3 H2 O) to CO2 , Flow rate (ml/min): 50] separated to obtain a brown solidChemical compound 4 (35.3 mg, 20.6% yield).LCMS: tR =0.698 min, in 5-95AB_1.5min_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=503.1 [M+H]+ .HPLC : tR =3.871 min in 10-80_CD_1.2ml chromatography (XBridge Shield RP 18 2.1×50mm 5μm). 1 H NMR (400MHz, CDCl3 ) δ 10.74 (br s, 1H), 7.84 (d,J =2 Hz, 1H), 7.59 (d,J =1.6 Hz, 1H), 7.55-7.36 (m, 2H), 7.14 (d,J =8.8 Hz, 1H), 6.91 (d,J =8.0 Hz, 1H), 6.79 (dd,J =2 Hz, 8.4 Hz, 1H), 6.56 (s, 1H), 4.94 (s, 1H), 4.50 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.22 (d,J =6.8 Hz, 1H), 4.16-4.07 (m, 1H), 3.73 (q,J =6 Hz, 2H), 3.59-3.50 (m, 1H), 3.29-3.14 (m, 2H), 3.05-2.91 (m, 3H), 2.69-2.59 (m, 3H), 1.82-1.72 (m, 2H ), 1.08 (d,J =6.4 Hz, 3H).SFC : tR =4.303 min; Method: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min Flow rate: 2.8 mL/min; Column temperature: 40 ℃.Examples 5 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-6-( Isoxazole -4- base )-3- methyl -2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image092
Used to prepare compounds 5 'S program:
Figure 02_image094
Compound1h (Prepared fromExamples 1 Medium, 150 mg, 0.25 mmol) and diborate5A (195 mg, 0.77 mmol) in a mixture of 1,4-dioxane (3 mL) was added triethylamine (152 mg, 1.5 mmol) and Pd(dppf)Cl2· DCM (20 mg, 0.025 mmol). The resulting mixture was stirred at 95°C for 1.5 hours under nitrogen. Mix the mixture with another batch of 30 mg of compound1h Combine, concentrate and purify by silica gel flash column chromatography (0-8% methanol in dichloromethane) to obtain the compound as a brown oil5a (100 mg, 57% yield).LCMS: tR =0.909 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=562.9 [M+H]+ .
Figure 02_image096
Compound5a (80 mg, 0.14 mmol) and compound5B (23 mg, 0.11 mmol) in THF/H2 Add Na to the mixture in O (1 mL/1 mL)2 CO3 (44 mg, 0.42 mmol), Pd2 (dba)3 (4 mg, 0.007 mmol) and P(t-Bu)3 .HBF4 (2 mg, 0.015 mmol). The resulting mixture was stirred under nitrogen at 8-10°C for one hour. Mix the mixture with another batch of 20 mg of compound5a combination. The mixture was concentrated in vacuo and purified by silica gel flash column chromatography (0-6% methanol in dichloromethane) to obtain 25 mg of product, which was additionally passed through chiral SFC [YMC CHIRAL Amylose-C (250 mm×30 mm , 10 μm, condition: 30% EtOH (0.1% NH3 .H2 O) to CO2 , Flow rate (ml/min): 70] separated to obtain compound 5 (10.3 mg, 11.5% yield) as a pink solid.LCMS: tR =0.685 min, in 5-95AB_1.5min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=504.2 [M+H]+ .HPLC : tR = 4.04 min in 10-80_cd_1.2ML.MET chromatography (XBridge Shield RP 18 2.1×50mm 5μm). 1 H NMR (400MHz, CDCl3 ) δ 8.63 (s, 1H), 8.52 (s, 1H), 7.85 (d,J =2.8 Hz, 1H), 7.23 (s, 1H), 7.18 (t,J =8.4 Hz, 2H), 6.93 (d,J =8 Hz, 1H), 6.82 (dd,J =2.8 Hz, 8.4 Hz, 1H), 4.94 (s, 1H), 4.51 (dt,J =47.2 Hz, 6 Hz, 2H), 4.24-4.13 (m, 2H), 3.83 (brs, 2H), 3.58-3.51 (m, 1H), 3.27-3.18 (m, 2H), 3.09 (brs, 2H) , 3.03-2.92 (m, 1H), 2.71 (t,J =7.2 Hz, 2H), 2.64 (dd,J =5.2 Hz, 16 Hz, 1H), 1.86-1.79 (m, 2H), 1.10 (d,J =6.4 Hz, 3H).SFC : tR =1.526 min; column: Chiralpak AD-3 50×3mm I.D., 3μm; mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 2.5 min and maintained at 40% for 0.35 min, then B from 5% to 40% to 5% over 0.15 min; Flow rate: 2.5 mL/min ; Column temperature: 40 ℃.Examples 6 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image098
Compound1h (Prepared fromExamples 1 Medium, 200 mg, 0.34 mmol) and borate6A (73 mg, 0.37 mmol) in 1,4-dioxane/H2 Add K to the mixture in O (5 mL/0.5 mL)2 CO3 (118 mg, 0.85 mmol) and Pd(dppf)Cl2 ·DCM (28 mg, 0.034 mmol). The resulting mixture was stirred at 95°C for 6 hours under nitrogen. The mixture was concentrated and purified by silica gel flash column chromatography (0-10% methanol in dichloromethane) to obtain 80 mg of product, which was combined with another batch of 20 mg of product and additionally passed through chiral SFC [DAICEL CHIRALPAK AD -H (250 mm×30 mm, 5 μm), condition: 35% IPA (0.1% NH3 H2 O) to CO2 , Flow rate (ml/min): 50] separated to obtain a white solidChemical compound 6 (44.7 mg, 7.1% yield).LCMS: tR =0.829 min, in 5-95AB_1.5min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=503.3 [M+H]+ .HPLC : tR =4.79 min in 10-80_1.5ML_LONG.MET chromatography (YMC-C18 4.6×150mm 5μm_long column). 1 H NMR (400MHz, CDCl3 ) δ 7.85 (d,J =2.4 Hz, 1H), 7.76 (s, 2H), 7.25-7.16 (m, 3H), 6.88 (d,J =8.4 Hz, 1H), 6.81 (dd,J =2.8 Hz, 8.8 Hz, 1H), 4.93 (s, 1H), 4.50 (dt,J =47.2 Hz, 6 Hz, 2H), 4.17-4.07 (m, 2H), 3.78-3.71 (m, 2H), 3.58-3.49 (m, 1H), 3.28-3.15 (m, 2H), 3.06-2.92 ( m, 3H), 2.66-2.58 (m, 3H), 1.85-1.70 (m, 2H), 1.10 (d,J =6.8 Hz, 3H).SFC : tR =1.880 min; column: Chiralpak AD-3 50×3mm I.D., 3μm; mobile phase: A: CO2 ; B: Isopropyl alcohol (0.05% DEA); Gradient: B from 5% to 40% within 2.5 min and maintained at 40% for 0.35 min, then B from 5% to 40% to 5% over 0.15 min; Flow rate: 2.5 mL /min; column temperature: 40°C.Examples 7 6-((1S,3R)-6-(1- Ethyl -1H- Pyrazole -4- base )-3- methyl -2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine
Figure 02_image100
At 11-21 ℃ to the compound1h (Prepared fromExamples 1 Medium, 100 mg, 0.171 mmol), K2 CO3 (36 mg, 0.256 mmol) and Pd(dppf)Cl2 ·CH2 Cl2 (50 mg, 0.0855 mmol) in 1,4-dioxane/H2 Borate is added to the solution in O (3 mL/0.3 mL)7A (45 mg, 0.205 mmol). The resulting mixture was stirred at 100°C for 2 hours. Then the reaction mixture was diluted with water and then extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (30 mL), washed with Na2 SO4 Dry and then filter, and concentrate the filtrate in vacuo to obtain a crude residue, which was purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to obtain the title product as a yellow solidExamples 7 (36.3 mg, 97% purity, 39% yield).LCMS: tR =1.283 min, in 10-80AB_3min_220&254 chromatography (A: Xtimate C18, 2.1×30mm, 3μm; B: XBrige Shield RP18 2.1×50mm), MS (ESI) m/z=531.3 [M+H]+ .HPLC : tR =3.95 min in 10-80_CD_1.2ml. met XBridge Shield RP 18 2.1×50mm 5μm.SFC law : tR =1.707 min; 100% optical purity; column: Chiralpak AD-3 50×3mm I.D., 3μm; mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% and maintained at 40% for 0.35 min in 2.5 min, then B from 40% to 5% over 0.15 min; Flow rate: 2.5 mL/min ; Column temperature: 40 ℃. 1 H NMR (400MHz, CDCl3 ) δ=7.84 (s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.22 (s, 1H), 7.16 (d,J= 8.0 Hz, 2H), 6.83 (d,J= 7.6 Hz, 1H), 6.79 (d,J= 8.4 Hz, 1H), 4.90 (s, 1H), 4.49 (dt,J= 46.8 Hz, 6.0 Hz, 2H), 4.18 (q,J= 7.2 Hz, 2H), 4.14-4.04 (m, 2H), 3.79-3.70 (m, 2H), 3.57-3.47 (m, 1H), 3.27-3.13 (m, 2H), 3.05-2.89 (m, 3H) , 2.68-2.56 (m, 3H), 1.83-1.70 (m, 2H), 1.50 (t,J= 7.2 Hz, 3H), 1.07 (d,J= 6.4 Hz, 3H).Examples 8 6-((1S,3R)-6-(1- Cyclopropyl -1H- Pyrazole -4- base )-3- methyl -2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine
Figure 02_image102
At 11-21 ℃ to the compound1h (Prepared fromExamples 1 Medium, 100 mg, 0.171 mmol), K2 CO3 (36 mg, 0.256 mmol) and Pd(dppf)Cl2 ·CH2 Cl2 (50 mg, 0.0855 mmol) in 1,4-dioxane/H2 Borate is added to the solution in O (3 mL/0.3 mL)8A (45 mg, 0.205 mmol). The resulting mixture was stirred at 100°C for 2 hours. Then the reaction mixture was diluted with water and then extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (30 mL), washed with Na2 SO4 Dry and then filter, concentrate the filtrate in vacuo to obtain a crude residue, which is purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to obtain the title product as an off-white solidChemical compound 8 (29.2 mg, 97.3% purity, 30.6% yield).LCMS: tR =1.736min, in 10-80AB_4min_220&254.lcm chromatography (A: Xtimate C18, 2.1×30mm, 3μm B: XBrige Shield RP18 2.1×50mm), MS (ESI) m/z=543.3 [M+H]+ .HPLC: tR =2.59 min in 10-80_AB_1.2ml.met. HPLC-AUltimate C18 3×50mm 3μm.SFC law : tR =1.928 min; column: Chiralpak AD-3 50×3mm I.D., 3μm; mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% and maintained at 40% for 0.35 min in 2.5 min, then B from 40% to 5% over 0.15 min; Flow rate: 2.5 mL/min ; Column temperature: 40 ℃. 1 H NMR (400 MHz, CD3 OD) δ=7.98 (s, 1H), 7.78 (d,J= 2.8 Hz, 1H), 7.76 (s, 1H), 7.33 (s, 1H), 7.23-7.18 (m, 1H), 7.12 (d,J= 8.4 Hz, 1H), 6.94 (dd,J= 2.4, 8.4 Hz, 1H), 6.70 (d,J= 8.0 Hz, 1H), 4.85 (s, 1H), 4.48 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.23-4.11 (m, 1H), 3.94 (br s, 2H), 3.72-3.60 (m, 1H), 3.57-3.46 (m, 1H), 3.39-3.32 (m , 1H), 3.29-3.23 (m, 1H), 3.18 (br s, 2H), 2.97-2.91 (m, 1H), 2.80 (t,J =7.2 Hz, 2H), 2.68 (dd,J= 4.4, 16.0 Hz, 1H), 1.91-1.66 (m, 2H), 1.13-1.03 (m, 7H).Examples 9 6-((1S,3R)-6-(1-( Difluoromethyl )-1H- Pyrazole -4- base )-3- methyl -2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine
Figure 02_image104
At 11-21 ℃ to the compound1h (Prepared fromExamples 1 Medium, 100 mg, 0.171 mmol), K2 CO3 (36 mg, 0.256 mmol) and Pd(dppf)Cl2 ·CH2 Cl2 (50 mg, 0.0855 mmol) in 1,4-dioxane/H2 Borate is added to the solution in O (3 mL/0.3 mL)9A (45 mg, 0.205 mmol). The resulting mixture was stirred at 100°C for 2 hours. Then the reaction mixture was diluted with water and then extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (30 mL), washed with Na2 SO4 Dry and then filter, and the filtrate was concentrated in vacuo to obtain a crude residue, which was purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to obtain the title product as a gray solidChemical compound 9 (36.5 mg, 96% purity, 38.61% yield).LCMS: tR =1.569 min, in 10-80AB_3min_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=553.2 [M+H]+ .HPLC: tR =3.32 min, in 10-80_AB_1.2ml chromatography (Ultimate C18 3×50mm 3μm).SFC law : tR =1.736 min; column: Chiralcel OJ-3 100×4.6 mm I.D., 3 μm; mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min, flow rate: 2.8 mL/min; Column temperature: 40℃ 1 H NMR (400 MHz, CD3 OD) δ=8.36 (s, 1H), 8.05 (s, 1H), 7.78 (d,J =2.8 Hz, 1H), 7.47 (t,J =59.6 Hz, 1H), 7.42 (s, 1H), 7.29 (dd,J =2.0 Hz, 8.0 Hz, 1H), 7.13 (d,J =8.8 Hz, 1H), 6.95 (dd,J =2.8, 8.8 Hz, 1H), 6.76 (d,J =8.0 Hz, 1H), 4.82 (s, 1H), 4.47 (dt,J =47.2 Hz, 6.0 Hz, 2H), 4.18-4.08 (m, 1H), 3.93-3.85 (m, 2H), 3.60-3.50 (m, 1H), 3.40-3.33 (m, 1H), 3.30-3.26 ( m, 1H), 3.14-3.07 (m, 2H), 3.00-2.89 (m, 1H), 2.78-2.66 (m, 3H), 1.86-1.73 (m, 2H), 1.09 (d,J =6.4 Hz, 3H).Examples 10 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(1- methyl -1H- Pyrazole -3- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine method one:
Figure 02_image106
For preparationChemical compound 10 'S program:
Figure 02_image108
Compound1d (1.9 g, 5.87 mmol) in toluene (50 mL) and acetic acid (0.8 mL) was added compound1E (1.09 g, 5.87 mmol). The mixture was stirred at 80°C for 2 days. The mixture was concentrated and the residue was dissolved in dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL), and the aqueous layer was extracted with dichloromethane (30 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by flash column (0-30% ethyl acetate in petroleum ether) to obtain the compound as an oil10a (1.7 g, containing 1.5 equivalents of compound1E ) And 0.8 g of compound1d Loop again. contain10a The mixture was used without further purification. Only one major isomer was observed by H NMR and is characterized as follows.LCMS: tR =1.033 min, in 5-95AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=491.0 and 493.0 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=8.55 (d,J =2 Hz, 1H), 7.72 (dd,J =2.4 Hz, 8.8 Hz, 1H), 7.43-7.32 (m, 6H), 6.80 (d,J =8.4 Hz, 1H), 6.74-6.71 (m, 2H), 5.02 (s, 2H), 4.93 (s, 1H), 3.50-3.42 (m, 1H), 3.29-3.18 (m, 1H), 3.15 ( dd,J =4.4 Hz, 16.4 Hz, 1H), 3.00-2.88 (m, 1H), 2.58 (dd,J =5.6 Hz, 16 Hz, 1H), 1.08 (d,J =6.8 Hz, 3H).
Figure 02_image110
Compound10a (1.7 g, 3.46 mmol) and compound1F (2.25 g, 4.64 mmol, 67% purity) To a mixture of 1,4-dioxane (60 mL) was added t-BuONa (2.7 g, 27.68 mmol) and Brettphos Pd G3 (313 mg, 0.34 mmol). The resulting mixture was stirred under nitrogen at 80°C for 16 hours. The mixture was concentrated. Water (30 mL) was added and extracted with ethyl acetate (30 mL×4). The combined organic layer was washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was passed through preparative TLC (petroleum ether/ethyl acetate=25/1 4 times, and petroleum Ether/ethyl acetate = 20/1 4 times), followed by column chromatography (0-50% ethyl acetate in petroleum ether to 0-10% methanol in dichloromethane) to obtain a yellow oil product10b (700 mg, 21.9% yield (two steps)).LCMS: tR =0.761 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=543.2 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.84 (d,J =2.8 Hz, 1H), 7.44-7.30 (m, 5H), 7.15 (d,J =8.4 Hz, 1H), 6.81-6.76 (m, 2H), 6.74-6.69 (m, 2H), 5.01 (s, 2H), 4.87 (s, 1H), 4.50 (dt,J =47.2 Hz, 6.0 Hz, 2H), 3.97 (brs, 1H), 3.78-3.71 (m, 2H), 3.53-3.47 (m, 1H), 3.23-3.12 (m, 2H), 3.04-2.87 (m, 3H), 2.63-2.57 (m, 3H), 1.83-1.69 (m, 2H), 1.07 (d,J =6.8 Hz, 3H).
Figure 02_image112
Compound10b (0.7 g, 1.29 mmol) to a mixture of methanol (30 mL) was added 10% Pd/C (100 mg). The resulting mixture was stirred at 50°C under a hydrogen atmosphere (50 psi) for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (0-10% methanol in methylene chloride) to obtain the compound as an oil1g (380 mg, 65% yield). 1 H NMR (400MHz, CDCl3 ) δ=7.81 (d,J =2.8 Hz, 1H), 7.18 (d,J =8.8 Hz, 1H), 6.79 (dd,J =2.4 Hz, 8.4 Hz, 1H), 6.68 (d,J =8.4 Hz, 1H), 6.54 (d,J =2.4 Hz, 1H), 6.48 (dd,J =2.4 Hz, 8.4 Hz, 1H), 4.85 (s, 1H), 4.50 (dt,J =47.2 Hz, 5.6 Hz, 2H), 4.13-4.02 (m, 2H), 3.78-3.74 (m, 2H), 3.51-3.41 (m, 1H), 3.22-3.05 (m, 2H), 3.02-2.94 ( m, 3H), 2.65 (t,J =7.2 Hz, 2H), 2.51 (dd,J =6 Hz, 16.4 Hz, 1H), 1.86-1.71 (m, 3H), 1.06 (d,J =6.8 Hz, 3H).
Figure 02_image114
Compound1g (335 mg, 0.74 mmol), triethylamine (224 mg, 2.22 mmol) in methylene chloride (15 mL) was added to the compound10A (555 mg, 1.48 mmol). The resulting mixture was stirred at 25°C for 5 hours. The mixture was quenched with water (20 mL) and extracted with dichloromethane (30 mL×4). The water layer also contains products, so the organic layer and the water layer are concentrated separately. The organic layer was purified by column chromatography (0-10% methanol in dichloromethane) to obtain the compound as a yellow solid1h (198 mg). The aqueous layer was purified by column chromatography (0-10% methanol in dichloromethane) to obtain the compound as a yellow solid1h (100 mg), 60.7% total yield.LCMS: tR =0.761 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=585.1 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=11.30 (brs, 1H), 8.05-7.90 (m, 1H), 7.51 (brs, 2H), 7.38 (s, 1H), 7.31-7.22 (m, 1H), 7.10-7.04 (m, 1H) , 5.36 (brs, 1H), 4.65-4.43 (m, 5H), 4.28 (brs, 1H), 4.09 (brs, 1H), 3.96-3.87 (m, 2H), 3.60 (dd,J =9.6 Hz, 15.6 Hz, 1H), 3.45-3.38 (m, 1H), 3.24-3.16 (m, 1H), 3.07-3.01 (m, 2H), 2.75 (dd,J =4.4 Hz, 16.4 Hz, 1H), 2.00-1.90 (m, 2H), 1.01 (d,J =6.4 Hz, 3H).
Figure 02_image116
Compound1h (140 mg, 0.24 mmol) and compound10B (55 mg, 0.26 mmol) in a mixture of 1,4-dioxane/water (10 mL/1 mL) was added potassium carbonate (83 mg, 0.60 mmol) and Pd(dppf)Cl2· CH2 Cl2 (20 mg, 0.024 mmol). The resulting mixture was stirred under nitrogen at 100°C for 16 hours. The mixture was concentrated and purified by column chromatography (0-10% methanol in dichloromethane), then purified by preparative TLC (dichloromethane/methanol=15/1 2 times) to obtain 52 mg of product, which was combined with 18 mg1h Scale experimental reactant combinations. Chiral HPLC spectrum showed that the optical purity was 85%. The product additionally passes through chiral SFC [column: DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm), condition: 40% ETOH (0.1% NH3. H2 O), flow rate (mL/min): 70] separated to obtain a yellow solidChemical compound 10 (46.7 mg, 26.7% yield). The stereochemistry of the final compound was confirmed by 2D NMR.LCMS: tR =0.710 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=517.1 [M+H]+ .LCMS: tR =0.700 min, in 5-95AB_1.5min_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=517.1 [M+H]+ .HPLC : tR =4.04 min, in 10-80_CD_1.2ml chromatography (Ultimate C18 2.1×50mm 5μm) 1 H NMR (400MHz, CDCl3 ) δ 7.85 (d,J =2.8 Hz, 1H), 7.58 (s, 1H), 7.43 (dd,J =1.2 Hz, 8 Hz, 1H), 7.35 (d,J =2.4 Hz, 1H), 7.13 (d,J =8.8 Hz, 1H), 6.87 (d,J =8 Hz, 1H), 6.78 (dd,J =2.8 Hz, 8.4 Hz, 1H), 6.48 (d,J =2.4 Hz, 1H), 4.92 (s, 1H), 4.50 (dt,J =47.2 Hz, 6 Hz, 2H), 4.16-4.07 (m, 1H), 4.01 (brd,J =7.6 Hz, 1H), 3.94 (s, 3H), 3.75 (q,J =6 Hz, 2H), 3.57-3.50 (m, 1H), 3.30-3.14 (m, 2H), 3.07-2.97 (m, 1H), 2.95-2.89 (m, 2H), 2.70-2.59 (m, 3H ), 1.83-1.70 (m, 2H), 1.08 (d,J =6.4 Hz, 3H).SFC : tR =1.853 min; Method: Column: Chiralpak AD-3 50×3 mm I.D., 3 μm; Mobile phase: A: CO2 ; B: IPA (0.05% DEA); Gradient: B from 5% to 40% within 2.5 min and maintained at 40% for 0.35 min, then B from 5% to 40% to 5% within 0.15 min; Flow rate: 2.5 mL/ min; column temperature: 40°C. Method Two:
Figure 02_image118
For preparationChemical compound 10 'S program:
Figure 02_image120
At -65 ℃ to -70 ℃ under nitrogen to the compound10c (14.0 g, 49.38 mmol) in THF (160 mL) was added n-BuLi solution (921.7 ml, 54.32 mmol, 2.5 M in hexane) dropwise. A yellow solution appeared. After the addition, the compound is added dropwise at -65°C to -70°C1A (10 g, 42.15 mmol) in THF (50 mL). The reaction mixture was stirred at this temperature for 2 hours. Next, 1 M citric acid solution (100 mL) was added to the above mixture at -65°C to -70°C, and a white suspension appeared. The mixture was allowed to warm to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-5% ethyl acetate in petroleum ether) to obtain the pure compound as a white solid10d (8.10 g) and impure product (1.90 g, 50% purity). Yield: 68%. 1 H NMR (400MHz, CDCl3 ): δ=7.40-7.32 (m, 2H), 7.17 (t,J= 7.6 Hz, 1H), 7.12 (d,J= 7.6 Hz, 1H), 4.37 (br s, 1H), 3.89 (br s, 1H), 2.91-2.77 (m, 1H), 2.64 (dd,J= 7.2, 13.2 Hz, 1H), 1.43 (s, 9H), 1.09 (d,J= 6.4 Hz, 3H).
Figure 02_image122
Compound10d (4.2 g, 13.4 mmol), compound10B (3.07 g, 14.7 mmol), Pd(dppf)Cl2 ·CH2 Cl2 A mixture of (1.1 g, 1.34 mmol) and potassium carbonate (4.6 g, 33.5 mmol) in 1,4-dioxane/water (60/6 mL) was stirred at 100° C. for 15 hours under a nitrogen atmosphere. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (300 mL×2). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to obtain a crude residue, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-20%), Obtain the title product as a brown oil10e (3.3 g, 78% yield).LCMS : tR =0.856 min, in 5-95AB_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z= 338.0 [M+Na]+ . 1 H NMR : (400MHz, CDCl3 ) δ=7.64 (d,J =7.6 Hz, 1H), 7.62 (s, 1H), 7.38 (d,J= 2.0 Hz, 1H), 7.32 (t,J= 8.0 Hz, 1H), 7.13 (d,J= 7.6 Hz, 1H), 6.54 (d,J= 2.0 Hz, 1H), 4.41 (brs, 1H), 4.01-3.91 (m, 1H), 3.96 (s, 3H), 2.90 (dd,J= 5.6 Hz and 12.8 Hz, 1H), 2.70 (dd,J =7.2 and 13.6 Hz, 1H), 1.43 (s, 9H), 1.11 (d,J= 6.4 Hz, 3H).
Figure 02_image124
will10e A mixture of (3.0 g, 9.5 mmol) and HCl/methanol (40 mL, 4 M) in methanol (20 mL) was stirred at 10°C for 2 hours. The reaction was concentrated in vacuo to remove most of the solvent and the residue was treated with sodium hydroxide solution (1.0 mL, 15%), ethyl acetate (50 mL) and methanol (4 mL). The mixture was stirred for 10 minutes and filtered. The filtrate was concentrated in vacuo to obtain the crude product. The crude material and filter cake were purified by silica gel flash column chromatography (eluted with A/B=5%-20%, A: 2% NH3 .H2 O/MeOH mixture solvent, B: CH2 Cl2 ) And combined with elution to obtain the product as a yellow solid10f (1.7 g, 83% yield).LCMS: tR =0.724 min, in 5-95AB_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=216.0 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ) δ=7.68-7.63 (m, 2H), 7.62 (d,J= 2.0 Hz, 1H), 7.37 (t,J= 8.0 Hz, 1H), 7.18 (d,J= 7.6 Hz, 1H), 6.63 (d,J= 2.8 Hz, 1H), 3.95 (s, 3H), 3.37-3.33 (m, 1H), 2.86-2.71 (m, 2H), 1.18 (d,J= 6.4 Hz, 3H).
Figure 02_image126
will4f (1.4 g, 6.5 mmol) and CF3 CH2 A mixture of OTf (1.82 g, 7.8 mmol) and DIEA (1.67 g, 13.0 mmol in 1,4-dioxane (20 mL) was stirred at 80° C. for 5 hours. The reaction mixture was concentrated in vacuo to obtain crude material, It was purified by column chromatography (eluted with 0-20% ethyl acetate/petroleum ether) to obtain the product as a colorless oil10g (1.7 g, 88% yield).LCMS: tR = 0.674 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=298.0 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ) δ=7.69-7.61 (m, 2H), 7.39 (d,J= 2.4 Hz, 1H), 7.34 (t,J =8.0 Hz, 1H), 7.12 (d,J= 7.6 Hz, 1H), 6.55 (d,J= 2.4 Hz, 1H), 3.97 (s, 3H), 3.18 (q,J= 9.6 Hz, 2H), 3.13-3.04 (m, 1H), 2.78 (dd,J =6.8 Hz and 13.6 Hz, 1H), 2.67 (dd,J =6.4 Hz and 13.6 Hz, 1H), 1.10 (d,J= 6.0 Hz, 3H).
Figure 02_image128
Compound10g (400 mg, 1.35 mmol) and compound1E To a mixture of (300 mg, 1.61 mmol) in dichloroethane (6 mL), trifluoroacetic acid (462 mg, 4.05 mmol) was added and the mixture was stirred at 100°C under nitrogen for 10 hours. Combine the reaction mixture with three other parallel batches of the same size (total 1.6 g of compound10g ). To the combined mixture was added a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (eluted with 0-20% ethyl acetate/petroleum ether) to obtain the product as a brown oil10h (1.4 g, 56% yield), and loop again to obtain the starting material as a brown oil10g (400 mg). Compounds obtained10h It is an inseparable mixture and the ratio is about 8.3:1 according to the H NMR spectrum. The main isomers are characterized as follows.LCMS: tR =1.101 min in 5-95AB_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=464.8 and 466.8 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ) δ=8.58 (d,J= 2.4 Hz, 1H), 7.73 (dd,J= 2.4, 8.4 Hz, 1H), 7.61 (s, 1H), 7.46 (dd,J= 1.6 Hz and 8.4 Hz, 1H), 7.36 (d,J= 2.0 Hz, 1H), 7.32 (d,J= 8.4 Hz, 1H), 6.90 (d,J= 8.0 Hz, 1H), 6.49 (d,J= 2.0 Hz, 1H), 5.00 (s, 1H), 3.95 (s, 3H), 3.57-3.48 (m, 1H), 3.32-3.20 (m, 2H), 3.03-2.93 (m, 1H), 2.69 (dd ,J= 5.2, 16.0 Hz, 1H), 1.09 (d,J= 6.4 Hz, 3H).
