TW202327583A - Methods of treating cancer using a cdk7 inhibitor - Google Patents
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Abstract
Description
本揭示案係關於使用CDK7抑制劑作為單藥療法或與一或多種額外治療劑組合來治療癌症之方法。The disclosure relates to methods of treating cancer using CDK7 inhibitors as monotherapy or in combination with one or more additional therapeutic agents.
細胞週期蛋白依賴性激酶(CDK)係在細胞週期進程(例如CDK 1、2、4、6、7)及轉錄(例如CDK 7、8、9、12、13)之調控中起到作用的蛋白質激酶家族。由遺傳及表觀遺傳變化引起之異常CDK活性導致不受控制之細胞增殖，此通常與多種人類癌症相關。抑制CDK會導致細胞週期停滯及細胞凋亡。因此，CDK係開發新抗癌療法之可行目標。細胞週期蛋白依賴性激酶7 (CDK7)藉由磷酸化並活化CDK 1、2、4及6來影響細胞週期進程，且亦藉由磷酸化RNA聚合酶II之C末端域(CTD)來調控轉錄之起始，參見圖1之示意圖，該圖描繪CDK7細胞週期進程及轉錄之作用。已在多種腫瘤類型中報導CDK7過度表現。由於CDK7在細胞週期及轉錄調控中之雙重作用以及在促進免疫刺激、抗腫瘤微環境中之潛在作用，故在開發治療癌症之新療法中抑制CDK7係有充分理由的。Cyclin-dependent kinases (CDKs) are proteins that play a role in the regulation of cell cycle progression (eg CDK 1, 2, 4, 6, 7) and transcription (eg CDK 7, 8, 9, 12, 13) Kinase family. Aberrant CDK activity resulting from genetic and epigenetic changes leads to uncontrolled cell proliferation, which is often associated with a variety of human cancers. Inhibition of CDKs leads to cell cycle arrest and apoptosis. Therefore, CDKs are viable targets for the development of new anticancer therapies. Cyclin-dependent kinase 7 (CDK7) affects cell cycle progression by phosphorylating and activating CDK 1, 2, 4, and 6, and also regulates transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II For initiation, see Figure 1 for a schematic diagram depicting CDK7 cell cycle progression and the role of transcription. CDK7 overexpression has been reported in various tumor types. Due to CDK7's dual role in cell cycle and transcriptional regulation and its potential role in promoting an immune-stimulating, anti-tumor microenvironment, inhibition of CDK7 is well-reasoned in the development of new therapies for the treatment of cancer.
仍然需要新穎癌症療法，包括使用CDK抑制劑且特別是CDK7抑制劑之療法。There remains a need for novel cancer therapies, including those using CDK inhibitors, and particularly CDK7 inhibitors.
本發明滿足此等及其他需求，本發明係針對治療包括卵巢癌、乳癌及***癌在內之癌症的方法。These and other needs are met by the present invention, which is directed to methods of treating cancers, including ovarian, breast and prostate cancers.
在一個態樣中，本發明包括一種治療癌症之方法，該方法包括向有需要之受試者投與治療有效量的式(I)之化合物： 或其醫藥學上可接受之鹽或立體異構物； 其中： 環A係環烷基、芳基、雜芳基或雜環基； 環B係芳基、環烷基、雜環基或不存在； R 1係氫或烷基； R 2係氫、烷基或環烷基； R 3係氫、烷基或雜芳基； 或者，R 2與R 1或R 3連同其所連接之環原子一起形成5-7員環； R 4在每次出現時係鹵基、烷基、羥基、烷氧基、胺基、硝基、氰基或鹵烷基； R 5係 、 、 或 ；其中R 5'係氫、鹵基、烷基、烷氧基、烷氧基烷基或-(CH 2) 1-3-NR aR b；R 5''係H或烷基； R a及R b各自獨立地為氫、烷基、烷氧基或烷氧基烷基；或者，R a及R b與其所連接之氮原子一起形成含有0-2個獨立地選自N、O及S之額外雜原子的視情況經取代之環；其中視情況選用之取代基係一或多個鹵基、烷基、醯基、羥基、氰基、氰基烷基、鹵烷基、烷氧基、烷氧基烷基、-COOH或-COO-烷基； R 6在每次出現時係鹵基、烷基、羥基、烷氧基、胺基、硝基、氰基或鹵烷基； L 1係*-CR cR d-C(O)-、*-NR eC(O)-或不存在；其中*係與環A之連接點； R c及R d獨立地為氫、烷基或鹵烷基；或者，R c及R d與其所連接之碳一起形成環烷基環； R e係氢或烷基； L 2係-C(O)NH-、-C(O)O-或不存在； m係0、1或2； p係0或1；且 q係0至3； 其中該癌症係選自由以下組成之群：上皮性卵巢癌、三陰性乳癌、激素受體陽性乳癌及轉移性去勢抵抗性***癌；且其中該式(I)之化合物或其醫藥學上可接受之鹽或立體異構物的治療有效量係約5 mg至約500 mg之總每日劑量。 In one aspect, the invention includes a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): or its pharmaceutically acceptable salt or stereoisomer; wherein: ring A is cycloalkyl, aryl, heteroaryl or heterocyclic; ring B is aryl, cycloalkyl, heterocyclic or not Exist; R 1 is hydrogen or alkyl; R 2 is hydrogen, alkyl or cycloalkyl; R 3 is hydrogen, alkyl or heteroaryl; or, R 2 and R 1 or R 3 together with the ring to which they are attached Atoms taken together to form a 5-7 membered ring; R 4 in each occurrence is halo, alkyl, hydroxy, alkoxy, amine, nitro, cyano or haloalkyl; R 5 is , , or ; wherein R 5 'is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or -(CH 2 ) 1-3 -NR a R b ; R 5 '' is H or alkyl; R a and R b are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl; or, R a and R b together with the nitrogen atom to which they are attached contain 0-2 independently selected from N, O and Optionally substituted rings of additional heteroatoms of S; wherein the optional substituents are one or more of halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy radical, alkoxyalkyl, -COOH or -COO-alkyl; each occurrence of R is halo, alkyl, hydroxyl, alkoxy, amine, nitro, cyano or haloalkyl; L 1 is *-CR c R d -C(O)-, *-NR e C(O)- or does not exist; where * is the connection point with ring A; R c and R d are independently hydrogen, alkane Or, R c and R d form a cycloalkyl ring together with the carbon to which they are attached; R e is hydrogen or alkyl; L 2 is -C(O)NH-, -C(O)O - or absent; m is 0, 1 or 2; p is 0 or 1; and q is 0 to 3; wherein the cancer is selected from the group consisting of: epithelial ovarian cancer, triple negative breast cancer, hormone receptor positive Breast cancer and metastatic castration-resistant prostate cancer; and wherein the therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof is a total daily dose of about 5 mg to about 500 mg .
在另一態樣中，本發明包括用於治療有需要之受試者的癌症之方法中的式(I)之化合物或其醫藥學上可接受之鹽或立體異構物；其中該癌症係選自由以下組成之群：上皮性卵巢癌、三陰性乳癌、激素受體陽性乳癌及轉移性去勢抵抗性***癌；且其中該式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係以約5 mg至約500 mg之總每日劑量提供。In another aspect, the invention includes a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, for use in a method of treating cancer in a subject in need thereof; wherein the cancer is selected from the group consisting of: epithelial ovarian cancer, triple negative breast cancer, hormone receptor positive breast cancer and metastatic castration-resistant prostate cancer; and wherein the compound of formula (I) or its pharmaceutically acceptable salt or stereo The isomers are provided in a total daily dosage of about 5 mg to about 500 mg.
在另一態樣中，本發明包括式(I)之化合物或其醫藥學上可接受之鹽或立體異構物用於製造供治療癌症用之藥劑中的用途；其中該癌症係選自由以下組成之群：上皮性卵巢癌、三陰性乳癌、激素受體陽性乳癌及轉移性去勢抵抗性***癌；且其中該用途包含約5 mg至約500 mg之總每日劑量。In another aspect, the present invention includes the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for treating cancer; wherein the cancer is selected from the following The group consisting of: epithelial ovarian cancer, triple negative breast cancer, hormone receptor positive breast cancer, and metastatic castration-resistant prostate cancer; and wherein the use comprises a total daily dose of about 5 mg to about 500 mg.
此等態樣之實施例包括以下視情況存在之特徵中的一或多者。Embodiments of these aspects include one or more of the following optional features.
在一些實施例中，癌症係上皮性卵巢癌。In some embodiments, the cancer is epithelial ovarian cancer.
在一些實施例中，癌症係三陰性乳癌。In some embodiments, the cancer is triple negative breast cancer.
在一些實施例中，癌症係激素受體陽性乳癌。In some embodiments, the cancer is hormone receptor positive breast cancer.
在癌症係激素受體陽性乳癌之一些實施例中，該方法進一步包括向該受試者投與治療有效量的氟維司群(fulvestrant)或其醫藥學上可接受之鹽。In some embodiments where the cancer is hormone receptor positive breast cancer, the method further comprises administering to the subject a therapeutically effective amount of fulvestrant or a pharmaceutically acceptable salt thereof.
在一些實施例中，癌症係轉移性去勢抵抗性***癌。In some embodiments, the cancer is metastatic castration-resistant prostate cancer.
在癌症係轉移性去勢抵抗性***癌一些實施例中，該方法進一步包括向該受試者投與治療有效量的：(a)阿比特龍(abiraterone)或其醫藥學上可接受之鹽及(b)普賴松(prednisone)或其醫藥學上可接受之鹽。In some embodiments where the cancer is metastatic castration-resistant prostate cancer, the method further comprises administering to the subject a therapeutically effective amount of: (a) abiraterone or a pharmaceutically acceptable salt thereof and (b) Prednisone or a pharmaceutically acceptable salt thereof.
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物的治療有效量係約10 mg至約250 mg之總每日劑量。在一些實施例中，總每日劑量係約20 mg至約160 mg。在一些實施例中，總每日劑量係約20 mg至約80 mg。在一些實施例中，總每日劑量係約20 mg至約40 mg。在一些實施例中，總每日劑量係約40 mg至約160 mg。在一些實施例中，總每日劑量係約40 mg至約80 mg。在一些實施例中，總每日劑量係約80 mg至約160 mg。在一些實施例中，總每日劑量係約20 mg、約40 mg、約80 mg或約160 mg。In some embodiments, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is a total daily dose of about 10 mg to about 250 mg. In some embodiments, the total daily dosage ranges from about 20 mg to about 160 mg. In some embodiments, the total daily dosage ranges from about 20 mg to about 80 mg. In some embodiments, the total daily dosage is about 20 mg to about 40 mg. In some embodiments, the total daily dosage is about 40 mg to about 160 mg. In some embodiments, the total daily dosage is about 40 mg to about 80 mg. In some embodiments, the total daily dosage is about 80 mg to about 160 mg. In some embodiments, the total daily dosage is about 20 mg, about 40 mg, about 80 mg, or about 160 mg.
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係經口投與的。在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係每日投與一次。在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係每日投與兩次。In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered orally. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered once daily. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered twice daily.
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係每日兩次以約30 mg至約50 mg投與。In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered at about 30 mg to about 50 mg twice daily.
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物的劑量係每日兩次以40 mg投與。In some embodiments, the dose of the compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered at 40 mg twice daily.
在一些實施例中，氟維司群或其醫藥學上可接受之鹽的治療有效量係約500 mg，經由肌肉內注射投與。In some embodiments, the therapeutically effective amount of fulvestrant, or a pharmaceutically acceptable salt thereof, is about 500 mg, administered via intramuscular injection.
在一些實施例中，氟維司群或其醫藥學上可接受之鹽係前三次劑量每兩週一次且此後每四週一次經由肌肉內注射投與。In some embodiments, fulvestrant or a pharmaceutically acceptable salt thereof is administered by intramuscular injection every two weeks for the first three doses and every four weeks thereafter.
在一些實施例中，氟維司群係以經1至2分鐘投與的兩次250 mg注射液投與。In some embodiments, fulvestrex is administered as two 250 mg injections administered over 1 to 2 minutes.
在一些實施例中，阿比特龍或其醫藥學上可接受之鹽的治療有效量係約1000 mg之總每日劑量；且阿比特龍或其醫藥學上可接受之鹽係經口投與的。In some embodiments, the therapeutically effective amount of abiraterone or a pharmaceutically acceptable salt thereof is a total daily dose of about 1000 mg; and abiraterone or a pharmaceutically acceptable salt thereof is administered orally of.
在一些實施例中，阿比特龍或其醫藥學上可接受之鹽係每日投與一次；且阿比特龍或其醫藥學上可接受之鹽與式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係同時或依序投與的。In some embodiments, abiraterone or a pharmaceutically acceptable salt thereof is administered once a day; and abiraterone or a pharmaceutically acceptable salt thereof and a compound of formula (I) or a pharmaceutically acceptable salt thereof Acceptable salts or stereoisomers are administered simultaneously or sequentially.
在一些實施例中，普賴松之治療有效量係約5 mg之總每日劑量；且普賴松或其醫藥學上可接受之鹽係經口投與的。在一些實施例中，普賴松之治療有效量係約10 mg之總每日劑量；且普賴松或其醫藥學上可接受之鹽係經口投與的。In some embodiments, the therapeutically effective amount of Presone is a total daily dose of about 5 mg; and Presone or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the therapeutically effective amount of Presone is a total daily dose of about 10 mg; and Presone or a pharmaceutically acceptable salt thereof is administered orally.
在一些實施例中，普賴松或其醫藥學上可接受之鹽係每日投與一次；且普賴松或其醫藥學上可接受之鹽與式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係同時或依序投與的。In some embodiments, Presone or a pharmaceutically acceptable salt thereof is administered once a day; and Presone or a pharmaceutically acceptable salt thereof and a compound of formula (I) or a pharmaceutically acceptable salt thereof Acceptable salts or stereoisomers are administered simultaneously or sequentially.
在一些實施例中，癌症係不可手術的、局部晚期的、不可切除的、轉移性的、復發性的實體腫瘤，或其任何組合。In some embodiments, the cancer is an inoperable, locally advanced, unresectable, metastatic, recurrent solid tumor, or any combination thereof.
在一些實施例中，受試者已依序或並行接受至少一種既往內分泌抗癌療法及一種既往CDK4/6抑制劑療法。In some embodiments, the subject has received at least one prior endocrine anticancer therapy and one prior CDK4/6 inhibitor therapy sequentially or concurrently.
在一些實施例中，受試者已接受至少一種既往新穎激素療法。在一些實施例中，該至少一種新穎激素療法係選自以下一或多者：恩雜魯胺(enzalutamide)、阿帕魯胺(apalutamide)、達洛魯胺(darolutamide)、阿比特龍、加利特龍(galeterone)、奥特罗奈(orteronel)及司維特羅(seviteronel)。In some embodiments, the subject has received at least one prior novel hormone therapy. In some embodiments, the at least one novel hormone therapy is selected from one or more of the following: enzalutamide, apalutamide, darolutamide, abiraterone, plus Literone (galeterone), orteronel (orteronel), and seviteronel (seviteronel).
在一些實施例中，受試者已接受既往紫杉烷(taxane)類化學療法，諸如多西他賽(docetaxel)或卡巴他賽(cabazitaxel)。In some embodiments, the subject has received prior taxane-based chemotherapy, such as docetaxel or cabazitaxel.
在一些實施例中，受試者已接受既往全身化學療法。In some embodiments, the subject has received prior systemic chemotherapy.
在一些實施例中，癌症(例如卵巢癌)係鉑抗性的。In some embodiments, the cancer (eg, ovarian cancer) is platinum resistant.
在一些實施例中，受試者已接受既往全身抗癌療法。In some embodiments, the subject has received prior systemic anticancer therapy.
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係每日投與，持續至少28天。In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered daily for at least 28 days.
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係以膠囊投與。In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered in a capsule.
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係以錠劑投與。In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered as a lozenge.
在一些實施例中，受試者在投藥時處於禁食狀態且該受試者視情況在投藥後保持禁食狀態一或多個小時。In some embodiments, the subject is in a fasted state at the time of dosing and the subject optionally remains in a fasted state for one or more hours after dosing.
在一些實施例中，治療引起選自由以下組成之群的一或多種疾病狀態及進展標誌物的臨床相關改善：客觀反應率(ORR)、反應持續時間(DOR)、無進展生存期(PFS)及總體生存期(OS)。In some embodiments, treatment results in a clinically relevant improvement in one or more markers of disease state and progression selected from the group consisting of: Objective Response Rate (ORR), Duration of Response (DOR), Progression Free Survival (PFS) and overall survival (OS).
在一些實施例中，式(I)之化合物或其醫藥學上可接受之鹽或立體異構物係如本文所描述之化合物，例如式(IA)、式(IB)、式(IC)、式(ID)、式(IE)、式(IF)或式(IG)之化合物，或表1之化合物，或其醫藥學上可接受之鹽或立體異構物。In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is a compound as described herein, e.g., formula (IA), formula (IB), formula (IC), A compound of formula (ID), formula (IE), formula (IF) or formula (IG), or a compound of Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof.
在一些实施方案中，該式(I)之化合物係 (S)-(E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺(化合物44A)，其結構描繪於下： ， 或其醫藥學上可接受之鹽。 In some embodiments, the compound of formula (I) is (S) -(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl) Amino)-3-methyl-1-oxobut-2-yl)phenyl)pyridin-2-yl)-4-(N-alphalinyl)but-2-enamide (compound 44A) , whose structure is depicted below: , or a pharmaceutically acceptable salt thereof.
在一些實施例中，該式(I)之化合物係(E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺或其醫藥學上可接受之鹽或立體異構物(化合物44)。化合物44揭示於2016年12月8日公開的題為「Substituted heterocyclyl derivatives as cdk inhibitors」之WO 2016/193939 A1中，其全部內容以引用之方式併入本文中。化合物44A可為2022年6月23日公開的題為「Cocrystal of a cdk inhibitor」之WO 2022/130304 A1中所描述的反丁烯二酸鹽或共晶體形式，其全部內容以引用之方式併入本文中。In some embodiments, the compound of formula (I) is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)- 3-methyl-1-oxobut-2-yl)phenyl)pyridin-2-yl)-4-(N-alphalinyl)but-2-enamide or its pharmaceutically acceptable Salt or Stereoisomer (Compound 44). Compound 44 is disclosed in WO 2016/193939 A1 entitled "Substituted heterocyclyl derivatives as cdk inhibitors" published on December 8, 2016, the entire contents of which are incorporated herein by reference. Compound 44A may be in fumarate or co-crystal form as described in WO 2022/130304 A1 entitled "Cocrystal of a cdk inhibitor" published on June 23, 2022, the entire contents of which are incorporated by reference. into this article.
在另一個態樣中，本發明包括一種治療需要治療之受試者之***癌的方法，該方法包括向該受試者投與治療有效量的： (S)-(E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺(化合物44A)，其結構描繪於下： 化合物44A 或其醫藥學上可接受之鹽； 以及阿比特龍或其醫藥學上可接受之鹽。 In another aspect, the invention includes a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of: (S) -(E)-N-( 5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobut-2-yl)phenyl)pyridine- 2-yl)-4-(N-𠰌linyl)but-2-enamide (compound 44A), the structure of which is depicted below: compound 44A or a pharmaceutically acceptable salt thereof; and abiraterone or a pharmaceutically acceptable salt thereof.
在一些實施例中，該方法進一步包括向該受試者投與普賴松或其醫藥學上可接受之鹽。In some embodiments, the method further comprises administering Presone or a pharmaceutically acceptable salt thereof to the subject.
在一些實施例中，癌症係轉移性去勢抵抗性***癌。In some embodiments, the cancer is metastatic castration-resistant prostate cancer.
在一些實施例中，阿比特龍或其醫藥學上可接受之鹽係每日一次以1000 mg劑量經口投與。In some embodiments, abiraterone, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of 1000 mg once daily.
在一些實施例中，普賴松或其醫藥學上可接受之鹽係每日兩次以5 mg劑量經口投與。In some embodiments, presone or a pharmaceutically acceptable salt thereof is orally administered twice daily at a dose of 5 mg.
本發明之額外態樣、實施例及優勢將在下文之描述中部分地闡述，且將自該描述中可知，或者可藉由本發明之實踐來學習。本發明之實施例及優勢將藉助於所附申請專利範圍中特別指出的要素及組合來實現及獲得。Additional aspects, embodiments and advantages of the invention will be set forth in part in the description which follows, and will be learned from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims.
應理解，前述概述及以下詳細描述僅為示例性及解釋性的，而非對所主張的本發明之限制。It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
相關申請案之交叉引用Cross References to Related Applications
本申請案主張以下各案之優先權及權益：印度專利申請案：2021年12月6日提交之第IN 202111056495號及2022年3月22日提交之第IN 202211015797號；以及美國臨時申請案：2021年12月6日提交之第63/286,364號及2022年3月22日提交之第63/322,298號，該等申請案以全文引用之方式併入本文中。 定義 This application claims priority and benefit from: Indian patent applications: IN 202111056495, filed December 6, 2021 and IN 202211015797, filed March 22, 2022; and U.S. provisional applications: 63/286,364, filed December 6, 2021, and 63/322,298, filed March 22, 2022, which are hereby incorporated by reference in their entirety. definition
除非另外定義，否則本文所使用之所有技術及科學術語均具有與主體內容所屬領域之一般技術者通常所理解相同的含義。如說明書及所附申請專利範圍中所使用，除非有相反說明，否則以下術語具有為便於理解本發明而指示之含義。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter belongs. As used in the specification and appended claims, unless stated to the contrary, the following terms have the meanings indicated to facilitate understanding of the present invention.
如本文所使用，除非另有定義，否則單獨或與其他術語組合的術語「烷基」係指飽和脂族烴鏈，包括C 1-C 10直鏈或C 3-C 10分支鏈烷基。「烷基」之實例包括但不限於甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、異戊基或新戊基，及類似基團。 As used herein, unless otherwise defined, the term "alkyl" alone or in combination with other terms refers to a saturated aliphatic hydrocarbon chain, including C 1 -C 10 straight chain or C 3 -C 10 branched chain alkyl. Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, or neopentyl, and the like group.
如本文所使用，單獨或與其他術語組合的術語「鹵基」或「鹵素」係指氟、氯、溴或碘。As used herein, the term "halo" or "halogen", alone or in combination with other terms, refers to fluorine, chlorine, bromine or iodine.
如本文所使用，術語「鹵烷基」係指經一或多個鹵素原子取代之烷基，其中該等烷基如上文所定義。術語「鹵基」在本文中可與術語「鹵素」互換使用，意謂F、Cl、Br或I。「鹵烷基」之實例包括但不限於氟甲基、二氟甲基、氯甲基、三氟甲基、2,2,2-三氟乙基及類似基團。As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein the alkyl groups are as defined above. The term "halo" is used interchangeably with the term "halogen" herein to mean F, Cl, Br or I. Examples of "haloalkyl" include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.
如本文所使用，單獨或與其他術語組合的術語「羥基(hydroxy)」或「羥基(hydroxyl)」係指-OH。As used herein, the term "hydroxy" or "hydroxyl", alone or in combination with other terms, refers to -OH.
如本文所使用，術語「烷氧基」係指基團烷基-O-或-O-烷基，其中烷基如上文所定義。例示性烷氧基-基團包括但不限於甲氧基、乙氧基、正丙氧基、正丁氧基、三級丁氧基及類似基團。烷氧基可為未經取代的或經一或多個適合的基團取代。As used herein, the term "alkoxy" refers to the group alkyl-O- or -O-alkyl, wherein alkyl is as defined above. Exemplary alkoxy-groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, and the like. An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
如本文所使用，術語「烷氧基烷基」係指基團烷基-O-烷基-，其中烷基及烷氧基如上文所定義。例示性烷氧基烷基-基團包括但不限於甲氧基甲基、乙氧基甲基、甲氧基乙基、異丙氧基甲基及類似基團。As used herein, the term "alkoxyalkyl" refers to the group alkyl-O-alkyl-, wherein alkyl and alkoxy are as defined above. Exemplary alkoxyalkyl-groups include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
如本文所使用，術語「氰基」係指-CN；且術語「氰基烷基」係指經-CN取代之烷基；其中該烷基如上文所定義。As used herein, the term "cyano" refers to -CN; and the term "cyanoalkyl" refers to an alkyl group substituted with -CN; wherein the alkyl group is as defined above.
如本文所使用，術語「胺基」係指-NH 2； 如本文所使用，術語「硝基」係指-NO 2； 如本文所使用，術語「醯基」係指基團-C(O)-烷基，其中烷基如上文所定義。例示性烷氧基-基團包括但不限於乙醯基、丙醯基及丙烯醯基。烷氧基可為未經取代的或經一或多個適合的基團取代。 As used herein, the term "amino" refers to -NH 2 ; as used herein, the term "nitro" refers to -NO 2 ; as used herein, the term "acyl" refers to the group -C(O )-alkyl, wherein alkyl is as defined above. Exemplary alkoxy-groups include, but are not limited to, acetyl, propionyl, and acryl. An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
如本文所使用，單獨或與其他術語組合的術語「環烷基」係指-C 3-C 10飽和環狀烴環。環烷基可為單環，其典型地含有3至7個碳環原子。單環環烷基之實例包括但不限於環丙基、環丁基、環戊基、環己基、環庚基及類似基團。或者，環烷基可為多環的或含有多於一個環。多環環烷基之實例包括橋接的、稠合的及螺環基，及類似基團。 As used herein, the term "cycloalkyl" alone or in combination with other terms refers to a -C 3 -C 10 saturated cyclic hydrocarbon ring. Cycloalkyl groups can be monocyclic, which typically contain from 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Alternatively, a cycloalkyl group may be polycyclic or contain more than one ring. Examples of multicyclic cycloalkyl groups include bridged, fused and spirocyclic groups, and the like.
如本文所使用，術語「芳基」係具有約6至14個碳原子的視情況經取代之單環、雙環或多環芳族烴環系統。C 6-C 14芳基之實例包括但不限於苯基、萘基、蒽基、四氫萘基、茀基、二氫茚基、聯苯基及苊基(acenaphthyl)。芳基可為未經取代的或經一或多個適合的基團取代。 As used herein, the term "aryl" refers to an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system having about 6 to 14 carbon atoms. Examples of C 6 -C 14 aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fenyl, indenyl, biphenyl, and acenaphthyl. An aryl group can be unsubstituted or substituted with one or more suitable groups.
術語「雜環烷基」係指具有至少一個選自O、N、S、S(O)、S(O) 2、NH及C(O)之雜原子或雜基團且其餘環原子獨立地選自由碳、氧、氮及硫組成之群的3至15員非芳族、飽和或部分飽和單環或多環環系統。單環雜環烷基可典型地含有4至7個環原子。「雜環烷基」之實例包括但不限於氮雜環丁烷基、氧雜環丁烷基、咪唑啶基、吡咯啶基、噁唑啶基、噻唑啶基、吡唑啶基、四氫呋喃基、哌啶基、哌𠯤基、四氫哌喃基、𠰌啉基、噁哌𠯤基、噁哌啶基、四氫呋喃基、四氫哌喃基、四氫噻吩基、二氫哌喃基、吲哚啉基、吲哚啉基甲基、氮呯基及其N-氧化物。雜環烷基取代基可經由碳原子或雜原子連接。雜環烷基可視情況藉由一或多個上述基團經一或多個適合的基團取代。 The term "heterocycloalkyl" refers to having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) 2 , NH and C(O) and the remaining ring atoms are independently A 3 to 15 membered non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system selected from the group consisting of carbon, oxygen, nitrogen and sulfur. Monocyclic heterocycloalkyl groups can typically contain 4 to 7 ring atoms. Examples of "heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuryl , piperidinyl, piperyl, tetrahydropyranyl, mercaptolinyl, oxapiperyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, ind Indolinyl, indolinylmethyl, azolinyl and N-oxides thereof. A heterocycloalkyl substituent can be attached via a carbon atom or a heteroatom. Heterocycloalkyl is optionally substituted by one or more of the above groups with one or more suitable groups.