Figure 02_image130
Compound10h (400 mg, 0.86 mmol), compound1F (148 mg, 1.12 mmol), Brettphos Pd G3 A mixture of (195 mg, 0.215 mmol) and t-BuONa (232 mg, 2.4 mmol) in 1,4-dioxane (5 mL) was stirred under nitrogen at 60°C for 15 hours. Combine the reactants with three other parallel batches (total 1.6 g compound10h ) And concentrate the combined mixture in vacuo. The residue was suspended in 70 mL of the mixture solvent (dichloromethane/methanol=55 mL/15 mL). The mixture was stirred for 30 minutes and filtered, concentrated in vacuo to obtain the crude material, and directly purified by column chromatography (eluted with 0-5% methanol/dichloromethane) to obtain the product as a brown oil.Chemical compound 10 (1.4 g, 89% optical purity, 78% yield). The main isomers are characterized as follows.LCMS: tR =0.723 min, in 5-95AB_1.5min_shimadzu.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=517.1 [M+H]+ .Chiral SFC : 89% optical purity. Column: Chiralpak AD-3 50 × 3 mm I. D., 3 μm OJ-3 100 × 4.6 mm I. D., 3 μm; mobile phase: A: CO2 ; B: Isopropanol (0.05% DEA); Gradient: B from 5% to 40% in 2.5 min and maintained at 40% for 0.35 min, followed by B from 40% to 5% in 0.15 min; Flow rate: 2.5 mL/min; column temperature: 40°C. 1 H NMR: (400MHz, CDCl3 ) δ=7.85 (d,J= 2.4 Hz, 1H), 7.58 (s, 1H), 7.43 (dd,J= 1.6 Hz and 8.0 Hz, 1H), 7.35 (d,J= 2.4 Hz, 1H), 7.13 (d,J= 8.8 Hz, 1H), 6.87 (d,J= 8.0 Hz, 1H), 6.78 (dd,J= 2.8, 8.8 Hz, 1H), 6.48 (d,J= 2.4 Hz, 1H), 4.92 (s, 1H), 4.50 (dt,J= 47.2 Hz and 6.0 Hz, 2H), 4.11-4.07 (m, 1H), 3.94 (s, 3H), 4.00-3.90 (m, 1H), 3.74 (q,J= 5.6 Hz, 2H), 3.57-3.51 (m, 1H), 3.31-3.18 (m, 2H), 3.07-2.95 (m, 1H), 2.92-2.87 (m, 2H), 2.66 (dd,J= 4.8, 16.0 Hz, 1H), 2.60 (t,J= 7.2 Hz, 2H), 1.82-1.77 (m, 1H), 1.76-1.71 (m, 1H), 1.08 (d,J= 6.8 Hz, 3H).Examples 11 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(4H-1,2,4- Triazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image132
For preparation11F 'S program:
Figure 02_image134
Compound11F_1 (13.7 g, 157.4 mmol) in DMF (150 mL) was added thionyl chloride (46.4 g, 393.6 mmol). The mixture was then stirred at 12°C for 48 hours. The precipitate was filtered and washed with DMF (10 mL), followed by methyl tert-butyl ether (10 mL). After drying in vacuo, the product was obtained as a white solid (29 g, 86.1% yield).LCMS: tR =0.123 min in 5-95AB_220&254 _Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=142.8 [M+H]+ . 1 H NMR (400MHz, D2 O): δ=8.33 (s, 2H), 3.21 (br s, 12H). For preparationChemical compound 11 'S program:
Figure 02_image136
Compound10d (Prepared fromExamples 10 To a solution of 5.60 g, 17.82 mmol) in dichloromethane (90 mL), trifluoroacetic acid (30 mL) was added, and the reaction mixture was stirred at 12-26°C for 0.5 hour. The mixture was poured into a saturated aqueous solution of sodium bicarbonate (400 mL) with stirring and basified with potassium carbonate solid to pH=8-9. The mixture was extracted with ethyl acetate (200 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound as a colorless oil.11a (4.20 g, 90% purity, 100% yield).LCMS: tR =0.555 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 213.9 and 215.9 [M+H]+ . 1 H NMR (400MHz, CD3 OD): δ=7.46-7.34 (m, 2H), 7.22 (t,J= 7.6 Hz, 1H), 7.18 (d,J= 7.6 Hz, 1H), 3.20-3.04 (m, 1H), 2.71-2.57 (m, 2H), 1.09 (d,J= 6.4 Hz, 3H).
Figure 02_image138
Compound11a (4.20 g, 17.65 mmol, 90% purity) To a solution in 1,4-dioxane (80 mL) was added N,N-diisopropylethylamine (6.2 mL, 35.30 mmol), followed by the compound1C (4.10 g, 17.65 mmol). The reaction mixture was stirred at 80°C under nitrogen for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-5% ethyl acetate/petroleum ether) to obtain the compound as a colorless oil11b (3.70 g, 70.8% yield).LCMS: tR =0.656 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 295.9 and 297.9 [M+H]+ . 1 H NMR (CD3 OD 400MHz): δ=7.39 (s, 1H), 7.35 (dt,J= 7.2, 2.0 Hz, 1H), 7.23-7.15 (m, 2H), 3.29-3.15 (m, 2H), 3.03-2.90 (m, 1H), 2.81 (dd,J= 5.6, 13.2 Hz, 1H), 2.50 (dd,J= 7.6, 13.2 Hz, 1H), 1.01 (d,J= 6.4 Hz, 3H).
Figure 02_image140
Pd(OAc) under nitrogen2 Compound was added to a mixture of (561 mg, 2.498 mmol), BINAP (3.19 g, 4.996 mmol) and cesium carbonate (12.21 g, 37.47 mmol)11b (3.70 g, 12.49 mmol) solution and compound in toluene (60 mL)11B (3.75 g, 20.69 mmol) in toluene (10 mL). The reaction mixture was stirred under nitrogen at 100°C for 16 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-5% ethyl acetate/petroleum ether) to obtain the compound as a yellow oil11c (3.70 g, 80% purity, 59.8% yield).LCMS: tR =0.788 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 397.2 [M+H]+ .
Figure 02_image142
Compound11c A mixture of (3.70 g, 80% purity, 7.47 mmol), hydroxylamine hydrochloride (1.04 g, 14.94 mmol) and sodium acetate (1.59 g, 19.42 mmol) in methanol (370 mL) was stirred at 16-24°C. hour. The mixture was concentrated in vacuo, and the residue was treated with a saturated aqueous solution of sodium bicarbonate (100 mL) and ethyl acetate (30 mL) and then separated. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-10% ethyl acetate/petroleum ether) to obtain the compound as a yellow gum11d (1.90 g, 90% purity, 97.7% yield).LCMS: tR =0.126 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 233.0 [M+H]+ . 1 H NMR (400MHz, CD3 OD): δ=7.07-6.96 (m, 1H), 6.63-6.56 (m, 2H), 6.54 (d,J= 7.2 Hz, 1H), 3.22 (q,J= 9.6 Hz, 2H), 3.01-2.89 (m, 1H), 2.69 (dd,J= 6.4, 13.2 Hz, 1H), 2.44 (dd,J= 7.6, 13.2 Hz, 1H), 1.03 (d,J= 6.4 Hz, 3H).
Figure 02_image144
Compound11d (1.90 g, 7.36 mmol, 90% purity),1E A mixture of (1.37 g, 7.36 mmol) and water (662 mg, 36.8 mmol) in acetic acid (20 ml) was stirred at 80°C under nitrogen for one hour. The mixture was poured into a saturated aqueous solution of sodium bicarbonate (300 mL) with stirring, basified with solid potassium carbonate to pH=8-9 and extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-10% ethyl acetate/petroleum ether) to obtain the compound as an orange gum11e (2.87 g, 90% purity, 87.8% yield). The product is an inseparable diastereomer and according to the H NMR spectrum, the ratio is about 4:1. The main isomers are characterized as follows:LCMS: tR =0.745 min, in 5-95AB_1.5min_220&254.lcm chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z 400.1 and 402.1 [M+H]+ . 1 H NMR (400MHz, CD3 OD): δ=8.51 (d,J= 2.4 Hz, 1H), 7.86 (dd,J= 2.8, 8.8 Hz, 1H), 7.30 (d,J= 8.8 Hz, 1H), 6.57-6.49 (m, 2H), 6.46 (dd,J= 2.4, 8.4 Hz, 1H), 4.85 (s, 1H), 3.48-3.33 (m, 2H), 3.11 (dd,J= 4.8, 16.0 Hz, 1H), 3.00-2.83 (m, 1H), 2.55 (dd,J= 4.8, 16.0 Hz, 1H), 1.06 (d,J= 6.4 Hz, 3H).
Figure 02_image146
At 12 ℃ to the compound11e (200 mg, 0.5 mmol) in pyridine (5 mL) was added compound11F (362.5 mg, 1.5 mmol). Next, the mixture was stirred at 130°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by a flash column (0-15% methanol/ethyl acetate) to obtain a colorless oil.11f (200 mg, 88% yield).LCMS: tR =0.885 min, in 5-95AB_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=452.0 and 454.0 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.57 (d,J =2.4 Hz, 1H), 8.45 (s, 2H), 7.79 (dd,J= 2.4, 8.4 Hz, 1H), 7.41 (d,J= 8.4 Hz, 1H), 7.17 (s, 1H), 7.14-7.10 (m, 2H), 5.06 (s, 1H), 3.55-3.49 (m, 1H), 3.35-3.19 (m, 2H), 3.02-2.89 (m, 1H), 2.69 (dd,J= 6.0, 16.8 Hz, 1H), 1.12 (d,J= 6.8 Hz, 3H).
Figure 02_image148
Under nitrogen11f (150 mg, 0.33 mmol),1F (231.0 mg, 0.43 mmol, 67% purity) and t-BuONa (319.6 mg, 3.3 mmol) in 1,4-dioxane (3 mL) were added Brettphos-Pd G3 (45.9 mg, 0.05 mmol). The reaction was then heated to 80°C and stirred at 80°C for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and water (30 mL). After separation, the aqueous layer was extracted with ethyl acetate (300 mL×2). The combined organic layer was washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was passed through a flash column (0-5% ethyl acetate/petroleum ether), followed by chirality SFC (column: DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm); condition: 55% B(A: CO2 , B: EtOH (0.1% NH3. H2 O)); flow rate: 70 ml/min) purification to obtain a white solidChemical compound 11 (27.8 mg, 16.6% yield, tR : 2.647 min) and the stereochemistry was confirmed by 2D NMR. Another isomer is obtained as a white solidChemical compound 11a (8.2 mg, 4.9% yield).Chiral SFC Analytical method : TR =2.153 min, 85.81% optical purity; method: column: Chiralpak IC100×4.6 mm I.D., 3 μm; mobile phase: 40% methanol (0.05% DEA) in CO2 Medium; flow rate: 3 mL/min; column temperature: 40°C.Chemical compound 11 :LCMS: tR =0.676 min, in 5-95AB_220&254 _Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=504.3 [M+H]+ .HPLC: tR = 2.31 min in 10-80_AB_1.2ml.met (Ultimate C18 3×50mm 3μm).SFC: tR =2.647 min in IC_3_40_3ML_8min_10CM.M (column: Chiralpak IC 100×4.6mm I.D., 3μm; mobile phase: 40% methanol (0.05% DEA) in CO2 Medium; flow rate: 3 mL/min; column temperature: 40°C). 1 H NMR (400MHz, CDCl3 ): δ=8.44 (s, 2H), 7.85 (d,J= 2.8 Hz, 1H), 7.23 (d,J= 8.4 Hz, 1H), 7.14 (s, 1H), 7.10-7.05 (m, 2H), 6.85 (dd,J= 2.8, 8.4 Hz, 1H), 4.99 (s, 1H), 4.51 (dt,J= 47.2 Hz and 6.0 Hz, 2H), 4.34 (br s, 1H), 4.22-4.13 (m, 1H), 3.85 (t,J =7.2 Hz, 2H), 3.61-3.51 (m, 1H), 3.31-3.18 (m, 2H), 3.18-3.08 (m, 2H), 3.05-2.91 (m, 1H), 2.74 (t,J =7.2 Hz, 2H), 2.67 (dd,J =5.6 Hz and 16.8 Hz, 1H), 1.81-1.73 (m, 2H), 1.11 (d,J= 6.4 Hz, 3H).Chemical compound 11a :LCMS: tR =0.712 min, in 5-95AB_220&254 _Shimadzu.lcm (Xtimate C18 2.1×30mm), MS (ESI) m/z=504.3 [M+H]+ .HPLC: tR = 2.33 min in 10-80_AB_1.2ml.met (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CDCl3 ): δ=8.43 (s, 2H), 7.91 (s, 1H), 7.31 (d,J= 8.4 Hz, 1H), 7.12-7.07 (m, 3H), 6.91 (d,J= 7.2 Hz, 1H), 5.21 (s, 1H), 4.92 (br s, 1H), 4.53 (dt,J= 46.8 Hz and 5.6 Hz, 2H), 4.36-4.26 (m, 1H), 4.09-3.99 (m, 2H), 3.61-3.39 (m, 3H), 3.34-3.18 (m, 2H), 3.01-2.92 (m , 2H), 2.83 (d,J= 6.4 Hz, 2H), 2.07-1.88 (m, 2H), 1.35 (d,J= 6.0 Hz, 3H).Examples 12 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(2H-1,2,3- Triazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image150
For preparationChemical compound 12 'S program:
Figure 02_image152
Compound1h (Prepared fromExamples 1 In, 500 mg, 0.855 mmol), CuI (16 mg, 0.0856 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (ii) dichloride (31 mg, 0.0428 mmol) in Diisopropylamine (173 mg, 1.71 mmol) was added to the mixture in N,N-dimethylformamide (5 mL), followed by compound12A (168 mg, 1.71 mmol) The mixture was then stirred under nitrogen at 80 °C for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography and eluted with 0-3% methanol/dichloromethane to obtain the compound as a brown gum12a (300 mg, 61.2% yield, 90% purity).LCMS: tR =0.795 min in 5-95AB_220&254_Shimadzu.lcm (Merck RP18 2.5-2mm), MS (ESI) m/z=533.4 [M+H]+ .
Figure 02_image154
At room temperature (4-20 ℃) to the compound12a (300 mg, 0.507 mmol, 90% purity) in tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (1.0 mL, 1.014 mmol, 1 M in tetrahydrofuran). The reaction mixture was then stirred at room temperature (4-20°C) for 1 hour. The resulting reaction mixture was diluted with saturated sodium bicarbonate (30 mL) and then extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with saturated sodium bicarbonate (40 mL×2), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain the compound as a purple solid12b (150 mg, 64.3% yield).LCMS: tR = 0.760 min in 5-95AB_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=461.3 [M+H]+ . 1 H NMR (400 MHz, CD3 OD): δ=7.77 (d,J= 2.4 Hz, 1H), 7.26 (s, 1H), 7.17-7.06 (m, 2H), 6.94 (dd,J= 2.8, 8.8 Hz, 1H), 6.71 (d,J= 8.4 Hz, 1H), 4.86 (s, 1H), 4.46 (dt,J= 47.6, 5.6 Hz, 2H), 4.17-1.04 (m, 1H), 3.82 (t,J= 7.2 Hz, 2H), 3.58-3.46 (m, 1H), 3.41 (s, 1H), 3.36-3.32 (m, 1H), 3.28-3.17 (m, 1H), 3.01 (br s, 2H), 2.97- 2.86 (m, 1H), 2.73-2.56 (m, 3H), 1.87-1.69 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H).
Figure 02_image156
Compound12b (120 mg, 0.261 mmol), azidotrimethylsilane (285 mg, 2.476 mmol) and copper(I) iodide (12.4 mg, 0.0653 mmol) in N,N-dimethylformamide (9.6 mL) ) Was stirred at 100°C for 2 hours. The reaction mixture was then concentrated in vacuo to obtain the crude product, which was purified by reverse phase silica gel column chromatography (0-100% methanol/water (0.1% ammonium hydroxide)) and then additionally by preparative TLC (dichloromethane/methanol= 6:1 (0.1% ammonium hydroxide)) purification to obtain a chemically pure product (25 mg) as a colorless gum. Then by chiral SFC [column: Phenomenex-Amylose-1 (250 mm×30 mm, 5 μm); conditions: 35% ethanol (0.1% ammonium hydroxide) in carbon dioxide; flow rate: 50 mL/min] purification chemistry Pure product, obtained as a white solidChemical compound 12 (12.8 mg, 94.90% chemical purity, 99.48% optical purity, 9.8% yield).LCMS: tR =3.134 min, in 10-80CD_7min_220&254.lcm chromatography (A: Xtimate C18, 2.1×30mm, 3μm B: XBrige Shield RP18 2.1×50mm), MS (ESI) m/z 504.3[M+H]+ .HPLC: tR = 2.92 min in 10-80_CD_1.2ml.met. chromatography (XBridge Shield RP 18 2.1×50mm 5μm).SFC: tR =3.577 min; column: Chiralcel OD-3 100×4.6mm I.D., 3μm; mobile phase: A: CO2 ; B: methanol (0.05% DEA); gradient B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min; flow rate: 2.8 mL/min; column temperature: 40 ℃. 1 H NMR (400MHz, CD3 OD): δ=8.10 (s, 1H), 7.78 (d,J= 2.8 Hz, 1H), 7.63 (s, 1H), 7.49 (d,J= 8.0 Hz, 1H), 7.14 (d,J= 8.8 Hz, 1H), 6.95 (dd,J= 2.8, 8.4 Hz, 1H), 6.81 (d,J= 8.0 Hz, 1H), 4.91 (s, 1H), 4.47 (dt,J= 47.2, 6.0 Hz, 2H), 4.19-4.05 (m, 1H), 3.92-3.78 (m, 2H), 3.61-3.49 (m, 1H), 3.41-3.33 (m, 1H), 3.30-3.26 (m, 1H), 3.12-3.02 (m, 2H), 3.02-2.87 (m, 1H), 2.78-2.65 (m, 3H), 1.88-1.70 (m, 2H), 1.10 (d,J= 6.4 Hz, 3H).Examples 13 5- fluorine -N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image158
For preparationExamples 13 'S program:
Figure 02_image160
Compound13a (400 mg, 1.72 mmol) and compound13A (526.3 mg, 2.58 mmol) ati- To the solution in PrOH (20 mL) was added TFA (0.4 mL, 5.16 mmol). The mixture was stirred under nitrogen at 25°C for 16 hours. Pour the reaction into NaHCO3 A mixed solution of an aqueous solution (10 mL) and brine (50 mL) and extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether) as an inseparable 13:1 diastereomer as a yellow solid (550 mg, 76.6% yield). Confirm the main trans isomer by 2D NMR (NOE)13b .LCMS: tR =0.917 min, in 5-95AB_ 1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=419.0 [M+H]+ .SFC( method 1): tR =3.326 min; 90.35% purity. Method: Column: Chiralpak AD-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5 min and maintained at 40% for 2.5 min, followed by 5% B for 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.SFC( method 2): tR = 3.255 min; 90.38% purity. Method: Column: Chiralcel OD-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA) Gradient: B within 5 min from 5% to 40% and maintained at 40% for 2.5 min, followed by 5% B for 2.5 min; flow rate: 2.5 mL/min; column temperature: 35 ℃. 1 H NMR (400MHz, CDCl3 ) δ=8.30 (d,J= 1.6 Hz, 1H), 7.49 (dd,J= 8.8, 1.6 Hz, 1H), 6.57 (d,J= 8.8 Hz, 1H), 6.53 (d,J= 2.0 Hz, 1H), 6.45 (dd,J= 8.0, 2.4 Hz, 1H), 5.15 (s, 1H), 3.53-3.45 (m, 1H), 3.20-3.10 (m, 1H), 2.97 (dd,J= 16.4, 4.8 Hz, 1H), 2.93-2.86 (m, 1H), 2.47 (dd,J= 16.8, 7.2 Hz, 1H), 0.99 (d,J= 6.4 Hz, 3H).
Figure 02_image162
At 24-31 ℃ under nitrogen to the compound13b (500 mg, 1.2 mmol) and compound13B (857 mg, 1.8 mmol) in 1,4-dioxane (20 mL) was added t-BuONa (634 mg, 6.6 mmol), followed by Brettphos-Pd-G3 (54 mg, 0.06 mmol). The reaction mixture was stirred at 80°C under nitrogen for 16 hours. Then use the mixture with H2 O (100 mL) was diluted and extracted with ethyl acetate (100 mL×3), washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product. The crude material was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to obtain the compound as a yellow solid13c (500 mg, 89.1% yield).LCMS: tR =0.739 min, in 5-95AB_ 1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=471.2 [M+H]+ .
Figure 02_image164
At 28 ℃ to the compound13c (450 mg, 0.96 mmol) and PhNTf2 (985.9 mg, 1.92 mmol) in dichloromethane (20 mL) was added triethylamine (291.4 mg, 2.88 mmol). The reaction mixture was stirred at 80°C under nitrogen for 5 hours. The mixture was then diluted with water (100 mL) and extracted with dichloromethane (100 mL×3), washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated to obtain the crude product. The crude material was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain the compound as a yellow solid13d (550 mg, 95.5% yield), which contains some Et3 N.LCMS: tR =0.860 min, in 5-95AB_1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=603.3 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.69 (d,J= 2.0 Hz, 1H), 7.05 (d,J= 2.4 Hz, 1H), 6.97 (dd,J= 8.4, 2.4 Hz, 1H), 6.87 (d,J= 8.4 Hz, 1H), 6.57 (dd,J= 11.6, 2.0 Hz, 1H), 5.21 (s, 1H), 5.05 (d,J= 6.4 Hz, 1H), 4.51 (dt,J= 46.8, 5.6 Hz, 2H), 4.34-4.28 (m, 1H), 4.11 (br s, 2H), 3.68-3.63 (m, 1H), 3.53 (br s, 2H), 3.03-2.99 (m, 3H) , 2.61 (br dd,J= 16.8, 6.8 Hz, 1H), 1.94-1.82 (m, 2H), 1.08 (d,J= 6.8 Hz, 3H).
Figure 02_image166
Under nitrogen13d (150 mg, 0.25 mmol),6A (97 mg, 0.50 mmol), potassium carbonate (103.4 mg, 0.75 mmol) was added Pd(dppf)Cl to a mixture of 1,4-dioxane (3 mL) and water (0.3 mL)2 ∙CH2 Cl2 (40.8 mg, 0.05 mmol). The reaction was then heated to 100°C and stirred at 100°C for 16 hours under nitrogen. The mixture was then diluted with water (50 mL) and extracted with dichloromethane (150 mL×3), washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product, which passed through a silica gel column Chromatography (0-10% methanol/dichloromethane) purification to obtain crude product. Pass chiral SFC (92.59% purity, column: DAICEL CHIRALCEL OJ-H (250mm×30mm, 5μm)); condition: 35% B (A: CO2 , B: 0.1% NH3 H2 O/EtOH); flow rate: 60 mL/min) to separate the crude product to obtain a yellow solidExamples 13 (11.3 mg, 8.7% yield).LCMS: tR =0.743 min, in 5-95AB_1.5min_220&254_Shimadzu.lcm (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=521.4 [M+H]+ .HPLC: tR =3.44 min, in 10-80_AB_1.2ml.met. chromatography (Ultimate C18 3.0μm 3.0×50mm).SFC: tR = 2.289 min; 100% purity. Method: Column: Chiralcel OJ-3 100×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.1% ethanolamine); Gradient: B from 5% to 40% within 4.5 min, followed by maintaining 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40°C. 1 H NMR (400MHz, CD3 OD) δ=7.89 (br s, 2H), 7.63 (d,J= 2.0 Hz, 1H), 7.34 (s, 1H), 7.24 (dd,J= 8.0, 1.6 Hz, 1H), 6.70 (s, 1H), 6.69-6.66 (m, 1H), 5.11 (s, 1H), 4.46 (dt,J= 47.2, 5.6 Hz, 2H), 4.15-4.11 (m, 1H), 3.91 (br t,J= 6.8 Hz, 2H), 3.61-3.54 (m, 1H), 3.31-3.30 (m, 1H), 3.24-3.08 (m, 3H), 3.00-2.87 (m, 1H), 2.77 (t,J= 7.6 Hz, 2H), 2.65 (dd,J= 16.0, 5.2 Hz, 1H), 1.87-1.71 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H). Used to synthesize intermediates13B 'S program:
Figure 02_image168
Compound1F_2 (23 g, 99.01 mmol) in toluene (150 mL) was added TsOH∙H2 O (37.7 g, 198.02 mmol) and TfOH (575 mg, 3.83 mmol). The resulting mixture was stirred at 50°C for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and the solid was quickly collected by filtration. The filter cake was washed with ethyl acetate (150 mL) and dried under high vacuum to give the compound as a white solid13B (47 g TsOH salt, 99% yield).LCMS : tR =0.099 min, in 0-60AB_2min_E_50_Agilent.M chromatography (Xtimate C18, 2.1×30mm, 3μm), MS (ESI) m/z= 133.1 [M+H]+ . 1 H NMR (400MHz, MeOD): δ=7.73 (d,J= 8.0 Hz, 4H), 7.27 (d,J= 8.0 Hz, 4H), 4.70-4.20 (m, 7H), 3.50 (br t,J= 6.8 Hz, 2H), 2.39 (s, 6H), 2.09-2.01 (m, 1H), 2.00-1.92 (m, 1H).Examples 14 3-((1S,3R)-1-(2,6- Difluoro -4-((1-(3- Fluoropropyl ) Azetidine -3- base ) Amine ) Phenyl )-3- methyl -6-(1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base )-2,2- Difluoropropene -1- alcohol
Figure 02_image170
For preparationExamples 14 'S program:
Figure 02_image172
At room temperature (0-6 ℃) to the compound2D (1.60 g, 6.63 mmol) in a mixture of 1,4-dioxane (30 mL) was added DIEA (3.5 mL, 19.89 mmol), followed by the compound-containing1c (3.20 g, 6.63 mmol) of 1,4-dioxane (2 mL). The reaction mixture was then stirred at 80°C under nitrogen for 24 hours. The reaction mixture was then diluted with water (40 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (80 mL×3), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to obtain a crude product, which was passed through a silica gel column chromatography (0-5% ethyl acetate/petroleum ether) ) Purification to obtain the compound as colorless gum14a (1.9 g, 50% yield).LCMS: tR =0.996 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=574.1 [M+H]+ . 1 H NMR (400 MHz, CDCl3 ):δ =7.73-7.63 (m, 4H), 7.48-7.30 (m, 11H), 7.20 (t,J= 8.0 Hz, 1H), 6.87-6.81 (m, 2H), 6.79 (d,J= 7.6 Hz, 1H), 5.05 (s, 2H), 3.94-3.74 (m, 2H), 3.26-3.04 (m, 2H), 3.04-2.93 (m, 1H), 2.75 (dd,J= 13.2, 6.4 Hz, 1H), 2.57 (dd,J= 13.6, 7.2 Hz, 1H), 1.10-1.03 (m, 9H).
Figure 02_image174
Compound14a (400 mg, 0.697 mmol) in ethyl acetate (30 mL) was added 10% Pd/C (80 mg, 50 w% water). The reaction mixture was then placed at 40°C in a hydrogen atmosphere (15 psi, H2 Balloon) for 16 hours. The reaction mixture was then filtered through celite. Add 10% Pd/C (80 mg, 50 w% water) to the filtrate. The resulting mixture was heated at 50°C in H2 Atmosphere (15 psi, H2 Balloon) for 5 hours. The reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether) to obtain the compound as a colorless gum.14b (300 mg, 89% yield).LCMS: tR =0.936 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=484.1 [M+H]+ . 1 H NMR (400 MHz, CDCl3 ):δ =7.76-7.63 (m, 4H), 7.52-7.36 (m, 6H), 7.14 (t,J= 8.0 Hz, 1H), 6.74 (d,J= 7.2 Hz, 1H), 6.68 (dd,J= 8.4, 2.4Hz, 1H), 6.64 (s, 1H), 3.91-3.72 (m, 2H), 3.25-3.05 (m, 2H), 3.05-2.97 (m, 1H), 2.71 (dd,J= 13.6, 6.8Hz, 1H), 2.57 (dd,J= 13.6, 6.4Hz, 1H), 1.09 (d,J= 6.4 Hz, 3H), 1.07 (s, 9H).
Figure 02_image176
At room temperature (15-23 ℃) to the compound14b (600 mg, 1.24 mmol)) in toluene (27 mL) was added acetic acid (3 mL) and14A (300 mg, 1.36 mmol). Next, the reaction mixture was stirred at 80°C for 20 hours. Then the reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate (20 mL) and water (20 mL), and then separated. The aqueous layer was extracted with ethyl acetate (20 mL×3). Combine the combined organic layers with saturated NaHCO3 The solution (20 mL×3) was washed, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (0-20% ethyl acetate/petroleum ether) to obtain a 9:1 inseparable diastereomer (400 mg, 46.7%) as a yellow oil. . Chemical compound14c It is the main diastereomer.LCMS: tR =1.120 min, in 5-95AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=688.3 [M+2+H]+ .
Figure 02_image178
Add to a mixture of Brettphos Pd G3 (69.7 mg, 0.077 mmol) and t-BuONa (440.6 mg, 4.59 mmol) at room temperature (13-25°C)14c (350 mg, 0.510 mmol) and1F (367.4 mg, 1.02 mmol) in 1,4-dioxane (9 mL). Next, the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was treated with ethyl acetate (20 mL) and water (20 mL), and then separated. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (20 mL×3), dried over anhydrous sodium sulfate and filtered. Concentrate the filtrate in vacuo and pass through a silica gel column (0-10% MeOH/CH2 Cl2 ) Purification to obtain a yellow oil5 (230 mg, 61.1%).LCMS: tR =0.887 min, in 5-95AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=738.4 [M+H]+ . 1 H NMR (400 MHz, MeOD):δ =7.63-7.57 (m, 4H), 7.50-7.33 (m, 6H), 6.52-6.39 (m, 3H), 5.89 (d,J= 11.6 Hz, 2H), 4.96 (s, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 4.01-3.82 (m, 2H), 3.78-3.67 (m, 2H), 3.59-3.35 (m, 2H), 3.06 (br dd,J= 15.2, 4.8 Hz, 2H), 2.90 (t,J= 7.2 Hz, 2H), 2.64 (br t,J= 7.2 Hz, 3H), 2.40 (dd,J= 15.2, 2.4 Hz, 1H), 1.85-1.65 (m, 2H), 1.07-0.95 (m, 12H).