如本文所使用，單獨或與其他術語組合的術語「雜芳基」意謂含有總計5至14個環原子的完全不飽和之環系統。至少一個環原子係雜原子(亦即，氧、氮或硫)，且其餘環原子/基團獨立地選自由碳、氧、氮及硫組成之群。雜芳基可為有單個環(單環)或多環之環系統。「雜芳基」之實例包括但不限於吡啶基、吲哚基、苯并咪唑基、苯并噻唑基及類似基團。As used herein, the term "heteroaryl", alone or in combination with other terms, means a fully unsaturated ring system containing a total of 5 to 14 ring atoms. At least one ring atom is a heteroatom (ie, oxygen, nitrogen, or sulfur), and the remaining ring atoms/groups are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl group can be a ring system having a single ring (monocycle) or multiple rings. Examples of "heteroaryl" include, but are not limited to, pyridyl, indolyl, benzimidazolyl, benzothiazolyl, and the like.
如本文所使用，單獨或與其他術語組合的術語「雜環基」包括如上文所定義的「雜環烷基」及「雜芳基」。As used herein, the term "heterocyclyl", alone or in combination with other terms, includes "heterocycloalkyl" and "heteroaryl" as defined above.
如本文所使用，術語「雜原子」係指硫、氮或氧原子。As used herein, the term "heteroatom" refers to a sulfur, nitrogen or oxygen atom.
如以上定義中所使用，術語「視情況經取代」或「經取代」或「視情況經適合的基團取代」係指用指定取代基之基團置換給定結構中之一或多個氫基團，該指定取代基之基團包括但不限於：鹵基、烷基、烯基、炔基、芳基、雜環基、硫醇、烷硫基、芳硫基、烷硫基烷基、芳硫基烷基、烷基磺醯基、烷基磺醯基烷基、芳基磺醯基烷基、烷氧基、芳氧基、芳烷氧基、胺基羰基、烷基胺基羰基、芳基胺基羰基、烷氧基羰基、芳氧基羰基、鹵烷基、胺基，三氟甲基、氰基、硝基、烷基胺基、芳基胺基、烷基胺基烷基、芳基胺基烷基、胺基烷基胺基、羥基、烷氧基烷基、羧基烷基、烷氧基羰基烷基、胺基羰基烷基、醯基、芳烷氧基羰基、羧酸、磺酸、磺醯基、膦酸、芳基及雜芳基。應理解，取代基可進一步經取代。As used in the definitions above, the term "optionally substituted" or "substituted" or "optionally substituted with a suitable group" refers to the replacement of one or more hydrogens in a given structure with a radical of the specified substituent Group, the designated substituent group includes but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl , arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylamino Carbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylamino Alkyl, arylaminoalkyl, aminoalkylamino, hydroxyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl , carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl and heteroaryl. It is understood that substituents may be further substituted.
如本文所使用，術語「化合物」包含本發明中所揭示之化合物。As used herein, the term "compound" includes compounds disclosed in the present invention.
如本文所使用，術語「包含(comprise)」或「包含(comprising)」一般以包括之意義使用，亦即，允許存在一或多種特徵或組分。As used herein, the terms "comprise" or "comprising" are generally used in an inclusive sense, that is, allowing for the presence of one or more features or components.
除非另有說明，否則如本文所使用，術語「或」意謂「及/或」。As used herein, the term "or" means "and/or" unless stated otherwise.
如本文所使用，術語「包括(including)」以及諸如「包括(include)」、「包括(includes)」及「包括(included)」之類其他形式並非限制性的。As used herein, the term "including" and other forms such as "include", "includes" and "included" are not limiting.
如本文所使用，術語「組成物」意圖涵蓋包含指定量之指定成分的產物，以及由指定量之指定成分的組合直接或間接產生的任何產物。As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from the combination of the specified ingredients in the specified amounts.
術語「治療(treatment)」/「治療(treating)」意謂對哺乳動物疾病之任何治療，包括：(a)抑制疾病，亦即，減慢或停滯臨床症狀之發展；及/或(b)緩解疾病，亦即，引起臨床症狀之消退；及/或(c)減輕或消除疾病及/或其伴隨症狀。The term "treatment"/"treating" means any treatment of a disease in a mammal, including: (a) inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or (b) Alleviate the disease, ie, cause resolution of clinical symptoms; and/or (c) alleviate or eliminate the disease and/or its accompanying symptoms.
如本文所使用，術語「預防(prevent)」、「預防(preventing)」及「預防(prevention)」係指預防疾病及/或其伴隨症狀之發作或者阻止受試者患上疾病的方法。如本文所使用，「預防(prevent)」、「預防(preventing)」及「預防(prevention)」亦包括延緩疾病及/或其伴隨症狀之發作以及降低受試者患疾病之風險。As used herein, the terms "prevent", "preventing" and "prevention" refer to methods of preventing the onset of a disease and/or its accompanying symptoms or preventing a subject from developing a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its accompanying symptoms and reducing a subject's risk of developing the disease.
「醫藥學上可接受」意謂可用於製備醫藥組成物的大體上安全、無毒且在生物學上及在其他方面皆非不合需要的物質，且包括獸醫學及人類醫藥使用可接受者。"Pharmaceutically acceptable" means a substantially safe, non-toxic and neither biologically nor otherwise undesirable substance that can be used in the preparation of a pharmaceutical composition, and includes those acceptable for veterinary and human pharmaceutical use.
術語「醫藥學上可接受之鹽」係指由本發明之化合物與適合酸或鹼反應而獲得的產物。本發明之化合物的醫藥學上可接受之鹽包括衍生自適合無機鹼的鹽，諸如Li、Na、K、Ca、Mg、Fe、Cu、Al、Zn及Mn鹽。醫藥學上可接受之無毒酸加成鹽的實例係胺基與無機酸形成的鹽，諸如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、異菸鹼酸鹽、乙酸鹽、乳酸鹽、柳酸鹽、檸檬酸鹽、酒石酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、琥珀酸鹽、順丁烯二酸鹽、龍膽酸鹽、反丁烯二酸鹽、葡糖酸鹽、葡糖醛酸鹽、蔗糖酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、4-甲基苯磺酸鹽或對甲苯磺酸鹽，及類似鹽。某些本發明之化合物可以與各種有機鹼，諸如離胺酸、精胺酸、胍、二乙醇胺及二甲雙胍形成醫藥學上可接受之鹽。適合的鹼鹽包括但不限於鋁鹽、鈣鹽、鋰鹽、鎂鹽、鉀鹽、鈉鹽及鋅鹽。The term "pharmaceutically acceptable salt" refers to the products obtained by reacting a compound of the present invention with a suitable acid or base. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amine groups with inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogensulfate, phosphate , Isonicotinate, Acetate, Lactate, Salicylate, Citrate, Tartrate, Pantothenate, Bitartrate, Ascorbate, Succinate, Maleate, Gentisate , fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate acid, 4-methylbenzenesulfonate or p-toluenesulfonate, and similar salts. Certain compounds of the present invention can form pharmaceutically acceptable salts with various organic bases, such as lysine, arginine, guanidine, diethanolamine, and metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc salts.
術語「立體異構物」係指式(I)、式(IA)、式(IB)、式(IC)、式(ID)、式(IE)、式(IF)及式(IG)之化合物的任何鏡像異構物、非鏡像異構物或幾何異構物，不管該等異構物具有對掌性還是當其帶有一或多個雙鍵時。當式(I)、式(IA)、式(IB)、式(IC)、式(ID)、式(IE)、式(IF)及式(IG)之化合物具有對掌性時，其可以外消旋形式或光學活性形式存在。應理解，本發明涵蓋所有立體化學異構形式，包括非鏡像異構、鏡像異構及差向異構形式，以及d-異構物及l-異構物，以及其混合物。化合物之個別立體異構物可由含有對掌性中心的市售起始物質，以合成方式製備，或者藉由製備鏡像異構產物之混合物，隨後分離，諸如轉化為非鏡像異構物混合物，隨後進行分離或再結晶、層析技術、在對掌性層析管柱上直接分離鏡像異構物，或此項技術中已知之任何其他適當的方法製備。具有特定立體化學之起始化合物為市售的或可利用此項技術中已知之技術製備及解析。此外，本發明之化合物可以幾何異構物存在。本發明包括所有順式/反式、同側/異側、反式(entgegen，E)/順式(zusammen，Z)、(R)/(S)異構物及其適當混合物。The term "stereoisomer" refers to compounds of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), formula (IF) and formula (IG) Any enantiomer, diastereoisomer or geometric isomer of , whether such isomer is chiral or when it bears one or more double bonds. When the compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IE), formula (IF) and formula (IG) has chirality, it can Exist in racemic or optically active form. It is to be understood that the present invention encompasses all stereochemical isomeric forms, including diastereomers, enantiomers and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of compounds may be prepared synthetically from commercially available starting materials containing anti-chiral centers, or by preparing a mixture of enantiomerically isomeric products, followed by isolation, such as conversion into a diastereomer mixture, followed by Preparation by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on opposed chiral chromatography columns, or any other suitable method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be prepared and resolved using techniques known in the art. Furthermore, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis/trans, ipsi/iso, trans (entgegen, E)/cis (zusammen, Z), (R)/(S) isomers and appropriate mixtures thereof.
在某些實施例中，本發明之化合物亦可在構成此類化合物之一或多個原子處含有非天然比例之原子同位素。舉例而言，本發明亦包括本發明的同位素標記之變體，該等變體與本文所描述者相同，但實際上，化合物之一或多個原子經原子質量或質量數不同於通常在自然界中發現的該原子之主要原子質量或質量數的原子置換。指定的任何特定原子或元素之所有同位素皆涵蓋在本發明之化合物及其用途的範圍內。可以併入本發明之化合物中的例示性同位素包括氫、碳、氮、氧、磷、硫、氟、氯及碘之同位素，諸如 2H (「D」)、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 32P、 33P、 35S、 18F、 36Cl、 123I及 125I。本發明的同位素標記之化合物一般可藉由遵循此項技術中熟知之程序，諸如藉由用同位素標記之試劑取代非同位素標記之試劑來製備。 In certain embodiments, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the invention also includes isotopically labeled variants of the invention that are identical to those described herein, but in which one or more atoms of the compound differ by atomic mass or mass number from those normally found in nature. atomic substitution of the principal atomic mass or mass number of the atom found in . All isotopes of any particular atom or element specified are encompassed within the scope of the compounds of the invention and their uses. Exemplary isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H ("D"), 3 H, 11 C, 13 C , 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Isotopically labeled compounds of the invention can generally be prepared by following procedures well known in the art, such as by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
如本文所使用，術語「醫藥學上可接受之載劑」係指任何標準醫藥載劑，諸如磷酸鹽緩衝鹽水溶液、水、乳液(例如油/水或水/油乳液)及各種類型之潤濕劑。該等組成物亦可包括穩定劑及防腐劑。載劑、穩定劑及佐劑之實例在文獻，如Martin, Remington's Pharmaceutical Sciences, 第15版, Mack Publ. Co., Easton, PA (1975)中有提及。As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate buffered saline solution, water, emulsions (such as oil/water or water/oil emulsions), and various types of lubricants. aerosol. The compositions may also include stabilizers and preservatives. Examples of carriers, stabilizers and adjuvants are mentioned in the literature, eg, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).
如本文所使用，術語「受試者」係指動物，較佳為哺乳動物，且最佳為人類患者。As used herein, the term "subject" refers to an animal, preferably a mammal, and most preferably a human patient.
如本文所使用，術語「治療有效量」係指在患有癌症之特定受試者中有效產生所希望之治療反應的本發明之化合物或其醫藥學上可接受之鹽或立體異構物，或包含本發明之化合物或其醫藥學上可接受之鹽或立體異構物之組成物的量。特定言之，術語「治療有效量」包括當投與時誘導待治療疾病或病症之積極改變或足以預防受試者正在治療之疾病或病症之一或多種症狀的發展或在某種程度上減輕該一或多種症狀的本發明之化合物或其醫藥學上可接受之鹽或立體異構物的量。就該化合物之治療量而言，用於治療受試者的化合物之量足夠低以避免不當或嚴重的副作用，亦可在合理醫學判斷範圍內考慮。該化合物或組成物之治療有效量將隨所治療之特定病況、所治療或預防之病況的嚴重程度、治療之持續時間、並行療法之性質、最終使用者之年齡及身體狀況、所採用之具體化合物或組成物及所用特定醫藥學上可接受之載劑而變化。 化合物 As used herein, the term "therapeutically effective amount" refers to a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, effective to produce a desired therapeutic response in a particular subject suffering from cancer, Or the amount of a composition comprising a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof. In particular, the term "therapeutically effective amount" includes an amount that, when administered, induces a positive change in the disease or condition being treated or is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of the disease or condition being treated in the subject. The amount of a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, for the one or more symptoms. With respect to therapeutic amounts of the compound, the amount of the compound used to treat the subject is low enough to avoid undue or serious side effects, and may also be considered within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific Depending on the compound or composition and the particular pharmaceutically acceptable carrier employed. compound
本發明之方法包括投與式(I)之化合物： 或其醫藥學上可接受之鹽或立體異構物； 其中： 環A係環烷基、芳基、雜芳基或雜環基； 環B係芳基、環烷基、雜環基或不存在； R 1係氫或烷基； R 2係氫、烷基或環烷基； R 3係氫、烷基或雜芳基； 或者，R 2與R 1或R 3連同其所連接之環原子一起形成5-7員環； R 4在每次出現時係鹵基、烷基、羥基、烷氧基、胺基、硝基、氰基或鹵烷基； R 5係 、 、 或 ；其中R 5'係氫、鹵基、烷基、烷氧基、烷氧基烷基或-(CH 2) 1-3-NR aR b；R 5”係H或烷基； R a及R b各自獨立地為氫、烷基、烷氧基或烷氧基烷基；或者，R a及R b與其所連接之氮原子一起形成含有0-2個獨立地選自N、O及S之額外雜原子的視情況經取代之環；其中視情況選用之取代基係一或多個鹵基、烷基、醯基、羥基、氰基、氰基烷基、鹵烷基、烷氧基、烷氧基烷基、-COOH或-COO-烷基； R 6在每次出現時係鹵基、烷基、羥基、烷氧基、胺基、硝基、氰基或鹵烷基； L 1係*-CR cR d-C(O)-、*-NR eC(O)-或不存在；其中*係與環A之連接點； R c及R d獨立地為氫、烷基或鹵烷基；或者，R c及R d與其所連接之碳一起形成環烷基環； R e係氢或烷基； L 2係-C(O)NH-、-C(O)O-或不存在； m係0、1或2； p係0或1；且 q係0至3。 The methods of the invention comprise administering a compound of formula (I): or its pharmaceutically acceptable salt or stereoisomer; wherein: ring A is cycloalkyl, aryl, heteroaryl or heterocyclic; ring B is aryl, cycloalkyl, heterocyclic or not Exist; R 1 is hydrogen or alkyl; R 2 is hydrogen, alkyl or cycloalkyl; R 3 is hydrogen, alkyl or heteroaryl; or, R 2 and R 1 or R 3 together with the ring to which they are attached Atoms taken together to form a 5-7 membered ring; R 4 in each occurrence is halo, alkyl, hydroxy, alkoxy, amine, nitro, cyano or haloalkyl; R 5 is , , or ; wherein R 5 ' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or -(CH 2 ) 1-3 -NR a R b ; R 5 "is H or alkyl; R a and Each R b is independently hydrogen, alkyl, alkoxy or alkoxyalkyl; or, R a and R b form together with the nitrogen atom to which they are attached, containing 0-2 independently selected from N, O and S Optionally substituted rings with additional heteroatoms; wherein the optional substituents are one or more of halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy , alkoxyalkyl, -COOH or -COO-alkyl; R in each occurrence is halo, alkyl, hydroxyl, alkoxy, amine, nitro, cyano or haloalkyl; L 1 is *-CR c R d -C(O)-, *-NR e C(O)- or does not exist; where * is the connection point with ring A; R c and R d are independently hydrogen, alkyl Or haloalkyl; Or, R c and R d form a cycloalkyl ring together with the carbon to which they are attached; R e is hydrogen or alkyl; L 2 is -C(O)NH-, -C(O)O- or absent; m is 0, 1 or 2; p is 0 or 1; and q is 0-3.
在一些實施例中，本發明之方法包括投與式(IA)表示的式(I)之化合物： 或其醫藥學上可接受之鹽或其立體異構物； 其中： 環A係環烷基、芳基、雜芳基或雜環基； 環B係芳基、環烷基、雜環基或不存在； R 1係氫或烷基； R 2係氫、烷基或環烷基； R 3係氫、烷基或雜芳基； 或者，R 2與R 1或R 3連同其所連接之環原子一起形成5-7員環； R 4在每次出現時係鹵基、烷基、羥基或烷氧基； R 5係 、 、 或 ；其中R 5'係氫、鹵基、烷基、烷氧基、烷氧基烷基或-(CH 2) 1-3-NR aR b；R 5”係H或烷基； R a及R b各自獨立地為氫或烷基；或者，R a及R b連同其所連接之氮原子一起形成含有0-2個獨立地選自N、O及S之額外雜原子的視情況經取代之環；其中視情況選用之取代基係一或多個鹵基、烷基、羥基、鹵烷基或烷氧基； L 1係*-CR cR d-C(O)-、*-NR eC(O)-或不存在；其中*係與環A之連接點； R c及R d獨立地為氫、烷基或鹵烷基；或者，R c及R d與其所連接之碳一起形成環烷基環； R e係氢或烷基； L 2係-C(O)NH-、-C(O)O-或不存在； m係0、1或2；且 p係0或1。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) represented by formula (IA): or its pharmaceutically acceptable salt or its stereoisomer; wherein: ring A is cycloalkyl, aryl, heteroaryl or heterocyclic; ring B is aryl, cycloalkyl, heterocyclic or Absent; R 1 is hydrogen or alkyl; R 2 is hydrogen, alkyl or cycloalkyl; R 3 is hydrogen, alkyl or heteroaryl; or, R 2 and R 1 or R 3 together with the The ring atoms are taken together to form a 5-7 membered ring; R4 in each occurrence is halo, alkyl, hydroxy or alkoxy; R5 is , , or ; wherein R 5 ' is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or -(CH 2 ) 1-3 -NR a R b ; R 5 "is H or alkyl; R a and Each R b is independently hydrogen or alkyl; alternatively, R a and R b together with the nitrogen atom to which they are attached form an optionally substituted The ring; where the optional substituents are one or more halo, alkyl, hydroxyl, haloalkyl or alkoxy; L 1 is *-CR c R d -C(O)-, *-NR e C(O)- or absent; where * is the point of attachment to ring A; R c and R d are independently hydrogen, alkyl or haloalkyl; or, R c and R d are together with the carbon to which they are attached Forms a cycloalkyl ring; Re is hydrogen or alkyl; L is -C(O)NH-, -C(O)O- or absent; m is 0, 1 or 2; and p is 0 or 1 .
在一些實施例中，本發明之方法包括投與式(IB)所表示的式(I)之化合物： 或其醫藥學上可接受之鹽或其立體異構物。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) represented by formula (IB): Or a pharmaceutically acceptable salt or a stereoisomer thereof.
在一些實施例中，本發明之方法包括投與式(IC)所表示的式(I)之化合物： 或其醫藥學上可接受之鹽或其立體異構物。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) represented by formula (IC): Or a pharmaceutically acceptable salt or a stereoisomer thereof.
在一些實施例中，本發明之方法包括投與式(ID)所表示的式(I)之化合物： 或其醫藥學上可接受之鹽或其立體異構物。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) represented by formula (ID): Or a pharmaceutically acceptable salt or a stereoisomer thereof.
在一些實施例中，本發明之方法包括投與式(IE)所表示的式(I)之化合物： 或其醫藥學上可接受之鹽或其立體異構物；其中L 1係*-CR cR d-C(O)-或*-NR eC(O)-；其中*係與苯環之連接點。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) represented by formula (IE): or its pharmaceutically acceptable salt or its stereoisomer; wherein L 1 is *-CR c R d -C(O)- or *-NR e C(O)-; Junction.
在一些實施例中，本發明之方法包括投與式(IF)所表示的式(I)之化合物： 或其醫藥學上可接受之鹽或其立體異構物；其中L 1係*-CR cR d-C(O)-或*-NR eC(O)-；其中*係與苯環之連接點。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) represented by formula (IF): or its pharmaceutically acceptable salt or its stereoisomer; wherein L 1 is *-CR c R d -C(O)- or *-NR e C(O)-; Junction.
在一些實施例中，本發明之方法包括投與式(IG)所表示的式(I)之化合物： 或其醫藥學上可接受之鹽或其立體異構物。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) represented by formula (IG): Or a pharmaceutically acceptable salt or a stereoisomer thereof.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中環A係芳基或雜芳基。In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is aryl or heteroaryl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中環A係芳基。In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is aryl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中環A係1,3-伸苯基。In some embodiments, the methods of the present invention comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is 1,3-phenylene.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中環B係單環或雙環環烷基、芳基、雜環烷基或雜芳基。In some embodiments, the methods of the present invention comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a monocyclic or bicyclic cycloalkyl, aryl, heterocycloalkyl or hetero Aryl.
根據另一個實施例，投與B環為芳基的式(I)之化合物或其醫藥學上可接受之鹽；較佳地，該芳基係苯基。According to another embodiment, the compound of formula (I) whose ring B is aryl or a pharmaceutically acceptable salt thereof is administered; preferably, the aryl is phenyl.
根據又一個實施例，投與環B係雜環基的式(I)之化合物或其醫藥學上可接受之鹽；較佳地，該雜環基係哌啶基、吡啶基、哌𠯤基、吡唑基、𠰌啉基、吲哚啉基或吡咯啶基。According to yet another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered with a ring B heterocyclic group; preferably, the heterocyclic group is piperidinyl, pyridyl, piperhexyl , pyrazolyl, 𠰌linyl, indolinyl or pyrrolidinyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 2係環烷基。在一些實施例中，本發明之方法包括式(I)之化合物或其醫藥學上可接受之鹽，其中R 5係 、 或 。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is cycloalkyl. In some embodiments, the methods of the present invention include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is , or .
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5'係-(CH 2) 1-3-NR aR b。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5 ' is -(CH 2 ) 1-3 -NR a R b .
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R a及R b與其所連接之氮原子一起形成具有0-2個選自O、S及N之額外雜原子的視情況經取代之雜環。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R a and R b form, together with the nitrogen atom to which they are attached, 0-2 Optionally substituted heterocycles with additional heteroatoms of O, S and N.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中L 1係*-CR cR d-C(O)-；其中*係與環A之連接點。 In some embodiments, the method of the present invention comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L 1 is *-CR c R d -C(O)-; wherein * is the same as The connection point of ring A.
根據前述實施例，投與式(I)之化合物或其醫藥學上可接受之鹽，其中R c及R d獨立地為氫或烷基，其中該烷基係甲基、乙基或異丙基。 According to the foregoing embodiments, administer a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R c and R d are independently hydrogen or an alkyl group, wherein the alkyl group is methyl, ethyl or isopropyl base.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中L 2不存在。 In some embodiments, the methods of the invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2 is absent.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中當L 1存在時，L 2不存在。 In some embodiments, the methods of the invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein when L1 is present, L2 is absent.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 2係烷基或環烷基；較佳地，該烷基係乙基且該環烷基係環丙基、環丁基或環戊基。 In some embodiments, the methods of the present invention include administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is alkyl or cycloalkyl; preferably, the alkyl is ethyl And the cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 3係氫及烷基；其中該烷基係甲基。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen and alkyl; wherein the alkyl is methyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 4係鹵基；較佳地，該鹵基係氟。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 is halo; preferably, the halo is fluorine.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5係 ；其中R 5'係氫或-CH 2-NR aR b。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is ; wherein R 5 'is hydrogen or -CH 2 -NR a R b .
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中當R 5連接至環B之雜原子時，R 5係 ；R 5'係氫或-CH 2-NR aR b。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein when R 5 is attached to a heteroatom of ring B, R 5 is ; R 5 'is hydrogen or -CH 2 -NR a R b .
根據前述兩個實施例，該R a及R b可以各自獨立地為氫或烷基；較佳地，該烷基係甲基。 According to the aforementioned two embodiments, the R a and R b can each independently be hydrogen or an alkyl group; preferably, the alkyl group is a methyl group.
根據前述實施例，該R a及R b與其所連接之氮一起可以形成含有0-2個獨立地選自N、O及S之額外雜原子的視情況經取代之環；其中視情況選用之取代基係一或多個鹵基、羥基、鹵烷基或烷氧基。 According to the foregoing embodiment, the R a and R b together with the nitrogen to which they are attached may form an optionally substituted ring containing 0-2 additional heteroatoms independently selected from N, O, and S; The substituents are one or more halo, hydroxy, haloalkyl or alkoxy groups.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中環A關於L 1及L 2為間位取代的。 In some embodiments, the methods of the invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is meta-substituted with respect to L1 and L2 .