Figure 02_image180
At room temperature (16-28 ℃) to the compound14d (230 mg, 0.312 mmol) in dichloromethane (7 mL) was added Et3 N (94.7 mg, 0.936 mmol), followed by PhNTf2 (223 mg, 0.624 mmol). The reaction mixture was then stirred at room temperature (16-28°C) for 16 hours. Then the reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate (20 mL) and water (20 mL), and then separated. The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (20 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain the compound as a gray-blue solid14e (220 mg, 76.9%).LCMS: tR =1.018 min, in 5-95AB_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=870.5 [M+H]+ . 1 H NMR (400 MHz, MeOD):δ =7.65-7.56 (m, 4H), 7.50-7.36 (m, 6H), 7.09 (d,J= 2.4 Hz, 1H), 7.00 (dd,J= 8.4, 2.4Hz, 1H), 6.85 (d,J= 8.4 Hz, 1H), 5.94 (br d,J= 11.6 Hz, 2H), 5.10 (s, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.96-3.86 (m, 2H), 3.79 (br s, 2H), 3.57 (br s, 1H), 3.50-3.39 (m, 1H), 3.20-3.05 (m, 2H) , 3.04-2.92 (m, 2H), 2.80-2.65 (m, 3H), 2.60 (dd,J= 16.0, 3.2 Hz, 1H), 1.85-1.68 (m, 2H), 1.06-0.94 (m, 12H).
Figure 02_image182
At room temperature (8-17 ℃) to the compound14B (25 mg, 0.086 mmol), Pd(dppf)Cl2 .CH2 Cl2 (9.3 mg, 0.015 mmol) and K2 CO3 (23.6 mg, 0.171 mmol) was added to the mixture14e (50 mg, 0.057 mmol) in 1,4-dioxane/H2 O (5 mL (v/v=10:1)) solution. Next, the reaction mixture was stirred at 100°C for 20 hours. Next, the reaction mixture was carried out in the same manner as the previous pilot batch (10 mg of compound14e )combination. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with ethyl acetate (10 mL) and water (10 mL), and then separated. Then the aqueous layer was extracted with ethyl acetate (10 mL×3) and the combined organic layer was washed with brine (10 mL×3), dried over anhydrous sodium sulfate and filtered. Concentrate the filtrate in vacuo and pass silica gel column chromatography (0-10% methanol/CH2 Cl2 ) Purification to obtain the compound as grayish blue solid14f (60 mg, 65.5%).LCMS: tR =1.046 min, in 5-95AB_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=788.6 [M+H]+ . 1 H NMR (400 MHz, MeOD):δ =7.88 (s, 2H), 7.67-7.55 (m, 4H), 7.50-7.33 (m, 6H), 7.27 (s, 1H), 7.20 (br d,J= 8.0 Hz, 1H), 6.67 (d,J= 8.0 Hz, 1H), 5.92 (d,J= 11.6 Hz, 2H), 5.04 (s, 1H), 4.45 (dt,J= 47.2, 6.0 Hz, 2H), 4.03-3.85 (m, 2H), 3.76 (br t,J= 7.2 Hz, 2H), 3.59 (br d,J= 7.2 Hz, 1H), 3.49-3.35 (m, 1H), 3.22-3.05 (m, 2H), 2.96 (br t,J= 6.8 Hz, 2H), 2.86-2.71 (m, 1H), 2.67 (t,J= 7.2 Hz, 2H), 2.55 (br dd,J= 2.8, 15.6 Hz, 1H), 1.86-1.66 (m, 2H), 1.04-0.96 (m, 12H).
Figure 02_image184
At room temperature (8-24 ℃) to the compound14f (40 mg, 0.063 mmol) in THF (5 mL) was added TBAF (0.189 mL, 0.189 mmol, 1 M in THF). The reaction mixture was then stirred at room temperature (8-24°C) for 3 hours. The reaction mixture was saturated with NaHCO3 The solution (10 mL) was diluted and the aqueous layer was extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (10 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and passed through preparative TLC (CH2 Cl2 /Methanol=9:1) purification to obtain crude product. Then the crude product was additionally passed through a chiral SFC (column: Lux Cellulose-2 150×4.6mm I.D., 3μm; gradient: 40% methanol (0.05% DEA) in CO2 Medium; flow rate: 2.5 mL/min; column temperature: 40°C) purification, to obtain an off-white solidExamples 14 (13.6 mg, 38.2%).LCMS: tR= 1.623 min, in 10-80AB_4min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=550.1H]+ .HPLC: tR= 1.91min in 10-80_AB_1.2ml.met. HPLC-A Ultimate C18 3×50mm 3μm.SFC: tR= 2.788 min, purity: 100%, column: Lux Cellulose-2 150×4.6mm I.D., 3μm; gradient: 40% methanol (0.05% DEA) in CO2 Medium; flow rate: 2.5 mL/min; column temperature: 40°C. 1 H NMR (400 MHz, MeOD):δ =7.91 (br s, 2H), 7.30 (s, 1H), 7.23 (d,J= 8.0 Hz, 1H), 6.71 (d,J= 8.0 Hz, 1H), 6.10 (d,J= 11.2 Hz, 2H), 5.07 (s, 1H), 4.45 (dt,J= 47.2, 6.0 Hz, 2H), 4.11 (br t,J= 6.4 Hz, 1H), 3.91 (br d,J= 4.8 Hz, 2H), 3.82-3.66 (m, 1H), 3.59 (br s, 1H), 3.43-3.32 (m, 1H), 3.24 (br d,J= 4.4 Hz, 1H), 3.20-3.04 (m, 3H), 2.82-2.75 (m, 2H), 2.75-2.67 (m, 1H), 2.64 (dd,J= 3.2, 15.6 Hz, 1H), 1.89-1.70 (m, 2H), 1.05 (d,J= 6.4 Hz, 3H).Examples 15 2,2- Difluoro -3-((1S,3R)-1-(3- fluorine -5-((1-(3- Fluoropropyl ) Azetidine -3- base ) Amine ) Pyridine -2- base )-3- methyl -6-(1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base ) C -1- alcohol
Figure 02_image186
For preparationExamples 15 'S program:
Figure 02_image188
Compound14b (200 mg, 0.414 mmol), compound13A (101.4 mg, 0.497 mmol) and Yb(OTf)3 (10.3 mg, 0.0166 mmol) in MeCN (6 mL) was added water (37.3 μL, 2.07 mmol). Thereafter, the reaction was stirred at 70°C for 12 hours under nitrogen. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (0-18% ethyl acetate/petroleum ether) to obtain a 10:1 inseparable diastereomer as a yellow oil (215.8 mg, 78.0 %Yield). Chemical compound15a It is the main diastereomer.LCMS: tR =1.133 min, in 5-95AB_1.5min_220&254.lcm chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=671.4 [M+H+2]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.33 (d,J= 1.2 Hz, 1H), 7.66-7.61 (m, 4H), 7.49-7.36 (m, 7H), 6.65-6.60 (m, 2H), 6.57-6.53 (m, 1H), 4.86 (s, 1H), 3.99 -3.87 (m, 1H), 3.77-3.69 (m, 1H), 3.63-3.55 (m, 1H), 3.32-3.19 (m, 1H), 2.99 (dd,J= 16.0, 4.0 Hz, 1H), 2.87-2.77(m, 1H), 2.53 (dd,J= 16.4, 6.8 Hz, 1H), 1.07-1.03 (m, 12H).
Figure 02_image190
To the compound under nitrogen15a (195.8 mg, 0.293 mmol),13B (209.0 mg, 0.439 mmol) in 1,4-dioxane (8 mL) was added Brettphos Pd-G3 (26.5 mg, 0.0293 mmol) and t-BuONa (154.7 mg, 1.612 mmol). The reaction mixture was then stirred at 80°C under nitrogen for 12 hours. Mix the mixture with parallel batches (90 mg compound14b )merge. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain the compound as a yellow oil15b (201.6 mg, 65.3% average yield).LCMS: tR =0.862 min, in 5-95AB_1.5min_220&254.lcm chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z= 721.6 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.67-7.59 (m, 5H), 7.45-7.35 (m, 6H), 6.59-6.52 (m, 2H), 6.44-6.34 (m, 2H), 5.17 (s, 1H), 4.48 (dt ,J= 47.2, 6.0 Hz, 2H), 4.46 (s, 1H), 4.05-3.92 (m, 2H), 3.73-3.66 (m, 3H), 3.59-3.53 (m, 1H), 3.18 (q,J= 14.8 Hz, 1H), 3.06-2.98 (m, 2H), 2.92 (dd,J= 16.4, 4.4 Hz, 1H), 2.78 (q,J= 14.8 Hz, 1H), 2.66 (t,J= 7.2 Hz, 2H), 2.49 (dd,J= 16.4, 7.6 Hz, 1H), 1.83-1.72 (m, 2H), 1.07-1.01 (m, 12H).
Figure 02_image192
Compound15b (201.6 mg, 0.280 mmol) in a mixture of dichloromethane (5 mL) was added triethylamine (188.5 μL, 1.12 mmol), followed by PhNTf2 (150.0 mg, 0.420 mmol). The reaction mixture was then stirred at room temperature (24-35°C) for 12 hours. Mix the mixture with another batch (48.3 mg of compound15b )merge. The mixture was then concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (0-8% methanol/dichloromethane) to obtain the compound as a yellow oil15c (227.1 mg, 76.8% yield).LCMS: tR =1.035 min, in 5-95AB_1.5min_220&254.lcm chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z= 853.6 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.67-7.60 (m, 5H), 7.49-7.35 (m, 6H), 7.04 (d,J= 2.4 Hz, 1H), 6.95 (dd,J =8.4, 2.0 Hz, 1H), 6.84 (d,J= 8.8 Hz, 1H), 6.39 (dd,J= 12.0, 2.0 Hz, 1H), 5.24 (s, 1H), 4.59-4.52 (br s, 1H), 4.50 (dt,J= 47.2, 5.6 Hz, 2H), 4.16-4.05 (m, 1H), 4.00-3.90 (m, 1H), 3.90-3.82 (m, 2H), 3.73-3.61 (m, 2H), 3.25-3.17 (m, 3H), 3.02 (dd,J= 16.4, 4.4 Hz, 1H), 2.87-2.76 (m, 3H), 2.59 (dd,J= 16.4, 6.4 Hz, 1H), 1.87-1.76 (m, 2H), 1.10-1.00 (m, 12H).
Figure 02_image194
Compound15c (227.1 mg, 0.267 mmol), compound6A (117.9 mg, 0.401 mmol), Pd(dppf)Cl2 .Dichloromethane (43.6 mg, 0.0534 mmol) and K2 CO3 The mixture (92.3 mg, 0.668 mmol) was purged with nitrogen. Then add 1,4-dioxane and H to the mixture under nitrogen2 O mixed solution (v/v=4:1) (7.5 mL). The resulting mixture was stirred at 100°C under nitrogen for 3 hours. The mixture was filtered and concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain the compound as a brown solid15d (Total 182.7 mg, 88.8% yield).LCMS: tR =0.918 min, in 5-95AB_1.5min_220&254.lcm chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=771.3 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.76 (s, 2H), 7.64-7.57 (m, 5H), 7.45-7.34 (m, 6H), 7.23 (s, 1H), 7.15 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 7.6 Hz, 1H), 6.38 (d,J= 11.6 Hz, 1H), 5.23 (s, 1H), 4.74-4.58 (br s, 1H), 4.46 (dt,J= 46.8, 5.2 Hz, 2H), 4.12-4.04 (m, 1H), 4.00-3.84 (m, 3H), 3.74-3.60 (m, 2H), 3.25-3.12 (m, 3H), 3.01 (d,J= 13.2 Hz, 1H), 2.86-2.73 (m, 3H), 2.58 (dd,J= 16.4, 7.2 Hz, 1H), 1.85-1.71 (m, 2H), 1.08-1.00 (m, 12H).
Figure 02_image196
Compound15d (182.7 mg, 0.237 mmol) to a mixture of tetrahydrofuran (5 mL) was added TBAF solution (356 μL, 0.356 mmol, 1 M in THF). The resulting mixture was stirred at 60°C under nitrogen for 12 hours. The mixture was saturated with NaHCO3 The solution is adjusted to a pH of about 8. The mixture was extracted with ethyl acetate (20 mL×3), washed with brine (20 mL×2), and dried over anhydrous Na2 SO4 Dry, filter and concentrate under reduced pressure to obtain crude material. The mixture was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain 80.9 mg of 10:1 inseparable diastereomer, which was additionally passed through a chiral SFC (column: DAICEL CHIRALCEL OJ-H( 250mm×30 mm, 5 μm); Conditions: (0.1% NH3 H2 O) MeOH; flow rate: 60 mL/min) purification to obtain the compound as a white solidExamples 15 (43.5 mg, 34.5% yield).HPLC: tR = 3.29 min in 0-60_AB_1.2ml.met. chromatography (Ultimate C18 3×50mm 3μm).SFC: tR =2.479 min; 99.84% purity. Method: Column: Chiralcel OJ-3 100×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: methanol (0.1% ethanolamine); gradient: B from 5% to 40% within 4.5 min, followed by maintaining 5% B 1 min; flow rate: 2.8 mL/min; column temperature: 40°C. 1 H NMR (400MHz, CDCl3 ): δ=7.80 (s, 2H), 7.75 (d,J= 1.6 Hz, 1H), 7.27-7.25 (m, 1H), 7.19 (d,J= 8.0 Hz, 1H), 6.74 (d,J= 8.4 Hz, 1H), 6.55 (dd,J= 11.6, 2.4 Hz, 1H), 5.18 (s, 1H), 4.50 (dt,J= 46.8, 5.6 Hz, 2H), 4.38 (d,J= 6.8 Hz, 1H), 4.11-4.03 (m, 1H), 3.95-3.79 (m, 1H), 3.72 (q,J= 6.0 Hz, 2H), 3.76-3.67 (m, 1H), 3.62-3.51 (m, 1H), 3.29 (dd,J= 16.0, 4.8 Hz, 1H), 3.23-3.13 (m, 1H), 3.00-2.91 (m, 2H), 2.90-2.76 (m, 1H), 2.69-2.58 (m, 3H), 1.82-1.77 (m, 2H), 1.12 (d,J= 6.4 Hz, 3H).Examples 16 2,2- Difluoro -3-((1S,3R)-1-(5-((1-(3- Fluoropropyl ) Azetidine -3- base ) Amine ) Pyridine -2- base )-3- methyl -6-(1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base ) C -1- alcohol
Figure 02_image198
For preparationExamples 16 'S program:
Figure 02_image200
Compound14b (1.2 g, 2.48 mmol) in a mixture of DCE (10 mL) was added compound1E (560 mg, 2.98 mmol) and TFA (0.554 mL, 7.44 mmol), the resulting mixture was stirred at 12-18 °C for 16 hours. NaHCO3 The saturated aqueous solution was alkalized to adjust to pH=8, followed by extraction with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain the crude product, which was passed through preparative HPLC [Boston Green ODS, 40×150 mm, 10 μm, 120A Conditions: 90-100% B (A: water (0.1% TFA) B: CH3 CN); flow rate: 25 mL/min] purification. Use NaHCO for the fraction containing the desired compound3 The saturated aqueous solution was basified to adjust to pH=8 and extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain the compound as a yellow solid16a (1.0 g, 61% yield).LCMS: tR =1.116 min, in 5-95AB_220&254.lcm chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=653.3 [M+H+2]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.51 (d,J= 2.0 Hz, 1H), 7.62 (br t,J= 6.4 Hz, 4H), 7.56 (dd,J= 8.4, 2.4 Hz, 1H), 7.47-7.42 (m, 2H), 7.38 (t,J= 7.6 Hz, 4H), 7.15 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 8.4 Hz, 1H), 6.60-6.52 (m, 2H), 4.98 (s, 1H), 4.82 (br s, 1H), 3.91-3.69 (m, 2H), 3.45-3.37 (m, 1H), 3.25- 3.10 (m, 1H), 2.97-2.75 (m, 2H), 2.54 (dd,J=16.4 , 6.4 Hz, 1H), 1.05 (d,J= 6.4 Hz, 3H), 1.01 (s, 9H).
Figure 02_image202
To the compound under nitrogen16a (0.9 g, 1.38 mmol) to a mixture of 1,4-dioxane (10 mL) was added compound1F (0.995 g, 2.76 mmol), Brettphos Pd G3 (313 mg, 0.345 mmol), t-BuONa (1.19 g, 12.42 mmol). The resulting mixture was stirred under nitrogen at 80°C for 4 hours. Combine the reaction mixture with parallel batches of reactants (100 mg of compound16a ) Combined and filtered, the filtrate was concentrated in vacuo to obtain a residue, which was diluted with ethyl acetate (200 mL) and water (150 mL), the organic layer was extracted with ethyl acetate (200 mL×3), the combined organic The layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to obtain a brown color Solid compound16b (450 mg, 42% yield).LCMS: tR =0.837 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=703.5 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.77 (d,J= 2.8 Hz, 1H), 7.66-7.60 (m, 4H), 7.47-7.40 (m, 2H), 7.40-7.33 (m, 4H), 6.98 (d,J= 8.4 Hz, 1H), 6.66 (d,J= 8.4 Hz, 1H), 6.61 (dd,J= 8.4, 2.8 Hz, 1H), 6.53 (d,J= 2.4 Hz, 1H), 6.44 (dd,J= 8.4, 2.4 Hz, 1H), 4.90 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.06-3.97 (m, 1H), 3.94-3.82 (m, 2H), 3.77-3.66 (m, 3H), 3.46-3.38 (m, 1H), 3.13 (q,J= 14.4 Hz, 1H), 2.91-2.83 (m, 3H), 2.60 (t,J =7.2 Hz, 2H), 2.49 (dd,J= 16.4, 7.6 Hz, 1H), 1.82-169 (m, 2H), 1.05-1.01 (m, 12H).
Figure 02_image204
Compound16b (380 mg, 0.54 mmol) in dichloromethane (6 mL) was added Et3 N (0.194 mL, 1.32 mmol), followed by PhNTf2 (387 mg, 1.08 mmol). The resulting mixture was stirred at 13-23°C for 16 hours. Combine the reaction mixture with parallel batches of reactants (70 mg16b ) Combined and concentrated in vacuo to give a residue, which was diluted with dichloromethane (200 mL) and water (150 mL). The organic layer was extracted with dichloromethane (200 mL×3), and the combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (methanol/dichloromethane=0-10%) and further concentrated in high vacuum to give the compound as a yellow solid16c (450 mg, 75% yield).LCMS: tR =0.949 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=835.5 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.76 (d,J= 2.4 Hz, 1H), 7.64-7.60 (m, 4H), 7.49-7.33 (m, 6H), 7.24-7.18 (m, 2H), 7.02 (s, 1H), 6.94 (s, 1H), 6.64 (dd ,J= 8.4, 2.4 Hz, 1H), 4.97 (s, 1H), 4.45 (dt,J= 47.2, 6.0 Hz, 2H), 4.11 (br s, 2H), 3.91-3.80 (m, 3H), 3.71 (q,J= 12.0 Hz, 1H), 3.54-3.44 (m, 1H), 3.14-3.12 (m, 3H), 2.97 (br dd,J= 16.4, 4.0 Hz, 1H), 2.87-2.77 (m, 1H), 2.72 (t,J= 7.2 Hz, 2H), 2.58 (br dd,J= 16.4, 6.8 Hz, 1H), 1.84-1.70 (m, 2H), 1.07-0.96 (m, 12H).
Figure 02_image206
Under nitrogen at 16-25 ℃ to the compound16c (150 mg, 0.179 mmol), K2 CO3 (75 mg, 0.539 mmol) and Brettphos Pd G3 (25 mg, 0.0239 mmol) in 1,4-dioxane/H2 Add compound to the solution in O (5.5 mL, 10/1 v/v)14B (106 mg, 0.359 mmol). The mixture was stirred under nitrogen at 100°C for 16 hours. The reaction was concentrated in vacuo to give a residue, diluted with ethyl acetate (100 mL) and water (80 mL), and separated. The aqueous layer was extracted with ethyl acetate (100 mL×3), and the combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude material, which was passed through preparative TLC (methanol /Dichloromethane=1/10) purification to obtain the compound as a yellow solid16d (65 mg, 48% yield).LCMS: tR= 0.861 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=753.6 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.82-7.77 (m, 3H), 7.67-7.61 (m, 4H), 7.48-7.41 (m, 2H), 7.40-7.35 (m, 4H), 7.24 (s, 1H), 7.18 (br d,J= 8.0 Hz, 1H), 6.99 (d,J= 8.4 Hz, 1H), 6.86 (d,J= 8.0 Hz, 1H), 6.60 (dd,J= 8.4, 3.2 Hz, 1H), 4.97 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.05-3.98 (m, 1H), 3.97-3.82 (m, 2H), 3.73 (s, 1H), 3.72-3.68 (m, 2H), 3.55-3.45 (m, 1H) , 3.17 (q,J= 14.0 Hz, 1H), 3.00 (br dd,J= 16.0, 4.0 Hz, 1H), 2.92-2.83 (m, 3H), 2.64-2.56 (m, 3H), 1.78-1.72 (m, 2H), 1.07 (d,J= 6.8 Hz, 3H), 1.02 (s, 9H).
Figure 02_image208
Compound16d To a mixture of (60 mg, 0.079 mmol) in THF (3 mL) was added a TBAF solution (0.24 mL, 0.237 mmol, 1 M in THF), and the mixture was stirred at room temperature (12-21°C) for 4 hours. NaHCO3 The saturated aqueous solution was alkalized to adjust to pH=8 and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the crude material, which was purified by preparative TLC (methanol/dichloromethane=1/10) to obtain the product as a pale yellow oil, and then lyophilized to obtain the desired product as a yellow solidExamples 16 (18.0 mg, 43% yield).LCMS: tR =0.988 min in 10-80AB_3min_220&254_Agilent, XBrige Shield RP18 2.1×50mm, MS (ESI) m/z=515.3 [M+H]+ . 1 H NMR (400MHz, CD3 OD): δ=7.91 (br s, 2H), 7.79 (d,J= 2.4 Hz, 1H), 7.37 (s, 1H), 7.26 (br d,J= 8.0 Hz, 1H), 7.05 (d,J= 8.4 Hz, 1H), 6.92 (dd,J= 8.4, 2.8 Hz, 1H), 6.74 (d,J= 8.0 Hz, 1H), 4.83 (s, 1H), 4.47 (dt,J= 47.2, 6.0 Hz, 2H), 4.16-4.07 (m, 1H), 3.86 (br t,J= 7.2 Hz, 2H), 3.71 (q,J= 13.2 Hz, 1H), 3.59-3.48 (m, 2H), 3.20-3.12 (m, 2H), 3.07 (br s, 2H), 2.82-2.64 (m, 4H), 1.85-1.71 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H).HPLC: tR =3.02 min, in 10-80_CD_1.2ml.met, chromatography (XBridge Shield RP 18 2.1×50mm 5μm).SFC: tR =4.451 min. Method: Column: Chiralcel OD-3 100×4.6 mm I.D., 3 μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40℃.real Give example 17 6-((1S,3R)-8- fluorine -3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine
Figure 02_image210
For preparationExamples 17 'S program:
Figure 02_image212
At -70 ℃ within 10 minutes to the compound17a (4.0 g, 14 mmol) in THF (20 mL) was added n-BuLi (6.8 mL, 17 mmol, 2.5 M in hexane) dropwise. After stirring for 30 minutes, the compound was added dropwise at -70°C1A (3.3 g, 14 mmol) in THF (20 mL). The resulting mixture was stirred at -70°C for 2 hours. The reaction was then quenched with 1 N citric acid (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated in vacuo and the residue was purified by C18-flash chromatography with an elution gradient of 40% to 90% MeCN/water (0.02% FA). Evaporate the pure fractions to dryness to obtain the compound as a white solid17b (480 mg, 9.4% yield).LCMS: tR =1.95 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 360.4 [M+H]+ .
Figure 02_image214
Compound17b A solution of (460 mg, 1.3 mmol) in TFA (2 mL) was stirred at 20°C for 1 hour. The reaction mixture was then concentrated and the residue was purified by C18-flash chromatography with an elution gradient of 5% to 40% MeCN/water (0.02% FA). Evaporate the pure fractions to dryness to obtain the compound as a white solid17c (380 mg, 97% yield).LCMS: tR =1.32 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 260.2 [M+H]+ .
Figure 02_image216
Compound17c (350 mg, 1.1 mmol) and DIEA (290 mg, 2.2 mmol) in 1,4-dioxane (5 mL) were added CF3CH2OTf (520 mg, 2.2 mmol). The resulting mixture was stirred at 80°C for 5 hours. The mixture was concentrated in vacuo and the residue was purified by C18-flash chromatography with an elution gradient of 5% to 60% MeCN/water (0.02% FA). Evaporate the pure fractions to dryness to obtain the compound as a white solid17d (320 mg, 82% yield).LCMS: tR =1.44 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 342.4 [M+H]+ .
Figure 02_image218
Compound17d (320 mg, 0.94 mmol) in methanol (5 mL) was added Pd/C (64 mg, 10% by weight). The resulting mixture was stirred at 20°C for 16 hours. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by C18-flash chromatography with an elution gradient of 5% to 60% MeCN/water (0.02% FA). Evaporate the pure fractions to dryness to obtain the compound as a white solid17e (180 mg, 76%).LCMS: tR =0.96 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 252.2 [M+H]+ .
Figure 02_image220
Compound17e (180 mg, 0.72 mmol) in isopropanol (5 mL) was added compound1E (270 mg, 2.2 mmol) and TFA (245 mg, 2.2 mmol). The resulting mixture was stirred at 20° C. for 2 hours, then the mixture was concentrated in vacuo and the residue was purified by C18-flash chromatography with an elution gradient of 5% to 70% MeCN/water (0.02% FA). Evaporate the pure fractions to dryness to obtain the compound as a white solid17f (110 mg, 37%).LCMS: tR =1.81 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 419.2, 421.2 [M+H]+ . 1 H NMR (500 MHz, DMSO-d6): δ 9.88-9.59 (s, 1H), 8.54-8.53 (d, J=2.4 Hz, 1H), 8.06-8.03 (dd, J=2.4, 8.4 Hz, 1H), 7.42 -7.37 (d, J=8.5 Hz, 1H), 6.42-6.41 (d, J=2.2 Hz, 1H), 6.37-6.33 (dd, J=2.3, 11.3 Hz, 1H), 5.04-5.02 (s, 1H ), 3.60-3.51 (m, 1H), 3.09-3.01 (m, 2H), 2.59-2.55 (m, 2H), 1.02-0.99 (d, J=6.6 Hz, 3H).
Figure 02_image222
Compound17f To a mixture of (187 mg, 0.39 mmol) and Brettphos-Pd-G3 (24 mg, 0.026 mmol) in 1,4-dioxane (4 mL) was added sodium tert-butoxide (150 mg, 1.6 mmol). The resulting mixture was stirred under nitrogen at 70°C for 1 hour. The mixture was then directly purified by C18-flash chromatography with an elution gradient of 5% to 60% MeCN/water (0.02% TFA). The pure fractions were evaporated to dryness to obtain the compound as a yellow solid17g (120 mg, 87% yield).LCMS: tR =1.14 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 471.5 [M+H]+ .
Figure 02_image224
Compound17g (120 mg, 0.21 mmol) and triethylamine (62 mg, 0.62 mmol) in DCM (5 mL) were added PhNTf2 (147 mg, 0.41 mmol). The resulting mixture was stirred at 25°C for 16 hours. The mixture was then concentrated in vacuo and the residue was purified by C18-flash chromatography with an elution gradient of 5% to 80% MeCN/water (0.02% FA). Evaporate the pure fractions to dryness to obtain the compound as a white solid17h (90 mg, 59% yield).LCMS: tR =1.49 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 603.5 [M+H]+ .