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中環B係單環或雙環環烷基、芳基、雜環烷基或雜芳基。In some embodiments, the methods of the present invention comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a monocyclic or bicyclic cycloalkyl, aryl, heterocycloalkyl or hetero Aryl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中環B係雜環基；在一些實施例中，該雜環基係哌啶基、吡啶基、1,2,3,6-四氫吡啶基、哌𠯤基、吡𠯤基、吡唑基、𠰌啉基、吲哚啉基或吡咯啶基。In some embodiments, the methods of the present invention comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a heterocyclyl; in some embodiments, the heterocyclyl is piperidine Base, pyridyl, 1,2,3,6-tetrahydropyridyl, piperyl, pyridyl, pyrazolyl, pyridyl, indolinyl or pyrrolidinyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中m係0或1。In some embodiments, the methods of the present invention comprise administering a compound of formula (I), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中m係1。In some embodiments, the methods of the present invention comprise administering a compound of formula (I), wherein m is 1, or a pharmaceutically acceptable salt thereof.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中m係1或2。In some embodiments, the methods of the present invention comprise administering a compound of formula (I), wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中n係1。In some embodiments, the methods of the present invention comprise administering a compound of formula (I), wherein n is 1, or a pharmaceutically acceptable salt thereof.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 2係環烷基；在一些實施例中，該環烷基係環丙基、環丁基或環戊基。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is cycloalkyl; in some embodiments, the cycloalkyl is cyclopropyl base, cyclobutyl or cyclopentyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 2及R 1與其所連接之原子一起形成5員或6員環。 In some embodiments, the methods of the invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2 and R1 together with the atoms to which they are attached form a 5- or 6-membered ring.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 2及R 3與其所連接之原子一起形成5員或6員環。 In some embodiments, the methods of the invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the atoms to which they are attached form a 5- or 6-membered ring.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 2及R 3與其所連接之原子一起形成6員環。 In some embodiments, the methods of the invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the atoms to which they are attached form a 6-membered ring.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5係 或 ；其中R 5'係氫、鹵基、烷基、烷氧基或烷氧基烷基；且R 5”係H或烷基。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is or ; wherein R 5 ' is hydrogen, halo, alkyl, alkoxy or alkoxyalkyl; and R 5 " is H or alkyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5係 或 ；其中R 5'係-CH 2-NR aR b；R 5”係H或烷基；且R a及R b各自獨立地為氫、烷基、烷氧基或烷氧基烷基。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is or ; wherein R 5 ' is -CH 2 -NR a R b ; R 5 " is H or alkyl; and R a and R b are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5係 或 ；其中R 5'係-CH 2-NR aR b；R 5”係H或烷基；R a及R b與其所連接之氮原子一起形成含有0-2個獨立地選自N、O及S之額外雜原子的視情況經取代之4-7員雜環基環；其中視情況選用之取代基係一或多個鹵基、烷基、醯基、羥基、氰基、氰基烷基、鹵烷基、烷氧基、烷氧基烷基、-COOH或-COO-烷基。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is or ; wherein R 5 ' is -CH 2 -NR a R b ; R 5 "is H or an alkyl group; R a and R b are formed together with the nitrogen atom to which they are attached, containing 0-2 independently selected from N, O and Optionally substituted 4-7 membered heterocyclyl rings with additional heteroatoms to S; wherein the optional substituents are one or more of halo, alkyl, acyl, hydroxy, cyano, cyanoalkyl , haloalkyl, alkoxy, alkoxyalkyl, -COOH or -COO-alkyl.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5係 ；其中p、R a及R b如上文所定義。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is ; wherein p, R a and R b are as defined above.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5係 、 、 、 或 ；其中 係與環B之連接點。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R is , , , or ;in It is the connection point with Ring B.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中R 5'係-(CH 2) 1-3-NR aR b；其中R a及R b如上文所定義。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 ' is -(CH 2 ) 1-3 -NR a R b ; wherein R a and R b are as defined above.
在一些實施例中，本發明之方法包括投與式(I)之化合物或其醫藥學上可接受之鹽，其中當L 1係-CR cR d-C(O)-或-NR eC(O)-時，L 2不存在。 In some embodiments, the methods of the present invention comprise administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein when L 1 is -CR c R d -C(O)- or -NR e C (O)-, L 2 does not exist.
在一些實施例中，本發明之方法包括投與選自下表1中所列化合物的式(I)之化合物或其醫藥學上可接受之鹽或其立體異構物。
表1. 式(I)之化合物的IUPAC名稱列表
在一些實施例中，本發明之方法包括投與選自以下的式(I)之化合物： (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)-4-((S)-3-氟吡咯啶-1-基)丁-2-烯醯胺； N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)丙烯醯胺； (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺； (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺； (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)-4-(吡咯啶-1-基)丁-2-烯醯胺； (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(二甲基胺基)丁-2-烯醯胺； (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)-4-(哌啶-1-基)丁-2-烯醯胺； (E)-N-(3'-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)-3-氟-[1,1'-聯苯]-4-基)-4-(二甲基胺基)丁-2-烯醯胺；及 (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)-4-(3-氟哌啶-1-基)丁-2-烯醯胺； 或其醫藥學上可接受之鹽或其立體異構物。 In some embodiments, the methods of the invention comprise administering a compound of formula (I) selected from: (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) Pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide; N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridine-2- base) acrylamide; (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutane-2- Base) phenyl) pyridin-2-yl) -4- (N- 𠰌linyl) but-2-enamide; (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) Pyridin-2-yl)-4-(N-𠰌linyl)but-2-enamide; (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) Pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutane-2- Base) phenyl) pyridin-2-yl) -4- (dimethylamino) but-2-enamide; (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) Pyridin-2-yl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(3'-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl) -3-fluoro-[1,1'-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; and (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) Pyridin-2-yl)-4-(3-fluoropiperidin-1-yl)but-2-enamide; Or a pharmaceutically acceptable salt or a stereoisomer thereof.
在一些實施例中，本發明之方法包括投與選自以下的式(I)之化合物： (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺； (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)-4-(吡咯啶-1-基)丁-2-烯醯胺；及 (E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-1-側氧基丙-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺； 或其醫藥學上可接受之鹽或立體異構物。 In some embodiments, the methods of the invention comprise administering a compound of formula (I) selected from: (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutane-2- Base) phenyl) pyridin-2-yl) -4- (N- 𠰌linyl) but-2-enamide; (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; and (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl) Pyridin-2-yl)-4-(N-𠰌linyl)but-2-enamide; or a pharmaceutically acceptable salt or stereoisomer thereof.
在一些實施例中，本發明之方法包括投與式(I)之化合物，即化合物44-A，或其醫藥學上可接受之鹽。In some embodiments, the methods of the present invention comprise administering a compound of formula (I), ie, compound 44-A, or a pharmaceutically acceptable salt thereof.
根據前述實施例，化合物44-A係 (S)-(E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺。 According to the foregoing examples, compound 44-A is (S) -(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)- 3-methyl-1-oxobut-2-yl)phenyl)pyridin-2-yl)-4-(N-alphalinyl)but-2-enamide.
在一些實施例中，本發明之方法包括投與( S)-(E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺反丁烯二酸鹽。 治療方法 In some embodiments, the methods of the invention comprise administering ( S )-(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amine Base)-3-methyl-1-oxobut-2-yl)phenyl)pyridin-2-yl)-4-(N-𠰌linyl)but-2-enamide fumaric acid Salt. treatment method
在美國，上皮性卵巢癌(EOC)係一種侵襲性惡性疾病且為由婦科癌症引起之死亡的主要原因。2018年報告約295,000例新增病例及184,000例由EOC引起之死亡。儘管進行了最佳手術及基於卡鉑(carboplatin)-紫杉烷之一線組合化學療法，但仍有約75%的受試者會出現疾病復發。在一線鉑類化學療法期間復發(鉑難治性)或在完成該化學療法方案後數月內復發(鉑抗性)的受試者具有不良預後。復發性鉑抗性EOC之標準護理療法係單藥化學療法(太平洋紫杉醇(paclitaxel)、聚乙二醇化脂質體多柔比星(doxorubicin)或托泊替康(topotecan))，該化學療法具有適度的臨床活性及10%-20%之客觀反應率(ORR)；3-4個月之中值無進展生存期(PFS)及約12個月之總體生存期(OS)。最近，有若干聚(ADP-核糖)聚合酶(PARP)抑制劑已被批准在既往化學療法後用於患有生殖系BRCA突變型EOC的受試者，或作為對復發性EOC之化學療法有反應之受試者的維持療法(例如奥拉帕尼(olaparib)、鲁卡帕尼(rucaparib)、尼拉帕尼(niraparib))。然而，對於改善在標準護理療法時進展的患復發性鉑難治性/抗性EOC之受試者之臨床結果的醫療需求仍亟待滿足。Epithelial ovarian cancer (EOC) is an aggressive malignant disease and the leading cause of death from gynecological cancers in the United States. Approximately 295,000 new cases and 184,000 deaths attributable to EOC were reported in 2018. Despite optimal surgery and first-line carboplatin-taxane-based combination chemotherapy, approximately 75% of subjects experienced disease recurrence. Subjects who relapse during first-line platinum-based chemotherapy (platinum refractory) or within months of completion of the chemotherapy regimen (platinum resistant) have a poor prognosis. The standard of care for recurrent platinum-resistant EOC is single-agent chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) with modest The clinical activity and the objective response rate (ORR) of 10%-20%; the median progression-free survival (PFS) of 3-4 months and the overall survival (OS) of about 12 months. Recently, several poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for use in subjects with germline BRCA-mutant EOC after prior chemotherapy, or as an effective therapy for recurrent EOC. Maintenance therapy (eg, olaparib, rucaparib, niraparib) for responding subjects. However, there remains an unmet medical need to improve the clinical outcomes of subjects with recurrent platinum-refractory/resistant EOC progressing on standard-of-care regimens.
乳癌係女性最常見的惡性疾病。2018年，全球報告約2,000,000例新增病例及約600,000例乳癌死亡病例。約三分之二的被診斷患有乳癌之女性具有激素受體陽性(HR+)、HER-2陰性腫瘤。在患有復發性或轉移性HR+ BC之受試者中，內分泌療法係較佳的全身治療選擇。內分泌療法之實例包括芳香酶抑制劑(非類固醇型芳香酶抑制劑[NSAI；例如來曲唑(letrozole)、阿那曲唑(anastrozole)]及類固醇芳香酶抑制劑[SAI；例如依西美坦(exemestane)])、選擇性***受體調節劑(SERM；例如他莫昔芬(tamoxifen)、托瑞米芬(toremifene))或選擇性***受體降解劑(SERD；例如氟維司群)。CDK4/6抑制劑作為單藥或與內分泌療法組合時亦展示出臨床益處。對於具有PIK3CA突變且利用化學療法之受試者，在後期治療中投與的其他全身療法包括PI3K抑制劑阿培利司(alpelisib)與氟維司群之組合。儘管有可用的治療方式，但在標準療法時進展的患有侵襲性疾病之受試者仍需要新的治療選擇。Breast cancer is the most common malignant disease in women. In 2018, approximately 2,000,000 new cases and approximately 600,000 breast cancer deaths were reported globally. About two-thirds of women diagnosed with breast cancer have hormone receptor positive (HR+), HER-2 negative tumors. Endocrine therapy is the preferred systemic treatment option in subjects with recurrent or metastatic HR+ BC. Examples of endocrine therapy include aromatase inhibitors (nonsteroidal aromatase inhibitors [NSAI; e.g. letrozole, anastrozole] and steroidal aromatase inhibitors [SAI; e.g. exemestane ( exemestane)]), selective estrogen receptor modulators (SERMs; such as tamoxifen, toremifene), or selective estrogen receptor degraders (SERDs; such as fulvestrant ). CDK4/6 inhibitors have also shown clinical benefit as monotherapy or in combination with endocrine therapy. For subjects with a PIK3CA mutation and on chemotherapy, other systemic therapies administered in later stages of treatment included the combination of the PI3K inhibitor alpelisib and fulvestrant. Despite available treatment modalities, new treatment options are needed for subjects with aggressive disease that progresses on standard therapy.
三陰性乳癌(TNBC)佔所有乳癌的約15%且不表現***及助孕素受體以及HER-2。其構成預後不良之乳癌腫瘤中最具侵襲性的亞型。患有轉移性TNBC之受試者的中值OS僅為約18個月。TNBC通常呈現高級別浸潤性導管癌形式且具有較高的早期復發率，通常伴有遠端轉移。標準護理療法係使用諸如以下藥劑之全身化學療法：紫杉烷類(太平洋紫杉醇)、蒽環類(多柔比星、脂質體多柔比星)、抗代謝藥(吉西他濱(gemcitabine)、卡培他濱(capecitabine))、微管抑制劑(艾瑞布林(eribulin)、長春瑞濱(vinorelbine))或鉑類藥劑(卡鉑、順鉑(cisplatin)；對於具有生殖系BRCA 1/2突變之受試者)。依序給予的單藥療法一般為較佳的，因為其降低毒性及劑量減少之可能性。有關給予單藥療法作為第二線或後期治療之若干後期試驗的統合分析得到11%之匯集ORR (95%信賴區間[CI]，9-14%)及8.1至15.2個月之中值OS範圍。組合化學療法適用於疾病進展迅速或具有疾病相關症狀之受試者，但伴隨毒性增加且僅在OS方面有適度益處。針對TNBC之靶向療法包括用於具有BRCA 1/2突變之受試者的PARP抑制劑(奧拉帕尼、他拉唑帕尼(talazoparib))以及用於接受過至少兩種針對轉移性疾病之既往療法之受試者的戈沙妥珠单抗(sacituzumab govitecan)-hziy。Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers and does not express estrogen and gestogen receptors and HER-2. It constitutes the most aggressive subtype of breast cancer tumors with poor prognosis. The median OS for subjects with metastatic TNBC was only about 18 months. TNBC usually presents as a high-grade invasive ductal carcinoma with a high rate of early recurrence, often with distant metastases. Standard of care therapy is systemic chemotherapy with agents such as taxanes (paclitaxel), anthracyclines (doxorubicin, liposomal doxorubicin), antimetabolites (gemcitabine, Capecitabine), microtubule inhibitors (eribulin, vinorelbine), or platinum agents (carboplatin, cisplatin); for those with germline BRCA 1/2 mutations subjects). Monotherapy administered sequentially is generally preferred because of reduced toxicity and the potential for dose reductions. A pooled ORR of 11% (95% confidence interval [CI], 9-14%) and a median OS range of 8.1 to 15.2 months were obtained from a meta-analysis of several late-stage trials administering monotherapy as second-line or later treatment . Combination chemotherapy is indicated for subjects with rapidly progressive disease or disease-related symptoms, but with increased toxicity and only modest benefit in terms of OS. Targeted therapies for TNBC include PARP inhibitors (olaparib, talazoparib) for subjects with BRCA 1/2 mutations and Gosatuzumab govitecan-hziy for subjects with prior therapy.
2018年，***癌係全球第四大最常診斷之惡性疾病，僅次於肺癌、乳癌及結直腸癌。據報導，有130萬男性患有偶發性***癌，且佔當年所有新增癌症診斷病例的7.1%。***癌係全球男性中最常見的癌症，且亦為美國癌症死亡的第二大主導原因，其中在2018年，其發病率超過膀胱癌、腎癌及睪丸癌之發病率總和。腺癌係最常見的組織學亞型，且典型地與血清***特異性抗原(PSA)升高有關。新發轉移性疾病(轉移性去勢敏感性***癌[mCSPC])佔已開發國家新增***癌病例的3-7%，且在美國，由於近期基於群體之PSA監督下降，其發病率可能會不斷上升。約三分之二的患有放射學攝影定位之晚期疾病的男性係利用手術(根治性***切除術)或放射療法治愈。其餘人將經歷PSA升高、局部放射學攝影復發及/或轉移性疾病所預示之復發。In 2018, prostate cancer was the fourth most commonly diagnosed malignant disease in the world, second only to lung cancer, breast cancer and colorectal cancer. Incidental prostate cancer was reported in 1.3 million men and accounted for 7.1% of all new cancer diagnoses that year. Prostate cancer is the most common cancer among men worldwide, and it is also the second leading cause of cancer death in the United States. In 2018, its incidence exceeded that of bladder cancer, kidney cancer, and testicular cancer combined. Adenocarcinoma is the most common histologic subtype and is typically associated with elevated serum prostate-specific antigen (PSA). De novo metastatic disease (metastatic castration-sensitive prostate cancer [mCSPC]) accounts for 3-7% of new prostate cancer cases in developed countries, and its incidence is likely to decrease in the United States due to the recent decline in population-based PSA surveillance. constant increase. About two-thirds of men with radiographically localized advanced disease are cured with surgery (radical prostatectomy) or radiation therapy. The remainder will experience PSA elevations, focal radiographic recurrences, and/or recurrences heralded by metastatic disease.
由於晚期或轉移性***腺癌具有雄激素依賴性，故雄激素剝奪療法(ADT)係當前該種疾病之治療選擇。去勢抵抗性***癌(CRPC)定義為在ADT期間或之後PSA升高或放射學攝影進展。患有轉移性去勢抵抗性***癌(mCRPC)之受試者的治療替代方案包括化學療法、免疫療法、AR信號傳導路徑受體抑制劑及放射性核素療法。與米托蒽醌加普賴松相比，利用多西他賽加普賴松之化學療法在患有晚期激素難治性(去勢抵抗性)疾病之男性中展示出改善的OS。相對於米托蒽醌，作為結合微管蛋白之紫杉烷類藥物的卡巴他賽在預先用多西他賽治療的經普賴松治療之患有mCRPC之男性中亦顯示出OS及PFS之改善。Due to the androgen-dependent nature of advanced or metastatic prostate adenocarcinoma, androgen deprivation therapy (ADT) is currently the treatment of choice for this disease. Castration-resistant prostate cancer (CRPC) was defined as PSA elevation or radiographic progression during or after ADT. Treatment alternatives for subjects with metastatic castration-resistant prostate cancer (mCRPC) include chemotherapy, immunotherapy, AR signaling pathway receptor inhibitors, and radionuclide therapy. Chemotherapy with docetaxel plus presone showed improved OS compared to mitoxantrone plus presone in men with advanced hormone refractory (castration-resistant) disease. Cabazitaxel, a tubulin-binding taxane, also showed improved OS and PFS relative to mitoxantrone in presone-treated men with mCRPC pretreated with docetaxel improve.
約三分之一的患有轉移性疾病之CRPC受試者對新穎抗雄激素藥(例如阿比特龍、恩雜魯胺)展示出新生抗性，且絕大多數最初有反應的受試者對此等新藥發展出獲得性抗性。因此，針對患有mCRPC之受試者的新穎治療策略尚未得到滿足。Approximately one-third of CRPC subjects with metastatic disease exhibit de novo resistance to novel antiandrogens (e.g., abiraterone, enzalutamide), and the vast majority of subjects who respond initially Acquired resistance to these new drugs develops. Therefore, novel therapeutic strategies for subjects with mCRPC are unmet.
本發明提供治療上皮性卵巢癌、三陰性乳癌、激素受體陽性乳癌及轉移性去勢抵抗性***癌之方法。該等方法包括投與如本文所描述的式(I)之化合物或其醫藥學上可接受之鹽或立體異構物。在一個特定實施例中，該式(I)之化合物係化合物44A或其醫藥學上可接受之鹽。The present invention provides methods of treating epithelial ovarian cancer, triple negative breast cancer, hormone receptor positive breast cancer, and metastatic castration-resistant prostate cancer. The methods comprise administering a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof. In a specific embodiment, the compound of formula (I) is compound 44A or a pharmaceutically acceptable salt thereof.
在一些實施例中，該方法係單藥療法，其中該式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽(例如化合物44-A反丁烯二酸鹽)或其立體異構物係該療法中投與的唯一活性劑。在其他實施例中，將一或多種額外活性劑與式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物聯合投與。In some embodiments, the method is monotherapy, wherein the compound of formula (I) (such as compound 44-A) or a pharmaceutically acceptable salt thereof (such as compound 44-A fumarate) or a stereoisomer thereof is the only active agent administered in the therapy. In other embodiments, one or more additional active agents are administered in combination with a compound of Formula (I) (eg, Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof.
在一些實施例中，本發明提供治療上皮性卵巢癌之方法。在一些實施例中，上皮性卵巢癌係藉由將式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物投與有需要之受試者進行治療。在一些實施例中，上皮性卵巢癌之治療方法係一種單藥療法，其中唯一活性劑係式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物。在一些實施例中，上皮性卵巢癌係鉑抗性的。在一些實施例中，患有上皮性卵巢癌之受試者已接受既往全身抗癌療法。In some embodiments, the present invention provides methods of treating epithelial ovarian cancer. In some embodiments, epithelial ovarian cancer is treated by administering a compound of formula (I), such as compound 44-A, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof treat. In some embodiments, the method of treatment of epithelial ovarian cancer is a monotherapy wherein the sole active agent is a compound of formula (I) (eg Compound 44-A) or a pharmaceutically acceptable salt or stereoisomer thereof thing. In some embodiments, the epithelial ovarian cancer is platinum resistant. In some embodiments, the subject with epithelial ovarian cancer has received prior systemic anticancer therapy.
在一些實施例中，本發明提供治療三陰性乳癌之方法。在一些實施例中，上皮性卵巢癌係藉由將式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物投與有需要之受試者進行治療。在一些實施例中，三陰性乳癌之治療方法係一種單藥療法，其中唯一活性劑係式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物。在一些實施例中，患有三陰性乳癌之受試者已接受既往全身化學療法。In some embodiments, the present invention provides methods of treating triple negative breast cancer. In some embodiments, epithelial ovarian cancer is treated by administering a compound of formula (I), such as compound 44-A, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof treat. In some embodiments, the method of treatment of triple negative breast cancer is a monotherapy wherein the sole active agent is a compound of formula (I) (e.g. compound 44-A) or a pharmaceutically acceptable salt or stereoisomer thereof . In some embodiments, the subject with triple negative breast cancer has received prior systemic chemotherapy.
在一些實施例中，本發明提供治療激素受體陽性乳癌之方法。在一些實施例中，激素受體陽性乳癌係藉由將式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物投與有需要之受試者進行治療。在一些實施例中，激素受體陽性乳癌之治療方法係一種組合療法，其中將以下化合物之治療組合投與有需要之受試者：(i)式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物；以及(ii)氟維司群或其醫藥學上可接受之鹽。在一些實施例中，激素受體陽性乳癌之治療方法係一種單藥療法，其中唯一活性劑係式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物。在一些實施例中，受試者已依序或並行接受至少一種既往內分泌抗癌療法及一種既往CDK4/6抑制劑療法。In some embodiments, the present invention provides methods of treating hormone receptor positive breast cancer. In some embodiments, hormone receptor positive breast cancer is obtained by administering a compound of formula (I) (eg compound 44-A) or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need thereof for treatment. In some embodiments, the method of treatment for hormone receptor positive breast cancer is a combination therapy, wherein a therapeutic combination of the following compounds is administered to a subject in need thereof: (i) a compound of formula (I) (eg, compound 44-A ) or a pharmaceutically acceptable salt or stereoisomer thereof; and (ii) fulvestrant or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treatment of hormone receptor positive breast cancer is a monotherapy wherein the sole active agent is a compound of formula (I) (e.g. compound 44-A) or a pharmaceutically acceptable salt or stereoisomeric structure. In some embodiments, the subject has received at least one prior endocrine anticancer therapy and one prior CDK4/6 inhibitor therapy sequentially or concurrently.
在一些實施例中，本發明提供治療轉移性去勢抵抗性***癌之方法。在一些實施例中，轉移性去勢抵抗性***癌係藉由向有需要之受試者投與化合物44-A(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物進行治療。在一些實施例中，轉移性去勢抵抗性***癌之治療方法係一種組合療法，其中將式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物與以下之治療劑組合投與該受試者：(i)阿比特龍或其醫藥學上可接受之鹽；(ii)普賴松或其醫藥學上可接受之鹽；或(i)及(ii)之組合。在一些實施例中，阿比特龍之醫藥學上可接受之鹽係醋酸阿比特龍。在一些實施例中，轉移性去勢抵抗性***癌之治療方法係一種單藥療法，其中唯一活性劑係式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物。在一些實施例中，受試者已接受至少一種既往新穎激素療法。在一些實施例中，該至少一種新穎激素療法係選自以下一或多者：恩雜魯胺、阿帕魯胺、達洛魯胺、阿比特龍、加利特龍、奥特罗奈及司維特羅。在一些實施例中，受試者已接受既往紫杉烷類化學療法，諸如多西他賽或卡巴他賽。In some embodiments, the present invention provides methods of treating metastatic castration-resistant prostate cancer. In some embodiments, metastatic castration-resistant prostate cancer is obtained by administering Compound 44-A (e.g., Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof for treatment. In some embodiments, the method of treating metastatic castration-resistant prostate cancer is a combination therapy, wherein a compound of formula (I) (such as compound 44-A) or a pharmaceutically acceptable salt or stereoisomer thereof The subject is administered in combination with the following therapeutic agents: (i) abiraterone or a pharmaceutically acceptable salt thereof; (ii) presone or a pharmaceutically acceptable salt thereof; or (i) and Combinations of (ii). In some embodiments, the pharmaceutically acceptable salt of abiraterone is abiraterone acetate. In some embodiments, the method of treatment of metastatic castration-resistant prostate cancer is a monotherapy wherein the sole active agent is a compound of formula (I) (e.g. Compound 44-A) or a pharmaceutically acceptable salt thereof or Stereoisomers. In some embodiments, the subject has received at least one prior novel hormone therapy. In some embodiments, the at least one novel hormonal therapy is selected from one or more of the following: enzalutamide, apalutamide, darolutamide, abiraterone, galiterone, otronai, and Svetro. In some embodiments, the subject has received prior taxane-based chemotherapy, such as docetaxel or cabazitaxel.
在一些實施例中，用於如本文所描述的治療癌症之方法中的式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物的治療有效量係約5 mg至約500 mg的總每日劑量。在一些實施例中，總每日劑量係約10 mg至約250 mg。在一些實施例中，總每日劑量係約20 mg至約160 mg。在一些實施例中，總每日劑量係約20 mg至約80 mg。在一些實施例中，總每日劑量係約20 mg至約40 mg。在一些實施例中，總每日劑量係約40 mg至約160 mg。在一些實施例中，總每日劑量係約40 mg至約80 mg。在一些實施例中，總每日劑量係約80 mg至約160 mg。在一些實施例中，總每日劑量係約15 mg至約25 mg、或約35 mg至約45 mg、或約75 mg至約85 mg、或約155 mg至約165 mg。在一些實施例中，總每日劑量係約18 mg至約22 mg、或約38 mg至約42 mg、或約78 mg至約82 mg、或約158 mg至約162 mg。In some embodiments, a therapeutically effective amount of a compound of Formula (I) (e.g. Compound 44-A) or a pharmaceutically acceptable salt or stereoisomer thereof for use in a method of treating cancer as described herein The total daily dose is from about 5 mg to about 500 mg. In some embodiments, the total daily dosage ranges from about 10 mg to about 250 mg. In some embodiments, the total daily dosage ranges from about 20 mg to about 160 mg. In some embodiments, the total daily dosage ranges from about 20 mg to about 80 mg. In some embodiments, the total daily dosage is about 20 mg to about 40 mg. In some embodiments, the total daily dosage is about 40 mg to about 160 mg. In some embodiments, the total daily dosage is about 40 mg to about 80 mg. In some embodiments, the total daily dosage is about 80 mg to about 160 mg. In some embodiments, the total daily dosage is about 15 mg to about 25 mg, or about 35 mg to about 45 mg, or about 75 mg to about 85 mg, or about 155 mg to about 165 mg. In some embodiments, the total daily dosage is about 18 mg to about 22 mg, or about 38 mg to about 42 mg, or about 78 mg to about 82 mg, or about 158 mg to about 162 mg.
在一些實施例中，總每日劑量係約20 mg、約40 mg、約80 mg或約160 mg。在一些實施例中，總每日劑量係約20 mg。在一些實施例中，總每日劑量係約30 mg。在一些實施例中，總每日劑量係約40 mg。在一些實施例中，總每日劑量係約50 mg。在一些實施例中，總每日劑量係約60 mg。在一些實施例中，總每日劑量係約80 mg。在一些實施例中，總每日劑量係約100 mg。在一些實施例中，總每日劑量係約120 mg。在一些實施例中，總每日劑量係約160 mg。In some embodiments, the total daily dosage is about 20 mg, about 40 mg, about 80 mg, or about 160 mg. In some embodiments, the total daily dosage is about 20 mg. In some embodiments, the total daily dosage is about 30 mg. In some embodiments, the total daily dosage is about 40 mg. In some embodiments, the total daily dosage is about 50 mg. In some embodiments, the total daily dosage is about 60 mg. In some embodiments, the total daily dosage is about 80 mg. In some embodiments, the total daily dosage is about 100 mg. In some embodiments, the total daily dosage is about 120 mg. In some embodiments, the total daily dosage is about 160 mg.