Figure 02_image226
Compound17h (90 mg, 0.15 mmol), compound14B (88 mg, 0.30 mmol), Pd2(dba)3 (7 mg, 0.0075 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6- Potassium carbonate (62 mg, 0.45 mmol) was added to a mixture of phosphamantane (4 mg, 0.015 mmol) in 1,4-dioxane (3 mL) and water (1 mL). The resulting mixture was heated in the microwave at 120°C for 15 minutes. The mixture was then directly purified by C18-flash chromatography with an elution gradient of 5% to 60% MeCN/water (0.02% TFA). The pure fractions were evaporated to dryness to obtain the compound as a yellow solidExamples 17 (52 mg, 67% yield).LCMS: tR =1.14 min, in 3 min chromatography (3 min-5-95% MeCN/water (0.02% FA), Warters Acquity UPLC BEH C18 1.7μm, 2.1×50 mm, 40℃), MS (ESI) m/ z 521.5 [M+H]+ . 1 H NMR (500 MHz, DMSO-d6) : δ10.23-9.95 (d, J=58.8 Hz, 1H), 8.16-8.01 (s, 2H), 7.84-7.71 (dd, J=2.8, 23.6 Hz, 1H), 7.32-7.28 (d, J= 8.6 Hz, 1H), 7.28-7.26 (s, 1H), 7.24-7.18 (d, J=10.9 Hz, 1H), 7.16-7.05 (m, 1H), 6.98-6.58 (s, 1H), 5.11-5.08 (s, 1H), 4.59-4.55 (m, 2H), 4.49-4.46 (m, 1H), 4.35-4.30 (m, 2H), 4.09-4.07 (m, 1H), 3.90-3.87 (m, 1H) , 3.63-3.56 (m, 1H), 3.37-3.28 (m, 2H), 3.23-3.15 (m, 1H), 3.10-3.01 (m, 1H), 2.79-2.60 (m, 2H), 1.96-1.84 ( m, 2H), 1.06-0.98 (d, J=6.7 Hz, 3H).Examples 18 6-((1S,3R)-7- fluorine -3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine
Figure 02_image228
preparationExamples 18 The procedure is similar to preparationExamples 17 Program. The key steps are as follows:
Figure 02_image230
Compound18a (240 mg, 0.955 mmol) was added to the mixture in DCE (5 mL)1E (213 mg, 1.15 mmol), followed by the addition of TFA (327 mg, 2.87 mmol), and the resulting mixture was stirred at 90°C under nitrogen for 12 hours. NaHCO3 The saturated aqueous solution was alkalized to adjust to pH=8, followed by extraction with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was passed through a silica gel column chromatography (ethyl acetate/petroleum ether=0-20%) Purify to give the compound as a yellow solid18b (240 mg, 57% yield).LCMS: tR =2.395 min, in 10-80AB_3min_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=418.9 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.58-8.55 (m, 1H), 7.79 (dd,J= 8.4, 2.4 Hz, 1H), 7.40 (d,J= 8.4 Hz, 1H), 6.74-6.71 (m, 1H), 6.63 (d,J= 11.6 Hz, 1H), 4.91 (s, 1H), 3.45-3.36 (m, 1H), 3.31-3.12 (m, 2H), 3.08-2.97 (m, 1H), 2.52 (dd,J= 16.4, 6.4 Hz, 1H), 1.08 (d,J= 6.8 Hz, 3H).
Figure 02_image232
Compound18b (240 mg, 0.572 mmol) was added to a mixture of 1,4-dioxane (5 mL)13B (545 mg, 1.144 mmol), Brettphos-Pd-G3 (52 mg, 0.0572 mmol) and t-BuONa (495 mg, 5.148 mmol), the resulting mixture was stirred at 80°C under nitrogen for 4 hours. Combine the reaction mixture with parallel batches of reactants (300 mg of compound18b ) Combined and filtered, the filtrate was concentrated in vacuo to obtain a residue, which was diluted with dichloromethane (100 mL) and water (50 mL), the organic layer was extracted with dichloromethane (50 mL×3), the combined organic The layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to obtain pale Yellow oily compound18c (510 mg, 84% yield). Based on H NMR, the trans/cis ratio is about 3/1.LCMS: tR =0.797 min, in 10-80AB_2.0min_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=471.1 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.79 (d,J= 2.8 Hz, 1H), 7.21 (d,J= 8.4 Hz, 1H), 6.81 (dd,J =8.8, 2.8 Hz, 1H), 6.61 (d,J= 8.8 Hz, 1H), 6.51 (d,J =12.0 Hz, 1H), 4.80 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H), 4.16-4.11 (m, 2H), 3.81-3.68 (m, 2H), 3.47-3.38 (m, 1H), 3.19-3.13 (m, 1H), 3.05-2.87 (m, 4H), 2.70-2.59 (m, 2H), 2.45 (dd,J= 16.0, 6.4 Hz, 1H), 1.83-1.72 (m, 2H), 1.04 (d,J= 6.4 Hz, 3H).
Figure 02_image234
Compound18c (300 mg, 0.637 mmol) in dichloromethane (5 mL) was added Et3 N (195 mg, 1.911 mmol), followed by PhNTf2 (456 mg, 1.28 mmol), the mixture was stirred at 26-33°C for 4 hours. The reaction was concentrated in vacuo to obtain a residue, which was diluted with dichloromethane (100 mL) and water (50 mL), the organic layer was extracted with dichloromethane (30 mL×3), and the combined organic layer was washed with brine (50 mL) washed, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to obtain the compound as a yellow oil18d (370 mg, 96% yield).LCMS: tR =1.066 min, in 10-80AB_2min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=603.1 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) : δ=7.83 (d,J= 2.8 Hz, 1H), 7.18 (d,J =8.4 Hz, 1H), 7.07 (d,J= 7.2 Hz, 1H), 6.83-6.79 (m, 2H), 4.89 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H), 4.24-4.08 (m, 2H), 3.83-3.73 (m, 2H), 3.56-3.47 (m, 1H), 3.30-3.09 (m, 2H), 3.02-2.90 (m, 3H), 2.65 (t,J= 7.2 Hz, 2H), 2.58 (br dd,J= 16.4, 5.6 Hz, 1H), 1.86-1.67 (m, 2H), 1.08 (d,J= 6.8 Hz, 3H).
Figure 02_image236
At 27-36 ℃ to the compound18d (300 mg, 0.498 mmol), K2 CO3 (207 mg, 1.49 mmol) and Brettphos-Pd-G3 (45 mg, 0.0498 mmol) in dioxane-EtOH-H2 Add compound to the solution in O (5 mL, 5/2/1 v/v/v)14B (193 mg, 0.995 mmol). The mixture was stirred under nitrogen at 100°C for 12 hours. The reaction was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (100 mL) and water (50 mL), the aqueous layer was separated and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude material, which was purified by silica gel column chromatography (methanol/dichloromethane=0-10%), The crude product was obtained as a yellow solid (200 mg, 77% yield). The crude product passes through chiral SFC [column: DAICEL CHIRALPAK AD-H (250 mm×30 mm, 5 μm), condition: (0.1% NH3 ·H2 O) EtOH; start B: 30%, end B: 30%; flow rate: 50 mL/min] separation and additionally by acidic preparative HPLC in TFA system [Boston Green ODS 150×30 5u; conditions: 24-54% B(A: water (0.075% TFA) B: CH3 CN); flow rate: 25 mL/min] to obtain a yellow solidreal Give example 18 Title product (51.8 mg TFA salt, 72% yield).LCMS : tR =0.858 min, chromatography at 10-80AB_2min_220&254 (Xtimate C18, 2.1×30mm, 3μm), MS (ESI) m/z=521.1 [M+H]+ . 1 H NMR (400MHz, D2 O): δ=8.11 (s, 2H), 7.97-7.87 (m, 1H), 7.70-7.60 (m, 2H), 7.56 (br d,J= 7.6 Hz, 1H), 6.88 (br d,J= 11.2 Hz, 1H), 5.30 (s, 1H), 4.70-4.59 (m, 3H), 4.55 (br t,J= 5.6 Hz, 1H), 4.52-4.44 (m, 1H), 4.41-4.26 (m, 1H), 4.12-4.04 (m, 1H), 3.64-3.45 (m, 3H), 3.27 (br d,J= 5.2 Hz, 1H), 3.15-2.97 (m, 2H), 2.68 (dd,J= 16.4, 7.6 Hz, 1H), 2.16-1.97 (m, 2H), 1.13 (d,J= 6.0 Hz, 3H).HPLC: tR = 3.64 min in 10-80_CD_1.2ml. met, XBridge Shield RP 18 2.1×50mm 5μm.SFC: tR =4.710 min. Method: Column: Chiralcel AD-3 150×4.6 mm I.D., 3 μm; mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% in 5.5 min, followed by maintaining 5% B for 1.5 min; Flow rate: 2.5 mL/min.Examples 19 6-((1S,3R)-5- fluorine -3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine real Give example 19 The preparation is similar toreal Give example 18 Of preparation.real Give example 19 The analysis data is shown below:LCMS : tR =1.593 min, in 10-80AB_4min_220&254_Shimadzu chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=521.2 [M+H]+ .HPLC : tR = 2.85 min in 10-80_AB_1.2ml.met. chromatography (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CDCl3 ): δ=7.97- 7.73 (m, 3H), 7.27- 7.16 (m, 2H), 6.83 (dd,J =8.8, 2.8 Hz, 1H), 6.71 (d,J =8.4 Hz, 1H), 4.97 (s, 1H), 4.49 (dt,J =47.2, 6.0 Hz, 2H), 4.32 (d,J =7.2 Hz, 1H), 4.16- 4.04 (m, 1H), 3.71 (t,J =7.2 Hz, 2H), 3.55- 3.43 (m, 1H), 3.29- 3.14 (m, 1H), 3.05- 2.88 (m, 4H), 2.68- 2.57 (m, 3H), 1.85- 1.66 (m, 2H), 1.11 (d,J =6.8 Hz, 3H).SFC : tR =1.434 min; 100% purity. Method: Column: Chiralpak IC-3 150×4.6 mm I.D., 3 μm; mobile phase: 40% ethanol (0.05% DEA) in CO2 Medium; flow rate: 2.5 mL/min; column temperature: 35°C; ABPR: 1500 psi.real Give example 20 6-((1S,3R)-6-(3- fluorine -1H- Pyrazole -4- base )-3- methyl -2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine
Figure 02_image238
For preparationExamples 20 'S program: Compound5a (102.5 mg, 0.18 mmol) and compound20A (45.0 mg, 0.28 mmol) and Cs2 CO3 (176 mg, 0.54 mmol) in 1,4-dioxane/EtOH/H2 The stirred mixture in the mixed solvent of O (5.0 mL/2.0 mL/1.0 mL, 5/2/1 v/v/v) was degassed and purged with nitrogen three times, and Pd-118 (11.7 mg, 0.018 mmol) was quickly added The resulting mixture was degassed again and purged with nitrogen, and then stirred at 100°C for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude product (120 mg) as a brown oil, which was purified by preparative TLC (dichloromethane: methanol = 8:1) to give an impure product (50 mg) . The impure product was additionally passed through preparative HPLC [column: Boston Prime C18 150×30 mm 5 μm, condition: 50-80% (A: water/0.05% NH3 .H2 O, B: CH3 CN), flow rate: 25 mL/min] purification. Lyophilize the fraction containing the desired compound to obtain a white solidExamples 20 (3.0 mg, 3% yield).LCMS: tR =1.616 min, in 10-80AB_4min_220&254_Shimadzu (Xtimate C18 2.1×30 mm), MS (ESI) m/z=521.2 [M +H]+ .HPLC: tR =2.94 min, in 10-80AB_1.2ml.met; chromatography (Ultimate C18 3×50mm 3μm). 1 H NMR: (400MHz, CDCl3 ) δ=10.58 (br s, 1H), 7.83 (d,J= 2.4 Hz, 1H), 7.34 (d,J= 2.0 Hz, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.18 (d,J= 8.0 Hz, 1H), 6.89 (d,J= 8.8 Hz, 1H), 6.84 (dd,J= 8.8, 3.2 Hz, 1H), 4.96 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.18-4.08 (m, 2H), 3.78-3.73 (m, 2H), 3.55-3.45 (m, 1H), 3.30-3.07 (m, 2H), 3.03-2.89 (m, 3H), 2.66-2.56 (m, 3H), 1.85-1.74 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H).Examples twenty one N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(5- methyl -1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image240
For preparationExamples twenty one 'S program: In N2 Downward compound1h (200 mg, 0.34 mmol), potassium carbonate (140 mg, 1.02 mmol), Pd(dppf)Cl2 .CH2 Cl2 (27.7 mg, 0.034 mmol) and compound21A To a mixture of (107 mg, 0.51 mmol), a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL) was added. The resulting mixture was stirred at 100°C for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was treated with CH2 Cl2 (30 mL) and water (30 mL) diluted, the organic layer was separated, using CH2 Cl2 (20 mL×2) Extract the water layer. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (0-5% methanol/dichloromethane) to give 80 mg of impure product, which was additionally passed through Chiral SFC (column: DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm), condition: 35% EtOH (0.1% NH3. H2 O), flow rate: 50 mL/min) purification to obtain a yellow solidreal Give example twenty one (21.2 mg, 12% yield).LCMS: tR =2.800 min, in 0-60AB_7min_220&254_1500_Shimadzu.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=517.3 [M+H]+ .HPLC : tR =2.03 min in 10-80_AB_1.2ml. method (Ultimate C18 3×50mm 3μm).SFC: tR =1.812 min, 99.69% purity. Column: Chiralpak AD-3 50×3 mm I.D., 3 μm; mobile phase: A: CO2 ; B: Isopropanol (0.05% DEA); Gradient: B from 5% to 40% in 2.5 min and maintained at 40% for 0.35 min, followed by B from 40% to 5% in 0.15 min; Flow rate: 2.5 mL/min; column temperature: 40°C. 1 H NMR (400MHz, CDCl3 ) δ=7.86 (d,J= 2.4 Hz, 1H), 7.67 (br s, 1H), 7.20 (d,J= 8.8 Hz, 1H), 7.15 (s, 1H), 7.11 (d,J= 8.0 Hz, 1H), 6.89 (d,J= 8.4 Hz, 1H), 6.82 (dd,J= 8.4, 2.8 Hz, 1H), 4.94 (s, 1H), 4.51 (dt,J= 47.2, 6.0 Hz, 2H), 4.12 (br s, 2H), 3.78 (br s, 2H), 3.59-3.50 (m, 1H), 3.29-3.14 (m, 2H), 3.08-2.94 (m, 3H) , 2.72-2.59 (m, 3H), 2.43 (s, 3H), 1.84-1.77 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H).Examples twenty two N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(2H- Tetrazole -5- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image242
For preparationreal Give example twenty two 'S program:
Figure 02_image244
At room temperature (14-23 ℃) to the compound11e (1.80 g, 4.498 mmol) and CuI (1.03 g, 5.397 mmol) in acetonitrile (27 mL) was slowly added t-BuONO (809 μL, 6.747 mmol) dropwise. The reaction mixture was then stirred at 50°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (0-5% ethyl acetate/petroleum ether) to obtain the compound as a brown gum22a (570 mg, 80% purity according to LCMS, 19.8% yield).LCMS : tR =1.101 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=512.9 [M+2+H]+ . 1 H NMR (400 MHz, methanol-d 4):δ =8.52 (d,J =2.0 Hz, 1H), 7.90 (dd,J =8.4, 2.4 Hz, 1H), 7.54 (s, 1H), 7.43-7.34 (m, 2H), 6.63 (d,J =8.0 Hz, 1H), 4.97 (s, 1H), 3.50-3.35 (m, 2H), 3.09 (dd,J =16.4, 4.8 Hz, 1H), 3.02-2.89 (m, 1H), 2.64 (dd,J =16.8, 6.0 Hz, 1H), 1.08 (d,J =6.8 Hz, 3H).
Figure 02_image246
Compound22a (570 mg, 0.892 mmol, 80% purity), Zn(CN)2 (79 mg, 0.669 mmol) and Pd(PPh3 )4 A mixture of (129 mg, 0.112 mmol) in DMF (14 mL) was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (0-5% ethyl acetate/petroleum ether) To obtain the compound as colorless gum22b (200 mg, 54.6% yield).LCMS: tR =0.988 min, in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2mm), MS (ESI) m/z=410.1 [M+H]+ . 1 H NMR (400 MHz, methanol-d 4 ):δ =8.53 (d,J= 2.4 Hz, 1H), 7.94 (dd,J= 8.4, 2.4 Hz, 1H), 7.56 (s, 1H), 7.47-7.38 (m, 2H), 7.09 (d,J= 8.4 Hz, 1H), 5.13 (s, 1H), 3.54-3.40 (m, 2H), 3.13 (dd,J= 16.8, 4.4 Hz, 1H), 3.06-2.92 (m, 1H), 2.75 (dd,J= 16.8, 6.8 Hz, 1H), 1.10 (d,J= 6.4 Hz, 3H).
Figure 02_image248
ZnBr2 Pre-dry under vacuum and heating. Then the compound22b (200 mg, 0.488 mmol), NaN3 (200 mg, 0.488 mmol) and ZnBr2 A mixture of (220 mg, 0.976 mmol) in DMF (4 mL) was stirred at 130 °C under nitrogen for 16 hours. The reaction mixture was concentrated in vacuo. By silica gel column chromatography (0-20% MeOH (0.1% ammonium hydroxide) in CH2 Cl2 (0.1% ammonium hydroxide) purified the residue to obtain the compound as a yellow solid22c (240 mg, according to1 80% purity of H NMR, 86.8% yield).LCMS: tR =0.898 min in 5-95AB_1.5 min_220&254 chromatography (Merck RP18 2.5-2 mm), MS (ESI) m/z=455.0 [M+2+H]+ . 1 H NMR (400 MHz, methanol-d 4 ):δ =8.55 (d,J= 2.4 Hz, 1H), 7.94 (dd,J= 8.4, 2.4 Hz, 1H), 7.86 (s, 1H), 7.73 (d,J= 8.4 Hz, 1H), 7.44 (d,J= 8.4 Hz, 1H), 7.09 (d,J= 8.0 Hz, 1H), 5.13 (s, 1H), 3.57-3.41 (m, 2H), 3.24 (dd,J= 16.4, 4.4 Hz, 1H), 3.08-3.00 (m, 1H), 2.81 (dd,J= 16.4, 6.0 Hz, 1H), 1.13 (d,J= 6.4 Hz, 3H).
Figure 02_image250
The compound was added dropwise to a mixture of sodium hydride (17 mg, 0.424 mmol, 60% purity) in DMF (1.2 mL) at room temperature (16-21°C)22c (120 mg, 0.212 mmol, 80% purity) in DMF (1.2 mL). After stirring the reaction mixture under nitrogen at room temperature (16-21°C) for 0.5 hour, SEMCl (53 mg, 0.318 mmol) in DMF (0.5 mL) was added dropwise at room temperature (16-21°C) under nitrogen. In the solution. Next, the reaction mixture was stirred at 50°C under nitrogen for 2 hours to obtain a yellow suspension. The reaction mixture was poured into water (20 mL) with stirring. Combine the resulting mixture with the lead reactant (50 mg of compound22c )merge. The combined mixture was extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to obtain a crude product, which was purified by preparative TLC (petroleum ether/ethyl acetate=4:1) , To obtain all compounds that are colorless colloid22d with22d' Product of the mixture (60 mg). The average yield is about 34%.LCMS: tR =1.100 & 1.146 min, in 5-95AB_1.5 min_220 &254 chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=583.3 [M+H]+ .
Figure 02_image252
To the compound under nitrogen22d with22d' (70 mg, 0.120 mmol), Brettphos Pd G3 (16.3 mg, 0.018 mmol) andt- BuONa (115 mg, 1.20 mmol) was added to the mixture1F (86 mg, 0.144 mmol, 60% purity) in 1,4-dioxane (3.5 mL). The reaction mixture was then stirred at 80°C under nitrogen for 2 hours. Mix the reaction mixture with the experimental reactant (10 mg of compound22d with22d' )merge. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give crude product, which was passed through preparative TLC (CH2 Cl2 /MeOH=10:1) Purification to obtain all compounds that are pale yellow gum22e with22e' Product of the mixture (40 mg). The average yield is about 46%.LCMS: tR =0.868 min, in 5-95AB_1.5 min_220&254 chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z= 635.4 [M+H]+ .
Figure 02_image254
At room temperature (22-29 ℃) to the compound22e with22e' (35 mg, 0.055 mmol) in THF (2.1 mL) was added TBAF (1.4 mL, 1 M in THF). The reaction mixture was then stirred at 40°C under nitrogen for 2 hours. Next, the reaction mixture and the lead reactant (5 mg compound22e with22e' )merge. The combined mixture was saturated with NaHCO3 (30 mL) was diluted and extracted with ethyl acetate (10 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give the crude product, which was passed through preparative TLC (CH2 Cl2 /MeOH=5:1, (0.1% ammonium hydroxide)) purification to obtain 15 mg of impure product. Next, the product was additionally passed through chiral SFC [column: DAICEL CHIRALPAK AS-H (250 mm×30 mm, 5 μm); conditions: 30% EtOH (0.1% ammonium hydroxide) in CO2 Medium; flow rate: 65 mL/min] purified to obtain a pale yellow solidExamples twenty two (7.6 mg, 23.9% yield)LCMS: tR =2.585 min, in 0-60AB_7 min_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=505.1 [M+H]+ .HPLC: tR = 3.69 min in 0-60AB_1.2ml. met; column: Ultimate C18 3×50 mm 3 μm.SFC law : tR =3.003 min; 99.004% purity; column: Chiralpak AS-3 100×4.6mm I.D., 3μm; mobile phase: A: CO2 ; B: Ethanol (0.1% ethanolamine), gradient: B from 5% to 40% and maintained at 40% for 0.5 min in 4.5 min, followed by 5% B 1 min, flow rate: 2.8 mL/min; column temperature: 40℃. 1 H NMR (400 MHz, methanol-d 4 ):δ =7.88-7.80 (m, 2H), 7.68 (d,J= 8.0 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 7.00 (dd,J= 8.4, 2.4 Hz, 1H), 6.81 (d,J= 8.0 Hz, 1H), 4.93 (s, 1H), 4.64-4.42 (m, 5H), 4.02-3.88 (m, 2H), 3.63-3.50 (m, 1H), 3.43-3.32 (m, 4H), 3.04 -2.87 (m, 1H), 2.76 (dd,J= 16.4, 4.4 Hz, 1H), 2.09-1.91 (m, 2H), 1.11 (d,J= 6.4 Hz, 3H).Examples twenty three 5-((1S,3R)-1-(5-((1-(3- Fluoropropyl ) Azetidine -3- base ) Amine ) Pyridine -2- base )-3- methyl -2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -6-6- base ) Pyridine -2(1H)- ketone
Figure 02_image256
For preparationExamples twenty three 'S program: Compound1h (180 mg, 0.308 mmol), compound23A (51 mg, 0.369 mmol), Pd(dppf)Cl2 .CH2 Cl2 A mixture of (25 mg, 0.0308 mmol) and potassium carbonate (107 mg, 0.77 mmol) was purged with nitrogen, and then a mixed solvent of 1,4-dioxane and water (5.5 mL, v/v = 10) was added under nitrogen :1). The resulting mixture was stirred at 95°C under nitrogen for 2 hours. Mix the mixture with the pilot batch (30 mg compound1 ) Combined and concentrated under vacuum to obtain crude product, which was purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain 100 mg of crude product. It additionally passes chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm×30 mm, 5 μm); conditions: 35% IPA (0.1% ammonia) in CO2 Medium; flow rate: 50 mL/min) purification to obtain a white solidExamples twenty three (Peak 1, 27.4 mg, 100% chemical purity; 99.07% optical purity, 6.9% yield), together with a yellow solidExamples twenty three Cis isomer (peak 2, 5 mg, 100% chemical purity).Examples twenty three( peak 1) 'S spectrum : LCMS: tR =2.644 min, in 0-60AB_7min_220&254_Shimadzu.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=530.2 [M+H]+ .HPLC: tR = 3.80 min, in 0-60_AB_1.2ml.met, chromatography (Ultimate C18 3.0μm 3.0×50mm).SFC: tR = 2.108 min; 99.07% purity. Method: Column: Chiralpak AD-3 50×3 mm I.D., 3 μm; mobile phase: A: CO2 ; B: Isopropanol (0.05% DEA); Gradient: B from 5% to 40% in 2.5 min and maintained at 40% for 0.35 min, followed by B from 40% to 5% in 0.15 min; Flow rate: 2.5 mL/min; column temperature: 40°C. 1 H NMR (400MHz, CDCl3 ): δ=7.85 (d,J= 2.4 Hz, 1H), 7.75 (dd,J= 9.6, 2.8 Hz, 1H), 7.54 (d,J= 2.0 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 7.16 (s, 1H), 7.11 (d,J= 8.0 Hz, 1H), 6.93 (d,J= 8 Hz, 1H), 6.81 (dd,J= 8.4, 2.8 Hz, 1H), 6.66 (d,J= 9.6 Hz, 1H), 4.95 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H), 4.16-4.10 (m, 2H), 3.78-3.71 (m, 2H), 3.59-3.50 (m, 1H), 3.27-3.15 (m, 2H), 3.06-2.92 (m, 3H), 2.67-2.59 (m, 3H), 1.82-1.69 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H).Examples twenty three Cis isomer ( peak 2) Spectrum of isomers LCMS: tR =2.653 min, in 0-60AB_7.0min_220 &254_Shimadzu.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=530.1 [M+H]+ .HPLC: tR = 3.83 min, in 0-60_AB_1.2ml.met. chromatography (Ultimate C18 3.0μm 3.0×50mm). 1 H NMR (400MHz, MeOD): δ=7.91 (dd,J= 9.2, 2.4 Hz, 1H), 7.84 (d,J= 2.4 Hz, 1H), 7.65 (d,J= 2.8 Hz, 1H), 7.36 (d,J= 8.8 Hz, 1H), 7.29 (d,J= 1.2 Hz, 1H), 7.20 (dd,J= 8, 1.2 Hz, 1H), 7.04 (dd,J= 8.4, 2.8 Hz, 1H), 6.84 (d,J= 8.4 Hz, 1H), 6.62 (d,J= 9.6 Hz, 1H), 5.10 (s, 1H), 4.65-4.45 (m, 6H), 4.00 (brs, 2H), 3.46-3.37 (m, 3H), 3.23-3.18 (m, 1H), 2.92-2.78 (m, 2H), 2.09-2.03 (m, 1H), 2.00-1.94 (m, 1H), 1.31 (d,J= 6.0 Hz, 3H).Examples twenty four 4-((1S,3R)-1-(5-((1-(3- Fluoropropyl ) Azetidine -3- base ) Amine ) Pyridine -2- base )-3- methyl -2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -6-6- base ) Pyridine -2(1H)- ketone
Figure 02_image258
preparationExamples twenty four The procedure is similar to preparationExamples twenty three Program.Examples twenty four( peak 1) 'S spectrum LCMS: tR =2.717 min, in 0-60AB_7min_220& 254_Shimadzu.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=530.1 [M+H]+ .HPLC: tR =3.77 min, in 0-60_AB_1.2ml.met, chromatography (Ultimate C18 3.0μm 3.0×50mm).SFC: tR =2.083 min; 100% purity. Method: Column: Chiralpak AD-3 50×3 mm I.D., 3 μm; mobile phase: A: CO2 ; B: Isopropanol (0.05% DEA); Gradient: B from 5% to 40% in 2.5 min and maintained at 40% for 0.35 min, followed by B from 40% to 5% in 0.15 min; Flow rate: 2.5 mL/min; column temperature: 40°C. 1 H NMR (400MHz, CDCl3 ): δ=7.85 (d,J= 2.8 Hz, 1H), 7.39 (d,J= 7.2 Hz, 1H), 7.35 (s, 1H), 7.31-7.28 (m, 1H), 7.20 (d,J= 8.8 Hz, 1H), 6.98 (d,J= 8.0 Hz, 1H), 6.82 (dd,J= 8.4, 2.8 Hz, 1H), 6.76 (d,J= 1.2 Hz, 1H), 6.53 (dd,J= 6.8, 1.6 Hz, 1H), 4.97 (s, 1H), 4.50 (dt,J= 46.8, 5.6 Hz, 2H), 4.18-4.08 (m, 2H), 3.79-3.72 (m, 2H), 3.60-3.53 (m, 1H), 3.29-3.18 (m, 2H), 3.05-2.94 (m, 3H), 2.71-2.60 (m, 3H), 1.84-1.70 (m, 2H), 1.10 (d,J= 6.8 Hz, 3H).Examples twenty four Cis isomer ( peak 2) Spectrum of isomers LCMS: tR =2.757 min, in 0-60AB_7.0min_220& 254_Shimadzu.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=530.1 [M+H]+ .HPLC: tR = 3.78 min, in 0-60_AB_1.2ml.met. chromatography (Ultimate C18 3.0μm 3.0×50mm). 1 H NMR (400MHz, MeOD): δ=7.81 (d,J= 2.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.37 (d,J= 10 Hz, 1H), 7.30 (d,J= 8.8 Hz, 1H), 6.99 (dd,J= 8.8, 2.8 Hz, 1H), 6.90 (d,J= 8 Hz, 1H), 6.75-6.70 (m, 2H), 5.12 (s, 1H), 4.62 (brs, 3H), 4.48 (dt,J= 46.8, 5.6 Hz, 2H), 4.18-4.11 (m, 1H), 3.92-3.84 (m, 2H), 3.50-3.41 (m, 1H), 3.12-3.03 (m, 2H), 2.97-2.85 (m, 2H), 2.73 (brt,J= 7.2 Hz, 2H), 1.86-1.72 (m, 2H), 1.33 (d,J= 6.0 Hz, 3H).Examples 25 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-((1S,3R)-3- methyl -6-(1H-1,2,4- Triazole -3- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image260
For preparationExamples 25 'S program:
Figure 02_image262
At 0 ℃ to the compound22b (240 mg, 0.585 mmol) in a mixture of DMSO (6 mL) was added H2 O2 Aqueous solution (0.88 mL, 8.78 mmol, 30%), then NaOH aqueous solution (2.94 mL, 2.93 mmol, 1 M) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour to obtain a colorless solution. The mixture was mixed with Na at 0-10°C2 SO3 The saturated aqueous solution (50 mL) was quenched and extracted with ethyl acetate (50 ml×3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (0-60% ethyl acetate/petroleum ether) to obtain Yellow oily compound25a (270 mg, 93% purity, 100% yield).LCMS: tR =0.862 min, in 5-95AB_220&254 chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=430.0 [M+2+H]+ . 1 H NMR (400MHz, CD3 OD) δ=8.54 (d,J= 2.4 Hz, 1H), 7.93 (dd,J= 8.4, 2.0 Hz, 1H), 7.70 (d,J= 1.6 Hz, 1H), 7.57 (dd,J= 8.4, 2.0 Hz, 1H), 7.39 (d,J= 8.4 Hz, 1H), 6.96 (d,J= 8.0 Hz, 1H), 5.09 (s, 1H), 3.56-3.40 (m, 2H), 3.22 (dd,J= 16.4, 4.8 Hz, 1H), 3.00-2.92 (m, 1H), 2.76 (dd,J= 16.4, 6.0 Hz, 1H), 1.10 (d,J= 6.8 Hz, 3H).