在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係經口投與的。在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係每日一次(QD)投與。在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係每日兩次(BID)投與。In some embodiments, a compound of Formula (I) (eg, Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered orally. In some embodiments, a compound of Formula (I) (eg, Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered once daily (QD). In some embodiments, a compound of Formula (I) (eg, Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered twice daily (BID).
在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽(例如化合物44-A反丁烯二酸鹽)或其立體異構物的總劑量係約60 mg至約100 mg，每日分兩次投與，例如每日兩次(BID)以約30 mg至約50 mg投與。在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽(例如化合物44-A反丁烯二酸鹽)或立體異構物的總劑量係80 mg，每日分兩次投與，例如每日兩次(BID)以40 mg投與。In some embodiments, the total dose of a compound of formula (I) (such as Compound 44-A) or a pharmaceutically acceptable salt thereof (such as Compound 44-A fumarate) or a stereoisomer thereof From about 60 mg to about 100 mg, administered in two divided doses per day, eg, from about 30 mg to about 50 mg twice daily (BID). In some embodiments, the total dose of a compound of formula (I) (eg Compound 44-A) or a pharmaceutically acceptable salt thereof (eg Compound 44-A fumarate) or stereoisomer is 80 mg administered in two divided doses per day, e.g. 40 mg administered twice daily (BID).
關於治療激素受體陽性乳癌之組合療法，在一些實施例中，氟維司群或其醫藥學上可接受之鹽的治療有效量係約500 mg，經由肌肉內注射投與。更一般而言，氟維司群或其醫藥學上可接受之鹽的治療有效量可為約100 mg至約2000 mg。在一些實施例中，氟維司群或其醫藥學上可接受之鹽係前三次劑量每兩週一次且此後每四週一次經由肌肉內注射投與。在一些實施例中，氟維司群係以經1至2分鐘投與的兩次250 mg注射液投與。For combination therapy to treat hormone receptor positive breast cancer, in some embodiments, the therapeutically effective amount of fulvestrant, or a pharmaceutically acceptable salt thereof, is about 500 mg, administered by intramuscular injection. More generally, a therapeutically effective amount of fulvestrant, or a pharmaceutically acceptable salt thereof, may range from about 100 mg to about 2000 mg. In some embodiments, fulvestrant or a pharmaceutically acceptable salt thereof is administered by intramuscular injection every two weeks for the first three doses and every four weeks thereafter. In some embodiments, fulvestrex is administered as two 250 mg injections administered over 1 to 2 minutes.
關於治療轉移性去勢抵抗性***癌之組合療法，在一些實施例中，阿比特龍或其醫藥學上可接受之鹽的治療有效量係約1000 mg的總每日劑量；且阿比特龍或其醫藥學上可接受之鹽係經口投與的。更一般而言，阿比特龍或其醫藥學上可接受之鹽的總每日劑量可為約200 mg至約4000 mg。在一些實施例中，阿比特龍或其醫藥學上可接受之鹽係每日一次投與；且阿比特龍或其醫藥學上可接受之鹽與式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係同時或依序投與的。在一些實施例中，普賴松之治療有效量係約5 mg之總每日劑量；且普賴松或其醫藥學上可接受之鹽係經口投與的。在一些實施例中，普賴松之治療有效量係約10 mg之總每日劑量；且普賴松或其醫藥學上可接受之鹽係經口投與的。更一般而言，普賴松之總每日劑量可為約0.5 mg至約50 mg。在一些實施例中，普賴松或其醫藥學上可接受之鹽係每日一次投與；且普賴松或其醫藥學上可接受之鹽與式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係同時或依序投與的。With regard to combination therapy for the treatment of metastatic castration-resistant prostate cancer, in some embodiments, the therapeutically effective amount of abiraterone or a pharmaceutically acceptable salt thereof is a total daily dose of about 1000 mg; and abiraterone or The pharmaceutically acceptable salts thereof are administered orally. More generally, the total daily dosage of abiraterone or a pharmaceutically acceptable salt thereof may be from about 200 mg to about 4000 mg. In some embodiments, abiraterone or a pharmaceutically acceptable salt thereof is administered once a day; and abiraterone or a pharmaceutically acceptable salt thereof and a compound of formula (I) (such as compound 44- A) or pharmaceutically acceptable salts or stereoisomers thereof are administered simultaneously or sequentially. In some embodiments, the therapeutically effective amount of Presone is a total daily dose of about 5 mg; and Presone or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the therapeutically effective amount of Presone is a total daily dose of about 10 mg; and Presone or a pharmaceutically acceptable salt thereof is administered orally. More generally, the total daily dosage of presone may be from about 0.5 mg to about 50 mg. In some embodiments, Presone or a pharmaceutically acceptable salt thereof is administered once a day; and Presone or a pharmaceutically acceptable salt thereof and a compound of formula (I) (such as compound 44- A) or pharmaceutically acceptable salts or stereoisomers thereof are administered simultaneously or sequentially.
在一些實施例中，癌症係不可手術的、局部晚期的、不可切除的、轉移性的、復發性的或其任何組合的實體腫瘤。In some embodiments, the cancer is a solid tumor that is inoperable, locally advanced, unresectable, metastatic, recurrent, or any combination thereof.
在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係以膠囊投與的。在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係以錠劑投與的。在一些實施例中，式(I)之化合物(例如化合物44-A)或其醫藥學上可接受之鹽或立體異構物係每日投與，持續至少28天。在一些實施例中，受試者在投藥時處於禁食狀態且該受試者視情況在投藥後保持禁食狀態一或多個小時。In some embodiments, a compound of Formula (I) (eg, Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered in a capsule. In some embodiments, a compound of Formula (I) (eg, Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered as a lozenge. In some embodiments, a compound of Formula (I) (eg, Compound 44-A), or a pharmaceutically acceptable salt or stereoisomer thereof, is administered daily for at least 28 days. In some embodiments, the subject is in a fasted state at the time of dosing and the subject optionally remains in a fasted state for one or more hours after dosing.
在一些實施例中，治療引起選自由以下組成之群的一或多種疾病狀態及進展標誌物的臨床相關改善：客觀反應率(ORR)、反應持續時間(DOR)、無進展生存期(PFS)及總體生存期(OS)。 醫藥組成物 In some embodiments, treatment results in a clinically relevant improvement in one or more markers of disease state and progression selected from the group consisting of: Objective Response Rate (ORR), Duration of Response (DOR), Progression Free Survival (PFS) and overall survival (OS). Pharmaceutical composition
在某些實施例中，本發明之方法包括醫藥組成物，該醫藥組成物包含如本文所揭示的式(I)之化合物或其醫藥學上可接受之鹽或立體異構物，視情況與醫藥學上可接受之載劑或稀釋劑混合。In certain embodiments, the methods of the present invention include pharmaceutical compositions comprising a compound of formula (I) as disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, optionally with A pharmaceutically acceptable carrier or diluent is mixed.
如本文所使用，術語「醫藥組成物」係指含有治療有效量的至少一種式(I)之化合物或其醫藥學上可接受之鹽以及習知醫藥學上可接受之載劑的組成物。As used herein, the term "pharmaceutical composition" refers to a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a conventional pharmaceutically acceptable carrier.
本發明之醫藥組成物可經口投與，例如以錠劑、包衣錠劑、丸劑、膠囊、顆粒劑或酏劑之形式投與。然而，亦可經直腸投與，例如以栓劑形式投與；或以可注射之無菌溶液或懸浮液形式非經腸投與，例如靜脈內、肌肉內或皮下投與；或表面投與，例如以軟膏或乳膏或透皮劑、以貼片形式，或以其他方式，例如以氣霧劑或鼻噴霧劑形式投與。The pharmaceutical composition of the present invention can be administered orally, for example, in the form of tablets, coated tablets, pills, capsules, granules or elixirs. However, it can also be administered rectally, e.g. in the form of a suppository; or parenterally, e.g. intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions; or topically, e.g. Administered as an ointment or cream or transdermally, as a patch, or otherwise, eg, as an aerosol or nasal spray.
醫藥組成物通常含有以重量計約1%至99%，例如約5%至75%、或約10％至約30％的式(I)之化合物或其醫藥學上可接受之鹽。該醫藥組成物中式(I)之化合物或其醫藥學上可接受之鹽的量可在約1 mg至約1000 mg、或約2.5 mg至約500 mg、或約5 mg至約250 mg、或1 mg至1000 mg範圍內或者高於或低於上述範圍之更寬範圍內的任何範圍內。Pharmaceutical compositions generally contain from about 1% to 99%, eg, from about 5% to 75%, or from about 10% to about 30%, by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may be from about 1 mg to about 1000 mg, or from about 2.5 mg to about 500 mg, or from about 5 mg to about 250 mg, or Any range within the range of 1 mg to 1000 mg or a wider range above or below the above range.
本發明之組成物及方法可用於治療有需要之個體。在某些實施例中，個體係哺乳動物，諸如人類或非人類哺乳動物。當投與動物，諸如人類時，該組成物或該化合物較佳以包含例如本發明之化合物及醫藥學上可接受之載劑的醫藥組成物形式投與。醫藥學上可接受之載劑係此項技術熟知的且包括例如水溶液，諸如水或生理緩衝鹽水、或者其他溶劑或媒劑，諸如二醇；甘油；油，諸如橄欖油；或可注射有機酯。The compositions and methods of the invention can be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to animals, such as humans, the composition or the compound is preferably administered in the form of a pharmaceutical composition comprising, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiologically buffered saline, or other solvents or vehicles, such as glycols; glycerol; oils, such as olive oil; or injectable organic esters. .
在一個較佳實施例中，當此類醫藥組成物用於人類投與時，特別是用於侵入性投與途徑(亦即，避免轉運或擴散通過上皮障壁之途徑，諸如注射或植入)時，水溶液係無熱原質的，或實質上無熱原質的。賦形劑可經選擇以例如實現藥劑之延遲釋放或選擇性靶向一或多種細胞、組織或器官。醫藥組成物可以呈劑量單元形式，諸如錠劑、膠囊(包括微丸膠囊及明膠膠囊)、顆粒劑、供復原之凍乾劑、粉劑、溶液、糖漿、栓劑、注射劑或類似形式。該組成物亦可存在於經皮遞送系統，例如皮膚貼片中。該組成物亦可存在於適合表面投與之溶液中，諸如滴眼劑。In a preferred embodiment, when such pharmaceutical compositions are for human administration, especially for invasive routes of administration (i.e., routes that avoid transport or diffusion across epithelial barriers, such as injection or implantation) , the aqueous solution is pyrogen-free, or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in the form of dosage units such as tablets, capsules (including pellet capsules and gelatin capsules), granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections or the like. The composition may also be presented in a transdermal delivery system, such as a skin patch. The compositions may also be presented in solutions suitable for topical administration, such as eye drops.
醫藥學上可接受之載劑可含有生理上可接受之試劑，該等試劑例如起到穩定化合物，諸如本發明之化合物；增加其溶解度；或增加其吸收的作用。此類生理上可接受之試劑包括例如碳水化合物，諸如葡萄糖、蔗糖或葡聚醣；抗氧化劑，諸如抗壞血酸或麩胱甘肽；螯合劑；低分子量蛋白質；或者其他穩定劑或賦形劑。醫藥學上可接受之載劑，包括生理上可接受之試劑的選擇取決於例如組成物之投與途徑。醫藥組成物之製劑可為自乳化藥物遞送系統或自微乳化藥物遞送系統。醫藥組成物(製劑)亦可為脂質體或其他聚合物基質，其中摻入例如本發明之化合物。脂質體例如包含磷脂或其他脂質，其為無毒、生理上可接受的且可代謝之載劑，該等載劑之製備及投與相對簡單。A pharmaceutically acceptable carrier may contain a physiologically acceptable agent which acts, for example, to stabilize a compound, such as a compound of the invention; increase its solubility; or increase its absorption. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose, or dextran; antioxidants, such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or excipients. The choice of pharmaceutically acceptable carriers, including physiologically acceptable agents, depends, for example, on the route of administration of the composition. The formulation of the pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. Pharmaceutical compositions (formulations) may also be liposomes or other polymer matrices into which, for example, a compound of the invention is incorporated. Liposomes, for example comprising phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable vehicles that are relatively simple to prepare and administer.
可用作醫藥學上可接受之載劑之材料的一些實例包括：(1)糖類，諸如乳糖、葡萄糖及蔗糖；(2)澱粉類，諸如玉米澱粉及馬鈴薯澱粉；(3)纖維素及其衍生物，諸如羧甲基纖維素鈉、乙基纖維素及醋酸纖維素；(4)粉末狀黃蓍膠；(5)麥芽；(6)明膠；(7)滑石；(8)賦形劑，諸如可可脂及栓劑蠟；(9)油類，諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油；(10)二醇類，諸如丙二醇；(11)多元醇類，諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇；(12)酯，諸如油酸乙酯及月桂酸乙酯；(13)瓊脂；(14)緩沖劑，諸如氫氧化鎂及氫氧化鋁；(15)褐藻酸；(16)無熱原質水；(17)等張鹽水；(18)林格氏溶液(Ringer's solution)；(19)乙醇；(20)磷酸鹽緩衝溶液；以及(21)醫藥調配物中使用的其他無毒相容性物質。Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its Derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and Aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline and (21) other non-toxic compatible substances used in pharmaceutical formulations.
醫藥組成物(製劑)可藉由多種投與途徑中之任一者投與受試者，包括例如口服(例如在水性或非水性溶液或懸浮液中之灌藥劑、錠劑、膠囊(包括微丸膠囊)及明膠膠囊)、大丸劑、粉劑、顆粒劑、供施用於舌之糊劑)；經由口腔黏膜吸收(例如舌下)；經肛門、直腸或***(例如呈子宮托、乳膏或泡沫劑)；非經腸(包括肌肉內、靜脈內、皮下或鞘內，例如無菌溶液或懸浮液)；經鼻；腹膜內；皮下；經皮(例如呈施用於皮膚之貼片)；以及表面(例如呈施用於皮膚之乳膏、軟膏或噴霧劑，或滴眼液)。該化合物亦可調配成用於吸入。在某些實施例中，化合物可簡單地溶解或懸浮於無菌水中。適合投與途徑及適合該等途徑之組成物的詳情可見於例如美國專利第6110973號、第5763493號、第5731000號、第5541231號、第5427798號、第5358970號及第4172896號，以及其中引用之專利中。Pharmaceutical compositions (formulations) can be administered to a subject by any of a variety of routes of administration, including, for example, orally (eg, drench in aqueous or non-aqueous solution or suspension, lozenges, capsules (including microparticles). capsules) and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); oral mucosal absorption (e.g. sublingual); anal, rectal or vaginal (e.g. in pessary, cream or foams); parenteral (including intramuscular, intravenous, subcutaneous or intrathecal, e.g., sterile solutions or suspensions); nasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); Topical (eg, in the form of a cream, ointment, or spray applied to the skin, or eye drops). The compounds may also be formulated for inhalation. In certain embodiments, compounds can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for such routes can be found, for example, in U.S. Pat. of the patent.
該等調配物可便利地以單位劑型存在且可藉由藥學領域中熟知之任何方法製備。可與載劑材料組合以製造單一劑型的活性成分之量將取決於所治療之宿主、特定投與模式而變化。可與載劑材料組合以製造單一劑型的活性成分之量一般為產生治療效果的化合物之量。一般而言，在百分之一百中，該量範圍為約百分之一至約百分之九十九，較佳地為約百分之五至約百分之七十，最佳地為約百分之十至約百分之三十的活性成分。The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally speaking, out of one hundred percent, the amount ranges from about one percent to about ninety-nine percent, preferably from about five percent to about seventy percent, most preferably From about ten percent to about thirty percent active ingredient.
在某些實施例中，醫藥組成物包含佔該組成物至少約50重量%之量的活性成分。在某些實施例中，醫藥組成物包含佔該組成物至少約60重量%之量的活性成分。在某些實施例中，醫藥組成物包含佔該組成物至少約70重量%之量的活性成分。在某些實施例中，醫藥組成物包含佔該組成物至少約80重量%之量的活性成分。在某些實施例中，醫藥組成物包含佔該組成物至少約90重量%之量的活性成分。In certain embodiments, pharmaceutical compositions comprise the active ingredient in an amount of at least about 50% by weight of the composition. In certain embodiments, pharmaceutical compositions comprise the active ingredient in an amount of at least about 60% by weight of the composition. In certain embodiments, pharmaceutical compositions comprise the active ingredient in an amount of at least about 70% by weight of the composition. In certain embodiments, pharmaceutical compositions comprise the active ingredient in an amount of at least about 80% by weight of the composition. In certain embodiments, pharmaceutical compositions comprise the active ingredient in an amount of at least about 90% by weight of the composition.
在某些實施例中，包含本發明之活性成分的口服醫藥組成物係單位劑量組成物。在某些實施例中，醫藥組成物含有約1 mg至約5000 mg的活性成分。In certain embodiments, oral pharmaceutical compositions comprising the active ingredients of the invention are unit dosage compositions. In certain embodiments, pharmaceutical compositions contain from about 1 mg to about 5000 mg of active ingredient.
在某些實施例中，活性成分係式(I)之化合物。In certain embodiments, the active ingredient is a compound of formula (I).
製備此等調配物或組成物的方法包括將諸如本發明之化合物的活性化合物與載劑及視情況存在之一或多種輔助成分結合的步驟。通常，藉由將本發明之化合物與液體載劑或細粉狀固體載劑或兩者均勻且緊密地結合，且接著必要時，使產物成型來製備調配物。Methods of preparing such formulations or compositions include the step of bringing into association the active compound, such as a compound of this invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
適於經口投與的本發明之調配物可呈以下形式：膠囊(包括微丸膠囊及明膠膠囊)、扁囊劑、丸劑、錠劑、***劑(使用調味基料，通常為蔗糖及***膠或黃蓍膠)、凍乾劑、粉劑、顆粒劑，或呈於水性或非水性液體中之溶液或懸浮液形式，或呈水包油或油包水液體乳液形式，或呈酏劑或糖漿形式，或呈丸粒(使用惰性基質，諸如明膠及甘油，或蔗糖及***膠)及/或呈漱口水形式及類似形式，其各自含有預定量的本發明之化合物作為活性成分。組成物或化合物亦可以大丸劑、舐劑或糊劑投與。Formulations of the invention suitable for oral administration may be in the form of capsules (including pellet capsules and gelatin capsules), cachets, pills, lozenges, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilized formulations, powders, granules, or in the form of solutions or suspensions in aqueous or non-aqueous liquids, or in the form of oil-in-water or water-in-oil liquid emulsions, or in elixirs Or in syrup form, or in pellets (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or in the form of mouthwashes and the like, each containing a predetermined amount of a compound of the invention as active ingredient. The composition or compound may also be administered as a bolus, bolus or paste.
為製備經口投與之固體劑型(膠囊(包括微丸膠囊及明膠膠囊)、錠劑、丸劑、糖衣錠、粉劑、顆粒劑及類似劑型)，可將活性成分與一或多種醫藥學上可接受之載劑混合，諸如檸檬酸鈉或磷酸二鈣，及/或以下任一者：(1)填充劑或增量劑，諸如澱粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或矽酸；(2)黏合劑，諸如羧甲基纖維素、褐藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及/或***膠；(3)保濕劑，諸如甘油；(4)崩解劑，諸如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、褐藻酸、某些矽酸鹽及碳酸鈉；(5)溶解延遲劑，諸如石蠟；(6)吸收加速劑，諸如四級銨化合物；(7)潤濕劑，諸如鯨蠟醇及單硬脂酸甘油酯；(8)吸附劑，諸如高嶺土及膨潤土；(9)潤滑劑，諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉及其混合物；(10)錯合劑，諸如改質及未改質之環糊精；以及(11)著色劑。在膠囊(包括微丸膠囊及明膠膠囊)、錠劑及丸劑之情況下，醫藥組成物亦可包含緩沖劑。類似類型之固體組成物亦可用作使用諸如乳糖(lactose/milk sugar)以及高分子量聚乙二醇及類似物之類賦形劑之軟質及硬質填充明膠膠囊中的填充劑。For the preparation of solid dosage forms for oral administration (capsules (including pelleted capsules and gelatin capsules), troches, pills, dragees, powders, granules and the like), the active ingredient may be combined with one or more pharmaceutically acceptable Carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) Binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar , calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents , such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) colorants. In the case of capsules (including pellet capsules and gelatin capsules), lozenges and pills, the pharmaceutical composition may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (milk sugar) and high molecular weight polyethylene glycols, and the like.
錠劑可藉由壓縮或模製，視情況利用一或多種輔助成分來製成。壓縮錠劑可以使用黏合劑(例如明膠或羥丙基甲基纖維素)、潤滑劑、惰性稀釋劑、防腐劑、崩解劑(例如羥基乙酸澱粉鈉或交聯羧甲基纖維素鈉)、表面活性劑或分粉劑來製備。模製錠劑可以藉由在適合的機器中模製用惰性液體稀釋劑潤濕之粉末狀化合物的混合物來製備。A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed lozenges may use binders (such as gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or croscarmellose sodium), Surfactant or sub-powder to prepare. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
錠劑及醫藥組成物之其他固體劑型，諸如糖衣錠、膠囊(包括微丸膠囊及明膠膠囊)、丸劑及顆粒劑，可以視情況經刻痕或製備成具有包衣及殼，諸如腸溶包衣及醫藥調配領域中熟知之其他包衣。該等劑型亦可使用例如提供所希望之釋放概貌的不同比例之羥丙基甲基纖維素、其他聚合物基質、脂質體及/或微球調配以提供其中活性成分之緩慢或控制釋放。其可藉由例如經細菌截留過濾器(bacterial-retaining filter)過濾，或藉由併入呈無菌固體組成物形式之滅菌劑進行滅菌，該等無菌固體組成物可在臨用前溶解於無菌水或一些其他的無菌可注射介質中。此等組成物可視情況含有失透劑且可具有使其僅僅或優先在腸道某一部分，視情況以延遲方式釋放活性成分之組成。可使用之包埋組成物的實例包括聚合物質及蠟。活性成分亦可呈微囊封形式，適當時，具有一或多種如上所描述之賦形劑。Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including pellets and gelatin capsules), pills and granules, which may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. Such dosage forms can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water just before use or some other sterile injectable medium. These compositions may optionally contain devitrification agents and may be of such a composition that they release the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more excipients as above described.
可用於經口投與之液體劑型包括醫藥學上可接受之乳劑、供復原之凍乾劑、微乳劑、溶液、懸浮液、糖漿及酏劑。除活性成分之外，液體劑型亦可含有此項技術中常用之惰性稀釋劑，諸如水或其他溶劑、環糊精及其衍生物、增溶劑及乳化劑，諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特別是棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫糠醇、聚乙二醇及脫水山梨糖醇脂肪酸酯，以及其混合物。Liquid dosage forms that can be used for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate Esters, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin , tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof.
除惰性稀釋劑之外，口服組成物亦可包括佐劑，諸如潤濕劑、乳化劑及懸浮劑、甜味劑、調味劑、著色劑、芳香劑及防腐劑。Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
除活性化合物外，懸浮液亦可含有助懸劑，諸如乙氧基化異硬脂醇、聚氧乙烯山梨糖醇及脫水山梨糖醇酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂及黃蓍膠，以及其混合物。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
供直腸、***或尿道投與之醫藥組成物的調配物可呈栓劑形式，其可藉由混合一或多種活性化合物與一或多種適合的非刺激性賦形劑或載劑來製備，該一或多種非刺激性賦形劑或載劑包含例如可可脂、聚乙二醇、栓劑蠟或柳酸鹽，且在室溫下為固體，但在體溫下為液體且因此在直腸或***腔中熔融並釋放活性化合物。Formulations of pharmaceutical compositions for rectal, vaginal or urinary administration may be in the form of suppositories, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, which or more non-irritating excipients or carriers containing, for example, cocoa butter, polyethylene glycol, suppository waxes, or salicylic acid salts, and are solid at room temperature, but liquid at body temperature and thus in the rectum or vaginal cavity Melts and releases the active compound.
供口腔投與之醫藥組成物的調配物可呈漱口水、或口腔噴霧劑或口腔軟膏形式存在。Formulations of pharmaceutical compositions for oral administration may be in the form of mouthwashes, or mouth sprays or mouth ointments.
或者或另外地，組成物可調配成供經導管、支架、線或其他腔內裝置遞送。經由此類裝置遞送對於遞送至膀胱、尿道、輸尿管、直腸或腸可能特別有用。Alternatively or additionally, the composition may be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum or bowel.
適於***投與之調配物亦包括含此項技術中已知適當之載劑的子宮托、衛生棉條、乳膏、凝膠劑、糊劑、泡沫劑或噴霧調配物。Formulations suitable for vaginal administration also include pessary, tampon, cream, gel, paste, foam or spray formulations with such carriers known in the art to be appropriate.
供表面及/或經皮投與之劑型包括粉劑、噴霧劑、軟膏劑、糊劑、乳膏、洗劑、凝膠劑、溶液、貼片及吸入劑。活性化合物可以在無菌條件下與醫藥學上可接受之載劑以及可能需要的任何防腐劑、緩沖劑或推進劑混合。Dosage forms for topical and/or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants which may be required.
除活性化合物外，糊劑、乳膏及凝膠劑亦可含有賦形劑，諸如動物及植物脂肪、油、蠟、石蠟、澱粉、黃蓍膠、纖維素衍生物、聚乙二醇、聚矽氧、膨潤土、矽酸、滑石及氧化鋅，或其混合物。Pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, polysaccharides, etc. Silica, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.
除活性化合物之外，粉劑及噴霧劑亦可含有賦形劑，諸如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣及聚醯胺粉末，或此等物質之混合物。噴霧劑可另外含有常用的推進劑，諸如氯氟烴及揮發性未取代烴，諸如丁烷及丙烷。Powders and sprays can contain, in addition to the active compounds, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
經皮貼片具有提供本發明化合物至身體之控制性遞送的附加優勢。此類劑型可以藉由將活性化合物溶解或分散於適當介質中來製備。吸收增強劑亦可用於增加化合物穿過皮膚之通量。此類通量之速率可以藉由提供速率控制膜或將化合物分散於聚合物基質或凝膠中來控制。Transdermal patches have the added advantage of providing controlled delivery of compounds of the invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
眼用調配物、眼膏、粉劑、溶液及類似物亦涵蓋於本發明之範圍內。例示性眼用調配物描述於美國公開案第2005/0080056號、第2005/0059744號及美國專利第6,583,124號中，其內容以引用之方式併入本文中。必要時，液體眼用調配物具有與淚液、前房液或玻璃體液相似之特性或與此等液體相容。較佳的投與途徑係局部投與(例如表面投與，諸如滴眼劑，或經由植入物投與)。Ophthalmic formulations, eye ointments, powders, solutions and the like are also encompassed within the scope of this invention. Exemplary ophthalmic formulations are described in US Publication Nos. 2005/0080056, 2005/0059744, and US Patent No. 6,583,124, the contents of which are incorporated herein by reference. Liquid ophthalmic formulations have properties similar to or are compatible with tear fluid, anterior chamber fluid, or vitreous humor, as desired. A preferred route of administration is topical (eg, topical, such as eye drops, or via an implant).