Figure 02_image264
At 20-32 ℃ to the compound25a (230 mg, 0.497 mmol, 92.6% purity) DMF-DMA (330 μL, 2.49 mmol) was added to a mixture in toluene (5.8 mL). The mixture was degassed and purged with nitrogen 3 times, followed by stirring at 110°C under nitrogen for 1 hour to obtain a yellow solution. Concentrate the mixture directly in vacuo to give the compound25b (240.3 mg, 100% yield), which was used directly in the next step without further purification.LCMS: tR =0.811 min, in 5-95AB_220&254 chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=483.1 [M+H]+ .
Figure 02_image266
At 20-32 ℃ to the compound25b (240.3 mg, 0.497 mmol) in ethanol (5.8 mL) was added NH2 NH2 .H2 O (173 μL, 3.48 mmol, 98%). The mixture was degassed and purged with nitrogen 3 times, followed by stirring at 20-32°C under nitrogen for 1 hour to obtain a yellow solution. Combine the reactants with the leading batch (41.8 mg of compound25b ) Combine and dilute with ethyl acetate (100 mL). The organic phase was washed with brine (30 mL×3) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified twice by preparative TLC (dichloromethane: methanol=20:1), The compound is obtained as a yellow solid25c (95 mg, 36.0% average yield).LCMS: tR =0.870 min, in 5-95AB_220&254 chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=454.1 [M+2+H]+ .
Figure 02_image268
Compound25c (70 mg, 0.155 mmol), compound1F (119.5 mg, 0.232 mmol, 70% purity) andt- BuONa (148.7 mg, 1.55 mmol) in dioxane (3.5 mL) was added Brettphos-Pd-G3 (28.1 mg, 0.031 mmol). Use the mixture with N2 Purge, seal, and stir at 80°C under nitrogen for 2 hours to obtain a dark brown solution. The mixture was filtered and concentrated in vacuo to give a residue, which was purified by preparative TLC (dichloromethane: methanol = 12:1 with 1% ammonia) to give the product (45 mg), which was additionally passed through chiral SFC ( Column: DAICEL CHIRALCEL OD-H (250 mm×30 mm, 5 μm); Conditions: 30% EtOH (0.1% ammonia) in CO2 Medium; flow rate: 60 mL/min) separated to obtain a white solidExamples 25 Title product (Peak 2, 25.1 mg, 98.81% purity, 32% yield), together with a yellow solidExamples 25 Isomer (peak 1, 2.5 mg, 98.88% chemical purity).Examples 25( peak 2) of Spectrum : LCMS: tR =1.714 min, in 0-60AB_3min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=504.2 [M+H]+ .HPLC: tR = 2.40 min, in 10-80_AB_1.2ml.met. chromatography (Ultimate C18 3.0μm 3.0×50mm).SFC: tR =4.565 min; 98.81% purity. Method: Column: ChiralCel OD-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5.5 min and maintained at 40% for 3 min, followed by 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 40℃. 1 H NMR (400MHz, CDCl3 ): δ=8.04 (s, 1H), 7.78 (d,J= 2.4 Hz, 1H), 7.68 (s, 1H), 7.46 (br d,J= 7.2 Hz, 1H), 7.29 (s, 1H), 6.90 (d,J= 8.0 Hz, 1H), 6.85 (dd,J= 8.8, 2.8 Hz, 1H), 4.98 (s, 1H), 4.54 (t,J= 6.0 Hz, 1H), 4.48-4.36 (m, 2H), 4.20-4.05 (m, 1H), 3.74 (q,J= 6.0 Hz, 2H), 3.61-3.45 (m, 1H), 3.30-3.13 (m, 1H), 3.08-2.88 (m, 4H), 2.66 (t,J= 7.2 Hz, 2H), 2.56 (dd,J= 16.8, 7.2 Hz, 1H), 1.87-1.68 (m, 2H), 1.07 (d,J= 6.4 Hz, 3H).Examples 25 Isomer ( peak 1) of Spectrum : LCMS: tR =1.984 min, in 0-60AB_220&254 chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=504.3 [M+H]+ .HPLC: tR =2.43 min in 10-80_AB_1.2ml.met (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CDCl3 ): δ=8.15 (s, 1H), 7.89 (d,J= 2.4 Hz, 1H), 7.76 (s, 1H), 7.68-7.64 (m, 1H), 7.26 (s, 1H), 6.96 (d,J= 8.0 Hz, 1H), 6.82 (dd,J= 8.8, 2.4 Hz, 1H), 5.18 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.19-4.06 (m, 2H), 3.79-3.71 (m, 2H), 3.48-3.36 (m, 1H), 3.31-3.21 (m, 2H), 3.01-2.93 (m, 2H), 2.84-2.79 (m, 2H), 2.63 (t,J= 7.2 Hz, 2H), 1.85-1.71 (m, 2H), 1.31 (d,J= 6.0 Hz, 3H).Examples 26 6-(2-( Shuanghuan [1.1.1] E -1- base )-3- methyl -6-(1H- Pyrazole -4- base )-1,2,3,4- Tetrahydroisoquinoline -1- base )-N-(1-(3- Fluoropropyl ) Azetidine -3- base ) Pyridine -3- amine
Figure 02_image270
For preparationExamples 26 Trans isomer 1 withExamples 26 Trans isomer 2 'S program:
Figure 02_image272
Compound26A (1.146, 9.6 mmol) and Et3 A mixture of N (0.970 g, 9.6 mmol) in methanol (26 mL) was stirred at 50°C for 30 minutes, and then the compound was added26a (2.0 g, 8.0 mmol) in methanol (4 mL) and adjusted to pH=6 with AcOH. The resulting mixture was stirred at 50°C for 2 hours. Add NaBH to the mixture at 0°C3 CN (0.992 g, 16 mmol), and the mixture was stirred at 50° C. for 2.5 hours (as a white suspension). Cool the reaction to 20°C and use NaHCO3 The saturated aqueous solution (50 mL) was quenched and extracted with ethyl acetate (200 mL×3), the combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain crude The product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-30%) to obtain the compound as a white solid26b (2.5 g, 98% yield).LCMS: tR =0.737 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=317.6 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.26-7.19 (m, 2H), 7.16 (s, 1H), 6.86 (d,J= 7.2 Hz, 1H), 6.45 (br s, 1H), 3.06-3.02 (m, 1H), 2.73 (dd,J= 13.2, 6.4 Hz, 1H), 2.53 (dd,J= 13.2, 7.2 Hz, 1H), 2.37 (s, 1H), 1.85-1.75 (m, 6H), 1.53 (s, 9H), 1.05 (d,J= 6.4 Hz, 3H).
Figure 02_image274
At 14-24 ℃ to containing compounds26b (2.5 g, 7.9 mmol) in dichloromethane (30 mL) was added TFA (6 mL) and the mixture was stirred at 14-24°C for 4 hours. The reaction mixture was washed with NaHCO3 The saturated aqueous solution (50 mL) was quenched and extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain the crude product, which was passed through a silica gel column chromatography (washed with 0-50% ethyl acetate/petroleum ether) Mentioned) Purification to obtain the product as brown oil26c (1.3 g, 76%).LCMS: tR =1.673 min, in 10-80CD_220&254.lcm chromatography (A: Xtimate C18, 2.1 × 30 mm, 3 μm, B: XBrige Shield RP18 2.1 × 50 mm), MS (ESI) m/z=217.1 [M+ H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.08 (t,J= 7.6 Hz, 1H), 6.61-6.54 (m, 2H), 6.52 (s, 1H), 3.63 (br s, 2H), 3.01 (m, 1H), 2.66 (dd,J= 13.2, 6.8 Hz, 1H), 2.48 (dd,J= 13.2, 6.8 Hz, 1H), 2.37 (s, 1H), 1.81 (dq,J= 9.6, 1.6 Hz, 6H), 1.06 (d,J= 6.0 Hz, 3H).
Figure 02_image276
Seal the pipe to the compound at 15-23℃26c (300 mg, 1.39 mmol), compound1E (284 mg, 1.53 mmol) in CH3 Yb(OTf) was added to the mixture of CN (9 mL) and water (125.1 mg, 6.95 mmol)3 (17.5 mg, 0.0278 mmol). The mixture was stirred at 70°C for 2 hours (as a brown solution). Combine the reaction mixture with four parallel batches of reactants (each 300 mg of compound26c ) Combine and quench with water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain the crude product, which was passed through a silica gel flash column chromatography (with 0-10% ethyl acetate/petroleum ether) Elution) purification to obtain the compound as a brown solid26d (1.9 g, trans/cis based on H NMR=3.5/1, 73% average yield).LCMS: tR =1.146 min, in 10-80AB_220&254.lcm chromatography (Xtimate C18 2.1 × 30 mm), MS (ESI) m/z=383.9 [M+H]+ . 1 H NMR: (400MHz, CDCl3 ): δ=8.56 (d,J= 2.0 Hz, 1H), 7.62 (dd,J= 2.4, 8.4 Hz, 1H), 7.31 (d,J= 8.4 Hz, 1H), 6.72 (d,J= 8.4 Hz, 1H), 6.41 (s, 1H), 6.40-6.35 (m, 1H), 4.95 (s, 1H), 3.65-3.59 (m, 1H), 3.53 (br s, 2H), 3.29 (dd,J= 15.2, 4.8 Hz, 1H), 2.47 (d,J= 17.2 Hz, 1H), 2.23 (s, 1H), 1.76 (dd,J= 9.6, 1.2 Hz, 3H), 1.48 (dd,J=9.2, 1.6 Hz, 3H), 1.03 (d,J= 6.4 Hz, 3H).
Figure 02_image278
To the compound at 5 °C under nitrogen26d (700 mg, 1.82 mmol) in dichloromethane (8.4 mL) and water (7.0 mL) was added CH2 I2 (976 mg, 3.6 mmol), NaNO2 (628 mg, 9.1 mmol) in water (1.4 mL) and AcOH (2184 mg, 36.4 mmol). The resulting mixture was stirred at 20-25°C for 5 minutes, at which time the light brown solution changed to a black solution. After stirring for another 1 hour at 20-25°C, the reaction was mixed with parallel batches of the reaction (700 mg of compound26d ) Combine and dilute with ethyl acetate (20 mL), followed by NaHCO3 Saturated aqueous solution treatment to adjust to pH=9. The mixture was filtered and the filtrate was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo at 30° C. to obtain a crude product, which was passed through preparative TLC (petroleum ether/ethyl acetate=4/ 1) Purification to obtain the compound as a brown solid26e (540 mg, 30%).LCMS: tR =0.880 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=495.1 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.57 (d,J= 2.0 Hz, 1H), 7.64 (dd,J= 8.4, 2.4 Hz, 1H), 7.45 (s, 1H), 7.33 (br d,J= 8.4 Hz, 1H), 7.29 (d,J= 8.4 Hz, 1H), 6.72 (d,J= 8.4 Hz, 1H), 4.99 (s, 1H), 3.69-3.60 (m, 1H), 3.32 (dd,J= 15.6, 4.4 Hz, 1H), 2.54 (dd,J= 15.6, 2.0 Hz, 1H), 2.24 (s, 1H), 1.75 (dd,J= 9.6, 1.6 Hz, 3H), 1.48 (dd,J= 9.2, 1.6 Hz, 3H), 1.02 (d,J= 6.4 Hz, 3H).
Figure 02_image280
Compound26e (270 mg, 0.545 mmol), compound26B (211 mg, 0.708 mmol), Pd(PPh3 )4 (63 mg, 0.0545 mmol), Cs2 CO3 (357 mg, 1.09 mmol) and Et3 A mixture of N (110 mg, 1.09 mmol) in EtOH (5 mL) and water (1.1 mL) was stirred at 40 °C under nitrogen for 15 hours (as a brown solution). The reaction was diluted with ethyl acetate (10 mL) and water (5 mL). The mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to give the crude product, which was passed through silica gel flash column chromatography (0-15% ethyl acetate/petroleum ether) Elution) purification to obtain the product as a brown oil26f (200 mg, 64% yield).LCMS: tR =0.901 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=567.2 [M+H+2]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.62 (d,J= 2.4 Hz, 1H), 7.76 (s, 1H), 7.75 (s, 1H), 7.67 (dd,J= 8.4, 2.4 Hz, 1H), 7.36 (d,J= 8.4 Hz, 1H), 7.26 (s, 1H), 7.19 (d,J= 8.0 Hz, 1H), 7.00 (d,J= 8.0 Hz, 1H), 5.46 (s, 2H), 5.09 (s, 1H), 3.73-3.68 (m, 1H), 3.56 (t,J= 8.0 Hz, 2H), 3.42 (dd,J= 15.2, 4.8 Hz, 1H), 2.65 (d,J= 15.2 Hz, 1H), 2.28 (s, 1H), 1.81 (dd,J= 9.2, 1.2 Hz, 3H), 1.53 (dd,J= 9.2, 1.2 Hz, 3H), 1.08 (d,J= 6.4 Hz, 3H), 0.91 (t,J= 8.0 Hz, 2H), 0.00 (s, 9H).
Figure 02_image282
Compound26f (200 mg, 0.355 mmol), compound13B (253 mg, 0.53 mmol), BrettPhos-Pd-G3 A mixture of (64 mg, 0.071 mmol), t-BuONa (187 mg, 1.95 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. under nitrogen for 4 hours (as a black solution). NH44 Diluted with a saturated aqueous solution of Cl (15 mL) and extracted with ethyl acetate (50 mL×3), the combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The product was purified by silica gel column chromatography (eluted with 0-15% methanol/dichloromethane) to obtain the product as a brown solid26g (136 mg, 62% yield).LCMS: tR =1.747 min, in 10-80AB_220&254.lcm chromatography (Xtimate C18 2.1×30 mm), MS (ESI) m/z=617.4 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.8 Hz, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.21 (s, 1H), 7.14 (d,J= 8.4 Hz, 2H), 6.95 (d,J= 8.0 Hz, 1H), 6.73 (dd,J= 8.4, 2.8 Hz, 1H), 5.43 (s, 2H), 4.98 (s, 1H), 4.50 (dt,J= 46.8, 6.0 Hz, 2H), 4.12-4.06 (m, 1H), 3.97-3.93 (m, 1H), 3.78-3.71 (m, 2H), 3.68-3.65 (m, 1H), 3.55 (t,J= 8.0 Hz, 2H), 3.39 (dd,J= 4.8, 15.2 Hz, 1H), 2.95-2.88 (m, 2H), 2.66-2.54 (m, 3H), 2.22 (s, 1H), 1.83-1.71 (m, 5H), 1.50 (d,J= 8.8 Hz, 3H), 1.06 (d,J= 6.4 Hz, 3H), 0.90 (t,J= 8.0 Hz, 2H), -0.02 (s, 9H).
Figure 02_image284
Compound26g A mixture of (116 mg, 0.188 mmol) and TFA (2.0 mL) in dichloromethane (5.0 mL) was stirred at 21-25°C for 2.5 hours. Combine the reactants with the leading batch (10 mg of compound)26g ) Combine and use NaHCO3 The saturated aqueous solution was adjusted to pH=9, and extracted with dichloromethane (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain the crude product, which was passed through a silica gel column chromatography (eluted with 0-15% methanol/dichloromethane) ) Purification to obtain a brown solidExamples 26 Trans isomer 1 withExamples 26 Trans isomer 2 1:1 mixture (70 mg, 70% yield).LCMS: tR =0.640 min, in 5-95AB_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=487.3 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.4 Hz, 1H), 7.79 (s, 2H), 7.22 (s, 1H), 7.18-7.13 (m, 2H), 6.94 (d,J= 8.0 Hz, 1H), 6.76 (dd,J= 8.4, 2.8 Hz, 1H), 4.99 (s, 1H), 4.50 (dt,J= 47.2, 5.6 Hz, 2H), 4.38-4.23 (m, 1H), 4.21-4.15 (m, 1H), 3.88-3.80 (m, 2H), 3.70-3.63 (m, 1H), 3.38 (dd,J= 15.8, 4.8 Hz, 1H), 3.26-3.15 (m, 2H), 2.74 (t,J= 7.2 Hz, 2H), 2.60 (d,J= 15.2 Hz, 1H), 2.22 (s, 1H), 1.89-1.83 (m, 2H), 1.80-1.77 (m, 3H), 1.50 (dd,J= 9.2, 1.2 Hz, 3H), 1.07 (d,J= 6.4 Hz, 3H).For mixtures SFC: tR =4.115 min and 5.539 min. Method: Column: Chiralcel OD-3 100×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40℃. The obtained mixture (70 mg, 0.14 mmol) was passed through chiral SFC [Phenomenex-Amylose (250 mm×30 mm, 5 μm); conditions: EtOH (0.1% NH3 H2 O) to CO2 Medium; flow rate: 50 mL/min] separated to obtain a yellow solidExamples 26 Trans isomer 1 (19.2 mg, 27% yield, peak 1) and yellow solidExamples 26 Trans isomer 2 (19.4 mg, 27% yield, peak 2).Examples 26 Trans isomer 1 of Spectrum : LCMS: tR =1.796 min, in 0-60AB_4min_220&254.lcm chromatography (Xtimate C18 2.1×30 mm), MS (ESI) m/z=487.2 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.4 Hz, 1H), 7.78 (s, 2H), 7.21 (s, 1H), 7.15 (d,J= 8.4 Hz, 2H), 6.94 (d,J= 8.0 Hz, 1H), 6.73 (dd,J= 8.4, 2.4 Hz, 1H), 4.98 (s, 1H), 4.49 (dt,J = 47.2, 6.0 Hz, 2H), 4.17-3.98 (m, 2H), 3.73 (q,J= 6.8 Hz, 2H), 3.69-3.63 (m, 1H), 3.44-3.32 (m, 1H), 2.95-2.88 (m, 2H), 2.63-2.57 (m, 3H), 2.22 (s, 1H), 1.80 -1.72 (m, 5H), 1.50 (d,J= 9.2 Hz, 3H), 1.06 (d,J= 6.8 Hz, 3H).HPLC: tR =3.43 min in 0-60_AB_1.2ml.met, chromatography (Ultimate C18 3×50 mm 3μm).SFC: tR =4.111 min. Method: Column: Chiralcel OD-3 100×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% and maintained at 40% for 2.5 min in 4.5 min, followed by 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40℃.Examples 26 Trans isomer 2 of Spectrum : LCMS: tR =1.798 min, in 0-60AB_4min_220&254.lcm chromatography (Xtimate C18 2.1×30 mm), MS (ESI) m/z=487.2 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=7.88 (d,J= 2.4 Hz, 1H), 7.79 (s, 2H), 7.22 (s, 1H), 7.15 (d,J= 8.8 Hz, 2H), 6.95 (d,J= 8.4 Hz, 1H), 6.74 (dd,J= 8.4, 2.4 Hz, 1H), 4.99 (s, 1H), 4.50 (dt,J = 47.2, 6.0 Hz, 2H), 4.15-4.09 (m, 1H), 4.05-3.99 (m, 1H), 3.79-3.71 (m, 2H), 3.70-6.65 (m, 1H), 3.42-3.33 (m, 1H), 2.99-2.92 (m, 2H), 2.65-2.57 (m, 3H), 2.22 (s, 1H), 1.78-1.75 (m, 5H), 1.50 (d,J= 9.5 Hz, 3H), 1.07 (d,J= 6.4 Hz, 3H).HPLC: tR =3.44 min, in 0-60_AB_1.2ml.met, chromatography (Ultimate C18 3×50 mm 3 μm).SFC: tR =5.500 min. Method: Column: Chiralcel OD-3 100×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40℃.Examples 27 N-(1-(3- Fluoropropyl ) Azetidine -3- base )-6-(3- methyl -2-(3- Methyl bicyclo [1.1.1] E -1- base )-6-(1H- Pyrazole -4- base )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image286
preparationExamples 27 Trans isomer 1 withExamples 27 Trans isomer 2 The procedure is similar to preparationExamples 26 'S program: willExamples 27 Trans mixture (100 mg, 0.199 mmol) through chiral SFC [column: DAICEL CHIRALCEL OD (250 mm×30 mm, 5 μm); conditions: (0.1% NH3 .H2 O)IPA to CO2 Medium; flow rate: 50 mL/min] separated to obtain a yellow solidExamples 27 Trans isomer 1 (30.9 mg, 30%, peak 1) andExamples 27 Trans isomer 2 (32.8 mg, peak 2).Examples 27 Trans isomer 1 of Spectrum : LCMS: tR =1.960 min, in 0-60AB_4min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=501.2 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.89 (d,J= 2.8 Hz, 1H), 7.79 (s, 2H), 7.21 (s, 1H), 7.14 (d,J= 8.4 Hz, 2H), 6.94 (d,J= 8.4 Hz, 1H), 6.73 (dd,J= 8.4, 2.8 Hz, 1H), 4.95 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.16-4.07 (m, 1H), 4.03-4.00 (m, 1H), 3.75 (q,J= 6.4 Hz, 2H), 3.67-3.63 (m, 1H), 3.38 (dd,J =15.2, 4.8 Hz, 1H), 2.99-2.91 (m, 2H), 2.66-2.56 (m, 3H), 1.81-1.73 (m, 2H), 1.63 (d,J= 9.6 Hz, 3H), 1.35 (d,J= 9.2 Hz, 3H), 1.09 (s, 3H), 1.05 (d,J= 6.4 Hz, 3H).HPLC: tR = 3.67 min in 0-60_AB_1.2ml.met, chromatography (Ultimate C18 38 50 mm 3 μm).SFC: tR =2.494 min. Method: Column: ChiralPak IC-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: IPA (0.1% ethanolamine); Isocratic: 40% B; Flow rate: 2.5 mL/min; Column temperature: 40°C.Examples 27 Trans isomer 2 of Spectrum : LCMS: tR= 1.871 min, in 10-80CDAB_3.0min_220 & 254.lcm chromatography (A: Xtimate C18, 2.1×30 mm, 3 μm, B: XBrige Shield RP18 2.1×50mm), MS (ESI) m/z=501.3 [M+ H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.89 (d,J= 2.4 Hz, 1H), 7.79 (s, 2H), 7.21 (s, 1H), 7.15 (d,J= 8.4 Hz, 2H), 6.94 (d,J= 8.0 Hz, 1H), 6.73 (dd,J= 8.4, 2.4 Hz, 1H), 4.95 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 4.18-4.08 (m, 1H), 4.06-4.00 (m, 1H), 3.77 (q,J= 6.8 Hz, 2H), 3.65-3.63 (m, 1H), 3.39 (dd,J= 15.2, 4.4 Hz, 1H), 2.98-2.97 (m, 2H), 2.68-2.55 (m, 3H), 1.82-1.73 (m, 2H), 1.64 (d,J= 9.6 Hz, 3H), 1.35 (d,J= 9.2 Hz, 3H), 1.09 (s, 3H), 1.05 (d,J= 6.4 Hz, 3H).HPLC: tR = 3.67 min in 0-60_AB_1.2ml.met, chromatography (Ultimate C18 38 50 mm 3 μm).SFC: tR =3.609 min. Method: Column: ChiralPak IC-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: IPA (0.1% ethanolamine); Isocratic: 40% B; Flow rate: 2.5 mL/min; Column temperature: 40°C.Examples 28 N-((S)-1-(3- Fluoropropyl ) Pyrrolidine -3- base )-6-((1S,3R)-3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine
Figure 02_image288
For preparation28A 'S program: Compound28A_1 (0.3 g, 1.6 mmol) in THF (5 mL) was added an aqueous NaOH solution (0.64 mL, 3.2 mmol, 5 M), followed by the compound-containing1F_1a (184 μL, 1.7 mmol) in THF (1 mL). The resulting mixture was stirred at 20-28°C for 16 hours. The mixture was diluted with ethyl acetate (15 mL) and washed with NH4 The saturated aqueous solution of Cl (15 mL) was washed, and the aqueous layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (dichloromethane/methanol=97/3) to obtain the product as a yellow oil28A_2 (0.27 g, 68% yield). 1 H NMR (400MHz, CDCl3 ) δ=4.90 (br s, 1H), 4.52 (dt,J= 47.2, 5.6 Hz, 2H), 4.19 (br s, 1H), 2.90 (brs, 1H), 2.68-2.57 (m, 4H), 2.41-2.21 (m, 2H), 2.00-1.82 (m, 3H), 1.44 (s, 9H). Compound28A_2 (0.27 g, 1.09 mmol) in dichloromethane (4 mL) was added TFA (1 mL) dropwise. The reaction mixture was stirred at 21-28°C for 1 hour. Concentrate the reaction in vacuo to obtain the product as a yellow oil28A (0.66 g TFA salt, purity: 61.7%), which was used directly in the next step without further purification. 1 H NMR (400MHz, MeOD) δ=4.58 (dt,J = 47.2, 5.2 Hz, 2H), 4.21-4.07 (m, 1H), 3.93-3.40 (m, 6H), 2.69-2.56 (m, 1H), 2.28-2.09 (m, 3H). For preparationExamples 28 'S program:
Figure 02_image290
To the compound under nitrogen1f (350 mg, 0.87 mmol),28A (593 mg, 0.97 mmol, 61.7% purity) in a mixture of 1,4-dioxane (13 mL) was added Brettphos-Pd-G3 (80 mg, 0.087 mmol) and t-BuONa (835 mg, 8.7 mmol). The resulting mixture was stirred under nitrogen at 80°C for 2 hours. Mix the mixture with the pilot batch (40 mg compound1f ) Combine and filter through a pad of diatomaceous earth and concentrate the filtrate in vacuo to obtain the crude product, which is purified by silica gel column chromatography (0-6% methanol/dichloromethane) to obtain the compound as a yellow oil28a (370 mg, 81% yield).LCMS: tR =0.647 min, in 5-95AB_1.5min_220&254.lcm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=467.4 [M+H]+. 1 H NMR (400MHz, CDCl3 ): δ=7.82 (d,J= 2.4 Hz, 1H), 7.15 (d,J= 8.4 Hz, 1H), 6.79 (dd,J= 8.8, 2.8 Hz, 1H), 6.68 (d,J= 8.4 Hz, 1H), 6.51 (d,J =2.0 Hz, 1H), 6.47 (dd,J =8.0, 2.0 Hz, 1H), 4.85 (s, 1H), 4.52 (dt,J= 47.2, 5.6 Hz, 2H), 4.05 (brs, 1H), 3.49-3.42 (m, 1H), 3.23-2.90 (m, 4H), 2.84-2.66 (m, 4H), 2.55-2.44 (m, 2H) , 2.41-2.32 (m, 1H), 2.03-1.88 (m, 2H), 1.82-1.73 (m, 1H), 1.05 (d,J= 6.8 Hz, 3H).
Figure 02_image292
At room temperature (21-27 ℃) to the compound28a (320 mg, 0.687 mmol) in a mixture of dichloromethane (9 mL) was added triethylamine (277 mg, 2.75 mmol), followed by PhNTf2 (368 mg, 1.03 mmol). The reaction mixture was then stirred at 21-27°C for 16 hours. Mix the mixture with the pilot batch (50 mg compound28a ) Combined and diluted with dichloromethane (10 mL), the organic layer was washed with brine (15 mL×2), dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated in vacuo to obtain the crude product, which was passed through silica gel column chromatography (0-5% methanol/dichloromethane) purification to obtain the compound as a yellow oil28b (0.4 g, 84% yield, based on NMR with a small amount of Et3 N).LCMS: tR =0.848 min, in 5-95AB_1.5min_220 & 254.l cm chromatography (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=599.4 [M+H]+. 1 H NMR (400MHz, CDCl3 ): δ=7.87 (d,J= 2.8 Hz, 1H), 7.14 (d,J= 8.4 Hz, 1H), 7.03 (s, 1H), 6.98-6.95 (m, 2H), 6.86 (dd,J= 8.4, 2.8 Hz, 1H), 4.93 (s, 1H), 4.53 (dt,J= 47.2, 5.6 Hz, 2H), 4.09-4.00 (m, 1H), 3.58-3.50 (m, 1H), 3.26-3.18 (m, 2H), 3.05-2.92 (m, 2H), 2.85-2.49 (m, 6H), 2.43-2.32 (m, 1H), 2.02-1.88 (m, 2H), 1.81-1.74 (m, 1H), 1.08 (d,J= 6.8 Hz, 3H).