如本文所使用，片語「非經腸投與(parenteral administration)」及「非經腸投與(administered parenterally)」係指除經腸及表面投與以外的投與方式，通常藉由注射投與，包括但不限於靜脈內、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊柱內及胸骨內注射及輸注。As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection and, including but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid , Intraspinal and intrasternal injections and infusions.
適於非經腸投與之醫藥組成物包含一或多種活性化合物與一或多種醫藥學上可接受之無菌等張水性或非水性溶液、分散液、懸浮液或乳液或者無菌粉末的組合，該等無菌粉末可在臨用前復原成無菌可注射溶液或分散液，其中可含有抗氧化劑、緩沖劑、抑菌劑、使調配物與預期接受者之血液等張的溶質、或者懸浮劑或增稠劑。Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders, which Such sterile powders may be reconstituted prior to use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostats, solutes to render the formulation isotonic with the blood of the intended recipient, or suspending agents or boosters. Thickener.
可用於本發明之醫藥組成物中的適合水性及非水性載劑之實例包括水、乙醇、多元醇(諸如甘油、丙二醇、聚乙二醇及類似醇)及其適合混合物、植物油，諸如橄欖油，及可注射之有機酯，諸如油酸乙酯。可以藉由例如使用包覆材料，諸如卵磷脂；在分散液的情況下藉由維持所需的粒度；以及藉由使用界面活性劑來維持適當的流動性。Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyalcohols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils, such as olive oil , and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin; in the case of dispersions, by maintaining the required particle size; and by using surfactants.
此等組成物亦可含有佐劑，諸如防腐劑、潤濕劑、乳化劑及分粉劑。藉由包括各種抗細菌劑及抗真菌劑，例如對羥基苯甲酸酯、氯丁醇、苯酚山梨酸及類似物，可以確保防止微生物的作用。亦可能需要在組成物中包括等張劑，諸如糖、氯化鈉及類似物。此外，可藉由包括延遲吸收之試劑，諸如單硬脂酸鋁及明膠來延長可注射醫藥形式之吸收。These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and powder-dividing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the composition. In addition, prolonged absorption of the injectable pharmaceutical forms may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
在一些情況下，為延長藥物之作用，常常需要減慢對來自皮下或肌肉內注射之藥物的吸收。此可藉由使用具有弱水溶性之結晶或非晶形材料之液體懸浮液來實現。藥物之吸收速率則取決於其溶解速率，溶解速率又可取決於晶體大小及結晶形式。或者，藉由將藥物溶解或懸浮於油媒劑中來實現非經腸投與之藥物形式的延遲吸收。In some cases, it is often necessary to slow the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the action of the drug. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
可注射之積存形式係藉由在諸如聚丙交酯-聚乙交酯之類可生物降解之聚合物中形成主題化合物的微囊化基質來製備。取決於藥物與聚合物之比率以及所用特定聚合物之性質，可以控制藥物釋放之速率。其他可生物降解之聚合物的實例包括聚(原酸酯)及聚(酸酐)。亦可藉由將藥物包裹在與身體組織相容之脂質體或微乳液中來製備積存式可注射調配物。Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
為了用於本發明之方法中，活性化合物可以獨自給予或以含有例如約0.1至約99.5％ (更佳地約0.5至約90％)活性成分與醫藥學上可接受之載劑之組合的醫藥組成物形式給予。For use in the methods of this invention, the active compound may be administered alone or in a medicament containing, for example, from about 0.1 to about 99.5% (more preferably from about 0.5 to about 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier. Administered in composition form.
引入方法亦可由可裝填或生物可降解裝置提供。近年來，已經開發出各種緩慢釋放聚合物裝置並在活體內進行測試以用於藥物之控制性遞送，包括蛋白質生物醫藥劑。多種生物相容性聚合物(包括水凝膠)，包括生物可降解及不可降解之聚合物在內，均可用於形成植入物以在特定目標部位處持續釋放化合物。Methods of introduction may also be provided by refillable or biodegradable devices. In recent years, various slow release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers, including hydrogels, including biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.
可以改變醫藥組成物中活性成分之劑量水平，以便獲得有效實現特定受試者、組成物及投與模式所需之治療反應，同時不會對受試者產生毒性的活性成分之量。Dosage levels of active ingredients in pharmaceutical compositions can be varied in order to obtain an amount of active ingredient effective to achieve a desired therapeutic response for a particular subject, composition, and mode of administration without being toxic to the subject.
劑量水平取決於多種因素，包括所用特定化合物或化合物組合或者其酯、鹽或醯胺之活性；投與途徑；投與時間；所用特定化合物之***速率；治療持續時間；與所用特定化合物組合使用之其他藥物、化合物及/或材料；所治療之受試者的年齡、性別、體重、狀況、一般健康狀況及既往醫療史；以及類似因素。Dosage levels will depend on a variety of factors, including the activity of the particular compound or combination of compounds used, or its ester, salt, or amide; route of administration; time of administration; rate of excretion of the particular compound used; duration of treatment; use in combination with the particular compound used Other drugs, compounds, and/or materials; the age, sex, weight, condition, general health, and previous medical history of the subject being treated; and similar factors.
必要時，活性化合物之有效每日劑量可在一天中以適當時間間隔，按分開投與的一次、兩次、三次、四次、五次、六次或更多次分劑量投與，視情況以單位劑型投與。在本發明之某些實施例中，活性化合物可以每日投與兩次或三次。在較佳實施例中，活性化合物將每日投與一次。When necessary, an effective daily dose of the active compound may be administered in one, two, three, four, five, six or more divided doses administered at appropriate intervals throughout the day, as the case may be. Administered in unit dosage form. In certain embodiments of the invention, active compounds may be administered two or three times daily. In preferred embodiments, the active compounds will be administered once daily.
接受此類治療之受試者係任何有需要之動物，包括靈長類動物，特別是人類，以及其他哺乳動物，諸如馬、牛、豬及羊；以及一般的家禽及寵物。Subjects receiving such treatment are any animals in need, including primates, especially humans, and other mammals, such as horses, cows, pigs, and sheep; and poultry and pets in general.
潤濕劑、乳化劑及潤滑劑，諸如月桂基硫酸鈉及硬脂酸鎂，以及著色劑、脫模劑、包衣劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化劑亦可存在於該等組成物中。Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also present in these compositions.
醫藥學上可接受之抗氧化劑的實例包括：(1)水溶性抗氧化劑，諸如抗壞血酸、半胱胺酸鹽酸鹽、硫酸氫鈉、偏亞硫酸氫鈉、亞硫酸鈉及類似物；(2)油溶性抗氧化劑，諸如棕櫚酸抗壞血基酯、丁基化羥基苯甲醚(BHA)、丁基化羥基甲苯(BHT)、卵磷脂、沒食子酸丙酯、α-生育酚及類似物；(3)金屬螯合劑，諸如檸檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及類似物。Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oily Soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like (3) Metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
本發明之化合物可以與一種或多種其他藥物組合投與以(1)補充及/或增強本發明之化合物之預防性/或治療性藥物作用的預防及/或治療功效；(2)調節藥效學，改善吸收改善，或減少本發明之預防及/或治療化合物的劑量減小；及/或(3)減少或改善本發明之預防及/或治療化合物的副作用。不同的治療化合物可以同一調配物或以單獨調配物同時或依序投與。在某些實施例中，不同的治療化合物可彼此間隔在一小時、12小時、24小時、36小時、48小時、72小時或一周內投與。因此，接受此類治療之個體可以得益於不同治療化合物之組合作用。各別化合物可以藉由相同或不同途徑以及相同或不同的方法投與。The compound of the present invention can be administered in combination with one or more other drugs to (1) supplement and/or enhance the prophylactic and/or therapeutic efficacy of the preventive/or therapeutic drug action of the compound of the present invention; (2) regulate the drug effect and/or (3) reduce or improve the side effects of the preventive and/or therapeutic compound of the present invention. Different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or in separate formulations. In certain embodiments, different therapeutic compounds may be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or one week of each other. Individuals receiving such treatment may therefore benefit from the combined effects of different therapeutic compounds. The individual compounds may be administered by the same or different routes and the same or different methods.
包含本發明之化合物及其他藥物的聯合用藥可以在單一調配物中包含兩種組分之組合製劑形式投與，或者以單獨的調配物形式投與。藉由單獨調配物投與包括同時投與及或分開某一時間間隔投與調配物。在以某一時間間隔投與之情況下，可以先投與本發明之化合物，隨後投與另一種藥物，或者可以先投與另一種藥物，隨後投與本發明之化合物。各別藥物之投與方法可以利用相同或不同的途徑以及相同或不同的方法投與。Combinations comprising a compound of this invention and another drug may be administered as a combined preparation comprising both components in a single formulation, or as separate formulations. Administration by separate formulations includes simultaneous administration and or administration of the formulations separated by a certain time interval. In the case of administration at a certain time interval, the compound of the present invention may be administered first, followed by another drug, or another drug may be administered first, followed by the compound of the present invention. The methods of administration of the respective drugs may utilize the same or different routes and the same or different methods of administration.
其他藥物之劑量可以基於臨床上使用之劑量適當地選擇，或者可以為當與本發明之化合物組合投與時有效的降低之劑量。本發明之化合物與該其他藥物的混配比率可根據待投藥之受試者的年齡及體重、投與方法、投與時間、待治療之病症、症狀及其組合適當地選擇。舉例而言，基於1質量份的本發明之化合物計，該其他藥物可以按約0.01至約100質量份的量使用。該其他藥物可為呈適當比例的兩種或更多種任意藥物之組合。補充及/或增強本發明之化合物之預防及/或治療功效的其他藥物不僅包括已經發現之藥物，而且亦包括基於上述機制在未來將發現之藥物。Doses of other drugs may be appropriately selected based on clinically used doses, or may be reduced doses that are effective when administered in combination with the compound of the present invention. The compounding ratio of the compound of the present invention and the other drug can be appropriately selected according to the age and body weight of the subject to be administered, the method of administration, the time of administration, the condition to be treated, symptoms and combinations thereof. For example, the other drug may be used in an amount of about 0.01 to about 100 parts by mass based on 1 part by mass of the compound of the present invention. The other drug may be a combination of two or more arbitrary drugs in an appropriate ratio. Other drugs that supplement and/or enhance the preventive and/or therapeutic efficacy of the compound of the present invention include not only the drugs that have been discovered, but also the drugs that will be discovered in the future based on the above-mentioned mechanism.
在某些實施例中，本發明之化合物可以與非化學癌症治療方法組合投與。在某些實施例中，本發明之化合物可以與放射療法組合投與。在某些實施例中，本發明之化合物可以與手術、與熱消融、與超音聚焦療法、與冷凍療法或與此等療法之任何組合進行組合投與。 實例 實例 1 ：在患有不可手術之局部晚期或轉移性實體腫瘤之受試者中進行的化合物 44-A 單藥及組合療法之安全性及藥物動力學的劑量遞增及擴展研究目標及終點 劑量遞增階段(單藥及組合療法隊列) 主要目標： • 確定當單獨及以組合療法經口投與患有晚期實體腫瘤之受試者時的MTD及/或RD以進一步評價化合物44-A反丁烯二酸鹽 次要目標： • 評價化合物44-A反丁烯二酸鹽當單獨及以組合療法經口投與患有晚期實體腫瘤之受試者時的安全性及耐受性 • 評價在單獨及以組合療法經口投與化合物44-A反丁烯二酸鹽後化合物44-A反丁烯二酸鹽及其潛在代謝物的血漿藥物動力學(PK) • 評估化合物44-A反丁烯二酸鹽及組合劑之間的藥物-藥物相互作用 探索性目標： • 由研究者根據實體腫瘤反應評估標準1.1版(Response Evaluation Criteria in Solid Tumors version 1.1，RECIST v1.1)評估的客觀反應率(ORR) • 評價PK、藥效學、功效或安全性終點之間的關係 • 評價化合物44-A反丁烯二酸鹽在腫瘤及血液中之藥效學作用 • 評價化合物44-A在腫瘤及血液中之目標佔有率 隊列擴展階段(單藥及組合療法隊列) 主要目標： • 藉由估計研究者根據RECIST 1.1評估之ORR，評價化合物44-A反丁烯二酸鹽在單獨及以組合療法投與時的初步功效 次要目標： • 評價化合物44-A反丁烯二酸鹽在單獨及以組合療法投與時的安全性及耐受性 • 進一步評估化合物44-A反丁烯二酸鹽、其潛在代謝物及組合劑之PK 探索性目標： • 由研究者根據RECIST v1.1評估的反應持續時間(DOR)及無進展生存期(PFS) • 由盲法獨立放射學委員會(Blinded Independent Radiology Committee，BIRC)根據RECIST 1.1評估的選定隊列之ORR、DOR及PFS 總體生存期(OS)： • 評價PK、藥效學、功效或安全性終點之間的關係 • 評價化合物44-A反丁烯二酸鹽對腫瘤及血液生物標誌物的影響以及與反應之潛在相關性 • 評價選定適應症之腫瘤標誌物相對於基線的變化 研究設計 綜述 In certain embodiments, compounds of the present invention may be administered in combination with non-chemotherapy methods of cancer treatment. In certain embodiments, compounds of the invention may be administered in combination with radiation therapy. In certain embodiments, compounds of the invention may be administered in combination with surgery, with thermal ablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these therapies. EXAMPLES Example 1 : Dose Escalation and Expansion Study Target and Endpoint Dose of Safety and Pharmacokinetics of Compound 44-A Monotherapy and Combination Therapy in Subjects with Inoperable Locally Advanced or Metastatic Solid Tumors Escalation Phase (Monotherapy and Combination Therapy Cohorts) Primary Objectives: • To determine the MTD and/or RD when administered orally to subjects with advanced solid tumors alone and in combination therapy for further evaluation of Compound 44-A Acenoate Secondary Objectives: • To evaluate the safety and tolerability of Compound 44-A fumarate when administered orally, alone and in combination therapy, to subjects with advanced solid tumors • To evaluate in Plasma Pharmacokinetics (PK) of Compound 44-A Fumarate and Its Potential Metabolites Following Oral Administration of Compound 44-A Fumarate Alone and in Combination Therapy Evaluation of Compound 44-A Reaction Drug-Drug Interactions Between Butenoate and Combination Agents Exploratory Objectives: • Objective assessment by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) Response Rate (ORR) • Assess the relationship between PK, pharmacodynamics, efficacy or safety endpoints • Assess the pharmacodynamic effects of compound 44-A fumarate in tumor and blood • Assess compound 44-A Target Occupancy Cohort Expansion Phase in Tumor and Blood (Monotherapy and Combination Therapy Cohorts) Primary Objectives: • To evaluate the efficacy of Compound 44-A fumarate in monotherapy and Preliminary efficacy when administered in combination therapy Secondary objectives: • To evaluate the safety and tolerability of Compound 44-A fumarate when administered alone and in combination therapy • To further evaluate Compound 44-A fumarate PK of enoates, their potential metabolites, and combinations Exploratory objectives: • Duration of response (DOR) and progression-free survival (PFS) as assessed by investigator according to RECIST v1.1 • Blinded independent radiology ORR, DOR, and PFS for selected cohorts assessed by the Blinded Independent Radiology Committee (BIRC) according to RECIST 1.1 Overall Survival (OS): • To evaluate the relationship between PK, pharmacodynamics, efficacy or safety endpoints • To evaluate compound 44 -A Fumarate Effect on Tumor and Blood Biomarkers and Potential Correlation to Response • Review of Study Designs to Evaluate Changes from Baseline in Tumor Markers for Selected Indications
本研究係一項評價對患有晚期實體腫瘤之受試者經口投與單獨及呈多種組合方案形式的化合物44-A反丁烯二酸鹽之安全性、耐受性、PK、抗腫瘤活性及對生物標誌物之影響的1期、開放標記、劑量遞增及擴展研究。This study was an evaluation of the safety, tolerability, PK, antitumor effects of compound 44-A fumarate administered orally, alone and in various combination regimens, to subjects with advanced solid tumors. Phase 1, open-label, dose-escalation and extension studies of activity and effects on biomarkers.
本研究由在選定腫瘤類型中以單藥療法及組合療法投與化合物44-A反丁烯二酸鹽之劑量遞增及隊列擴展階段組成。首先，化合物44-A反丁烯二酸鹽單藥療法之評價係以單藥劑量遞增階段起始。隊列審查委員會(Cohort Review Committee)評價來自單藥劑量遞增階段之資料並選擇化合物44-A之安全劑量以在組合療法劑量遞增階段中起始多個腫瘤特異性隊列中不同組合方案之評價。組合療法中化合物44-A反丁烯二酸鹽之劑量遞增可與單藥化合物44-A反丁烯二酸鹽劑量遞增並行進行，並在測定單藥化合物44-A療法之安全劑量後起始。隊列審查委員會亦自兩個劑量遞增階段(單藥化合物44-A及各組合方案)測定MTD/RD以用於相應隊列擴展階段。關於化合物44-A反丁烯二酸鹽之劑量遞增及隊列擴展研究的概述示於圖2中。The study consisted of a dose-escalation and cohort expansion phase of administering Compound 44-A fumarate as monotherapy and combination therapy in selected tumor types. First, the evaluation of Compound 44-A fumarate monotherapy was initiated with a single-agent dose-escalation phase. A Cohort Review Committee evaluated data from the single agent dose escalation phase and selected safe doses of Compound 44-A to initiate the evaluation of different combination regimens in multiple tumor-specific cohorts in the combination therapy dose escalation phase. The dose escalation of compound 44-A fumarate in combination therapy can be carried out in parallel with the dose escalation of single agent compound 44-A fumarate, and starts after the safe dose of single agent compound 44-A therapy is determined. beginning. The cohort review committee also determined MTD/RD from both dose escalation phases (single agent compound 44-A and each combination regimen) for the corresponding cohort expansion phase. An overview of the dose escalation and cohort expansion studies for compound 44-A fumarate is shown in FIG. 2 .
在隊列擴展階段中需要有限數量的受試者來提供腫瘤及皮膚生物檢體。不需要進行此等生檢之受試者可視情況提供組織。 化合物44-A單藥療法評價 A limited number of subjects are required to provide tumor and skin biospecimens during the cohort expansion phase. Subjects who do not need to undergo such biopsy can provide tissues according to the situation. Compound 44-A monotherapy evaluation
在劑量遞增階段期間，使用經改良之i3+3設計，利用約5個劑量水平的化合物44-A反丁烯二酸鹽治療患有晚期實體腫瘤之受試者。在鑑別出MTD/RD 之後，在針對以下各者的四個腫瘤特異性擴展隊列(隊列擴展階段)中，使用西蒙氏兩階段設計(Simon’s Two-Stage design)進一步評價作為單藥療法之化合物44-A反丁烯二酸鹽的安全性及功效：EOC、TNBC、HR+ BC及mCRPC。單藥研究方案示於圖3中。 化合物44-A組合療法評價During the dose escalation phase, subjects with advanced solid tumors were treated with approximately 5 dose levels of Compound 44-A fumarate using the modified i3+3 design. Following identification of MTD/RD, compounds were further evaluated as monotherapy using Simon's Two-Stage design in four tumor-specific expansion cohorts (cohort expansion phase) for 44 - Safety and efficacy of A fumarate: EOC, TNBC, HR+ BC and mCRPC. The single-agent study protocol is shown in Figure 3. Compound 44-A combination therapy evaluation
執行多項另外的獨立腫瘤特異性劑量遞增評價以確定化合物44-A之不同組合方案的MTD/RD。化合物44-A反丁烯二酸鹽與氟維司群之組合係在患有HR+ BC之受試者中評價，且化合物44-A反丁烯二酸鹽與阿比特龍 + 普賴松之組合係在患有mCRPC之受試者中評價。對於各評價，利用經改良之i3+3設計，且起始化合物44-A反丁烯二酸鹽劑量水平係隊列審查委員會根據單藥劑量遞增階段中之經驗認為安全的劑量水平。投與標準劑量的氟維司群(HR+ BC)及阿比特龍+普賴松(mCRPC)。鑑別出組合方案之MTD/RD之後，在組合療法隊列擴展階段中，使用西蒙氏兩階段設計在相應HR+ BC及mCRPC擴展隊列中進一步評價該方案之安全性及功效。化合物44-A組合療法研究方案示於圖4中。 經改良之 i3+3 劑量遞增研究設計 Multiple additional independent tumor-specific dose-escalation evaluations were performed to determine the MTD/RD of the different combination regimens of Compound 44-A. The combination of Compound 44-A fumarate and fulvestrant was evaluated in subjects with HR+ BC, and the combination of Compound 44-A fumarate and abiraterone+presone Combinations were evaluated in subjects with mCRPC. For each evaluation, the modified i3+3 design was utilized, and the starting compound 44-A fumarate dose level was the dose level considered safe by the cohort review committee based on experience during the single-agent dose escalation phase. Standard doses of fulvestrant (HR+BC) and abiraterone+presone (mCRPC) were administered. After identifying the MTD/RD of the combination regimen, in the expansion phase of the combination therapy cohort, the safety and efficacy of the regimen were further evaluated in the corresponding HR+ BC and mCRPC expansion cohorts using a Simon's two-stage design. Compound 44-A combination therapy study protocol is shown in FIG. 4 . Modified i3+3 dose escalation study design
在劑量遞增階段中，使用經改良之i3+3設計鑑別化合物44-A作為單藥及在組合方案中之MTD/RD。組合療法之劑量遞增係以隊列審查委員會認為安全且適當之時間且以其認為安全且適當之劑量的化合物44-A反丁烯二酸鹽起始，且可以在確定單藥化合物44-A之MTD/RD之前發生。In the dose escalation phase, a modified i3+3 design was used to identify the MTD/RD of compound 44-A as a single agent and in combination regimens. Dose escalation of combination therapy was initiated with Compound 44-A fumarate at a time and dose deemed safe and appropriate by the Cohort Review Board, and could be established after single-agent Compound 44-A Occurs before MTD/RD.
劑量遞增/遞減決定係基於在劑量限制性毒性(DLT) 評價期間發生的事件且使用經改良之i3+3演算法指導，DLT評價期定義為在研究治療起始後的前28天。若受試者經歷DLT或完成DLT評價期但沒有經歷DLT，則該等受試者被認為可評價的以作出劑量遞增決定；由於安全以外的原因而未完成DLT評價期的受試者不被視為可評價的。Dose escalation/decrement decisions were based on events occurring during the dose-limiting toxicity (DLT) assessment period defined as the first 28 days after study treatment initiation and guided using a modified i3+3 algorithm. Subjects were considered evaluable for dose escalation decisions if they underwent a DLT or completed the DLT evaluation period but did not undergo a DLT; subjects who did not complete the DLT evaluation period for reasons other than safety were not considered evaluable. considered evaluable.
本研究中化合物44-A作為單藥或組合療法的MTD之目標毒性概率設定為25%之目標毒性率(pT= 0.25)及等價區間(EI)= [0.20, 0.30]。EI為定義及定位MTD提供較大的靈活性。毒性概率在0.20與0.30之間的劑量可被認為可接受作為MTD。選定的pT及EI之值比在舊的標準劑量遞增研究設計(例如3+3研究設計)中被認為MTD可接受之毒性率要稍微保守一些。實施經改良之i3+3i設計之操作計劃提供於下： • 在化合物44-A劑量水平下登記含3名受試者之隊列。 • 化合物44-A單藥之起始劑量水平係20 mg qd (每日一次)。 • 組合療法中化合物44-A之起始劑量水平係由隊列審查委員會根據單藥劑量遞增階段之經驗確定。 • 組合劑(即，氟維司群[HR+ BC]或阿比特龍加普賴松[mCRPC])係根據標籤以標準劑量投與。 • 在隊列完成28天之DLT評價期後，隊列審查委員會審查隊列之安全性及PK資料，並確定隊列中有多少可評價之受試者有DLT。 • 中間劑量水平可以***先前開放之劑量水平之間，並應隊列審查委員會之要求根據新出現之安全性及PK資料進行評價。若***新的劑量水平，則根據相同的經改良之i3+3設計，添加新劑量水平進行劑量發現。 劑量遞增之量值 In this study, the target toxicity probability of the MTD of compound 44-A as a single drug or combination therapy was set at 25% target toxicity rate (pT= 0.25) and equivalence interval (EI) = [0.20, 0.30]. EI provides greater flexibility for defining and locating MTD. A dose with a probability of toxicity between 0.20 and 0.30 may be considered acceptable as the MTD. The selected values of pT and EI are slightly more conservative than the toxicity rates considered acceptable for the MTD in older standard dose escalation study designs (eg 3+3 study designs). A protocol for implementing the modified i3+3i design is provided below: • Enroll a cohort of 3 subjects at the Compound 44-A dose level. • The starting dose level of compound 44-A monotherapy is 20 mg qd (once a day). • The starting dose level of compound 44-A in the combination therapy was determined empirically by the cohort review committee based on the experience of the single agent dose escalation phase. • Combination agents (ie, fulvestrant [HR+ BC] or abiraterone plus presone [mCRPC]) are administered at standard doses according to the label. • After the cohort completed the 28-day DLT evaluation period, the cohort review committee reviewed the cohort's safety and PK data and determined how many evaluable subjects in the cohort had a DLT. • Intermediate dose levels may be inserted between previously open dose levels and will be evaluated based on emerging safety and PK data at the request of the Cohort Review Board. If a new dose level is inserted, the new dose level is added for dose finding according to the same modified i3+3 design. magnitude of dose escalation
只有在至少三名受試者已在當前劑量水平下進行評價且尚未出現如上文所論述的中止登記之原因時，劑量遞增才可進行至下一個更高的劑量水平。當選擇新的更高劑量水平進行評估時，劑量遞增不超過化合物44-A劑量之兩倍，且隊列審查委員會可基於當前及先前隊列之安全性及PK結果評價決定在隊列之間進行小於兩倍之遞增(即，100%前一化合物44-A劑量的最大劑量增量)。 MTD/RD 測定 Dose escalation to the next higher dose level will only proceed if at least three subjects have been evaluated at the current dose level and no reasons for discontinuation of enrollment have arisen as discussed above. When selecting a new higher dose level for evaluation, the dose escalation should not exceed twice the dose of Compound 44-A, and the cohort review committee may decide to conduct less than two doses between cohorts based on the evaluation of safety and PK results of the current and previous cohorts. Fold escalation (ie, the maximum dose increment of 100% of the previous Compound 44-A dose). MTD/RD determination
劑量限制性毒性(DLT)係由隊列審查委員會在審查所有可用的安全性資料後確定，並根據DLT評價期間發生的治療期間出現之AE進行定義。在所有登記的受試者皆完成其DLT評價(或被認為不可評價的)且滿足停止進一步登記之標準後，使用保序回歸統計分析，根據由所有劑量水平觀察到的DLT資料選擇MTD。具體而言，毒性率最接近目標毒性率25% (pT = 0.25)且不超過EI上限(即，0.30)之最高測試劑量被選為MTD。Dose-limiting toxicities (DLTs) were determined by the cohort review committee after reviewing all available safety data and were defined based on treatment-emergent AEs that occurred during the DLT evaluation period. After all enrolled subjects had completed their DLT assessments (or were deemed non-evaluable) and met the criteria to stop further enrollment, the MTD was selected based on the DLT data observed for all dose levels using ordinal regression statistical analysis. Specifically, the highest tested dose with a toxicity rate closest to the target toxicity rate of 25% (pT = 0.25) and within the upper limit of the EI (ie, 0.30) was selected as the MTD.