Figure 02_image294
Compound28b (170 mg, 0.283 mmol), compound14B (125 mg, 0.426 mmol), Pd(dppf)Cl2 .CH2 Cl2 A mixture of (23 mg, 0.0283 mmol) and potassium carbonate (98 mg, 0.707 mmol) was purged with nitrogen, followed by the addition of 1,4-dioxane and H under nitrogen2 O mixed solvent (5 mL, v/v=4:1). The resulting mixture was stirred at 95°C under nitrogen for 4 hours. Mix the mixture with the pilot batch (30 mg compound)28b ) Combine and concentrate under vacuum to get the crude product, which is purified by silica gel column chromatography (0-7% methanol/dichloromethane) to obtain 100 mg of chemically pure product. It is additionally chiral SFC (DAICEL CHIRALCEL OD-H (250 mm×30 mm, 5 μm); conditions: 30% EtOH (0.1% ammonia) in CO2 Medium; flow rate: 60 mL/min] purified to obtain a white solidExamples 28 (53.9 mg, 31% average yield).LCMS: tR =2.698 min, in 0-60AB_7min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=517.1 [M+H]+.HPLC: tR =3.91 min, in 0-60_AB_1.2ml.met. chromatography (Ultimate C18 3×50mm 3μm).SFC ( method 1): tR =3.494 min; 98.58% purity. Method: Column: Chiralpak AS-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5 min and from 40% to 5% within 0.5 min, maintaining B 5% for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C.SFC ( method 2): tR =3.073 min; 97.51% purity. Method: Column: Chiralcel OJ-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5 min and 40% to 5% B within 0.5 min, maintain B 5% for 1.5 min; Flow rate: 2.5 mL/min ; Column temperature: 35 ℃. 1 H NMR (400MHz, CDCl3 ): δ=7.89 (d,J= 2.8 Hz, 1H), 7.78 (s, 2H), 7.24 (s, 1H), 7.19 (d,J= 8.8 Hz, 2H), 6.89 (d,J= 8.0 Hz, 1H), 6.85 (dd,J= 8.8, 2.8 Hz, 1H), 4.93 (s, 1H), 4.52 (dt,J= 46.8, 5.6 Hz, 2H), 4.11-3.95 (m, 2H), 3.59-3.49 (m, 1H), 3.28-3.14 (m, 2H), 3.08-2.87 (m, 2H), 2.76-2.55 (m, 5H), 2.49-2.41 (m, 1H), 2.40-2.29 (m, 1H), 2.00-1.85 (m, 2H), 1.77-1.68 (m, 1H), 1.10 (d,J= 6.8 Hz, 3H).Examples 29 N-((R)-1-(3- Fluoropropyl ) Pyrrolidine -3- base )-6-((1S,3R)-3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- amine Examples 29 The synthesis is similar toExamples 28 Synthesis.Examples 29 The spectrum is:LCMS: tR =2.687 min, in 0-60AB_7min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=517.2 [M+H]+ .HPLC: tR =3.90 min in 0-60_AB_1.2ml.met. chromatography (Ultimate C18 3×50mm 3μm).SFC: tR = 3.408 min; 93.26% purity. Method: Column: Chiralpak AS-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5 min and from 40% to 5% within 0.5 min, maintaining B 5% for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C. 1 H NMR (400MHz, CDCl3 ): δ=7.89 (d,J= 2.8 Hz, 1H), 7.78 (s, 2H), 7.25 (s, 1H), 7.22-7.16 (m, 2H), 6.89 (d,J= 8.0 Hz, 1H), 6.85 (dd,J= 8.4, 2.8 Hz, 1H), 4.93 (s, 1H), 4.53 (dt,J= 47.6, 6.0 Hz, 2H), 4.11-3.95 (m, 2H), 3.59-3.49 (m, 1H), 3.28-3.14 (m, 2H), 3.08-2.97 (m, 2H), 2.95-2.86 (m, 1H), 2.76-2.58 (m, 5H), 2.47-2.40 (m, 1H), 2.40-2.29 (m, 1H), 2.00-1.85 (m, 2H), 1.77-1.68 (m, 2H), 1.10 ( d,J= 6.8 Hz, 3H).Examples 30 3-((1S,3R)-1-(2,6- Difluoro -4-(((S)-1-(3- Fluoropropyl ) Pyrrolidine -3- base ) Amine ) Phenyl )-3- methyl -6-(1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base )-2,2- Difluoropropene -1- alcohol Examples 30 The synthesis is similar toExamples 28 Synthesis.Examples 30 The spectrum is:LCMS: tR =1.831 min, in 10-80CD_3min_220& 254_Agilent.lcm chromatography (A: Xtimate C18 2.1×30mm, 3μm; B: XBrige Shield RP18 2.1×50mm), MS (ESI) m/z=564.3 [M+H]+ .HPLC: tR = 4.49 min in 10-80_AB_15MIN.met. chromatography (YMCpack-ODS AQ 150×4.6MM 5μm).SFC: tR = 2.920 min; 100% purity. Method: Column: Chiralcel OJ-3 100×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 4.5 min and maintained at 40% for 2.5 min, followed by 5% B 1 min; Flow rate: 2.8 mL/min; Column temperature: 40℃. 1 H NMR (400MHz, CD3 OD): δ=7.89 (s, 2H), 7.35-7.26 (m, 1H), 7.23 (d,J =8.0 Hz, 1H), 6.73 (d,J =8.0 Hz, 1H), 6.13 (d,J =12.4 Hz, 2H), 5.07 (s, 1H), 4.48 (dt,J =47.2, 6.0 Hz, 2H), 3.99-3.88 (m, 1H), 3.84-3.67 (m, 1H), 3.66-3.54 (m, 1H), 3.43-3.32 (m, 1H), 3.30-3.21 (1H ), 3.19-3.04 (m, 1H), 2.92 (dd,J =10.0, 7.2 Hz, 1H), 2.82-2.68 (m, 2H), 2.68-2.54 (m, 4H), 2.49 (dd,J = 9.6, 4.4 Hz, 1H), 2.37-2.23 (m, 1H), 1.99-1.81 (m, 2H), 1.75-1.62 (m, 1H), 1.05 (d,J =6.4 Hz, 3H).Examples 31 3- fluorine -N-(3-(6-((1S,3R)-3- methyl -6-(1H- Pyrazole -4- base )-2-(2,2,2- Trifluoroethyl )-1,2,3,4- Tetrahydroisoquinoline -1- base ) Pyridine -3- base ) Propyl ) C -1- amine
Figure 02_image296
For preparation31A 'S program: Compound31A_1 (5 g, 26.9 mmol) in a mixture of EtOH (60 mL) and THF (20 mL) was added NaBH4 (406 mg, 10.7 mmol). The reaction mixture was stirred at 1-7°C for 45 minutes and 2.5 mL of water was added. TLC showed that the desired product was observed. The reaction mixture was diluted with DCM (50 mL) and water (50 mL) and separated. The aqueous layer was extracted with DCM (50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether) to give the compound as a white solid31A_2 (5 g, 99% yield). 1 H NMR (400MHz, CDCl3 ): δ=8.63 (d,J= 2.0 Hz, 1H), 7.82 (dd,J= 8.4, 2.4 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 4.74 (d,J= 3.6 Hz, 2H), 3.34 (br s,J= 5.2 Hz, 1H). At 0 ℃ to the compound31A_2 (5 g, 26.6 mmol) in THF (90 mL) was added sodium hydride (1.6 g, 39.9 mmol). The mixture was stirred at 2-9°C for 30 minutes. Then DPTBSCl (8 g, 29.3 mmol) was added and the resulting mixture was stirred at 2-9 °C for 2 hours. TLC showed that the desired product was observed. The reaction was diluted with ethyl acetate (80 mL) and water (50 mL) and separated. The aqueous layer was extracted with ethyl acetate (80 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether) to give the compound as a colorless oil.31A_3 (9 g, 81% yield). 1 H NMR (400MHz, CDCl3 ): δ=8.54 (d,J= 2.0 Hz, 1H), 7.87 (dd,J= 8.4, 2.4 Hz, 1H), 7.69 (d,J= 7.6 Hz, 4H), 7.60 (d,J= 8.4 Hz, 1H), 7.46-7.37 (m, 6H), 4.83 (s, 2H), 1.14 (s, 9H). Compound31A_3 (1.66 g, 10.5 mmol) in THF (70 mL) was added 9-BBN (21 ml, 10.5 mmol, 0.5 M in THF), and the resulting mixture was stirred at room temperature (21-25°C) 2 hour. Add 0.6 mL of water to the mixture. To a 250 mL three-necked round bottom flask equipped with a mechanical stirrer was added tert-butyl allylcarbamate (3 g, 7.0 mmol), Cs under nitrogen2 CO3 (6.9 g, 21.0 mmol), Pd(dppf)Cl2 (258 mg, 0.35 mmol) and Ph3 As (117 mg, 0.35 mmol) in DMF (70 mL). The above reaction solution was added and stirred at 60°C for 15 hours. The reaction was diluted with ethyl acetate (100 mL) and water (100 mL), and then separated. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (0-65% ethyl acetate/petroleum ether) to give a yellow oil. compound of31A_4 (3.1 g, 88% yield).LCMS: tR =0.938 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=505.8 [M+H]+ . 1 H NMR (400MHz, CDCl3 ): δ=8.31 (d,J= 1.6 Hz, 1H), 7.69 (dd,J= 8.0, 1.6 Hz, 4H), 7.63-7.53 (m, 2H), 7.47-7.33 (m, 6H), 4.86 (s, 2H), 3.20-3.10 (m, 2H), 2.64 (t,J =8.0 Hz, 2H), 1.83-1.76 (m, 2H), 1.46 (s, 9H), 1.13 (s, 9H). Compound31A_4 (3.1 g, 6.15 mmol) in THF (30 mL) was added TBAF solution (12.3 mL, 12.3 mmol, 1 M in THF). The reaction mixture was stirred at 19-26°C for 15 hours. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL), and then separated. The aqueous layer was extracted with ethyl acetate (20 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-30% ethyl acetate/petroleum ether) to obtain a yellow oil. Chemical compound31A_5 (1 g, 62% yield).LCMS: tR =0.608 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=267.2 [M+H]+ . Compound31A_5 (1 g, 3.76 mmol) in DCM (20 mL) was added MnO2 (3.9 g, 45.12 mmol). The mixture was stirred at 18-28°C for 4 hours. The reaction was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (0-50% ethyl acetate. petroleum ether) to give the compound as a yellow oil31A (700 mg, 70% yield).LCMS: tR =0.753 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=265.2 [M+H]+ . 1 H NMR (400MHz, CDCl3): δ=10.06 (s, 1H), 8.63 (d,J =1.6 Hz, 1H), 7.91 (d,J =7.6 Hz, 1H), 7.70 (dd,J =7.6, 1.6 Hz, 1H), 3.20 (q,J= 6.4 Hz, 2H), 2.76 (t,J =7.6 Hz, 2H), 1.91-1.83 (m, 2H), 1.45 (s, 9H). For preparation31A 'S program:
Figure 02_image298
Compound31A (626 mg, 2.68 mmol) ati- Add compound to solution in PrOH (31 mL)1e (780 mg, 2.95 mmol) and TFA (916 mg, 8.04 mmol). The resulting mixture was stirred at 21-28°C for 3 hours. The reaction was washed with DCM (30 mL) and saturated NaHCO3 The solution (30 mL) was diluted and separated. The aqueous layer was extracted with DCM (30 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether) to give the compound as a yellow oil.31a (850 mg, 66% yield).LCMS: tR =0.823 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=480.7 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=8.30 (s, 1H), 7.47 (dd,J= 8.0, 1.6 Hz, 1H), 7.38 (d,J= 8.0 Hz, 1H), 6.67 (d,J= 8.4 Hz, 1H), 6.52 (s, 1H), 6.49-6.43 (m, 1H), 4.94 (s, 1H), 4.61 (s, 1H), 3.50-3.34 (m, 1H), 3.27-3.11 (m , 3H), 3.06 (dd,J= 16.4, 4.4 Hz, 1H), 3.01-2.85 (m, 1H), 2.61 (t,J= 7.6 Hz, 2H), 2.51 (dd,J= 16.4, 6.4 Hz, 1H), 1.87-1.77 (m, 2H), 1.45 (s, 10H), 1.05 (d,J= 6.4 Hz, 3H).
Figure 02_image300
Compound31a (550 mg, 1.15 mmol) in DCM (11 mL) was added Et3 N (232 mg, 2.3 mmol) and PhNTf2 (492 mg, 1.38 mmol). The resulting mixture was stirred at 22-29°C for 15 hours. The reaction was diluted with DCM (30 mL) and water (25 mL) and separated. The aqueous layer was extracted with DCM (30 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-20% ethyl acetate/petroleum ether) to give the compound as a yellow oil31b (560 mg, 79% yield).LCMS: tR =0.933 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=612.4 [M+H]+ .
Figure 02_image302
Compound31b (560 mg, 0.9 mmoL), potassium carbonate (397 mg, 1.35 mmol), Pd(dppf)Cl2 .CH2 Cl2 (73 mg, 0.09 mmol) and compound14B A solution of (397 mg, 1.35 mmol) in 1,4-dioxane (12 mL) and water (1.2 mL) was stirred under nitrogen at 100 °C for 15 hours. The reaction was diluted with DCM (30 mL) and water (20 mL) and separated. The aqueous layer was extracted with DCM (30 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether) to give the compound as a yellow oil.31c (380 mg, 79% yield).LCMS: tR =0.803 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=530.4 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=8.27 (d,J= 1.6 Hz, 1H), 7.71 (s, 2H), 7.42-7.38 (m, 1H), 7.30 (d,J= 8.4 Hz, 1H), 7.18 (s, 1H), 7.12 (d,J= 7.6 Hz, 1H), 6.83 (d,J= 8.0 Hz, 1H), 4.95 (s, 1H), 4.52 (s, 1H), 3.54-3.40 (m, 1H), 3.25-3.15 (m, 1H), 3.20-3.13 (m, 3H), 2.99-2.85 (m, 1H), 2.62-2.52 (m, 3H), 1.77-1.69 (m , 2H), 1.37 (s, 9H), 1.03 (d,J= 6.4 Hz, 3H)
Figure 02_image304
to31c (380 mg, 0.718 mmol) in DCM (4 mL) was added HCl/MeOH (4 mL, 4 M), and the mixture was stirred at room temperature (22-24° C.) for 2 hours. The mixture was saturated with Na2 CO3 The solution was adjusted to pH=9, and then the mixture was extracted with DCM (5 mL×3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the compound as a brown oil31d (290 mg, 94% yield).LCMS: tR =0.658 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=430.3 [M+H]+ . 1 H NMR (400MHz, MeOD) δ=8.31 (d,J= 1.6 Hz, 1H), 7.91 (s, 2H), 7.63 (dd,J = 8.0, 2.0 Hz, 1H), 7.39 (s, 1H), 7.33 (d,J= 8.0 Hz, 1H), 7.25 (dd,J= 8.0, 1.2 Hz, 1H), 6.74 (d,J= 8.4 Hz, 1H), 4.97 (s, 1H), 3.58-3.50 (m, 1H), 3.44-3.35 (m, 1H), 3.30-3.26 (m, 1H), 3.01-2.88 (m, 1H), 2.74 -2.62 (m, 5H), 1.82-1.74 (m , 2H), 1.10 (d,J= 6.8 Hz, 3H)
Figure 02_image306
Compound31d (320 mg, 0.745 mmol) in DMF (10 mL) was added DIEA (192 mg, 1.488 mmol) and compound1F_1a (140 mg, 0.745 mmol). The resulting mixture was stirred at 20-28°C for 15 hours. The reaction was diluted with DCM (20 mL) and water (20 mL) and separated. The aqueous layer was extracted with DCM (10 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain 120 mg of impure product, which was additionally passed through SFC (column: Phenomenex-Amylose- 1(250 mm×30 mm, 5 μm), condition: 40% EtOH (0.1% NH3 H2 O), flow rate: 50 mL/min) purification to obtain a yellow solidExamples 31 (4.67 min, 38.6 mg) and yellow solidExamples 31 Cis isomer (5.17 min, 4.2 mg).Examples 31 'S spectrum : LCMS: tR =0.688 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=490.4 [M+H]+ .SFC: tR =4.679 min; 97.34% purity. Method: Column: Chiralpak AD-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5 min and maintained at 40% for 2.5 min, followed by 5% B for 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.HPLC : tR =2.77 min in 10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, MEOD) δ=8.32 (d,J= 1.2 Hz, 1H), 7.91 (s, 2H), 7.64 (dd,J= 8.4, 2.0 Hz, 1H), 7.39 (s, 1H), 7.34 (d,J= 8.4 Hz, 1H), 7.26 (d,J= 9.2 Hz, 1H), 6.75 (d,J= 8.0 Hz, 1H), 4.97 (s, 1H), 4.50 (dt,J= 47.2, 6.0 Hz, 2H), 3.64-3.49 (m, 1H), 3.48-3.35 (m, 1H), 3.30-3.24 (m, 1H), 2.87-3.07 (m, 1H), 2.74-2.61 (m, 7H), 1.96-1.88 (m, 1H), 1.88-1.78 (m, 3H), 1.10 (d,J= 6.8 Hz, 3H).Examples 31 Spectrum of cis isomer : LCMS: tR =0.683 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=490.4 [M+H]+ .S FC: tR =5.179 min; 90.59% purity. Method: Column: Chiralpak AD-3 150×4.6mm I.D., 3μm, mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5 min and maintained at 40% for 2.5 min, followed by 5% B for 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35℃.HPLC : tR =2.69 min in 10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, MeOD) δ=8.33 (d,J= 2.0 Hz, 1H), 7.90 (s, 2H), 7.68 (dd,J =8.0, 2.4 Hz, 1H), 7.54 (d,J= 8.0 Hz, 1H), 7.35 (s, 1H), 7.27 (dd,J= 8.0, 1.6 Hz, 1H), 6.84 (d,J= 8.0 Hz, 1H), 5.15 (s, 1H), 4.51 (dt,J =47.6, 6.0 Hz, 2H), 3.48-3.36 (m, 2H), 3.25-5.17 (m, 1H), 2.89-2.70 (m, 8H), 2.01-1.84 (m, 4H), 1.33 (d,J= 6.0 Hz, 3H).Examples 32 3-((1S,3R)-1-(2,6- Difluoro -4-(3-((3- Fluoropropyl ) Amine )-1- Hydroxypropyl ) Phenyl )-3- methyl -6-(1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base )-2,2- Difluoropropene -1- alcohol
Figure 02_image308
For preparation32A 'S program: Compound32A_1 (10 g, 133 mmol) in DMF (70 mL) was added DIEA (34.3 g, 266 mmol) and compound1F_1a (27.6 g, 146 mmol). The mixture was stirred at room temperature (24-32°C) for 15 hours. Then DIEA (17.1 g, 133 mmol) and Boc2 O (29 g, 133 mmol) was added to the above mixture and stirred at room temperature (24-32°C) for another 15 hours. The reaction was diluted with ethyl acetate (100 mL) and water (100 mL) and separated. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether) to give a yellow oil. compound of32A_2 (10.5 g, 33% yield). 1 H NMR (400MHz, CDCl3 ) δ=4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.81 (s, 1H), 3.53 (br s, 2H), 3.40-3.30 (m, 4H), 3.26 (t,J= 6.0 Hz, 1H), 1.98-1.77 (m, 2H), 1.73-1.60 (m, 2H), 1.43 (s, 9H). At 0 ℃ to the compound32A_2 (10.5 g, 44.6 mmol) in dichloromethane (100 mL) was added Dess-Martin reagent (28.4 g, 67.0 mmol). The mixture was stirred at room temperature (24-29°C) for 2 hours. The reaction was mixed with dichloromethane (50 mL) and NaHCO3 And Na2 SO3 The saturated solution of the mixture (v/v: 3/1, 100 mL) was diluted and separated. The aqueous layer was extracted with dichloromethane (100 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether) to give the compound as a colorless oil.32A_3 (7 g, 67% yield). 1 H NMR (400MHz, CDCl3 ) δ=9.78 (t,J= 1.6 Hz, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.52 (d,J= 6.4 Hz, 2H), 3.32 (t,J= 6.8 Hz, 2H), 2.70 (t,J= 6.0 Hz, 2H), 2.01-1.79 (m, 2H), 1.43 (s, 9H). To the compound at 0 °C under nitrogen32A_4 (3.58 g, 12.1 mmol) in THF (20 mL) was added dropwisei- PrMgCl solution (7.3 mL, 14.5 mmol, 2 M in THF). The reaction was stirred at room temperature (27-32°C) for 1 hour. Next, the compound32A_3 (3.39 g, 14.5 mmol) was added dropwise to the above reaction. Thereafter, the reaction was stirred at room temperature (27-32°C) under nitrogen for 2 hours. Use the mixture with NH4 The saturated aqueous Cl solution was quenched to pH=7. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (10-30% ethyl acetate/petroleum ether) to give a colorless oil. compound of32A_5 (2.88 g, 53% yield). 1 H NMR (400MHz, CDCl3 ): δ=6.91 (d,J= 9.2 Hz, 2H), 5.71 (s, 1H), 4.49 (dt,J= 47.2, 5.6 Hz, 2H), 4.52-4.45 (m, 1H), 3.82-3.70 (m, 2H), 3.66-3.55 (m, 2H), 3.50-3.26 (m, 4H), 2.03-1.88 (m, 4H), 1.48 (s, 9H), 1.25 (t,J= 6.8 Hz, 6H). Compound32A_5 A solution of (3.5 g, 7.79 mmol) and PPTS (783 mg, 3.89 mmol) in acetone (90 mL) and water (9 mL) was heated at 60 °C under nitrogen for 16 hours. The reaction mixture was concentrated in vacuo to obtain a residue. The residue was diluted with water (90 mL) and ethyl acetate (100 mL). After separation, the aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (10-20% ethyl acetate/petroleum ether) to give the compound as a brown solid32A (2.26 g, 77% yield).LCMS: tR =0.863 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=276.1 [M+H-100]+ . 1 H NMR (400MHz, CDCl3 ): δ=10.31 (s, 1H), 7.03 (d,J= 10.0 Hz, 2H), 4.67-4.36 (m, 4H), 3.57-3.02 (m, 4H), 2.03-1.86 (m, 4H), 1.48 (s, 9H). For preparationExamples 32 isomer 1 withreal Give example 32 isomer 2 'S program:
Figure 02_image310
Compound32a (800 mg, 1.66 mmol) and compound32A (624 mg, 1.66 mmol) in AcOH (6 mL) was added water (149 mg, 8.29 mmol), and the resulting mixture was stirred at 80° C. under nitrogen for one hour. Pour the reaction into NaHCO3 (20 mL) and a saturated aqueous solution of brine (25 mL) were extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (10-50% ethyl acetate/petroleum ether) to give the compound as a yellow oil.32b (900 mg, 64% yield).LCMS: tR =1.043 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=840.7 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.66-7.59 (m, 4H), 7.45-7.38 (m, 6H), 6.75-6.65 (m, 2H), 6.49 (dd,J= 7.6, 0.8 Hz, 1H), 6.43 (d,J= 2.0 Hz, 1H), 6.38-6.35 (m, 1H), 5.14 (s, 1H), 4.48 (dt,J= 47.2, 5.6 Hz 2H), 4.46-4.42 (m, 1H), 4.00-3.86 (m, 1H), 3.84-3.80 (m, 1H), 3.56-3.36 (m, 4H), 3.19-3.06 (m, 3H ), 2.77-2.65 (m, 1H), 2.42 (dd,J= 15.6, 3.6 Hz, 1H), 2.01-1.75 (m, 4H), 1.47 (s, 9H), 1.03 (s, 9H), 1.02 (d,J =6.0 Hz, 3H).
Figure 02_image312
At 0 ℃ to the compound32b (1.7 g, 2.02 mmol), TsOH (1.04 g, 6.06 mmol) in CH3 Add NaNO to the stirred mixture in CN (50 mL)2 (279 mg, 4.04 mmol) and KI (838 mg, 5.05 mmol) in water (10 mL). The mixture was stirred at room temperature (27-36°C) under nitrogen for 3 hours to obtain a brown solution. NaHCO3 The saturated aqueous solution (30 mL) was quenched and extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-20% ethyl acetate/petroleum ether) to give the compound as a yellow solid32c (860 mg, 45% yield). 1 H NMR (400MHz, CDCl3 ) δ=7.65-7.57 (m, 4H), 7.48-7.34 (m, 8H), 6.80-6.65 (m, 2H), 6.46 (d,J= 8.0 Hz, 1H), 5.17 (s, 1H), 4.48 (dt,J= 47.2, 5.6 Hz, 2H), 4.47-4.42 (m, 1H), 3.98-3.74 (m, 2H), 3.65-3.34 (m, 3H), 3.27-2.97 (m, 4H), 2.86-2.59 (m, 1H), 2.48 (dd,J= 14.0, 4.0 Hz, 1H), 2.05-1.64 (m, 4H), 1.47 (s, 9H), 1.04-0.99 (m, 12H).
Figure 02_image314
At room temperature (27-37 ℃) to the compound32c (360 mg, 0.053 mmol) and compound14B (223 mg, 0.758 mmol) in 1,4-dioxane (3.5 mL) was added K2 CO3 (209 mg, 1.516 mmol), followed by water (0.7 mL) and EtOH (1.4 mL), followed by rapid addition of Pd(dppf)Cl2 .CH2 Cl2 (46 mg, 0.057 mmol). After degassing and purging with nitrogen three times, the resulting mixture was stirred at 70°C under nitrogen for 16 hours. The reaction mixture was diluted with water (20 mL) and washed with CH2 Cl2 (30 mL×2) extraction. The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether) to give the compound as a yellow solid32d (220 mg, 65% yield).LCMS: tR =1.153 min in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=891.8 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.82 (s, 2H), 7.68-7.58 (m, 4H), 7.48-7.35 (m, 6H), 7.24 (d,J= 0.8 Hz 1H), 7.16 (d,J= 8.4 Hz, 1H), 6.80-6.70 (m, 3H), 5.25 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 4.48-4.42 (m, 1H), 4.03-3.78 (m, 2H), 3.67-3.39 (m, 3H), 3.32-2.96 (m, 4H), 2.83-2.66 (m, 1H), 2.57 (dd,J= 16.0, 4.0 Hz, 1H), 2.02-1.79 (m, 4H), 1.47 (s, 9H), 1.09-0.99 (m, 12H).
Figure 02_image316
Compound32d A solution of (220 mg, 0.247 mmol) in TFA (1 mL) and dichloromethane (3 mL) was stirred at room temperature (26-34°C) under nitrogen for one hour. Mix the mixture with Na2 CO3 The saturated aqueous solution (20 mL) was neutralized and extracted with dichloromethane (30 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound as a yellow solid32e (170 mg, 87% yield).LCMS: tR =0.968 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=791.6 [M+H]+ .
Figure 02_image318
To the compound under nitrogen32e (150 mg, 0.189 mmol) in THF (3 mL) was added TBAF (0.38 mL, 0.379 mmol, 1 M in THF), and the resulting mixture was stirred at room temperature (27-34° C.) for 2 hours. The reaction was diluted with dichloromethane (20 mL) and water (20 mL) and separated. The aqueous layer was extracted with dichloromethane (10 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-10% methanol/dichloromethane) to obtain 100 mg of crude product, which was additionally passed through chiral SFC (column: Phenomenex-Amylose -1 (250 mm×30 mm, 5 μm), condition: 30% EtOH (0.1% NH3. H2 O), flow rate: 50 mL/min) purification to obtain a white solidExamples 32 isomer 1 (15.5 mg) and yellow solidExamples 32 isomer 2 (22.4 mg). The overall yield is 39%.Examples 32 isomer 1 of Spectrum : LCMS: tR =0.733 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=553.4 [M+H]+ .SFC: tR =4.752 min; 92.42% purity. Method: Column: Chiralpak AD-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.1% ethanolamine); Gradient: B from 5% to 40% in 5.5 min, followed by maintaining 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C.HPLC : tR =3.02 min in 10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CD3 OD) δ=7.90 (s, 2H), 7.34 (s, 1H), 7.23 (d,J= 8.0 Hz, 1H), 6.95 (d,J= 10.0 Hz, 2H), 6.69 (d,J= 8.0 Hz, 1H), 5.25 (s, 1H), 4.75 (d,J =4.8 Hz, 1h), 4.59-4.56 (m, 1H), 4.45 (t,J= 5.6 Hz, 1H), 3.80-3.56 (m, 2H), 3.45-3.35 (m, 2H), 3.24-3.08 (m, 1H), 2.84-2.74 (m, 4H), 2.68 (dd,J= 15.6, 4.0 Hz, 2H), 2.02-1.81 (m, 4H), 1.40-1.28 (m, 1H), 1.07 (d,J= 6.4 Hz, 3H).Examples 32 isomer 2 of Spectrum : LCMS: tR =0.738 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=553.4 [M+H]+ .SFC: tR = 4.941 min; 83.59% purity. Method: Column: Chiralpak AD-3 150×4.6mm I.D., 3μm, mobile phase: A: CO2 ; B: Ethanol (0.1% ethanolamine); Gradient: B from 5% to 40% in 5.5 min, followed by maintaining 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C.HPLC : tR =3.02 min in 10-80_AB_1.2ml METHOD (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CD3 OD) δ=7.89 (s, 2H), 7.34 (s, 1H), 7.23 (d,J= 6.8 Hz, 1H), 6.98 (d,J= 10.0 Hz, 2H), 6.68 (d,J= 8.0 Hz, 1H), 5.26 (s, 1H), 4.90 (s, 1H), 4.58 (dt,J= 47.2, 5.6 Hz, 2H), 3.78-3.56 (m, 2H), 3.47-3.32 (m, 2H), 3.22-3.06 (m, 5H), 2.78-2.62 (m, 2H), 2.17-1.93 (m, 4H), 1.07 (d,J= 6.4 Hz, 3H).Examples 33 3-((1S,3R)-1-(2,6- Difluoro -4-(1- fluorine -3-((3- Fluoropropyl ) Amine ) Propyl ) Phenyl )-3- methyl -6-(1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base )-2,2- Difluoropropene -1- alcohol
Figure 02_image320
For preparationExamples 33 isomer 1 withExamples 33 isomer 2 'S program:
Figure 02_image322
At 0 ℃ to the compound32c (500 mg, 0.526 mmol) in dichloromethane (15 mL) was added DAST (593 mg, 3.682 mmol). The mixture was stirred at room temperature (26-31°C) for 2 hours. The reaction mixture was washed with NaHCO3 Saturated aqueous solution (20 mL) and dichloromethane (20 mL×2) were diluted and then separated. The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (10-50% ethyl acetate/petroleum ether) to give a yellow solid compound of33a (110 mg, 22% yield).LCMS: tR =1.357 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=953.6 [M+H]+ . 1 H NMR (400MHz, CDCl3 ) δ=7.65-7.57 (m, 4H), 7.51-7.31 (m, 8H), 6.69 (t,J= 9.2 Hz, 2H), 6.46 (d,J= 8.0 Hz, 1H), 5.45-5.30 (m, 1H), 5.20 (s, 1H), 4.46(dt,J= 47.6, 5.6 Hz, 2H), 3.99-3.80 (m, 1H), 3.65-3.43 (m, 2H), 3.40-3.11 (m, 6H), 2.80-2.62 (m, 1H), 2.48 (dd,J= 16.4, 4.0 Hz, 1H), 2.05-1.80 (m, 4H), 1.45 (s, 9H), 1.08-0.98 (m, 12H).
Figure 02_image324
At room temperature (23-31 ℃) to the compound33a (220 mg, 0.231 mmol) and compound14B (136 mg, 0.46 mmol) in a stirred solution of 1,4-dioxane (3 mL) was added K2 CO3 (127 mg, 1.0 mmol), followed by water (0.6 mL) and EtOH (1.2 mL), followed by rapid addition of Pd(dppf)Cl2 .CH2 Cl2 (28 mg, 0.0345 mmol). After degassing and purging with nitrogen three times, the resulting mixture was stirred at 70°C under nitrogen for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (30 mL×2). The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-50% ethyl acetate/petroleum ether) to give the compound as a yellow solid33b (110 mg, 53% yield).LCMS: tR =1.194 min in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=893.7 [M+H]+ .
Figure 02_image326
At room temperature (24-31 ℃) to the compound33b (110 mg, 0.123 mmol) in dichloromethane (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature (24-31°C) for 2 hours. Mix the mixture with Na2 CO3 The saturated aqueous solution (20 mL) was quenched to pH>7 and extracted with dichloromethane (30 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound as a yellow solid33c (90 mg, 92% yield).LCMS: tR =1.000 min, in 5-95AB_220&254 Shimadzu (Agilent Pursult 5 C18 20×2.0mm), MS (ESI) m/z=793.3 [M+H]+ .
Figure 02_image328
Under nitrogen at room temperature (24-31 ℃) to the compound33c (90 mg, 0.113 mmol) in THF (2 mL) was added TBAF (0.23 mL, 0.227 mmol). The resulting mixture was stirred at room temperature (24-31°C) for 2 hours. The reaction was diluted with dichloromethane (20 mL) and water (20 mL) and separated. The aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (0-10% methane/dichloromethane) to obtain 120 mg of product, which was additionally passed through a chiral SFC (column: DAICEL CHIRALPAK AD -H (250 mm×30 mm, 5 μm), condition: 20% EtOH (0.1% NH3 .H2 O) to CO2 Medium, flow rate: 50 mL/min), followed by preparative HPLC (column: Venusil ASB Phenyl 250×50 mm 10 μm, conditions: 38-68% B (A: water 0.05% HCl), B: CH3 CN), flow rate: 25 mL/min) separated to obtain a white solidExamples 33 isomer 1 (7.8 mg) and yellow solidExamples 33 isomer 2 (8.1 mg). The overall yield is 25%.Examples 33 isomer 1 of Spectrum : LCMS: tR =0.771 min, in 5-95AB_220&254 Shimadzu (Merck RP18e 25×3.0mm), MS (ESI) m/z=555.5 [M+H]+ .SFC: tR =4.696 min; 95.10% purity. Method: Column: Chiralpak AD-3 150×4.6mm I.D., 3μm; Mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5.5 min and maintained at 40% for 3 min, followed by 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 40℃.HPLC : tR =3.49 min in 10-80_AB_1.2mL METHOD (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CD3 OD) δ=8.12 (s, 2H), 7.50 (s, 1H), 7.40 (d,J= 8.0 Hz, 1H), 7.10 (d,J= 10.0 Hz, 2H), 6.90 (d,J= 7.6 Hz, 1H), 5.88-5.62 (m, 2H), 4.58 (dt,J= 47.2, 5.6 Hz, 2H), 3.88 (br s, 1H), 3.82-3.70 (m, 1H), 3.68-3.52 (m, 2H), 3.50-3.35 (m, 2H), 3.26-3.16 (m, 4H ), 2.92 (d,J= 13.6 Hz, 1H), 2.45-2.23 (m, 2H), 2.19-1.98 (m, 2H), 1.30 (d,J= 6.4 Hz, 3H).Examples 33 isomer 2 of Spectrum : LCMS: tR =0.767 min, in 5-95AB_220&254 Shimadzu (Merck RP18e 25×3.0mm), MS (ESI) m/z=577.4 [M+Na]+ .SFC: tR = 4.995 min; 94.43% purity. Method: Column: Chiralpak AD-3 150×4.6mm I.D., 3μm, mobile phase: A: CO2 ; B: Ethanol (0.05% DEA); Gradient: B from 5% to 40% within 5.5 min and maintained at 40% for 3 min, followed by 5% B for 1.5 min; Flow rate: 2.5 mL/min; Column temperature: 40℃.HPLC : tR =3.49 min in 10-80_AB_1.2mL METHOD (Ultimate C18 3×50mm 3μm). 1 H NMR (400MHz, CD3 OD) δ=8.11 (s, 2H), 7.59 (s, 1H), 7.49 (d,J= 8.0 Hz, 1H), 7.19 (d,J= 10.0 Hz, 2H), 7.06 (d,J= 8.4 Hz, 1H), 6.13 (s, 1H), 5.89-5.68 (m, 1H), 4.62 (dt,J= 46.8, 5.2 Hz, 2H), 4.21-4.06 (m, 1H), 4.03-3.77 (m, 3H), 3.63-3.39 (m, 2H), 3.30-3.17 (m, 4H), 3.15-3.03 (m, 1H), 2.43-2.24 (m, 2H), 2.22-2.04 (m, 2H), 1.46 (d,J= 6.4 Hz, 3H).Examples 34 3-((1S,3R)-1-(2,6- Difluoro -4-( fluorine (1-(3- Fluoropropyl ) Azetidine -3- base ) methyl ) Phenyl )-3- methyl -6-(1H- Pyrazole -4- base )-3,4- Dihydroisoquinoline -2(1H)- base )-2,2- Difluoropropene -1- alcohol
Figure 02_image330
For preparationExamples 34 isomer 1 withExamples 34 isomer 2 'S program:
Figure 02_image332
At 0 ℃ to the compound34a (430.0 mg, 0.476 mmol) in dichloromethane (13 mL) was added DAST (537 mg, 3.33 mmol). The mixture was stirred at room temperature (26-34°C) for 2 hours to obtain a red solution. Mix the mixture with the pilot batch (100 mg of compound34a )Merge, use NaHCO3 The saturated aqueous solution (60 mL) was quenched to pH=8 and then extracted with dichloromethane (100 mL×3). The organic phases were combined and washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether), Obtain the compound as a yellow oil34b (430 mg, 81% average yield).LCMS: tR =1.322 min, in 5-95AB_1.5min_220&254.l cm chromatography (Agilent pursult5 C18 20×2 mm), MS (ESI) m/z=927.5 [M+Na]+. 1 H NMR (CDCl3 400MHz): δ=7.66-7.59 (m, 4H), 7.50-7.33 (m, 8H), 6.71-6.64 (m, 2H), 6.46 (d,J= 8.4 Hz, 1H), 5.46-5.28 (m, 1H), 5.21 (s, 1H), 3.95-3.81 (m, 4H), 3.78-3.71 (m, 1H), 3.62-3.43 (m, 2H), 3.30 -3.12 (m, 2H), 2.90-2.61 (m, 2H), 2.49 (dd,J= 16.0, 3.6 Hz, 1H), 1.46-1.42 (m, 9H), 1.06-0.99 (m, 12H).
Figure 02_image334
At 0 ℃ to the compound34b (430 mg, 0.475 mmol) in a mixture of dichloromethane (6.5 mL) was added trifluoroacetic acid (2.2 mL) dropwise. The mixture was stirred at 0°C for 1 hour to obtain a yellow solution. By adding NaHCO at 0°C3 Saturated aqueous solution (50 mL) adjusted the mixture to pH=8, and extracted with dichloromethane (80 ml×3). The organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to give the compound as a yellow solid34c (378 mg, 99% yield).LCMS: tR =1.080 min, in 5-95AB_1.5min_220& 254.l cm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=805.1 [M+H]+ .
Figure 02_image336
Compound34c (378 mg, 0.470 mmol), compound1F_1a (102 mg, 0.540 mmol) and K2 CO3 A mixture of (325 mg, 2.35 mmol) in acetonitrile (7 mL) was stirred at room temperature (26-34°C) for 16 hours to obtain a yellow suspension. The mixture was diluted with ethyl acetate (100 mL). The combined organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography (0-1% methanol (0.1% ammonia)/dichloromethane) to obtain the compound as a yellow oil.34d (235 mg, 58% yield).LCMS: tR = 1.104 min, in 5-95AB_1.5min_220&254.l cm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=865.5 [M+H]+.
Figure 02_image338
Compound34d (185 mg, 0.214 mmol), compound14B (126 mg, 0.428 mmol) and K2 CO3 A mixture of (118 mg, 0.856 mmol) in 1,4-dioxane (1.9 mL), ethanol (0.7 mL) and water (0.4 mL) was degassed and purged with nitrogen 3 times. Then add Pd(dppf)Cl2 .DCM (26 mg, 0.032 mmol) and degassed and purged with nitrogen 3 times. The mixture was stirred at 70°C under nitrogen for 16 hours to obtain a brown solution. Mix the mixture with the pilot batch (50 mg compound34d ) Combine and dilute with ethyl acetate (200 mL). The combined organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography (0-1% methanol (0.1% ammonia)/dichloromethane) to obtain a mixture of diastereomers Chemical compound34e (145 mg, 66% average yield), which can be separated based on SFC.SFC: tR =3.114 min and 4.135 min (Method: Column: Lux Cellulose-2 150×4.6mm I.D., 3μm; Mobile phase: 40% methanol (0.05% DEA) in CO2 Medium, flow rate: 2.5 mL/min; column temperature: 40°C). Method: Column: Lux Cellulose-2 150×4.6mm I.D., 3μm; Mobile phase: 40% methanol (0.05% DEA) in CO2 Medium, flow rate: 2.5 mL/min; column temperature: 40°C.LCMS: tR =1.024 min, in 5-95AB_1.5min_220& 254.l cm chromatography (Agilent pursult5 C18 20×2mm), MS (ESI) m/z=805.3 [M+H]+ . 1 H NMR (CDCl3 400MHz): δ=7.83 (s, 2H), 7.68-7.59 (m, 4H), 7.48-7.36 (m, 6H), 7.26-7.24 (m, 1H), 7.18 (d,J= 8.0 Hz, 1H), 6.76-6.63 (m, 3H), 5.45-5.32 (m, 1H), 5.28 (br s, 1H), 4.46 (dt,J= 47.2, 6.0 Hz, 2H), 3.99-3.85 (m, 1H), 3.68-3.59 (m, 1H), 3.57-3.45 (m, 1H), 3.33-3.20 (m, 4H), 3.17-3.10 (m, 1H), 2.98-2.91 (m, 1H), 2.88-2.65 (m, 2H), 2.62-2.50 (m, 3H), 1.79-1.65 (m, 2H), 1.10-1.00 (m, 12H).
Figure 02_image340
Compound34e (125.0 mg, 0.155 mmol) in tetrahydrofuran (3 mL) was added TBAF (0.233 mL, 0.233 mmol, 1 M in THF). The mixture was stirred at room temperature (26-35°C) for 2 hours to obtain a yellow solution. The mixture was diluted with ethyl acetate (100 mL). The combined organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to give a residue, which was purified by preparative TLC (dichloromethane: methanol=20:1) to obtain the product as a yellow oil (86 mg). A total of 100 mg of this compound passed through the chiral SFC (column: Phenomenex-Cellulose-2 (250 mm×30 mm, 5 μm), condition: (0.1% NH3. H2 O) Methanol to CO2 , Start B 45%, end B 45%, flow rate: 50 mL/min) separation, to obtain a yellow solidExamples 34 isomer 1 (29.9 mg, tR = 2.579 min, peak 1, 100% purity, 29% yield) and yellow solidExamples 34 isomer 2 (32.9 mg, tR = 3.476 min, peak 2, 100% purity, 32% yield).Racemic SFC : tR = 2.473 min and 3.274 min. Method: Column: Lux Cellulose-2 150×4.6mm I.D., 3μm; Mobile phase: 40% methanol (0.05% DEA) in CO2 Medium; flow rate: 2.5 mL/min; column temperature: 40°C.Examples 34 isomer 1 of Spectrum : LCMS: tR =1.919 min, in 10-80AB_4min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=567.2 [M+H]+ .HPLC: tR = 3.29 min, in 10-80_AB_1.2ml.met. chromatography (Ultimate C18 3.0μm 3.0×50mm).SFC: tR =2.579 min; 99.71% purity. Method: Column: Lux Cellulose-2 150×4.6 mm I.D., 3 μm; Mobile phase: 40% methanol (0.05% DEA) in CO2 Medium, flow rate: 2.5 mL/min, column temperature: 40°C. 1 H NMR (400MHz, CDCl3 ): δ=7.83 (s, 2H), 7.28 (s, 1H), 7.20 (dd,J= 8.0, 2.0 Hz, 1H), 6.88-6.82 (m, 2H), 6.72 (d,J= 8.0 Hz, 2H), 5.52 (dd,J= 47.6, 6.0 Hz, 1H), 5.22 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 3.74-3.52 (m, 3H), 3.50-3.40 (m, 2H), 3.36 (dd,J= 16.0, 4.4 Hz, 1H), 3.30-3.21 (m, 2H), 3.20-3.12 (m, 1H), 3.03-2.91 (m, 1H), 2.87-2.75 (m, 1H), 2.72-2.61 (m, 3H), 1.84-1.71 (m, 2H), 1.10 (d,J= 6.4 Hz, 3H).Examples 34 isomer 2 of Spectrum : LCMS: tR =1.898 min, in 10-80AB_4min_220&254.lcm chromatography (Xtimate C18 2.1×30mm), MS (ESI) m/z=567.2 [M+H]+.HPLC: tR =3.32 min, in 10-80_AB_1.2ml.met. chromatography (Ultimate C18 3.0μm 3.0×50mm).SFC: tR =3.476min; 98.65% purity. 1 H NMR (400MHz, CDCl3 ): δ=7.83 (s, 2H), 7.28 (s, 1H), 7.21 (dd,J= 7.6, 1.2 Hz, 1H), 6.87-6.81 (m, 2H), 6.72 (d,J= 8.0 Hz, 1H), 5.52 (dd,J= 48.0, 6.4 Hz, 1H), 5.23 (s, 1H), 4.48 (dt,J= 47.2, 6.0 Hz, 2H), 3.74-3.51 (m, 3H), 3.50-3.41 (m, 2H), 3.36 (dd,J= 15.6, 4.8 Hz, 1H), 3.30-3.13 (m, 3H), 3.04-2.91 (m, 1H), 2.88-2.75 (m, 1H), 2.72-2.60 (m, 3H), 1.84-1.71 (m, 2H), 1.10 (d,J= 6.4 Hz, 3H).real Give example 35 TR-FRET ER-α Ligand binding domain binding analysis TrueGive The example involves the binding analysis of the test compound to the ER-α ligand binding domain. The test compound was prepared at 10 μM in DMSO and serially diluted by 2-fold titration to obtain a total of 22 points in a low-volume unbound polystyrene black 384-well plate (Geiner catalog number 784900). The ER-α ligand binding domain/Tb-anti-GST Ab complex screening buffer was freshly prepared on the day of the experiment by mixing the following: 10 ml nuclear receptor buffer, 50 μl 1 M DTT to a final concentration of 5 mM, 10 μl 20000 nM ER-α ligand binding domain recombinant protein to a final concentration of 20 nM and 22.8 μl Tb-anti-GST antibody (Lantha Screening TR-FRET Estrogen α Receptor Competitive Binding Kit, Thermofisher, catalog number A15887) to the end Concentration 4 nM. The complex screening buffer was mixed gently several times by inversion, and then incubated on ice for 30 minutes before use. Dispense 100 nl of each prepared compound dilution (usually at least twelve different concentrations for each compound to obtain a dose response curve), as well as a blank (DMSO) and a positive control sample (such as fulvestrin) in the designated wells Groups or drugs containing fulvestrant) to prepare reaction plates. 5 μl of complex screening buffer was also dispensed into each of the sample/control/blank wells, and the reaction plate was covered and incubated on ice for 30 minutes. Meanwhile, Fluoromone ES2 screening buffer was prepared by mixing the following: 3 ml nuclear receptor buffer, 15 μl of 1 M DTT to a final concentration of 5 mM, 12 μl of 10% Tween-20 to a final concentration of 0.02% and 40 μl 1800 nM Fluoromone ES2 to a final concentration of 24 nM, vortex the prepared buffer. After incubating the test compound and complex screening buffer for 30 minutes, then 5 μl of Fluoromone ES2 screening buffer was dispensed into each sample/control/blank well, and the reaction plate was covered and incubated on ice for another 60 minutes. The fluorescence emission signal of each well was measured at Ex337nm and Em490nm/520nm using Tecan Spark 20M. The percent inhibition value was calculated relative to the blank and fulvestrant controls. Use GraphPad Prism 7 software for curve fitting and IC50 Calculation.real Give example 36 Breast cancer cells ER-α Degradation analysis TrueGive The example relates to the degradation analysis of the test compound on the ER-α receptor expressed on the cell surface of breast cancer cells such as MCF7 cells. This analytical method identifies compounds with ER α degradation properties. Day 1-MCF7 breast cancer cells were treated with 96-well polylysine-coated tissue culture plates (Greiner code T-3101-4) containing 100% RPMI (Gibco, catalog number 11835-030) and 10% activated carbon Phenol-free L-glutamine FBS (BioSun, catalog number BS-004-500) was seeded at a density of 12,000 cells per well and incubated overnight. Place the culture plate at 37°C, 5% CO2 Incubate overnight. Day 2-Preparation of compound stock solutions (33 μM, 11 μM, 3.3 μM, 1.1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.001 μM) in DMSO, followed by Freedom Evo liquid processing workstation (liquid Handling Workstation) (TECAN) was diluted 1:33 in cell culture medium to obtain 9 working concentrations (1 μM, 333 nM, 100 nM, 33 nM, 10 nM, 3.3 nM, 1 nM, 0.3 nM, 0.03 nM). Dispense 11 μl of each compound dilution, control compound (1 μM fulvestrant working solution diluted in cell culture medium), and blank control (DMSO) to a pre-designated cell culture plate using Freedom Evo Liquid Processing Workstation (TECAN) In the wells, the following final concentrations were obtained: 100 nM, 33.3 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM, 0.03 nM, 0.003 nM for each compound, and 100 nM fulvestrant as the minimum control And 0.3% DMSO as the maximum control. The cell culture plate was incubated at 37°C overnight. Day 3-Perform fixation and penetration as follows: 1) After 24 hours of compound treatment, the tissue culture growth medium is removed. 2) Wash the cells by adding 100 μL of 1×PBS to each well. Vortex gently or tap for about 20 seconds, then completely remove all fluid by suction. 3) Fix cells by adding 100 μL of cell fixation buffer to each sample well. Incubate at room temperature for at least 7 minutes. Mix by gently swirling or tapping. 4) Remove the fixing solution and discard. 5) Wash each sample well 3 times with 250 μL 1×PBS, as described above. 6) Add 100 μL of cell infiltration buffer to each sample well and mix by gently vortexing or tapping. Incubate at room temperature for 8 minutes. 7) Remove the cell permeation solution and discard. 8) Wash each well 3 times with 250 μL 1×PBS, as described above. 9) Add 100 μL of blocking buffer to each sample well and incubate at room temperature for 1 hour. The blocking buffer was prepared as 1×PBST (0.05% Tween-20) with 3% BSA. 10) Remove the blocking buffer and add 100 μL of diluted primary antibody (1:10000 dilution in Antibody #1 Dilute) to each sample well by gently vortexing or tapping Mix and incubate at 4°C overnight. Day 4-Secondary antibody incubation and ELISA reading are performed as follows: 1) Remove the primary antibody and wash the sample well 3 times with 250 μL 1× wash buffer. After the last wash, the plate was inverted and patted on paper towels to remove residual fluid. (Proceed immediately to the next step. Do not allow the board to air dry between steps). 2) Prepare 1×HRP-conjugated anti-rabbit IgG antibody No. 2 (diluted 1:100 in antibody No. 2 diluent), add 100 μL of the second antibody mixture by gently vortexing or tapping and incubate at room temperature for 1 hour. 3) Wash the plate 3 times with 250 μL of 1× washing solution. After the last wash, the plate was inverted and patted on paper towels to remove residual fluid. (Proceed immediately to the next step. Do not let the plate dry before adding TMB substrate). 4) Add 100 μL of TMB substrate and cover the reaction plate. Immediately after adding TMB substrate, the reaction time was started. The plate was shaken manually for 1 minute to thoroughly mix the reactants. 5) Incubate at room temperature for 5-45 minutes, then add 100 μL of stop buffer to stop the enzyme reaction. 6) After adding the stop buffer, read the plate on the Multiscan Spectrum reader set to the wavelength of 450 nm (program "OD450-OD540") as soon as possible. Use GraphPad Prism 7 software for curve fitting and IC50 Calculation. ER degradation% = 1-(treated with compound-treated with 100 nM fulvestrant) / (treated with 0.3% DMSO-treated with 100 nM fulvestrant) × 100real Give example 37 PR Antagonist analysis TrueGive The example involves an antagonist analysis that indirectly identifies an antagonist of estradiol-stimulated ER α by measuring the effect on the progesterone receptor downstream of ER α. Day 1-MCF7 breast cancer cells were treated with 96-well polylysine-coated tissue culture plates (Greiner code T-3101-4) containing 100% RPMI (Gibco, catalog number 11835-030) and 10% activated carbon Phenol-free L-glutamine FBS (BioSun, catalog number BS-004-500) was seeded at a density of 12,000 cells per well and incubated overnight. Place the culture plate at 37°C, 5% CO2 Incubate overnight. Day 2-Prepare compound stock solutions (33 μM, 11 μM, 3.3 μM, 1.1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.001 μM) sequentially in DMSO and then use Freedom Evo Liquid Processing Workstation (TECAN) Dilute 1:33 in cell culture medium to obtain 9 working concentrations (1 μM, 333 nM, 100 nM, 33 nM, 10 nM, 3.3 nM, 1 nM, 0.3 nM, 0.03 nM). Before dosing, dispense 11 μl of 1 nM E2 working stock solution (diluted in cell culture medium) into each well to obtain a final concentration of 0.1 nM in CO2 Incubate in the incubator for 30 minutes. Then use Freedom Evo Liquid Processing Workstation (TECAN) to dispense 11 μl of each compound dilution and blank control (DMSO) into pre-designated wells of the cell culture plate to obtain the following final concentration: 100 nM for each compound, 33.3 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM, 0.03 nM, 0.003 nM, 0.1 nM E2 as the maximum control and 0.3% DMSO as the minimum control. The cell culture plate was incubated at 37°C overnight. Day 3-Perform fixation and penetration as follows: 1) After 24 hours of compound treatment, the tissue culture growth medium is removed. 2) Wash the cells by adding 100 μL of 1×PBS to each well. Vortex gently or tap for about 20 seconds, then completely remove all fluid by suction. 3) Fix cells by adding 100 μL of cell fixation buffer to each sample well. Incubate at room temperature for at least 7 minutes. Mix by gently swirling or tapping. 4) Remove the fixing solution and discard. 5) Wash each sample well 3 times with 250 μL 1×PBS, as described above. 6) Add 100 μL of cell infiltration buffer to each sample well and mix by gently vortexing or tapping. Incubate at room temperature for 8 minutes. 7) Remove the cell permeation solution and discard. 8) Wash each well 3 times with 250 μL 1×PBS, as described above. 9) Add 100 μL of diluted primary antibody (1:10000 dilution in Antibody No. 1 Diluent) to each sample well, mix by gently vortexing or tapping and incubate at 4°C overnight. Day 4-Conduct secondary antibody incubation and ELISA read as follows: 1) Remove the primary antibody and wash the sample well 3 times with 250 μL 1× wash buffer. After the last wash, the plate was turned upside down and gently patted on a paper towel to remove residual fluid. (Proceed immediately to the next step. Do not allow the board to air dry between steps). 2) Prepare 1×HRP-conjugated anti-mouse IgG antibody No. 2 (diluted 1:100 in antibody No. 2 diluent), add 100 μL of the second antibody mixture by gently vortexing or tapping the plate and incubate at room temperature 1 hour. 3) Wash the plate 3 times with 250 μL of 1× washing solution. After the last wash, the plate was turned upside down and gently patted on a paper towel to remove residual fluid. (Proceed immediately to the next step. Do not let the plate dry before adding TMB substrate). 4) Add 100 μL of TMB substrate and cover the reaction plate. Immediately after adding TMB substrate, the reaction time was started. The plate was manually shaken gently for 1 minute to thoroughly mix the reactants. 5) Incubate at room temperature for 5-45 minutes, then add 100 μL of stop buffer to stop the enzyme reaction. 6) After adding the stop buffer, read the plate on the Multiscan Spectrum reader set to the wavelength of 450 nm (program "OD450-OD540") as soon as possible. Use GraphPad Prism 7 software for curve fitting and IC50 Calculation. PR antagonism% = 1-(treated with compound plus 0.1 nM E2-treated with 0.3% DMSO) / (treated with 0.1 nM E2-treated with 0.3% DMSO) × 100 The results of ER-α ligand binding domain binding, ER-α degradation of breast cancer cells, and PR antagonist analysis of exemplary compounds 1-12 are listed in Table 2 below.