在審查完一種方案(即，化合物44-A單藥或組合療法)的所有可用安全性、PK及初步臨床活性資料後，隊列審查委員會將選擇化合物44-A之一個推薦劑量(RD)水平用於治療相應擴展隊列受試者的方案。對於各方案，化合物44-A反丁烯二酸鹽RD係MTD或更低的劑量水平。 隊列擴展階段研究設計 ( 西蒙氏兩階段 ) After reviewing all available safety, PK, and preliminary clinical activity data for a regimen (i.e., Compound 44-A monotherapy or combination therapy), the cohort review committee will select a recommended dose (RD) level of Compound 44-A for use in A protocol for treating the corresponding expansion cohort of subjects. Compound 44-A fumarate RD was at the MTD or lower dose level for each regimen. Cohort Expansion Phase Study Design ( Simon's Two-Phase )
在隊列擴展階段中，在四種腫瘤類型的總共六個擴展隊列中測試單藥及組合方案。此等隊列根據西蒙氏兩階段Minimax設計進行登記。在此設計中，最少數量的受試者必須在第一階段中經歷反應，才開放第二階段之登記。In the cohort expansion phase, single-agent and combination regimens were tested in a total of six expansion cohorts across four tumor types. The cohorts were enrolled according to a Simon's two-stage Minimax design. In this design, a minimum number of subjects must experience a response in Phase 1 before enrollment in Phase 2 is opened.
用單藥化合物44-A治療患有EOC及TNBC之受試者。患有HR+ BC及mCRPC之受試者可以接受單藥化合物44-A或利用化合物44-A及氟維司群(HR+ BC)或阿比特龍+普賴松(mCRPC)之組合療法。在資格審查程序之後，受試者被登記入適當的開放隊列中。Subjects with EOC and TNBC were treated with single agent Compound 44-A. Subjects with HR+ BC and mCRPC can receive single agent Compound 44-A or combination therapy with Compound 44-A and fulvestrant (HR+ BC) or abiraterone+presone (mCRPC). Following the eligibility process, subjects were enrolled in appropriate open cohorts.
需要總共18名受試者(在該兩階段設計之第一階段期間每一隊列中有3名受試者)在隊列擴展階段中提供篩選以及治療中之腫瘤及皮膚生物檢體。為了有資格提供此等樣本，受試者必須具有經當地介入治療放射學(IR)或首席研究者評估可安全接近之腫瘤病變(例如皮膚病變、皮下淋巴結病變、在藉由影像指導之生檢接近時風險較低的病變)。此外，此等受試者必須具有未經歷生檢之目標病變，以便根據RECIST 1.1標準測定反應。此等受試者之研究評估及訪視時間表與隊列擴展階段中之其他受試者相同。 化合物44-A單藥療法評價 單藥劑量遞增階段 A total of 18 subjects (3 subjects in each cohort during the first phase of the two-phase design) are required to provide screening and on-treatment tumor and skin biospecimens during the cohort expansion phase. To be eligible to provide these samples, subjects must have tumor lesions (e.g., skin lesions, subcutaneous lymph node lesions, lower risk lesions when approached). In addition, such subjects must have target lesions that have not undergone biopsy in order to measure response according to RECIST 1.1 criteria. The study assessment and visit schedule for these subjects was the same as for other subjects in the cohort expansion phase. Compound 44-A monotherapy evaluation single agent dose escalation phase
單藥劑量遞增由採用經改良之i3+3研究設計，向患有晚期實體腫瘤之受試者投與遞增劑量水平之化合物44-A組成。單藥劑量遞增將在經口投與化合物44-A之估計5個劑量水平下評價多達約36名受試者。該研究之起始化合物44-A劑量水平係20 mg。包括第29-35天(第5週第1天[W5D1]至W5D7)的洗除期(不投與研究藥物)。在劑量遞增期間，收集視情況選用之生物檢體(腫瘤及皮膚組織)用於藥效學評價。 研究訪視： Single agent dose escalation consisted of administering escalating dose levels of Compound 44-A to subjects with advanced solid tumors using a modified i3+3 study design. Single-Agent Dose Escalation Up to approximately 36 subjects will be evaluated at an estimated 5 dose levels of Compound 44-A administered orally. The starting Compound 44-A dose level for this study was 20 mg. A washout period (no administration of study drug) was included on Days 29-35 (Week 5 Day 1 [W5D1] to W5D7). During dose escalation, optional biological samples (tumor and skin tissue) were collected for pharmacodynamic evaluation. Study Visits:
處於單藥劑量遞增階段之受試者在研究期間到診所就診以進行研究評估，如下所示： 治療前期 ( 篩選 ) ：受試者同意並經歷篩选及基線評價以獲得研究資格。 Subjects in the single-agent dose escalation phase will visit the clinic during the study for study assessments as follows: Pre-Treatment ( Screening ) : Subjects consent and undergo screening and baseline evaluations for study eligibility.
DLT 評價期 ( 第 1-28 天 [W1D1 至 W4D7]) ：由隊列審查委員會在審查所有可用資料後確定DLT且DLT定義如上。 DLT Evaluation Period ( Days 1-28 [W1D1 to W4D7]) : DLTs are determined by the cohort review committee after reviewing all available data and are defined as above.
洗除期 ( 第 29-35 天，包括端點在內 [W5D1 至 W5D7]) ：接受單藥療法之受試者有一個洗除期(不投與研究藥物)以便確定穩態下化合物44-A的半衰期。 Washout Period ( Days 29-35 , inclusive [W5D1 to W5D7]) : Subjects receiving monotherapy had a washout period (no study drug administered) to determine compound 44- A's half-life.
治療擴展期 ( 第 36+ 天 [W6D1+]) ：對受試者進行治療並監測其安全性(包括實驗室評估)及毒性徵象。在不存在根據RECIST 1.1之放射線攝影PD及不可接受之毒性的情況下，受試者可以繼續接受化合物44-A治療長達12個月及額外的12個月。若研究者確定受試者仍然自治療中獲得臨床益處，則可以允許受試者在放射線攝影PD後繼續接受研究治療。 治療後期： Treatment Extension Phase ( Day 36+ [W6D1+]) : Subjects were treated and monitored for safety (including laboratory assessments) and signs of toxicity. Subjects may continue to receive Compound 44-A treatment for up to 12 months and an additional 12 months in the absence of radiographic PD according to RECIST 1.1 and unacceptable toxicity. Subjects may be allowed to continue study treatment after radiographic PD if the investigator determines that the subject is still deriving clinical benefit from treatment. After treatment:
治療後追踪訪視(FU)：治療後追踪安全訪視係在決定中止研究治療日(定義為決定永久中止研究治療之日或最後一劑研究治療之日期，以較晚者為準)後30(+14)天發生。若在追踪訪視時發生導致研究治療中止之相關AE、相關嚴重不良事件(SAE)或DLT(無論因果關係如何)，則應進行追踪直至解決或不可逆轉。Post-treatment follow-up visit (FU): The post-treatment follow-up safety visit is 30 days after the date of decision to discontinue study treatment (defined as the date of decision to permanently discontinue study treatment or the date of the last dose of study treatment, whichever is later). (+14) days to happen. If a related AE, related serious adverse event (SAE) or DLT (regardless of causality) occurs during the follow-up visit leading to discontinuation of study treatment, it should be followed until resolved or irreversible.
延長追踪(FU後每12週一次[±14天])：在治療後追踪訪視後，繼續追踪各受試者的生存情況及方案以外之抗癌療法(nonprotocol anticancer therapy，NPACT)之接受情況。研究者(或指定人員)在治療後追踪訪視後每12週與受試者聯繫一次，直至受試者過期、撤回關於此類聯繫之同意或決定停止收集此等研究資料。 單藥隊列擴展階段 Extended follow-up (every 12 weeks after FU [±14 days]): After the post-treatment follow-up visit, continue to track the survival of each subject and the acceptance of nonprotocol anticancer therapy (NPACT) . The investigator (or designee) will contact the subject every 12 weeks after the post-treatment follow-up visit until the subject expires, withdraws consent for such contact, or decides to stop collecting such research data. Single-drug cohort expansion phase
在劑量遞增階段中測定了單藥化合物44-A療法之MTD/RD後，可以起始該研究之單藥隊列擴展階段。隊列擴展階段進一步探索化合物44-A作為單藥在腫瘤特異性擴展隊列中的安全性、耐受性及初步功效。此等隊列中之受試者係以隊列審查委員會選擇的化合物44-A之MTD/RD治療。在患有晚期EOC、TNBC、HR+ BC及mCRPC之受試者的擴展隊列中評估化合物44-A單藥療法之安全性及功效。在西蒙氏兩階段設計之第一階段期間登記的各擴展隊列中有三名受試者需要提供腫瘤及皮膚組織生物檢體。 研究訪視： After the MTD/RD of single-agent Compound 44-A therapy was determined in the dose-escalation phase, the single-agent cohort expansion phase of the study could be initiated. The cohort expansion phase further explores the safety, tolerability and preliminary efficacy of compound 44-A as a single drug in the tumor-specific expansion cohort. Subjects in these cohorts were treated with the MTD/RD of Compound 44-A selected by the cohort review committee. The safety and efficacy of Compound 44-A monotherapy were evaluated in an expanded cohort of subjects with advanced EOC, TNBC, HR+ BC and mCRPC. Three subjects in each expansion cohort enrolled during Phase 1 of the Simon's two-stage design were required to provide tumor and skin tissue biospecimens. Study Visits:
化合物44-A單藥擴展隊列中各受試者之治療過程由以下時期組成： 治療前期：受試者同意並經歷篩选及基線評價以獲得研究資格。 The course of treatment for each subject in the Compound 44-A single-drug expansion cohort consisted of the following periods: Pre-treatment: subjects agreed and underwent screening and baseline evaluations to qualify for the study.
治療期：對受試者進行治療並監測安全性(包括實驗室評估)及毒性徵象。在不存在根據RECIST 1.1之放射線攝影PD及不可接受之毒性的情況下，受試者可以繼續接受化合物44-A治療長達12個月及額外的12個月。若研究者確定受試者仍然自治療中獲得臨床益處，則可以允許受試者在放射線攝影PD後繼續接受研究治療。 治療後期： Treatment Period: Subjects are treated and monitored for safety (including laboratory assessments) and signs of toxicity. Subjects may continue to receive Compound 44-A treatment for up to 12 months and an additional 12 months in the absence of radiographic PD according to RECIST 1.1 and unacceptable toxicity. Subjects may be allowed to continue study treatment after radiographic PD if the investigator determines that the subject is still deriving clinical benefit from treatment. After treatment:
治療後追踪訪視(FU)：治療後追踪安全訪視係在決定中止研究治療日(定義為決定永久中止研究治療之日或最後一劑研究治療之日期，以較晚者為準)後30(+14)天發生。若在追踪訪視時發生導致研究治療終止之相關AE或相關SAE，則對其進行追踪，直至解決或不可逆轉。Post-treatment follow-up visit (FU): The post-treatment follow-up safety visit is 30 days after the date of decision to discontinue study treatment (defined as the date of decision to permanently discontinue study treatment or the date of the last dose of study treatment, whichever is later). (+14) days to happen. If a related AE or related SAE leading to discontinuation of study treatment occurs at the follow-up visit, it will be followed until resolved or irreversible.
延長追踪(FU後每12週一次[±14天])：在治療後追踪訪視後，繼續追踪各受試者的生存情況及NPACT之接受情況。研究者(或指定人員)在治療後追踪訪視後每12週與受試者聯繫一次，直至受試者過期、撤回關於此類聯繫之同意或決定停止收集此等研究資料。 化合物44-A組合療法評價 組合療法劑量遞增階段 Extended follow-up (every 12 weeks [±14 days] after FU): After the post-treatment follow-up visit, the survival of each subject and the acceptance of NPACT will continue to be followed. The investigator (or designee) will contact the subject every 12 weeks after the post-treatment follow-up visit until the subject expires, withdraws consent for such contact, or decides to stop collecting such research data. Compound 44-A Combination Therapy Evaluation Combination Therapy Dose Escalation Phase
組合方案之劑量遞增由採用如以上所描述的經改良之i3+3研究設計，分別對患有HR+BC或mCRPC之受試者投與的遞增劑量水平之化合物44-A及標準劑量之氟維司群(肌肉內[IM]注射；前3劑每2週一次且接著每4週一次)或阿比特龍(qd)加普賴松(每日兩次[bid])組成。Dose escalation of the combination regimen consisted of escalating dose levels of Compound 44-A and standard doses of fluoride administered to subjects with HR+BC or mCRPC, respectively, using the modified i3+3 study design as described above. Vestrant (intramuscular [IM]; every 2 weeks for the first 3 doses and then every 4 weeks) or abiraterone (qd) plus presone (twice daily [bid]).
在以下條件下，在達到化合物44-A單藥療法之MTD之前，組合方案之劑量遞增可與單藥劑量遞增並行發生： 組合方案之化合物44-A的起始劑量必須為在藉由針對多個劑量水平評價受試者而獲得經驗後，隊列審查委員會認為使用化合物44-A進行單藥療法安全的劑量水平。此外，組合方案中化合物44-A之起始劑量必須為低於當前登記之單藥化合物44-A劑量的至少一個劑量水平，且必須反映隊列審查委員會基於可用資料而對化合物44-A劑量水平對受試者安全構成低風險的信心。Dose escalation of the combination regimen can occur in parallel with single agent dose escalation before reaching the MTD of Compound 44-A monotherapy under the following conditions: The initial dose of Compound 44-A for the combination regimen must be After experience gained from evaluating subjects at each dose level, the cohort review committee determined the dose level to be safe for monotherapy with Compound 44-A. In addition, the starting dose of Compound 44-A in the combination regimen must be at least one dose level lower than the currently registered single-agent Compound 44-A dose and must reflect the Cohort Review Committee's assessment of the Compound 44-A dose level based on available data. Confidence that there is a low risk to subject safety.
各組合療法劑量遞增在估計的經口投與之化合物44-A之2-3個劑量水平評價多達約15名受試者。組合療法之DLT評價期後沒有洗除期。在劑量遞增期間，收集視情況選用之生物檢體(腫瘤及皮膚組織)用於藥效學評價。Each combination therapy dose escalation evaluates up to about 15 subjects at estimated 2-3 dose levels of Compound 44-A administered orally. There is no washout period after the DLT evaluation period for combination therapy. During dose escalation, optional biological samples (tumor and skin tissue) were collected for pharmacodynamic evaluation.
基於安全性、PK及初步臨床活性，隊列審查委員會選出相應組合擴展隊列累積受試者的化合物44-A之一個劑量水平用於各組合方案(MTD/RD)。 研究訪視： Based on safety, PK, and preliminary clinical activity, the cohort review committee selected one dose level of Compound 44-A for each combination regimen (MTD/RD) accumulating subjects in the corresponding combination expansion cohort. Study Visits:
組合療法劑量遞增隊列中各受試者之治療過程由以下時期組成： 治療前期：受試者同意並經歷篩选及基線評價以獲得研究資格。 The course of treatment for each subject in the combination therapy dose escalation cohort consisted of the following periods: Pre-treatment: Subject consented and underwent screening and baseline evaluations for study eligibility.
DLT 評價期 ( 第 1-28 天 [W1D1 至 W4D7]) ：由隊列審查委員會在審查所有可用資料後確定DLT且DLT定義如上。 DLT Evaluation Period ( Days 1-28 [W1D1 to W4D7]) : DLTs are determined by the cohort review committee after reviewing all available data and are defined as above.
治療擴展期 ( 第 29+ 天 [W5D1+]) ：對受試者進行治療並監測安全性(包括實驗室評估)及毒性徵象。在不存在根據RECIST 1.1之放射線攝影PD及不可接受之毒性的情況下，受試者可以繼續接受化合物44-A治療長達12個月及額外的12個月。若研究者確定受試者仍然自治療中獲得臨床益處，則可以允許受試者在放射線攝影疾病進展後繼續接受研究治療。 治療後期： Treatment Extension Phase ( Day 29+ [W5D1+]) : Subjects were treated and monitored for safety (including laboratory assessments) and signs of toxicity. Subjects may continue to receive Compound 44-A treatment for up to 12 months and an additional 12 months in the absence of radiographic PD according to RECIST 1.1 and unacceptable toxicity. Subjects may be permitted to continue receiving study treatment after radiographic disease progression if the investigator determines that the subject is still deriving clinical benefit from the treatment. After treatment:
治療後追踪訪視(FU)：治療後追踪安全訪視係在決定中止研究治療日(定義為決定永久中止研究治療之日或最後一劑研究治療之日期，以較晚者為準)後30(+14)天發生。若在追踪訪視時出現導致研究治療中止的相關AE、相關SAE或DLT(無論因果關係如何)，則對其進行追踪，直至解決或不可逆轉。Post-treatment follow-up visit (FU): The post-treatment follow-up safety visit is 30 days after the date of decision to discontinue study treatment (defined as the date of decision to permanently discontinue study treatment or the date of the last dose of study treatment, whichever is later). (+14) days to happen. Related AEs, related SAEs, or DLTs (regardless of causality) that lead to discontinuation of study treatment at follow-up visits will be followed until resolved or irreversible.
延長追踪(FU後每12週一次[±14天])：在治療後追踪訪視後，繼續追踪各受試者的生存情況及NPACT之接受情況。研究者(或指定人員)在治療後追踪訪視後每12週與受試者聯繫一次，直至受試者過期、撤回關於此類聯繫之同意或決定停止收集此等研究資料。 組合療法隊列擴展階段 Extended follow-up (every 12 weeks [±14 days] after FU): After the post-treatment follow-up visit, the survival of each subject and the acceptance of NPACT will continue to be followed. The investigator (or designee) will contact the subject every 12 weeks after the post-treatment follow-up visit until the subject expires, withdraws consent for such contact, or decides to stop collecting such research data. Combination Therapy Cohort Expansion Phase
在劑量遞增階段確定了組合方案中化合物44-A之MTD/RD後，可以起始該組合方案研究的隊列擴展階段。隊列擴展階段進一步探索化合物44-A組合療法在以下兩個腫瘤特異性隊列中的安全性、耐受性及初步功效：HR+ BC(組合劑：氟維司群)及mCRPC (組合劑：阿比特龍及普賴松)。隊列擴展階段中之受試者係以在組合療法劑量遞增階段確定的化合物44-A加組合劑之MTD/RD治療。在西蒙氏兩階段設計之第一階段期間登記的各擴展隊列中有三名受試者需要提供腫瘤及皮膚組織生物檢體。 研究訪視： After the MTD/RD of Compound 44-A in the combination regimen has been determined during the dose escalation phase, the cohort expansion phase of the combination regimen study can be initiated. The cohort expansion stage will further explore the safety, tolerability and preliminary efficacy of compound 44-A combination therapy in the following two tumor-specific cohorts: HR+ BC (combination agent: fulvestrant) and mCRPC (combination agent: abitrate Long and Presson). Subjects in the cohort expansion phase were treated with the MTD/RD of Compound 44-A plus the combination as determined in the combination therapy dose escalation phase. Three subjects in each expansion cohort enrolled during Phase 1 of the Simon's two-stage design were required to provide tumor and skin tissue biospecimens. Study Visits:
組合療法劑量擴展隊列中各受試者之治療過程由以下時期組成： 治療前期：受試者同意並經歷篩选及基線評價以獲得研究資格。 The course of treatment for each subject in the combination therapy dose-expansion cohort consisted of the following periods: Pre-treatment: Subject consented and underwent screening and baseline evaluations for study eligibility.
治療期：對受試者進行治療並監測安全性(包括實驗室評估)及毒性徵象。在不存在根據RECIST 1.1之放射線攝影PD及不可接受之毒性的情況下，受試者可以繼續接受組合治療長達12個月及額外的12個月。若研究者確定受試者仍然自治療中獲得臨床益處，則可以允許受試者在放射線攝影PD後繼續接受研究治療。 治療後期： Treatment Period: Subjects are treated and monitored for safety (including laboratory assessments) and signs of toxicity. Subjects may continue to receive combination therapy for up to 12 months and an additional 12 months in the absence of radiographic PD according to RECIST 1.1 and unacceptable toxicity. Subjects may be allowed to continue study treatment after radiographic PD if the investigator determines that the subject is still deriving clinical benefit from treatment. After treatment:
治療後追踪訪視(FU)：治療後追踪安全訪視係在決定中止研究治療日(定義為決定永久中止研究治療之日或最後一劑研究治療之日期，以較晚者為準)後30(+14)天發生。若在追踪訪視時發生導致研究治療中止之相關AE或相關SAE，則對其進行追踪，直至解決或不可逆轉。Post-treatment follow-up visit (FU): The post-treatment follow-up safety visit is 30 days after the date of decision to discontinue study treatment (defined as the date of decision to permanently discontinue study treatment or the date of the last dose of study treatment, whichever is later). (+14) days to happen. If a related AE or related SAE leading to discontinuation of study treatment occurs at the follow-up visit, it will be followed until resolved or irreversible.
延長追踪(FU後每12週一次[±14天])：在治療後追踪訪視後，繼續追踪各受試者的生存情況及NPACT之接受情況。研究者(或指定人員)在治療後追踪訪視後每12週與受試者聯繫一次，直至受試者過期、撤回關於此類聯繫之同意或決定停止收集此等研究資料。 受試者數量 Extended follow-up (every 12 weeks [±14 days] after FU): After the post-treatment follow-up visit, the survival of each subject and the acceptance of NPACT will continue to be followed. The investigator (or designee) will contact the subject every 12 weeks after the post-treatment follow-up visit until the subject expires, withdraws consent for such contact, or decides to stop collecting such research data. Number of subjects
該研究可累積多達約298名受試者。在化合物44-A單藥療法評價中估計登記的受試者數量為約180名(劑量遞增隊列中約36名受試者及擴展隊列中約144名受試者)。在化合物44-A組合療法評價中估計登記的受試者數量為約118名(組合療法劑量遞增隊列中約30名受試者及擴展隊列中約88名受試者)。表2顯示單藥化合物44-A及單藥隊列擴展研究之受試者登記數估計。
表2：單藥化合物44-A評估之登記數估計
下表3顯示化合物44-A組合療法及隊列擴展評價的受試者登記數估計。
表3：化合物44-A組合療法評價的登記數估計
本研究中的受試者必須接受過標準的延長生命療法，或者沒有資格接受此類療法。Subjects in this study must have received standard life-prolonging therapy or be ineligible for such therapy.
為獲得研究資格，受試者必須滿足所有納入標準且不符合任何排除標準。此等資格標準之例外情況將為不允許的。 納入標準 To be eligible for the study, subjects must meet all inclusion criteria and not meet any exclusion criteria. Exceptions to these eligibility criteria will not be permitted. Inclusion criteria
注意：為了確定既往數線療法之數量，新輔助療法、輔助療法、腹膜內療法及維持療法不計入既往療法的最大允許數量，且再暴露於相同藥劑不被視為額外線療法。NOTE: For purposes of determining the number of prior lines of therapy, neoadjuvant, adjuvant, intraperitoneal, and maintenance therapy are not counted towards the maximum allowable number of prior therapies, and re-exposure to the same agent is not considered additional line therapy.
經細胞學或組織學及放射學證實的不可手術、局部晚期、轉移性或復發性實體腫瘤。不存在延長生命的措施，或可用療法無法耐受或不再有效； 劑量遞增階段隊列A (實體腫瘤)：受試者患有不可切除的或轉移性實體腫瘤，且對於該實體腫瘤，不存在延長生命的措施或可用療法不可耐受或不再有效。 劑量遞增階段隊列B以及隊列擴展階段隊列F及H ( 激素受體陽性乳癌 ) ： Inoperable, locally advanced, metastatic or recurrent solid tumors confirmed by cytology or histology and radiology. Life-prolonging measures do not exist, or available therapies cannot be tolerated or are no longer effective; Life-prolonging measures or available therapies are intolerable or no longer effective. Dose Escalation Phase Cohort B and Cohort Expansion Phase Cohorts F and H ( hormone receptor positive breast cancer ) :
患有激素受體陽性(***受體陽性[ER+]及/或孕激素受體陽性[PR+])及人類表皮生長因子受體2陰性(HER-2陰性[HER-2-])乳癌且在不可手術之局部晚期或轉移性疾病的最後一次全身抗癌療法期間或之後具有記錄之放射學攝影疾病進展的受試者。 激素受體陽性HER-2陰性乳癌(HR+BC)： have hormone receptor positive (estrogen receptor positive [ER+] and/or progesterone receptor positive [PR+]) and human epidermal growth factor receptor 2 negative (HER-2 negative [HER-2-]) breast cancer and Subjects with documented radiographic disease progression during or after last systemic anticancer therapy for inoperable locally advanced or metastatic disease. Hormone receptor positive HER-2 negative breast cancer (HR+BC):
***受體及孕激素受體陽性定義為經由免疫組織化學(IHC)分析測定表現激素受體之細胞≥ 1%。Estrogen receptor and progesterone receptor positivity was defined as ≥ 1% of cells expressing hormone receptors as determined by immunohistochemical (IHC) analysis.
HER-2陰性經當地實驗室評估而定義為以下任一情況：原位雜交(ISH)未擴增(HER-2與CEP17之比率＜ 2.0或單探針平均HER-2基因拷貝數＜ 4個信號/細胞)，或者IHC 0或IHC 1+ (若可獲得多個測試結果且並非所有結果皆滿足納入標准定義，則應考慮所有結果以確定受試者之資格)。HER-2 negative was defined by local laboratory assessment as any of the following: in situ hybridization (ISH) unamplified (HER-2 to CEP17 ratio < 2.0 or single-probe average HER-2 gene copy number < 4 signal/cell), or IHC 0 or IHC 1+ (if multiple test results are available and not all meet the inclusion criteria definition, all results should be considered to determine subject eligibility).
受試者須因手術/自然絕經或使用***釋放激素(GnRH)促效劑(例如戈舍瑞林)進行卵巢抑制而處於絕經後狀態。Subjects must be in a postmenopausal state due to surgical/natural menopause or ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists such as goserelin.
對於所有隊列：受試者必須依序或同時接受過針對不可手術之局部晚期或轉移性乳癌的至少一種既往內分泌抗癌療法及一種既往CDK4/6抑制劑療法。For all cohorts: Subjects must have received at least one prior endocrine anticancer therapy and one prior CDK4/6 inhibitor therapy sequentially or concurrently for inoperable locally advanced or metastatic breast cancer.
注意：既往數線內分泌抗癌療法之次數不限。實例包括氟維司群(選擇性***受體降解劑[SERD])、他莫昔芬(選擇性***受體調節劑[SERM])以及依西美坦(exemestane) (類固醇芳香酶抑制劑[SAI])，及來曲唑(非類固醇芳香酶抑制劑[NSAI])。Note: There is no limit to the number of previous lines of endocrine anticancer therapy. Examples include fulvestrant (selective estrogen receptor degrader [SERD]), tamoxifen (selective estrogen receptor modulator [SERM]), and exemestane (steroid aromatase inhibitor agent [SAI]), and letrozole (nonsteroidal aromatase inhibitor [NSAI]).
對於隊列B (組合療法劑量遞增階段)：受試者可能已接受最多三線針對局部晚期或轉移性疾病的額外既往全身抗癌療法(不包括內分泌及CDK4/6抑制劑療法)。For Cohort B (dose-escalation phase of combination therapy): Subjects may have received up to three lines of additional prior systemic anticancer therapy (excluding endocrine and CDK4/6 inhibitor therapy) for locally advanced or metastatic disease.
對於隊列F及H (单药及組合療法劑量遞增階段)：受試者可能已接受最多二線針對局部晚期或轉移性疾病的額外既往全身抗癌療法(不包括內分泌及CDK4/6 抑制劑療法)。For cohorts F and H (monotherapy and combination therapy dose-escalation phase): Subjects may have received up to second-line additional prior systemic anticancer therapy (excluding endocrine and CDK4/6 inhibitor therapy) for locally advanced or metastatic disease ).
劑量遞增階段隊列C以及隊列擴展階段隊列G及I (轉移性去勢抵抗性***癌)：患有***腺癌之受試者。注意：若腺癌為主要組織學的，則允許神經內分泌分化及其他組織學特徵。Dose Escalation Phase Cohort C and Cohort Expansion Phase Cohorts G and I (metastatic castration-resistant prostate cancer): subjects with prostate adenocarcinoma. Note: Neuroendocrine differentiation and other histologic features are allowed if adenocarcinoma is predominant histology.
受試者必須有藉由以下任一項記錄的***癌進展： • PSA進展：***特異性抗原(PSA)進展定義為由3或4次連續評估得到的PSA值中最少2個值升高，其中各評估之間的時間間隔為至少7天。 注意：若僅藉由 PSA 進展評估資格，則篩選 PSA 值必須為至少 2 ng/mL (2 µg/L) 且最早的合格值必須基於在簽署知情同意書 (ICF) 之前不超過一年抽取的血液樣本，且沒有改變***癌治療的全身方案；若非最新值，最多允許一次 PSA 值降低。若研究實驗室係抽取受試者先前 PSA 血液樣本之當地實驗室，則篩選當地實驗室 PSA 值必須係最高的。• 軟組織疾病之放射學攝影進展。 注意：僅患有骨病的受試者必須有經證明之PSA進展才能符合條件。 Subjects must have prostate cancer progression documented by any of the following: • PSA progression: Prostate-specific antigen (PSA) progression is defined as an increase in at least 2 of the PSA values from 3 or 4 consecutive assessments, Wherein the time interval between each assessment is at least 7 days. Note: If eligibility is assessed by PSA progression only , the screening PSA value must be at least 2 ng/mL (2 µg/L) and the earliest qualifying value must be based on a blood sample drawn no more than one year before signing the Informed Consent Form (ICF) . Blood sample and no change in systemic regimen for prostate cancer treatment; no more than one decrease in PSA value is allowed if not the most recent value. If the research laboratory is the local laboratory from which the subject's previous PSA blood samples were drawn, the PSA value of the screening local laboratory must be the highest. • Advances in Radiography for Soft Tissue Diseases. Note: Only subjects with bone disease must have documented PSA progression to be eligible.
對於所有隊列：受試者必須接受過至少一種針對去勢敏感性局部晚期(T3或T4)疾病、轉移性***癌(mCSPC)、M0去勢抵抗性***癌(CRPC)或mCRPC之既往新穎激素療法(NHT；例如恩雜魯胺、阿帕魯胺、達洛魯胺、阿比特龍、加萊特龍(galeterone)、奧特羅奈、司維特羅或等效藥物)。For all cohorts: Subjects must have received at least one prior novel hormone therapy for castration-sensitive locally advanced (T3 or T4) disease, metastatic prostate cancer (mCSPC), M0 castration-resistant prostate cancer (CRPC), or mCRPC ( NHT; eg, enzalutamide, apalutamide, darolutamide, abiraterone, galeterone, oteronide, seveterol, or equivalent).
對於隊列C (組合療法劑量遞增階段)：受試者必須接受過至少一種針對mCSPC或mCRPC的既往紫杉烷類化學療法(例如多西他賽、卡巴他賽)。For cohort C (combination therapy dose-escalation phase): Subjects must have received at least one prior taxane-based chemotherapy (eg, docetaxel, cabazitaxel) for mCSPC or mCRPC.
對於隊列G及I (隊列擴展單藥及組合療法)：受試者必須接受過一種且僅一種針對mCRPC的既往紫杉烷類化學療法(例如多西他賽、卡巴他賽)。For cohorts G and I (cohort expansion monotherapy and combination therapy): Subjects must have received one and only one prior taxane-based chemotherapy (eg, docetaxel, cabazitaxel) for mCRPC.
注意：若根據研究者評估不適合(例如受試者不適合)或受試者拒絕，則未接受過紫杉烷類化學療法之受試者有資格參加所有隊列。Note: Taxane chemotherapy naïve subjects are eligible to participate in all cohorts if ineligible based on investigator assessment (eg, subject is not suitable) or if subject refuses.
隊列擴展階段隊列 D ( 三陰性乳癌 ) ：患有HER-2、***受體及孕激素受體呈陰性之乳癌且在針對不可手術之局部晚期或轉移性疾病的最後一次全身抗癌療法期間或之後有經記錄之放射影像學疾病進展的受試者。 三陰性 (ER-/PR-/HER-2-) 乳癌： Cohort Expansion Phase Cohort D ( Triple Negative Breast Cancer ) : Breast cancer with HER-2, estrogen receptor, and progesterone receptor negative during last systemic anticancer therapy for inoperable locally advanced or metastatic disease or later subjects with documented radiographic disease progression. Triple negative (ER-/PR-/HER-2-) breast cancer:
***受體及孕激素受體陰性定義為IHC分析測定表現激素受體之細胞＜ 1%。Estrogen receptor and progesterone receptor negativity was defined as <1% of cells expressing hormone receptors as determined by IHC analysis.
HER-2陰性經當地實驗室評估而定義為以下任一情況：ISH未擴增(HER-2與CEP17之比率＜ 2.0或單探針平均HER-2基因拷貝數＜ 4個信號/細胞)，或者IHC 0或IHC 1+ (若可獲得多個測試結果且並非所有結果皆滿足納入標准定義，則應考慮所有結果以確定受試者之資格)。HER-2 negativity was defined by local laboratory assessment as any of the following: ISH unamplified (HER-2 to CEP17 ratio < 2.0 or single-probe average HER-2 gene copy number < 4 signals/cell), Either IHC 0 or IHC 1+ (if multiple test results are available and not all results meet the inclusion criteria definition, all results should be considered to determine subject eligibility).
受試者必須接受過至少一線既往全身化學療法，但不超過三線針對局部晚期或轉移性疾病之既往全身抗癌療法(例如細胞毒性療法、靶向療法、免疫療法)。Subjects must have received at least one line of prior systemic chemotherapy, but no more than three lines of prior systemic anticancer therapy (eg, cytotoxic therapy, targeted therapy, immunotherapy) for locally advanced or metastatic disease.
隊列擴展階段隊列 E ( 上皮性卵巢癌 ) ：在用含鉑化學療法治療後患上鉑抗性疾病的患有上皮性卵巢癌，包括原發性腹膜癌(PPC)及輸卵管癌(FTC)之受試者。不包括卵巢交界性上皮腫瘤(低度惡性潛能)。 Cohort Expansion Phase Cohort E ( Epithelial Ovarian Cancer ) : Subjects with epithelial ovarian cancer, including primary peritoneal carcinoma (PPC) and fallopian tube carcinoma (FTC), who develop platinum-resistant disease after treatment with platinum-containing chemotherapy tester. Ovarian borderline epithelial tumors (low malignant potential) were excluded.
鉑抗性疾病定義為在接受最後一劑鉑類藥物後4周與6個月之間出現疾病進展。患有鉑類藥物難治性疾病(定義為在鉑類藥物化學療法期間或在最後一劑鉑類藥物後4週內疾病進展)的受試者不符合條件。 注意：由於 AE 而中止鉑類藥物療法的受試者不能定義為鉑類藥物抗性的且因此不符合條件。 Platinum-resistant disease was defined as disease progression between 4 weeks and 6 months after the last dose of platinum. Subjects with platinum-refractory disease (defined as disease progression during platinum-based chemotherapy or within 4 weeks of the last platinum-based dose) were not eligible. Note: Subjects who discontinue platinum-based therapy due to AEs cannot be defined as platinum-resistant and are therefore not eligible.
受試者必須接受過至少一線但不超過三線針對鉑類藥物抗性卵巢癌的既往全身抗癌療法(例如細胞毒性療法、靶向療法、免疫療法)。 注意：激素療法不計入既往全身療法的最大允許線數。 Subjects must have received at least one but no more than three lines of prior systemic anticancer therapy (eg, cytotoxic therapy, targeted therapy, immunotherapy) for platinum-resistant ovarian cancer. Note: Hormone therapy does not count towards the maximum allowable number of lines of prior systemic therapy.
經研究者確定，隊列擴展階段中之受試者必須患有根據RECIST v1.1可量測之疾病。Subjects in the cohort expansion phase must have a disease measurable according to RECIST v1.1 as determined by the investigator.
注意：劑量遞增階段中之受試者不需要患有可量測之疾病。Note: Subjects in the dose escalation phase need not have measurable disease.
腫瘤組織材料(存檔或新鮮腫瘤組織[若該組織可安全地獲得])。有關腫瘤組織樣本之具體要求可能會有所不同。Tumor tissue material (archived or fresh tumor tissue [if the tissue is safely available]). Specific requirements for tumor tissue samples may vary.
注意：對於需要在隊列擴展階段中治療之前及期間提供腫瘤組織的受試者，治療前腫瘤組織樣本必須在第一劑研究治療前不超過Note: For subjects who are required to provide tumor tissue before and during treatment in the cohort expansion phase, the pre-treatment tumor tissue sample must be no more than 6060 天獲得。days to get.
自AE恢復至基線或≤ 1級嚴重程度(不良事件通用術語標準第5版[CTCAE v5])，除非AE在臨床上不顯著(例如脫髮)或穩定(例如周圍神經病變)。 • 在同意日年滿18歲或以上。 • 東部合作腫瘤組(Eastern Cooperative Oncology Group，ECOG)體能狀態(ECOG) PS為0-1分。 • 基於在第一劑研究治療前10天內滿足以下所有實驗室標準，適當的器官及骨髓功能： • 在篩選實驗室樣本收集前2週內嗜中性白血球絕對計數(ANC)≥ 1500個/mm 3(≥1.5 GI/L)，且沒有顆粒球集落刺激因子(G-CSF)補充。 • 在篩選實驗室樣本收集前2週內血小板≥ 100,000個/mm 3(≥ 100 GI/L)]且未輸血。 • 在篩選實驗室樣本收集前2週內血紅蛋白≥9 g/dL(≥90 g/L)且未輸血。 • 凝血酶原時間(PT)或活化部分凝血活酶時間(aPTT)＜ 1.2 ×正常值上限(ULN)或國際標準化比值(INR)＜ 1.5 (對於口服香豆素類抗凝劑INR ≤ 3的受試者)。 • 丙胺酸胺基轉移酶(ALT)、天冬胺酸胺基轉移酶(AST)及鹼性磷酸酶(ALP)≤ × 3 ULN(對於患有骨轉移記錄之mCRPC的受試者：ALP ≤ 10 × ULN)。 • 總膽紅素≤ 1.5 × ULN(對於已知患有吉爾伯特氏病(Gilbert’s disease)的受試者：≤ 3 × ULN)。 • 血清肌酐 ≤ 1.5 × ULN或使用Cockcroft-Gault方程計算的肌酐清除率 ≥ 45 mL/min (≥ 0.75 mL/sec)]。 排除標準 • 接受化合物44-A或任何其他選擇性CDK7抑制劑 • 在第一劑研究治療之前21天(對於亞硝基脲類或絲裂黴素C為42天)內接受過任何細胞毒性化學療法或抗癌抗體療法(例如抗VEGF單株抗體[mAb]、計劃性細胞死亡蛋白-1 [PD-1]/計劃性死亡蛋白配體-1 [PD-L1] mAb)，包括研究劑。 • 在第一劑研究治療前2週內接受任何類型之小分子激酶抑制劑(包括研究性激酶抑制劑)。 • 在第一劑研究治療之前2週內或該藥劑之5個半衰期內(以較短者為準)接受過任何抗癌激素療法。組合隊列B及H中登記的在第一劑研究治療之前接受氟維司群的HR+BC受試者被允許繼續進行其氟維司群治療。組合隊列C及I中登記的在第一劑研究治療之前接受阿比特龍的轉移性CRPC受試者被允許繼續進行其阿比特龍治療。 注意：同時使用醋酸甲地孕酮或促黃體激素釋放激素 (LHRH) 促效劑 ( 例如亮丙瑞林 (leuprolide) 、戈舍瑞林 (goserelin)) 係容許的。• 在第一劑研究治療前14天內接受過放射療法。因既往放射療法而正經歷臨床相關併發症的受試者不符合條件。 • 已知的腦轉移或顱腦硬膜外疾病，除非用放射療法及/或手術(包括放射手術治療)適當治療且在第一劑研究治療之前穩定至少4週。 注意：符合條件的受試者在第一劑研究治療時必須沒有神經系統症狀且未接受皮質類固醇治療。• 在第一劑研究治療前5個半衰期或4週內(以較短者為準)使用細胞色素P450 (CYP) 3A4之強抑制劑或誘導劑，以及P-醣蛋白(P-gp)或乳癌抗性蛋白(BCRP)轉運蛋白抑制劑。 • 在第一劑研究治療前5個半衰期或4週內(以較短者為準)使用CYP3A4、CYP2B6、CYP2C8、CYP2C9、CYP2C19或BCRP轉運蛋白之敏感性受質。對於接受化合物44-A及阿比特龍加普賴松組合治療的mCRPC受試者，在第一劑研究治療前5個半衰期或4週內(以較短者為準)使用具有窄治療指數之CYP2D6受質係禁止的。 • 實體器官、自體或同種異體幹細胞移植史。 • 在第一劑研究治療前2年內診斷出另一種惡性疾病，但淺表皮膚癌或被認為已治愈且未用全身療法治療之局部、低級別腫瘤除外。 • 不受控制或顯著的間歇性或近期病痛。 • 亦可使用另外的排除及納入標準。 估計的研究持續時間 Recovery from AE to baseline or ≤ Grade 1 severity (Common Terminology Criteria for Adverse Events 5th edition [CTCAE v5]), unless the AE is clinically insignificant (eg, alopecia) or stable (eg, peripheral neuropathy). • Be 18 years of age or older on the date of consent. • Eastern Cooperative Oncology Group (ECOG) performance status (ECOG) PS is 0-1. • Adequate organ and bone marrow function based on meeting all of the following laboratory criteria within 10 days prior to first dose of study treatment: • Absolute neutrophil count (ANC) ≥ 1500/ mm 3 (≥1.5 GI/L) without granule colony-stimulating factor (G-CSF) supplementation. • Platelets ≥ 100,000/mm 3 (≥ 100 GI/L)] within 2 weeks prior to screening laboratory sample collection and not transfused. • Hemoglobin ≥9 g/dL (≥90 g/L) within 2 weeks prior to screening laboratory sample collection without blood transfusion. • Prothrombin time (PT) or activated partial thromboplastin time (aPTT) < 1.2 × upper limit of normal (ULN) or International Normalized Ratio (INR) < 1.5 (for oral coumarin anticoagulants INR ≤ 3 subjects). • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ × 3 ULN (for subjects with documented mCRPC with bone metastases: ALP ≤ 10 × ULN). • Total bilirubin ≤ 1.5 × ULN (for subjects with known Gilbert's disease: ≤ 3 × ULN). • Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 45 mL/min (≥ 0.75 mL/sec) calculated using the Cockcroft-Gault equation]. Exclusion Criteria • Received Compound 44-A or any other selective CDK7 inhibitor • Received any cytotoxic chemotherapeutic drug within 21 days (42 days for nitrosoureas or mitomycin C) prior to the first dose of study treatment Therapy or anti-cancer antibody therapy (eg, anti-VEGF monoclonal antibody [mAb], planned cell death protein-1 [PD-1]/planned death protein ligand-1 [PD-L1] mAb), including investigational agents. • Received any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 2 weeks prior to the first dose of study treatment. • Received any anticancer hormone therapy within 2 weeks prior to the first dose of study treatment or within 5 half-lives of that agent, whichever is shorter. HR+BC subjects enrolled in combined cohorts B and H who received fulvestrant prior to the first dose of study treatment were allowed to continue their fulvestrant treatment. Metastatic CRPC subjects enrolled in combined cohorts C and I who received abiraterone prior to the first dose of study treatment were allowed to continue their abiraterone treatment. Note: Concomitant use of megestrol acetate or luteinizing hormone-releasing hormone (LHRH) agonists ( eg, leuprolide , goserelin ) is permitted. • Received radiation therapy within 14 days prior to first dose of study treatment. Subjects who are experiencing clinically relevant complications from prior radiation therapy are not eligible. • Known brain metastases or cranial epidural disease unless appropriately treated with radiation therapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to the first dose of study treatment. Note: Eligible subjects must have no neurologic symptoms and not be receiving corticosteroids at the time of the first dose of study treatment. • A strong inhibitor or inducer of cytochrome P450 (CYP) 3A4, and P-glycoprotein (P-gp) or Breast cancer resistance protein (BCRP) transporter inhibitor. • Use of sensitive substrates of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or BCRP transporters within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study treatment. For subjects with mCRPC receiving compound 44-A and the combination of abiraterone plus presone, use the compound with a narrow therapeutic index within 5 half-lives or 4 weeks before the first dose of study treatment, whichever is shorter. CYP2D6 substrates are prohibited. • History of solid organ, autologous or allogeneic stem cell transplantation. • Another malignancy diagnosed within 2 years prior to the first dose of study treatment, except for superficial skin cancer or localized, low-grade tumors considered cured and not treated with systemic therapy. • Uncontrolled or marked intermittent or recent illness. • Additional exclusion and inclusion criteria may also be used. Estimated study duration
據估計，在劑量遞增階段中登記受試者並確定MTD或RD需要18個月，且隊列擴展階段登記又需要12個月。真實的研究持續時間因與假設的差異或因COVID-19大流行對受試者登記及研究進行之其他態樣的影響而可能更長或更短。 研究方案劑量/途徑/時間間隔 化合物 44-A 膠囊 It was estimated that it would take 18 months to enroll subjects in the dose escalation phase and determine the MTD or RD, and another 12 months to enroll in the cohort expansion phase. Actual study durations may be longer or shorter due to variances from assumptions or due to the impact of the COVID-19 pandemic on subject enrollment and other aspects of study conduct. Study Protocol Dose/Route/Interval Compound 44-A Capsules
化合物44-A膠囊係以10-mg及40-mg規格提供，以供經口投與。膠囊應在受控的室溫下儲存。受試者QD口服化合物44-A，且在劑量遞增階段中化合物44-A反丁烯二酸鹽之初始起始劑量為20 mg。Compound 44-A capsules are provided in 10-mg and 40-mg strengths for oral administration. Capsules should be stored at controlled room temperature. Subjects took compound 44-A orally QD, and the initial starting dose of compound 44-A fumarate in the dose-escalation phase was 20 mg.
化合物44-A膠囊不應拆分、打開、壓碎或咀嚼。指示受試者在服用化合物44-A之前至少2小時及服用之後至少1小時禁食(水除外)。指導受試者用最少8盎司(240 mL)水經口服用其指定的化合物44-A劑量，並在每日早上的同一時間服用化合物44-A。服用化合物44-A後嘔吐的受試者不應嘗試補足劑量。 氟維司群 Compound 44-A capsules should not be split, opened, crushed or chewed. Subjects were instructed to fast for at least 2 hours before and at least 1 hour after administration of Compound 44-A, except for water. Subjects were instructed to take their assigned dose of Compound 44-A orally with a minimum of 8 ounces (240 mL) of water and to take Compound 44-A at the same time each morning. Subjects who vomit after taking Compound 44-A should not attempt to make up the dose. Fulvestrant
氟維司群係以標准給藥方案投與登記接受化合物44-A組合治療的患有HR+ BC之受試者：前3劑每2週一次且此後每4週一次500 mg (2 × 250 mg IM)。氟維司群係以兩次250 mg注射(總注射體積5 mL)，經肌肉內緩慢(1至2分鐘)投與，每個臀部注射一次。對於在研究治療期間發展中度肝損傷之受試者，氟維司群250 mg應以一次250 mg注射經肌肉內投與臀部。氟維司群係在研究地點投與。在投與化合物44-A及氟維司群當天，應先投與化合物44-A，且氟維司群應在約60分鐘後投與。 阿比特龍及普賴松 Fulvestrant was administered to subjects with HR+ BC enrolled in combination therapy with Compound 44-A with a standard dosing regimen: 500 mg (2 × 250 mg IM). Fulvestrant was administered slowly (1 to 2 minutes) intramuscularly as two 250 mg injections (total injection volume 5 mL), one in each buttock. For subjects who develop moderate hepatic impairment during study treatment, fulvestrant 250 mg should be administered intramuscularly into the buttocks as one 250 mg injection. Fulvestrex was administered at the study site. On the day of administration of Compound 44-A and Fulvestrant, Compound 44-A should be administered first, and Fulvestrant should be administered about 60 minutes later. Abiraterone and Presson
阿比特龍及普賴松係以標准給藥方案投與登記接受化合物44-A組合療法的患有mCRPC之受試者。阿比特龍之標准給藥方案係QD口服1000 mg，且普賴松之標准給藥方案係BID口服5 mg。受試者在餐前一小時或餐後兩小時根據處方資訊空腹服用阿比特龍。錠劑係用水整片吞服且不應壓碎或咀嚼。普賴松應整片吞服且不應破碎、分開或咀嚼。在投與化合物44-A及阿比特龍加普賴松當天，在受試者仍禁食時，應先投與化合物44-A，且在約60分鐘後投與阿比特龍。受試者在服用阿比特龍後應繼續禁食60分鐘。受試者應每日服用兩次普賴松，並根據醫學指導在化合物44-A劑量後約60分鐘服用第一劑。全部三種藥物(化合物44-A、阿比特龍及第一劑普賴松)皆應在每日早上的同一時間服用。 研究治療投與 Abiraterone and Presone were administered on a standard dosing schedule to subjects with mCRPC enrolled in Compound 44-A combination therapy. The standard dosing regimen for abiraterone is 1000 mg orally QD, and the standard dosing regimen for presone is 5 mg orally BID. Subjects took abiraterone on an empty stomach one hour before or two hours after meals according to the prescription information. Lozenges are to be swallowed whole with water and should not be crushed or chewed. Presone should be swallowed whole and should not be broken, split or chewed. On the day of administration of compound 44-A and abiraterone plus presone, while the subject is still fasting, compound 44-A should be administered first, and abiraterone should be administered about 60 minutes later. Subjects should continue to fast for 60 minutes after taking abiraterone. Subjects should take presone twice daily, with the first dose approximately 60 minutes after the dose of Compound 44-A according to medical guidance. All three drugs (compound 44-A, abiraterone and the first dose of presone) should be taken at the same time every morning. Study Treatment Administration
所有研究治療的第一次劑量均在研究地點投與。在投與第一劑化合物44-A後，受試者應在每日早上大約同一時間在家中服用後續的化合物44-A劑量(打算採集PK樣本之日除外)，且應遵守上述禁食要求。 單藥療法隊列： The first dose of all study treatments was administered at the study site. Following administration of the first dose of Compound 44-A, subjects should take subsequent doses of Compound 44-A at home at approximately the same time each morning (except on days when PK samples are intended) and should comply with the fasting requirements described above . Monotherapy cohort:
在劑量遞增階段，第1-28天(W1D1至W4D7)，對禁食受試者QD經口投與化合物44-A反丁烯二酸鹽。在第29-35天(W5D1至W5D7，包括端點在內)存在洗除期(不投與研究藥物)。研究藥物投與在第36天(W6D1)重新開始，且無額外的預定洗除期。During the dose escalation phase, Days 1-28 (W1D1 to W4D7), Compound 44-A fumarate was administered orally QD to fasted subjects. There is a washout period (no administration of study drug) on Days 29-35 (W5D1 to W5D7, inclusive). Study drug administration restarted on Day 36 (W6D1) with no additional scheduled washout period.
在隊列擴展階段，對禁食受試者QD經口投與化合物44-A反丁烯二酸鹽，且無洗除期。 組合療法隊列： In the cohort expansion phase, Compound 44-A fumarate was administered orally QD to fasting subjects with no washout period. Combination Therapy Cohort:
在劑量遞增階段及隊列擴展階段，對禁食受試者QD經口投與化合物44-A反丁烯二酸鹽膠囊。受試者亦接受如上所描述的標準劑量之組合療法。組合療法給予係在第一次給藥之日開始(研究安全性訪視1 [SSV1；亦即，W1D1])且在無洗除期之情況下投與，直至受試者終止研究治療。若必須中止組合劑(亦即，氟維司群或阿比特龍)，則受試者可以繼續接受化合物44-A。然而，中止化合物44-A之受試者亦需要中止組合治療之其他組分。Compound 44-A fumarate capsules were administered orally QD to fasted subjects during the dose escalation phase and the cohort expansion phase. Subjects also received combination therapy at standard doses as described above. Combination therapy administration was initiated on the day of the first dose (Study Safety Visit 1 [SSV1; ie, W1D1]) and administered without a washout period until the subject discontinued study treatment. If the combination agent (ie, fulvestrant or abiraterone) had to be discontinued, the subject could continue to receive Compound 44-A. However, subjects who discontinued Compound 44-A also required discontinuation of the other components of the combination therapy.
對於任一研究階段，只要研究者認為受試者仍然自研究治療中獲得臨床益處且繼續研究治療之潛在益處超過潛在風險，則在放射線攝影進展後，仍能繼續化合物44-A單藥或化合物44-A組合療法之治療。受試者可以繼續接受化合物44-A長達12個月及額外的12個月。 研究評估 安全性評估 For any study period, as long as the investigator believes that the subject still obtains clinical benefit from the study treatment and the potential benefit of continuing the study treatment outweighs the potential risks, after the progress of the radiograph, the compound 44-A monotherapy or the compound can still be continued. 44-A Treatment with Combination Therapy. Subjects may continue to receive Compound 44-A for up to 12 months and an additional 12 months. Research Evaluation Safety Evaluation
安全性評價包括對所有研究隊列之不良事件、生命徵象、ECG、實驗室測試及合併用藥之評估。研究者將評估不良事件之嚴重性、嚴重程度以及與研究治療之關係。嚴重程度等級係由美國國家癌症研究所(National Cancer Institute，NCI) CTCAE v5指南定義。Safety evaluation included assessment of adverse events, vital signs, ECG, laboratory tests, and concomitant medications for all study cohorts. The investigator will assess adverse events for severity, severity, and relationship to study treatment. The severity scale was defined by the National Cancer Institute (NCI) CTCAE v5 guidelines.