Figure 02_image342
real Give example 38 In vitro rat / Analysis of human hepatocyte clearance The rat/human hepatocyte metabolic stability analysis protocol was used to determine the clearance rate of the compound of the present invention in vitro. Male rat hepatocytes and mixed sex human hepatocytes were obtained from commercial suppliers (eg BioreclamationIVT) and stored at -150°C before use. Prepare a 10 mM stock solution of the test compound in DMSO. Place the thawed medium and supplemented incubation medium (without serum) in a 37°C water bath for at least 15 minutes before use. The stock solution was diluted to 100 μM by combining 198 μL of acetonitrile and 2 μL of 10 mM stock solution. Remove the vial of cryopreserved hepatocytes from storage and ensure that the vial is kept at a low temperature. The vial was thawed in a 37°C water bath with gentle shaking. Keep the vial in a water bath until all ice crystals are dissolved and no longer visible. Spray the vial with 70% ethanol and then transfer it to a biosafety cabinet. Then pour the contents into a 50 mL thawing medium conical tube. The vial was centrifuged at 100 g for 10 minutes at room temperature. Aspirate the thawing medium and resuspend the hepatocytes in serum-free culture medium to obtain about 1.5×106 Cells/ml. Count the viability and density of cells using Trypan Blue exclusion, and then dilute the cells with serum-free culture medium to achieve 1×106 Working cell density per viable cell/ml. Part of 1×106 Live cells/ml of hepatocytes were boiled for 10 minutes and then added to the plate as a negative control, which eliminated enzyme activity so that only minimal or no substrate conversion could be observed. Negative samples are prepared using inactivated liver cells, which are used to exclude misleading factors caused by the instability of the chemical substance itself. An aliquot of 247.5 μL of hepatocytes was dispensed into each well of a 96-well uncoated plate. Place the plate in an incubator on an orbital shaker for approximately 10 minutes. An aliquot of 2.5 μL of 100 μM test compound was added to the corresponding well of the uncoated 96-well plate to start the reaction. Two repeated experiments were performed for this analysis. Place the plate on the orbital oscillator in the incubator for incubation for the design time point. At 5, 15, 30, 45, 60, 80, and 100 minutes time points, 20 μL of content was transferred and mixed with 6 volumes (120 μL) of cold acetonitrile containing internal standard to terminate the reaction. The sample was centrifuged at 4000 g for 20 minutes and an aliquot of 100 μL of supernatant was used for LC-MS/MS analysis to measure the test compound. The elimination half-life (T1/2 ) To estimate in vitro hepatocyte clearance. Calculate the peak area ratio of each compound (test or control) to IS. Plot Ln (% of control) versus incubation time (minutes) and calculate the slope of the linear fit line. Drug elimination rate constant k(min-1), T1/2 (Min) and in vitro clearance rate CLint (μL/min/E6) calculated according to the following equation: k=-slope T1/2 =0.693/k CLint =k/Chep Where Chep (Cell×μL-1 ) Is the cell concentration in the cultivation system.Examples 39 For determination Log D of Program Place 10 μL of the working solution of each cassette in the corresponding 96-well shelf position (Log D plate) in sequence. Add 500 μL of saturated octanol to each vial of the above uncapped Log D plate, followed by 500 μL of saturated phosphate buffer. Seal with a molded PTDE/SIL 96-well plate cover. The Log D plate was transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C, 2,000 rpm for 2 hours. The samples were centrifuged at 4,000 rpm at 25°C for 30 minutes to separate the phases. Pipettes and syringes are used to draw approximately 100 μL from octanol and buffered liquid to a new 96-well plate, respectively. Transfer 5 μL of octanol sample to a new 96-well plate, then add 495 μL H2 A mixture of O and acetonitrile (1:1) with internal standard was used as a 100-fold octanol sample. Vortex at 1,000 rpm for 5 minutes. Transfer 50 μL of 100-fold sample to a new 96-well plate, then add 450 μL of H2 A mixture of O and acetonitrile (1:1) containing an internal standard was used as a 1,000-fold octanol sample. Vortex at 1,000 rpm for 5 minutes. Use H2 A mixture of O and acetonitrile (1:1) containing an internal standard serially dilutes a 1,000-fold octanol sample to 10,000, 100,000, and 1,000,000 times. Transfer 50 μL of buffer sample to a new 96-well plate, then add 450 μL H2 A mixture of O and acetonitrile (1:1) containing an internal standard was used as a 10-fold buffer sample. Vortex at 1,000 rpm for 5 minutes. Use H2 A mixture of O and acetonitrile (1:1) containing internal standards serially diluted the 10-fold buffer sample to 100, 1,000, and 10,000 times. The samples were evaluated by LC/MS/MS analysis. All compounds are tested in a single pass. All calculations are performed using Microsoft Excel. The concentration of the test compound in octanol/buffer solution was evaluated by LC/MS/MS. Calculate the Log D value of the test compound as follows:
Figure 02_image344
DF means dilution factor.real Give example 40 Program for measuring protein binding in human plasma by using balanced dialysis Add 597 μL of blank plasma to each well of a new plastic plate or a separate plastic tube and add 3 μL of the working solution to each, and vortex at 1,000 rpm for 5 minutes. The final volume percentage of the organic solvent is 0.5% and the final concentration of the test compound is 5 μM. Immediately thereafter, 50 μL of spiked plasma suspension was transferred to a 96-well plate to serve as a T=0 control sample. The sample was treated the same as the sample after incubation. All remaining spiked plasma was placed in the incubator for the duration of the study. Place the insert with the open end facing up in the hole in the base plate. 500 μL of phosphate buffer (pH 7.4) was added to the buffer chamber, which is indicated by a white circle. Add 300 μL of spiked plasma sample to the sample chamber, which is indicated by the red circle. Cover the unit with a breathable cover and2 Orbital oscillator in incubator with 5% CO2 Incubate at 300 rpm at 37°C for 18 hours. At the end of the incubation, the cover was removed and 50 μL of post-dialysis samples were drawn from the buffer and plasma chambers into separate 96-well plates for analysis. At the same time, place the spiked plasma samples remaining in the plastic plate or separate plastic tube in the CO2 5% CO in the incubator2 Incubate at 37°C for 18 hours. At T=18 hours, 50 μL of the original spiked plasma suspension was transferred to a 96-well plate for analysis. 50 μL of human plasma was added to the buffer sample, and an equal volume of PBS was added to the collected plasma sample. The plate was vortexed at 1,000 rpm for 2 minutes and 400 μL of acetonitrile containing the appropriate internal standard (IS) was added to precipitate the protein and release the compound. Vortex at 1,000 rpm for 10 minutes. Centrifuge at 4,000 rpm for 30 minutes. Transfer 250 μL of supernatant to a new 96-well plate and centrifuge again (4,000 rpm, 30 minutes). Then 100 μL of supernatant was transferred to a new 96-well plate for analysis. 100 μL of distilled water was added to each sample and vortexed at 1,000 rpm for 5 minutes to analyze by LC-MS/MS. All compounds were tested in human plasma at 5 μM in duplicates. All calculations are performed using Microsoft Excel. Calculate the percentage of unbound, bound, and recovered test compounds as follows:
Figure 02_image346
Exemplary data is shown in Table 3 below.
Figure 02_image348
real Give example 41 Immature uterine wet weight analysis Immature uterine wet weight analysis The study was conducted in immature female SD rats aged between 17-19 days. Rats were randomly divided into the following matching groups according to body weight: vehicle (peanut oil), 17-β-estradiol, fulvestrant alone or plus 17-β-estradiol, tamoxifen alone or plus Add 17-β-estradiol, test compound alone or add 17-β-estradiol. Peanut oil vehicle, 1 μg of 17-β-estradiol per rat, 0.2 mg/kg fulvestrant, and all test compounds were administered daily by subcutaneous route in a total volume of 0.2 ml per injection, while he Moxifen is administered by oral gavage once a day at 1 mg/kg. The test compound was administered in two doses of 10 µg and 100 µg. All animals were dosed daily for three days. 24 hours after the last dose, plasma was collected for pharmacokinetic analysis, and immediately after plasma collection, the animals were euthanized and the uterus was removed and weighed. Uterine weight gain and anti-uterine weight gain activity are calculated using uterine weight as
Figure 02_image350
Figure 02_image352
.
Figure 02_image354

Figure 108118751-A0101-11-0002-1
Figure 108118751-A0101-11-0002-1

Claims (19)

一種式(I)化合物，
Figure 03_image001
式(I) 或其藥學上可接受的鹽，其中， A1 、A2 和A3 各自獨立地為-C(R6 )=或-N=； 環Q為6元芳環，其中所述環原子獨立地選自碳或氮； 環B為5元或6元不飽和環，其可為碳連接的或氮連接的；其中如果所述5元或6元不飽和環含有-NH-部分，則所述氮可任選地經選自R7 的基團取代； X為-O-、-NR8 -、-C(R9 )(R10 )-或-S-； R1 和R3 為碳上的取代基且獨立地選自羥基、鹵素、硝基、氰基、羧基、胺基、胺甲醯基、巰基、胺磺醯基、甲基、乙基、氟甲基、二氟甲基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基、三氟乙氧基、甲胺基、二甲胺基或乙胺基；或鄰近原子上的兩個R1 基團形成五元或六元稠合碳環基或稠合雜環基環；其中所述五元或六元稠合碳環基或稠合雜環基環可任選地在碳上經R11 取代；且其中如果所述五元或六元稠合雜環基環含有-NH-部分，則所述氮可任選地經選自R12 的基團取代； R2 和R5 獨立地選自C1-12 烷基、3-10元飽和或不飽和碳環基，或3-10元飽和或不飽和雜環基；其中R2 和R5 可任選地在碳上經R13 取代；且其中如果所述3-10元飽和或不飽和雜環基含有-NH-部分，則所述氮可任選地經選自R14 的基團取代； R4 為C1-3 烷基或C3-4 環烷基；其中R4 可任選地經一個或多個羥基、鹵素或甲氧基取代； R8 為氫或任選地經一個或多個鹵基或羥基取代的C1-12 烷基； R6 、R9 和R10 各自獨立地為氫、羥基、鹵素、硝基、氰基、羧基、胺基、胺甲醯基、巰基、胺磺醯基、C1-12 烷基或C1-12 烷氧基；其中所述C1-12 烷基或C1-12 烷氧基可獨立地任選地經一個或多個鹵基或羥基取代； R11 和R13 為碳上的取代基，並且各自獨立地選自羥基、鹵素、硝基、氰基、羧基、三氟甲氧基、胺基、胺甲醯基、巰基、胺磺醯基、C1-12 烷基、C1-12 烷氧基、C1-12 烷醯基、C1-12 烷醯氧基、N-(C1-12 烷基)胺基、N,N-(C1-12 烷基)2 胺基、C1-12 烷醯胺基、N-(C1-12 烷基)胺甲醯基、N,N-(C1-12 烷基)2 胺甲醯基、C1-12 烷基S(O)a ，其中a為0至2，C1-12 烷氧基羰基、N-(C1-12 烷基)胺磺醯基、N,N-(C1-12 烷基)2 胺磺醯基、C1-12 烷基磺醯胺基、C1-12 烷基-OH、C1-12 鹵烷基、-Si(Ra Rb Rc )、3-10元飽和或不飽和碳環基、或3-10元飽和或不飽和雜環基；其中R11 和R13 各自獨立地可在碳上任選地經一個或多個R15 取代；且其中如果所述3-10元飽和或不飽和雜環基含有-NH-部分，則所述氮可任選地經選自R16 的基團取代； R7 、R12 、R14 和R16 獨立地選自C1-12 烷基、C1-12 烷醯基、C1-12 烷基磺醯基、C1-12 烷氧基羰基、胺甲醯基、N-(C1-12 烷基)胺甲醯基、N,N-(C1-12 烷基)2 胺甲醯基、3-10元飽和或不飽和碳環基、3-10元飽和或不飽和雜環基、3-10元飽和或不飽和碳環基C1-12 烷基、3-10元飽和或不飽和雜環基C1-12 烷基、苯甲基、苯甲氧基羰基、苯甲醯基或苯基磺醯基；其中R7 、R12 、R14 和R16 可獨立地任選地在碳上經R17 取代； R15 和R17 各自獨立地選自羥基、鹵素、硝基、氰基、羧基、三氟甲氧基、胺基、胺甲醯基、巰基、胺磺醯基、C1-12 烷基、C1-12 烷氧基、C1-12 鹵烷基、N-(C1-12 烷基)胺基、N-(C1-12 鹵烷基)胺基或C1-12 烷基-OH； Ra 、Rb 和Rc 各自獨立地選自羥基、C1-12 烷基或C1-12 烷基-OH；且 m為0、1、2、3或4； n為0、1或2。A compound of formula (I),
Figure 03_image001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein A 1 , A 2 and A 3 are each independently -C(R 6 )= or -N=; Ring Q is a 6-membered aromatic ring, wherein the Ring atoms are independently selected from carbon or nitrogen; Ring B is a 5-membered or 6-membered unsaturated ring, which may be carbon-linked or nitrogen-linked; wherein if the 5-membered or 6-membered unsaturated ring contains a -NH- moiety , Then the nitrogen may be optionally substituted with a group selected from R 7 ; X is -O-, -NR 8 -, -C(R 9 )(R 10 )- or -S-; R 1 and R 3 is a substituent on carbon and is independently selected from the group consisting of hydroxyl, halogen, nitro, cyano, carboxy, amine, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, fluoromethyl, and di Fluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, methylamino, dimethylamino or ethylamino; or adjacent atoms The two R 1 groups on the form a five-membered or six-membered fused carbocyclic group or a fused heterocyclic group ring; wherein the five-membered or six-membered fused carbocyclic group or fused heterocyclic group ring may be optionally Is substituted on the carbon by R 11 ; and wherein if the five- or six-membered fused heterocyclyl ring contains a -NH- moiety, the nitrogen may be optionally substituted with a group selected from R 12 ; R 2 and R 5 are independently selected from C 1-12 alkyl, 3-10 membered saturated or unsaturated carbocyclic group, or 3-10 membered saturated or unsaturated heterocyclic group; wherein R 2 and R 5 may be optionally Substituted by R 13 on the carbon; and wherein if the 3-10 membered saturated or unsaturated heterocyclic group contains a -NH- moiety, the nitrogen may be optionally substituted with a group selected from R 14 ; R 4 Is C 1-3 alkyl or C 3-4 cycloalkyl; wherein R 4 may be optionally substituted with one or more hydroxyl, halogen or methoxy; R 8 is hydrogen or optionally through one or more C 1-12 alkyl substituted with halo or hydroxy; R 6 , R 9 and R 10 are each independently hydrogen, hydroxy, halogen, nitro, cyano, carboxy, amine, carbamoyl, mercapto, amine Sulfonyl, C 1-12 alkyl or C 1-12 alkoxy; wherein the C 1-12 alkyl or C 1-12 alkoxy can independently optionally pass one or more halo groups or Hydroxy substitution; R 11 and R 13 are substituents on carbon, and are each independently selected from hydroxy, halogen, nitro, cyano, carboxy, trifluoromethoxy, amine, carbamoyl, mercapto, amine Sulfonyl, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkyl acetyl, C 1-12 alkoxy, N-(C 1-12 alkyl)amino, N , N-(C 1-12 alkyl) 2 amine group, C 1-12 alkyl amide group, N-(C 1-12 alkyl) amine methyl group, N, N-(C 1-12 alkyl group ) 2 amine carboxamide, C 1-12 alkyl S(O) a , where a is 0 to 2, C 1-12 alkoxycarbonyl, N-(C 1-12 alkyl) sulfamoyl, N,N-(C 1-12 alkyl) 2 sulfamoyl, C 1-12 alkylsulfonylamido, C 1-12 alkyl-OH, C 1-12 haloalkyl, -Si(R a R b R c ), 3-10 membered saturated or unsaturated carbocyclic group, Or a 3-10 membered saturated or unsaturated heterocyclic group; wherein R 11 and R 13 are each independently optionally substituted on the carbon with one or more R 15 ; and wherein if the 3-10 member is saturated or not The saturated heterocyclic group contains a -NH- moiety, then the nitrogen may be optionally substituted with a group selected from R 16 ; R 7 , R 12 , R 14 and R 16 are independently selected from C 1-12 alkyl, C 1-12 alkyl amide, C 1-12 alkyl sulfonamide, C 1-12 alkoxycarbonyl, amine methyl, N-(C 1-12 alkyl) amine methyl, N, N -(C 1-12 alkyl) 2 amine formyl, 3-10 membered saturated or unsaturated carbocyclic group, 3-10 membered saturated or unsaturated heterocyclic group, 3-10 membered saturated or unsaturated carbocyclic group C 1-12 alkyl, 3-10 membered saturated or unsaturated heterocyclic group C 1-12 alkyl, benzyl, benzyloxycarbonyl, benzoyl or phenylsulfonyl; wherein R 7 , R 12 , R 14 and R 16 may independently be optionally substituted on the carbon with R 17 ; R 15 and R 17 are each independently selected from hydroxyl, halogen, nitro, cyano, carboxy, trifluoromethoxy, Amino group, amine formyl group, mercapto group, sulfamoyl group, C 1-12 alkyl group, C 1-12 alkoxy group, C 1-12 haloalkyl group, N-(C 1-12 alkyl) amino group , N-(C 1-12 haloalkyl) amine or C 1-12 alkyl-OH; R a , R b and R c are each independently selected from hydroxyl, C 1-12 alkyl or C 1-12 Alkyl-OH; and m is 0, 1, 2, 3 or 4; n is 0, 1 or 2. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中A1 、A2 和A3 各自獨立地為-C(R6 )=或-N=；其中R6 各自獨立地為氫或鹵素。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein A 1 , A 2 and A 3 are each independently -C(R 6 )= or -N=; wherein R 6 is each Independently hydrogen or halogen. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中環Q為苯基或吡啶基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring Q is phenyl or pyridyl. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中環B為5元或6元不飽和環，其可為碳連接或氮連接的；其中如果所述5元或6元不飽和環含有-NH-部分，則所述氮可任選地經選自R7 的基團取代；其中 R7 選自C1-12 烷基或環丙基；其中R7 可獨立地任選地在碳上經一個或多個R17 取代；且 R17 各自獨立地選自鹵素。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is a 5-membered or 6-membered unsaturated ring, which may be carbon-linked or nitrogen-linked; Or a 6-membered unsaturated ring contains a -NH- moiety, then the nitrogen may be optionally substituted with a group selected from R 7 ; wherein R 7 is selected from C 1-12 alkyl or cyclopropyl; wherein R 7 may be Independently optionally substituted on the carbon with one or more R 17 ; and R 17 are each independently selected from halogen. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中X為-O-、-NR8 -或-C(R9 )(R10 )-；其中 R8 為氫；且 R9 和R10 各自獨立地為氫、羥基或鹵素。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is -O-, -NR 8 -or -C(R 9 )(R 10 )-; wherein R 8 is hydrogen ; And R 9 and R 10 are each independently hydrogen, hydroxyl, or halogen. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中R1 為碳上的取代基，並且獨立地選自羥基、鹵素或甲基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is a substituent on carbon, and is independently selected from hydroxyl, halogen, or methyl. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中R2 選自C1-12 烷基或5元飽和碳環基；其中R2 可任選地在碳上經一個或多個R13 取代；其中 R13 為碳上的取代基，並且各自獨立地選自羥基、鹵素或C1-12 烷基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from a C 1-12 alkyl group or a 5-membered saturated carbocyclic group; wherein R 2 may be optionally on carbon Substitution by one or more R 13 ; wherein R 13 is a substituent on carbon, and each is independently selected from hydroxyl, halogen, or C 1-12 alkyl. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中R3 為碳上的取代基，並且獨立地選自鹵素或甲氧基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 is a substituent on carbon, and is independently selected from halogen or methoxy. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中R4 為C1-3 烷基或C3-4 環烷基；其中R4 可任選地經一個或多個鹵素取代。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 is C 1-3 alkyl or C 3-4 cycloalkyl; wherein R 4 is optionally substituted by one or Multiple halogen substitutions. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中R5 選自C1-12 烷基或4元或5元飽和雜環基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中如果所述4元或5元飽和雜環基含有-NH-部分，則所述氮可任選地經選自R14 的基團取代；其中 R13 為碳上的取代基且獨立地選自N-(C1-12 烷基)胺基；其中R13 各自獨立地可任選地在碳上經一個或多個R15 取代； R14 獨立地選自C1-12 烷基；其中R14 可獨立地任選地在碳上經一個或多個R17 取代；且 R15 和R17 各自獨立地選自鹵素。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 is selected from a C 1-12 alkyl group or a 4-membered or 5-membered saturated heterocyclic group; wherein R 5 may be optionally Substituted by one or more R 13 on the carbon; and wherein if the 4-membered or 5-membered saturated heterocyclic group contains a -NH- moiety, the nitrogen may be optionally substituted with a group selected from R 14 ; Wherein R 13 is a substituent on carbon and is independently selected from N-(C 1-12 alkyl)amine groups; wherein R 13 each independently may be optionally substituted on the carbon with one or more R 15 ; R 14 is independently selected from C 1-12 alkyl groups; wherein R 14 may be independently optionally substituted on the carbon with one or more R 17 ; and R 15 and R 17 are each independently selected from halogen. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中m為0或1。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 0 or 1. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中： A1 、A2 和A3 各自獨立地為-C(R6 )=或-N=；其中R6 各自獨立地為氫或氟； 環Q為苯基或吡啶基； 環B為吡唑基、噁唑基、1,2,4-三唑-4-基、1,2,3-三唑-4-基、2,5-二氫噻吩-4-基-1,1-二氧化物、嘧啶基、噠嗪基、吡啶基、吡咯基、四唑基或咪唑基；其中如果所述吡唑基、1,2,3-三唑基、吡咯基、四唑基、1,2,4-三唑基和咪唑基含有-NH-部分，則所述氮可任選地經選自R7 的基團取代；其中R7 選自甲基、乙基或環丙基；其中R7 可獨立地任選地在碳上經一個或多個R17 取代；且R17 各自獨立地選自氟； X為-O-、-NH-、-CH2 -、-CH(OH)-或-CH(F)-； R1 為碳上的取代基且獨立地選自羥基、氟或甲基； R2 選自乙基、丙基或雙環[1.1.1]戊-1-基；其中R2 可任選地在碳上經一個或多個R13 取代；其中R13 為碳上的取代基且各自獨立地選自羥基、氟或甲基； R3 為碳上的取代基且獨立地選自氟或甲氧基； R4 為甲基、乙基或環丙基；其中R4 可任選地經一個或多個氟取代； R5 選自乙基、氮雜環丁烷-3-基或吡咯烷-3-基；其中R5 可任選地在碳上經一個或多個R13 取代；且其中所述氮雜環丁烷-3-基或吡咯烷-3-基可任選地在所述-NH-部分上經選自R14 的基團取代；其中R13 為碳上的取代基且獨立地選自丙胺基；其中R13 各自獨立地可任選地在碳上經一個或多個R15 取代；R14 獨立地選自丙基；其中R14 可獨立地任選地在碳上經一個或多個R17 取代；且R15 和R17 各自獨立地選自氟； m為0或1；且 n為0、1或2。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: A 1 , A 2 and A 3 are each independently -C(R 6 )= or -N=; wherein R 6 Each is independently hydrogen or fluorine; Ring Q is phenyl or pyridyl; Ring B is pyrazolyl, oxazolyl, 1,2,4-triazol-4-yl, 1,2,3-triazole- 4-yl, 2,5-dihydrothiophen-4-yl-1,1-dioxide, pyrimidinyl, pyridazinyl, pyridyl, pyrrolyl, tetrazolyl or imidazolyl; wherein if the pyrazole Group, 1,2,3-triazolyl, pyrrolyl, tetrazolyl, 1,2,4-triazolyl and imidazolyl contain -NH- moiety, then the nitrogen can be optionally selected from R 7 Substituted by a group; wherein R 7 is selected from methyl, ethyl or cyclopropyl; wherein R 7 may be independently optionally substituted on the carbon with one or more R 17 ; and R 17 is each independently selected from fluorine X is -O-, -NH-, -CH 2 -, -CH(OH)- or -CH(F)-; R 1 is a substituent on carbon and is independently selected from hydroxyl, fluorine or methyl; R 2 is selected from ethyl, propyl or bicyclo[1.1.1]pent-1-yl; wherein R 2 may be optionally substituted on the carbon with one or more R 13 ; wherein R 13 is a substituent on the carbon And each is independently selected from hydroxyl, fluorine or methyl; R 3 is a substituent on carbon and is independently selected from fluorine or methoxy; R 4 is methyl, ethyl or cyclopropyl; wherein R 4 is optional Optionally substituted with one or more fluorine; R 5 is selected from ethyl, azetidine-3-yl or pyrrolidin-3-yl; wherein R 5 may optionally be substituted by one or more R on carbon 13 substituted; and wherein the azetidine-3-yl or pyrrolidin-3-yl may be optionally substituted on the -NH- moiety with a group selected from R 14 ; wherein R 13 is carbon Substituents on and are independently selected from propylamine groups; wherein R 13 each independently may be optionally substituted on the carbon with one or more R 15 ; R 14 is independently selected from propyl; wherein R 14 may be independently selected Optionally substituted on the carbon with one or more R 17 ; and R 15 and R 17 are each independently selected from fluorine; m is 0 or 1; and n is 0, 1 or 2. 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其中所述式(I)化合物為式(Ia)化合物：
Figure 03_image003
(Ia)             。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia):
Figure 03_image003
(Ia). 根據請求項1所述的式(I)化合物或其藥學上可接受的鹽，其選自： N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 2,2-二氟-3-((1S,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-1-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-6-(異噁唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-((1S,3R)-6-(1-乙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3R)-6-(1-環丙基-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3R)-6-(1-(二氟甲基)-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1-甲基-1H-吡唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(4H-1,2,4-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(2H-1,2,3-三唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 5-氟-N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 3-((1S,3R)-1-(2,6-二氟-4-((1-(3-氟丙基)氮雜環丁-3-基)胺基)苯基)-3-甲基-6-(1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)-2,2-二氟丙-1-醇； 2,2-二氟-3-((1S,3R)-1-(3-氟-5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； 2,2-二氟-3-((1S,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-6-(1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)丙-1-醇； 6-((1S,3R)-8-氟-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3R)-7-氟-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3R)-5-氟-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； 6-((1S,3R)-6-(3-氟-1H-吡唑-4-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(5-甲基-1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(2H-四唑-5-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 5-((1S,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-6-基)吡啶-2(1H)-酮； 4-((1S,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-6-基)吡啶-2(1H)-酮； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-1,2,4-三唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-(2-(雙環[1.1.1]戊-1-基)-3-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-2-(3-甲基雙環[1.1.1]戊-1-基)-6-(1H-吡唑-4-基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 5-((1S,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-6-基)吡啶-2(1H)-酮； 4-((1S,3R)-1-(5-((1-(3-氟丙基)氮雜環丁-3-基)胺基)吡啶-2-基)-3-甲基-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-6-基)吡啶-2(1H)-酮； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-((1S,3R)-3-甲基-6-(1H-1,2,4-三唑-3-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 6-(2-(雙環[1.1.1]戊-1-基)-3-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫異喹啉-1-基)-N-(1-(3-氟丙基)氮雜環丁-3-基)吡啶-3-胺； N-(1-(3-氟丙基)氮雜環丁-3-基)-6-(3-甲基-2-(3-甲基雙環[1.1.1]戊-1-基)-6-(1H-吡唑-4-基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-((S)-1-(3-氟丙基)吡咯烷-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； N-((R)-1-(3-氟丙基)吡咯烷-3-基)-6-((1S,3R)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-胺； 3-((1S,3R)-1-(2,6-二氟-4-(((S)-1-(3-氟丙基)吡咯烷-3-基)胺基)苯基)-3-甲基-6-(1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)-2,2-二氟丙-1-醇； 3-氟-N-(3-(6-((1S,3R)-3-甲基-6-(1H-吡唑-4-基)-2-(2,2,2-三氟乙基)-1,2,3,4-四氫異喹啉-1-基)吡啶-3-基)丙基)丙-1-胺； 3-((1S,3R)-1-(2,6-二氟-4-(3-((3-氟丙基)胺基)-1-羥丙基)苯基)-3-甲基-6-(1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)-2,2-二氟丙-1-醇； 3-((1S,3R)-1-(2,6-二氟-4-(1-氟-3-((3-氟丙基)胺基)丙基)苯基)-3-甲基-6-(1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)-2,2-二氟丙-1-醇；和 3-((1S,3R)-1-(2,6-二氟-4-(氟(1-(3-氟丙基)氮雜環丁-3-基)甲基)苯基)-3-甲基-6-(1H-吡唑-4-基)-3,4-二氫異喹啉-2(1H)-基)-2,2-二氟丙-1-醇。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from: N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1-methyl-1H-pyrazole-4 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 2,2-difluoro-3-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl) -3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-1-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-3-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-6-(isoxazol-4-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-4-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-((1S,3R)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 , 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3R)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1, 2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3R)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1-methyl-1H-pyrazole-3 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(4H-1,2,4-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(2H-1,2,3-triazole- 4-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 5-fluoro-N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazole-4- Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 3-((1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- Methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2-difluoropropan-1-ol; 2,2-difluoro-3-((1S,3R)-1-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridine- 2-yl)-3-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; 2,2-difluoro-3-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl) -3-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-ol; 6-((1S,3R)-8-fluoro-3-methyl-6-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2, 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3R)-7-fluoro-3-methyl-6-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2, 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3R)-5-fluoro-3-methyl-6-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl)-1,2, 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; 6-((1S,3R)-6-(3-fluoro-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2, 3,4-tetrahydroisoquinolin-1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(5-methyl-1H-pyrazole-4 -Yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(2H-tetrazol-5-yl)-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 5-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2(1H)-one; 4-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2(1H)-one; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-1,2,4-triazole- 3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-(2-(Bicyclo[1.1.1]pent-1-yl)-3-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline -1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-2-(3-methylbicyclo[1.1.1]pent-1-yl)- 6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 5-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2(1H)-one; 4-((1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2 -(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2(1H)-one; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-1,2,4-triazole- 3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 6-(2-(Bicyclo[1.1.1]pent-1-yl)-3-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline -1-yl)-N-(1-(3-fluoropropyl)azetidin-3-yl)pyridin-3-amine; N-(1-(3-fluoropropyl)azetidin-3-yl)-6-(3-methyl-2-(3-methylbicyclo[1.1.1]pent-1-yl)- 6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-4-yl) -2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; N-((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((1S,3R)-3-methyl-6-(1H-pyrazol-4-yl) -2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-amine; 3-((1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)- 3-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2-difluoropropan-1-ol; 3-fluoro-N-(3-(6-((1S,3R)-3-methyl-6-(1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethyl )-1,2,3,4-tetrahydroisoquinolin-1-yl)pyridin-3-yl)propyl)propan-1-amine; 3-((1S,3R)-1-(2,6-difluoro-4-(3-((3-fluoropropyl)amino)-1-hydroxypropyl)phenyl)-3-methyl -6-(1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2-difluoropropan-1-ol; 3-((1S,3R)-1-(2,6-difluoro-4-(1-fluoro-3-((3-fluoropropyl)amino)propyl)phenyl)-3-methyl -6-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2-difluoropropan-1-ol; and 3-((1S,3R)-1-(2,6-difluoro-4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3 -Methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2-difluoropropan-1-ol. 一種藥物組合物，其包含根據請求項1至14中任一項所述的式(I)化合物或其藥學上可接受的鹽，和藥學上可接受的稀釋劑或載體。A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, and a pharmaceutically acceptable diluent or carrier. 根據請求項1至14中任一項所述的式(I)化合物或其藥學上可接受的鹽，其用作藥物。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which is used as a medicine. 一種根據請求項1至14中任一項所述的式(I)化合物或其藥學上可接受的鹽的用途，其係用於製造供選擇性下調例如人類的溫血動物中的雌激素受體的藥物。Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 for the production of a selective down-regulation of estrogen receptor in a warm-blooded animal such as human Body medicine. 根據請求項1至14中任一項所述的式(I)化合物或其藥學上可接受的鹽，其係用於在例如人類的溫血動物中產生抗癌效應。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which is used to produce an anticancer effect in, for example, a warm-blooded animal in humans. 一種藥物組合物，其包含根據請求項1至14中任一項所述的式(I)化合物或其藥學上可接受的鹽，和藥學上可接受的稀釋劑或載體，其係用於治療例如人類的溫血動物中的乳腺癌。A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, which is used for treatment For example, breast cancer in human warm-blooded animals.
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