安全性評估將在研究安全性訪視(SSV)期間進行。研究安全性訪視1 (SSV1)係在第一次研究給藥之日，即第1週第1天(W1D1)開始。在第一次給藥後，SSV預定每4週進行一次，無論是否在訪視時服用研究藥物。在某些情況下，SSV會以更高的頻率發生，但它們發生的時間間隔不會超過4週(±3天)。Safety assessments will be performed during the Study Safety Visit (SSV). Study Safety Visit 1 (SSV1) began on the day of the first study dose, Week 1 Day 1 (W1D1). After the first dose, SSV was scheduled every 4 weeks, regardless of whether study drug was taken at the visit. In some cases, SSV occurred with greater frequency, but they occurred no more than 4 weeks apart (±3 days).
若任何研究治療有劑量暫停或延遲，則受試者必須在劑量暫停期間每4週(±3天)返回該地點進行SSV且隨後根據臨床指示每週(或更頻繁地)進行額外的非預定訪視或電話訪問以監測受試者恢復研究治療之安全性及適合性。當非連續研究治療(亦即，氟維司群)之投與被延遲時，SSV必須在預定恢復該藥劑之給藥之前立即發生，即使計劃在最後一次SSV後不到4週內恢復給藥。再起始非連續藥劑之投與將重新設定SSV時間表，且隨後的SSV將在之後每4週(±3天)發生一次。If there is a dose suspension or delay of any study treatment, the subject must return to the site for SSV every 4 weeks (±3 days) during the dose suspension period and then for additional unscheduled weekly (or more frequently) as clinically indicated Visit or telephone interview to monitor subject's safety and suitability for resuming study treatment. When administration of discontinuous study treatment (i.e., fulvestrant) is delayed, SSV must occur immediately prior to scheduled resumption of dosing of that agent, even if resumption of dosing is scheduled for less than 4 weeks after last SSV . Reinitiating administration of discontinuous doses will reset the SSV schedule, and subsequent SSVs will occur every 4 weeks (±3 days) thereafter.
在劑量遞增階段，在DLT評價期間需要進行未指定為SSV的額外訪視以進行安全性及其他評估。 腫瘤評估 During the dose escalation phase, additional visits not designated as SSV were required during DLT evaluation for safety and other assessments. tumor assessment
在篩選期間及在第一次給予研究之日後定期使用RECIST v1.1標準，使用核磁共振成像(MRI)或電腦斷層攝影(CT)掃描評估腫瘤。Tumors were assessed using magnetic resonance imaging (MRI) or computed tomography (CT) scans using RECIST v1.1 criteria during screening and periodically after the date of first study administration.
胸部/腹部/骨盆(CAP)：在篩選時以及在起始研究治療後的前12個月內每8週(±5天)對所有受試者執行CAP之CT或胸部CT及腹部/骨盆MRI。完成12個月的研究後，每12週(±7天)執行一次此等評估。Chest/abdomen/pelvis (CAP): CT of CAP or CT of the chest and MRI of the abdomen/pelvis were performed on all subjects at screening and every 8 weeks (±5 days) for the first 12 months after initiation of study treatment . These assessments were performed every 12 weeks (±7 days) after completion of the 12-month study.
腦：在篩選時對劑量遞增階段有腦轉移史或臨床症狀的受試者及隊列擴展階段的所有受試者執行腦部MRI (或CT)。研究治療起始後，只有已知出現腦轉移之受試者或提示新腦轉移之徵象及症狀在臨床上指示時，才需要對腦部進行MRI (或CT)掃描。每8週(±5天)執行一次第一劑研究治療後評估。完成12個月的研究後，每12週(±7天)執行一次此等評估。MRI係較佳的腦部成像方法。若執行腦部CT而非MRI，則不明確的結果必須藉由MRI確認。Brain: Brain MRI (or CT) will be performed at Screening on subjects with a history of brain metastases or clinical symptoms in the dose escalation phase and all subjects in the cohort expansion phase. After initiation of study treatment, MRI (or CT) scans of the brain will be required only in subjects with known brain metastases or if signs and symptoms suggestive of new brain metastases are clinically indicated. Post-first dose study treatment assessments will be performed every 8 weeks (±5 days). These assessments were performed every 12 weeks (±7 days) after completion of the 12-month study. MRI is the preferred brain imaging method. If brain CT is performed instead of MRI, ambiguous results must be confirmed by MRI.
骨成像：針對骨轉移之锝骨掃描或正電子發射斷層攝影(PET)成像(例如18F-NaF)並非研究規定之腫瘤評估的一部分，但可根據標準臨床實踐使用以指導根據RECIST 1.1進行確證之CT/MRI成像。經CT/MRI確證之骨病變必須作為非目標或新病變報告。Bone Imaging: Technetium bone scan or positron emission tomography (PET) imaging (e.g., 18F-NaF) for bone metastases was not part of the study-specified tumor evaluation, but could be used according to standard clinical practice to guide confirmation according to RECIST 1.1 CT/MRI imaging. Bone lesions confirmed by CT/MRI must be reported as non-target or new lesions.
研究者根據RECIST 1.1進行的放射線攝影評估可用於治療決策；亦即，若受試者不再感到在臨床上受益，則可以在當地確定放射線攝影進展後中止研究治療。無論研究治療係減少、暫停、延遲還是中止，放射線攝影腫瘤評估皆會按照方案限定之時間表繼續進行，直至滿足中止放射線攝影評估之標準。Radiographic assessment by the investigator according to RECIST 1.1 was used for treatment decisions; that is, study treatment could be discontinued after locally determined radiographic progression if the subject no longer felt clinical benefit. Regardless of whether study treatment is reduced, suspended, delayed, or discontinued, radiographic tumor assessments will continue on a protocol-defined schedule until the criteria for discontinuing radiographic assessments are met.
為確定選定隊列之放射線攝影研究終點，BIRC可對放射線攝影圖像進行集中審查。針對此等隊列的所有方案要求之放射線攝影腫瘤評估皆被發送至BIRC，BIRC亦將審查既往放射史資料及既往當地療法資訊，以選擇目標病變。 總體生存狀況追踪評估 To determine radiographic study endpoints for selected cohorts, BIRC may conduct central review of radiographic images. All protocol-required radiographic tumor assessments for these cohorts were sent to BIRC, which also reviewed previous radiation history data and previous local therapy information to select target lesions. Overall survival follow-up assessment
在30天的治療後追踪訪視後大約每12週(±14天)聯繫所有受試者以評估生存狀態並記錄全身NPACT之接受情況，除非關於參與非干預性研究評估之同意被撤回或認為已收集到足夠的功效資料供研究。 藥物動力學評估 單藥化合物 44-A 之劑量遞增階段： All subjects were contacted approximately every 12 weeks (±14 days) after the 30-day post-treatment follow-up visit to assess survival status and document receipt of systemic NPACT unless consent to participate in non-interventional study evaluations was withdrawn or considered Sufficient efficacy data have been collected for the study. Pharmacokinetic Evaluation of Single-agent Compound 44-A Dose Escalation Phase:
獲得血液樣本以評估化合物44-A及其潛在代謝物之PK。在DLT評價期間，在第一次給予研究治療之日投與研究治療前(給藥前)以及在SSV1 (W1D1)及SSV2 (W4D7 [第28天])給藥時以最多8小時之時間間隔獲取血液樣本用於PK分析。此外，給藥前PK取樣係在W1D2進行，且給藥前及給藥後2小時取樣係在W2D1、W3D1及W4D1進行；亦在7天洗除期間(SSV2 [W4D7]後)，在W5D1、W5D2、W5D3及W5D5獲取樣本。在DLT評價及洗除期之後，在SSV3 (W6D1)、SSV4 (W10D1)及 SSV5 (W14D1)抽取血液樣本(給藥前及給藥後2小時)。單藥藥物動力學結果提供於實例2中。 化合物 44-A 組合療法之劑量遞增階段： Blood samples were obtained to assess the PK of Compound 44-A and its potential metabolites. During the DLT assessment, at intervals of up to 8 hours prior to study treatment administration (predose) on the day of first study treatment administration and at SSV1 (W1D1) and SSV2 (W4D7 [Day 28]) dosing Obtain blood samples for PK analysis. In addition, pre-dose PK sampling was performed at W1D2, and pre-dose and 2-hour post-dose samples were taken at W2D1, W3D1, and W4D1; W5D2, W5D3 and W5D5 get samples. Following the DLT evaluation and washout period, blood samples were drawn (pre-dose and 2 hours post-dose) at SSV3 (W6D1), SSV4 (W10D1) and SSV5 (W14D1). Single-agent pharmacokinetic results are provided in Example 2. Dose escalation phase of compound 44-A combination therapy:
獲得血液樣本以評估化合物44-A及其潛在代謝物之PK，並評估阿比特龍或氟維司群之PK。在投與化合物44-A及組合劑(亦即，氟維司群或阿比特龍/普賴松)當天，將先投與化合物44-A，且在約60分鐘後投與組合劑(氟維司群或阿比特龍/普賴松)。在DLT評價期間，在第一次給予研究治療之日投與研究治療前(給藥前)以及在SSV1 (W1D1)及W4D7給藥時以最多8小時之時間間隔獲取血液樣本用於PK分析。此外，給藥前PK取樣係在W1D2進行，且給藥前及給藥後2小時取樣係在W2D1及W4D1進行。在DLT評價後，在SSV2 (W5D1)、SSV3 (W9D1)及SSV4 (W13D1)抽取血液樣本(給藥前及給藥後2小時)。 注意：所有給藥後樣本收集時間點皆相對於化合物 44-A 投與而言。 隊列擴展階段 ( 化合物 44-A 單藥及組合療法 ) ： Blood samples were obtained to assess the PK of Compound 44-A and its potential metabolites, and to assess the PK of abiraterone or fulvestrant. On the day of administration of Compound 44-A and the combination (i.e., fulvestrant or abiraterone/presone), Compound 44-A will be administered first, and approximately 60 minutes later the combination (fluoride vestrant or abiraterone/presone). During the DLT evaluation, blood samples for PK analysis were obtained on the day of the first study treatment administration (pre-dose) and at intervals of up to 8 hours at the time of SSV1 (W1D1) and W4D7 dosing. In addition, pre-dose PK sampling was performed at W1D2, and pre-dose and 2-hour post-dose sampling were performed at W2D1 and W4D1. Blood samples (pre-dose and 2 hours post-dose) were drawn at SSV2 (W5D1 ), SSV3 (W9D1 ), and SSV4 (W13D1 ) after DLT assessment. Note: All post-dose sample collection time points are relative to Compound 44-A administration. Cohort expansion phase ( compound 44-A monotherapy and combination therapy ) :
獲得血液樣本以評估化合物44-A及其潛在代謝物之PK，及/或評估阿比特龍或氟維司群之PK。相對於在SSV1 (W1D1)、W3D1、SSV2 (W5D1)、SSV3 (W9D1)及 SSV4 (W13D1)給予化合物44-A，在給藥前及給藥後2小時獲得PK樣本。 生物標誌物評估 Blood samples were obtained to assess the PK of Compound 44-A and its potential metabolites, and/or to assess the PK of abiraterone or fulvestrant. PK samples were obtained at pre-dose and 2 hours post-dose relative to compound 44-A administered at SSV1 (W1D1), W3D1, SSV2 (W5D1), SSV3 (W9D1) and SSV4 (W13D1). Biomarker Assessment
收集外周血及腫瘤組織，且可對其進行評估以進行探索性生物標誌物分析。Peripheral blood and tumor tissue are collected and can be evaluated for exploratory biomarker analysis.
在隊列擴展階段(對於各擴展隊列中之3名受試者為強制的)中，在第一次給予研究治療前及在第一次給藥後約4週獲得新鮮腫瘤組織及皮膚生物檢體。在劑量遞增或隊列擴展階段中，亦可自沒有強制性組織生物檢體要求之受試者獲得視情況選用之存檔或新鮮腫瘤樣本。During the cohort expansion phase (mandatory for 3 subjects in each expansion cohort), fresh tumor tissue and skin biospecimens were obtained prior to and approximately 4 weeks after the first dose of study treatment . During the dose escalation or cohort expansion phase, optional archived or fresh tumor samples may also be obtained from subjects without mandatory tissue biopsy requirements.
探索性分析可包括以下： • 腫瘤及血液中之藥效學及目標佔有率評估 • 基因體(例如體細胞突變/改變、拷貝數變異[CNV])及表現分析) • 血液之藥物遺傳學評估 • 血液之血漿生物標誌物評估 • 外周血之免疫細胞概貌及細胞週期分析 • 血液中與特定適應症相關之其他分析(例如循環腫瘤細胞[CTC]、循環腫瘤DNA [ctDNA]及其他) Exploratory analysis can include the following: • Pharmacodynamics and target occupancy evaluation in tumor and blood • Genome (e.g., somatic mutation/alteration, copy number variation [CNV]) and expression analysis) • Pharmacogenetic evaluation of blood • Plasma biomarker assessment of blood • Peripheral blood immune cell profile and cell cycle analysis • Other assays in blood relevant to specific indications (e.g. circulating tumor cells [CTC], circulating tumor DNA [ctDNA] and others)
樣本亦可用於分析開發，以促進新生物標誌物之鑑別。生物標誌物樣本之收集可能會提前停止，或者可能會修改取樣頻率。 腫瘤標誌物評估 Samples can also be used for assay development to facilitate the identification of new biomarkers. Collection of biomarker samples may be stopped early, or sampling frequency may be modified. Tumor Marker Assessment
對於患有EOC之受試者，在研究之前12個月中，在篩選時、在起始研究治療後每8週(在SSV3 [W9D1]、SSV5 [W17D1]，以此類推)收集癌症抗原125 (CA125)。完成12個月的研究後，每12週及30天之追踪訪視時進行此等評估。For subjects with EOC, cancer antigen125 was collected at Screening, every 8 weeks after initiation of study treatment (at SSV3 [W9D1], SSV5 [W17D1], and so on) during the 12 months prior to the study (CA125). These assessments were performed at every 12-week and 30-day follow-up visits after completion of the 12-month study.
對於患有乳癌(TNBC或HR+ BC)之受試者，在研究之前12個月中，在篩選時、起始研究治療後(在SSV3 [W9D1]、SSV5 [W17D1]，以此類推)每8週收集癌症抗原15-3 (CA15-3)。完成12個月的研究後，每12週執行一次此等評估。For subjects with breast cancer (TNBC or HR+ BC), at Screening, after initiation of study treatment (at SSV3 [W9D1], SSV5 [W17D1], etc.) Cancer antigen 15-3 (CA15-3) was collected weekly. These assessments were performed every 12 weeks after completion of the 12-month study.
對於患有mCRPC之受試者，在研究之前12個月中，在篩選時、在起始研究治療後每8週(在SSV3 [W9D1]、SSV5 [W17D1]，以此類推)收集***特異性抗原(PSA)樣本。完成12個月的研究後，每12週執行一次此等評估。For subjects with mCRPC, prostate-specific collections were collected at screening and every 8 weeks after initiation of study treatment (at SSV3 [W9D1], SSV5 [W17D1], and so on) during the 12 months prior to the study. Antigen (PSA) sample. These assessments were performed every 12 weeks after completion of the 12-month study.
在本研究中不使用腫瘤標誌物評估確定PD或作出研究治療決定。 統計方法 Tumor marker assessments were not used in this study to determine PD or to make study treatment decisions. statistical methods
登記的受試者數量將取決於建立MTD/RD所需的劑量隊列及受試者之數量。根據劑量遞增及隊列擴展階段所選擇之設計，估計該研究將登記大約298名受試者。 劑量遞增階段： The number of subjects enrolled will depend on the dose cohort and number of subjects required to establish the MTD/RD. Based on the design chosen for the dose escalation and cohort expansion phases, it is estimated that approximately 298 subjects will be enrolled in the study. Dose escalation phase:
各劑量遞增隊列之受試者的數量係基於對已確定之第1期i3+3劑量遞增試驗設計之修改來選擇。受試者被分成3名受試者一個隊列，且根據所觀察到的DLT之數量，在一個劑量水平的受試者之數量可能會擴大至多達12名。預期在此階段中登記約36名受試者用於化合物44-A單藥評價，且預期登記估計30名受試者用於組合療法評價(各組合方案有約15名受試者)。劑量遞增評價中登記之受試者的總數將取決於建立MTD或RD所需之遞增隊列及受試者的數量，但根據經改良之i3+3研究設計，每次劑量遞增評價最多允許36名可評價之受試者。 隊列擴展階段： The number of subjects in each dose escalation cohort was selected based on modifications to the established Phase 1 i3+3 dose escalation trial design. Subjects were divided into cohorts of 3 subjects, and depending on the number of DLTs observed, the number of subjects at a dose level could be expanded up to 12. Approximately 36 subjects are expected to be enrolled in this phase for Compound 44-A single agent evaluation and an estimated 30 subjects are expected to be enrolled for combination therapy evaluation (approximately 15 subjects for each combination regimen). The total number of subjects enrolled in the dose escalation assessment will depend on the escalation cohort and number of subjects required to establish the MTD or RD, but a maximum of 36 per dose escalation assessment is allowed according to the modified i3+3 study design Evaluable subjects. Queue expansion phase:
各擴展隊列皆利用西蒙氏兩階段Minimax設計，假設功效為80%且單側α為15%。 單藥擴展隊列 Each expansion cohort utilized a Simon's two-stage Minimax design with an assumed power of 80% and a one-sided alpha of 15%. Single Drug Expansion Cohort
為了在TNBC、EOC、HR+ BC及mCRPC中研究單藥化合物44-A療法之擴展隊列，根據虛無假設，假定絕對無效藥物(p0)之最大ORR為5%，且根據對立假設，假定有效藥物(p1)的最小有臨床意義之ORR為15%。此等隊列各自在第1階段登記二十名受試者。若此等20名受試者中無有反應者，則隊列將因無效而停止。在給定隊列中，若在第1階段有至少一名有反應者，則將在第2階段再登記16名受試者。若在該隊列的總共36名受試者中有至少四名有反應者，則認為該隊列成功。根據虛無假設，即對於無效藥物，在第1階段後提前停止的概率為約36%。 組合療法擴展隊列 To study an expansion cohort of single-agent Compound 44-A therapy in TNBC, EOC, HR+ BC, and mCRPC, a maximum ORR of 5% was assumed for the absolute ineffective drug (p0) according to the null hypothesis and an effective drug ( The minimum clinically meaningful ORR for p1) was 15%. Each of these cohorts enrolled twenty subjects in Phase 1 . If there are no responders among these 20 subjects, the cohort will be stopped for futility. Within a given cohort, if there is at least one responder in Phase 1, an additional 16 subjects will be enrolled in Phase 2. A cohort was considered successful if there were at least four responders out of a total of 36 subjects in the cohort. According to the null hypothesis, that is, for ineffective drugs, the probability of early stopping after phase 1 is about 36%. Combination Therapy Expansion Cohort
對於在HR+ BC (組合劑：氟維司群)及mCRPC (組合劑：阿比特龍及普賴松)中使用化合物44-A之組合療法，根據虛無假設，假定絕對無效藥物(p0)之最大ORR為10%，且根據對立假設，假定有效藥物(p1)的最小有臨床意義之ORR為20%。此等隊列各自在第1階段登記二十五名受試者。若有反應者之數量為此等25名受試者中之一者或沒有，則隊列因無效而停止。在給定隊列中，若在第1階段有至少兩名有反應者，則將在第2階段再登記19名受試者。若在該隊列的總共44名受試者中有至少七名有反應者，則認為該隊列成功。根據虛無假設，即對於無效藥物，在第1階段後提前停止的概率為約27%。 分析及資料匯總 For combination therapy with compound 44-A in HR+ BC (combo: fulvestrant) and mCRPC (combo: abiraterone and presone), the maximum absolute ineffective drug (p0) was assumed to be maximal under the null hypothesis The ORR is 10%, and according to the alternative hypothesis, the minimal clinically meaningful ORR for the effective drug (p1) is assumed to be 20%. Each of these cohorts enrolled twenty-five subjects in Phase 1 . If the number of responders was one of these 25 subjects or none, the cohort was stopped for futility. In a given cohort, if there are at least two responders in Phase 1, an additional 19 subjects will be enrolled in Phase 2. A cohort was considered successful if there were at least seven responders out of a total of 44 subjects in the cohort. According to the null hypothesis, that is, for ineffective drugs, the probability of early stopping after phase 1 is about 27%. Analysis and data collection
安全性及耐受性概述以所有隊列及各隊列呈現。抗腫瘤概述係根據研究目標以隊列呈現。 安全性及耐受性 Safety and tolerability overviews are presented for all cohorts and for each cohort. Anti-tumor overviews are presented in cohorts according to study objectives. Safety and Tolerability
安全性主要根據AE及選擇的實驗室測試進行評估。耐受性係根據研究治療暴露、劑量強度、劑量調整及研究治療因AE中止進行評估。Safety was primarily assessed based on AEs and selected laboratory tests. Tolerability was assessed based on study treatment exposure, dose intensity, dose adjustments, and study treatment discontinuation due to AEs.
根據監管活動醫學詞典(Medical Dictionary for Regulatory Activities，MedDRA)，不良事件逐字術語映射至首選術語及系統器官類別。不良事件係根據總體發生率、報告的最差毒性等級以及與研究治療之關係進行匯總。嚴重不良事件係以類似方式匯總。Verbatim terms for adverse events were mapped to preferred terms and system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events are summarized by overall incidence, worst grade of toxicity reported, and relationship to study treatment. Serious adverse events were aggregated in a similar manner.
選擇的實驗室測試係根據所觀察到的基線後量測值自基線之平均變化以及自基線至最差基線後CTCAE等級之轉變來匯總。The selected laboratory tests were summarized according to the observed mean change from baseline in post-baseline measures and the transition from baseline to worst post-baseline CTCAE grade.
匯總各治療成分的研究治療暴露及劑量強度。匯總適於各治療組分的由AE引起之劑量調整及治療中止。 抗腫瘤活性 The study treatment exposures and dose intensities were summarized for each treatment component. Dose adjustments and treatment discontinuations due to AEs are summarized for each treatment component. antitumor activity
抗腫瘤活性係根據最佳總體反應(BOR)、ORR、DOR及PFS估計值進行評估。Antitumor activity was assessed based on best overall response (BOR), ORR, DOR, and PFS estimates.
提供有關劑量遞增及擴展隊列之BOR及ORR的描述性統計。在隊列擴展階段中該等隊列的中值DOR及PFS以及其相應95%信賴區間(CI)係利用Kaplan-Meier方法估計。Descriptive statistics are provided for BOR and ORR for the dose escalation and expansion cohorts. The median DOR and PFS and their corresponding 95% confidence intervals (CI) for the cohorts during the cohort expansion phase were estimated using the Kaplan-Meier method.
追踪所有受試者之OS，並提供劑量遞增及擴展隊列之OS估計值。 實例 2 ：由單藥化合物 44-A 及組合療法首次人體開放標籤試驗得到的藥物動力學及目標佔有率結果 目標及終點 OS is tracked for all subjects and OS estimates are provided for dose escalation and expansion cohorts. Example 2 : Pharmacokinetics and target occupancy results obtained from single-drug compound 44-A and combination therapy for the first time in human open-label trials Targets and endpoints
起始實例1之劑量遞增及擴展研究，並根據研究方案向受試者投與化合物44-A反丁烯二酸鹽。本實例呈現由劑量遞增階段禁食給予單藥化合物44-A得到的初步結果。The dose escalation and extension study of Example 1 was initiated and Compound 44-A fumarate was administered to subjects according to the study protocol. This example presents preliminary results from fasted administration of single agent compound 44-A during the dose escalation phase.
劑量遞增階段(給予單藥)： 主要目標： 確定化合物44-A之血漿藥物動力學(PL)；以及 評價每日一次及每日兩次給藥之血漿藥物動力學。 探索性目標： 經研究者根據實體腫瘤反應評價標準1.1版(RECIST v1.1)評估，測定客觀反應率(ORR)； 評價PK、藥效學、功效或安全性終點之間的關係T；及 評價化合物44-A在腫瘤及血液中之藥效學作用及目標佔有率。 研究設計 綜述 Dose Escalation Phase (Single Drug Administration): Primary Objectives: To determine the plasma pharmacokinetics (PL) of Compound 44-A; and to evaluate plasma pharmacokinetics for once-daily and twice-daily dosing. Exploratory objectives: Assessed by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), to determine the objective response rate (ORR); to evaluate the relationship T among PK, pharmacodynamics, efficacy or safety endpoints; and The pharmacodynamic effect and target occupancy of compound 44-A in tumor and blood were evaluated. Review of Research Design
本研究係在患有實體腫瘤之受試者中評價呈單藥形式之化合物44-A反丁烯二酸鹽的開放標記之首次人體試驗。實體腫瘤包括激素受體陽性乳癌(HR+BC)、三陰性乳癌(TNBC)、上皮性卵巢癌(EOC)及轉移性去勢抵抗性***癌(mCRPC)。研究設計類似於實例1的經改良之i3+3設計，其中初始隊列包括3名受試者(研究設計見圖2)。遞增或遞減劑量之決定係基於確定劑量限制性毒性(DLT)之規則。類似地，在各劑量水平，隊列擴展係基於DLT比率。任何單次劑量水平之最大登記數為12名，以允許在達到最大總隊列規模之前結束該階段。為確定MTD/RD，每日一次劑量係以低水平開始，且若受試者沒有不良事件，則逐漸增加。 治療及評估 This study is the first open-label human trial evaluating Compound 44-A fumarate as a single agent in subjects with solid tumors. Solid tumors include hormone receptor-positive breast cancer (HR+BC), triple-negative breast cancer (TNBC), epithelial ovarian cancer (EOC), and metastatic castration-resistant prostate cancer (mCRPC). The study design was similar to the modified i3+3 design of Example 1, where the initial cohort included 3 subjects (see Figure 2 for the study design). The decision to escalate or taper the dose is based on rules for determining dose-limiting toxicity (DLT). Similarly, at each dose level, cohort expansion was based on DLT ratios. The maximum number of enrollments at any single dose level was 12 to allow the phase to be completed before the maximum total cohort size was reached. To determine the MTD/RD, the once-daily dose was started at a low level and gradually increased if the subject had no adverse events. Treatment and Evaluation
該研究由每日一次(QD)或每日兩次(BID)在禁食≥ 2小時後經口投與化合物44-A反丁烯二酸鹽組成。為了管理不良作用，將化合物44-A反丁烯二酸鹽之劑量延遲或減少。每日單次劑量水平包括20 mg、40 mg、80 mg及120 mg QD；BID劑量為40 mg。在28天的給藥限制期間對受試者進行評價。觀察接受任何劑量之任何受試者的安全性。自第1天或第1週開始，每4週評估安全性且包括研究者根據美國國家癌症研究所不良事件通用術語標準(National Cancer Institute Common Terminology Criteria for Adverse Events) v5.0記錄不良事件。在第29-35天採用洗除期來確定化合物44-A的半衰期及穩態。治療延長期≥ 36天。在初始患者篩選時及前12個月每8週，之後每12週，使用RECIST v1.1標准，利用MRI或CT掃描評估腫瘤。對化合物44-A反丁烯二酸鹽PK、外周血生物標誌物、腫瘤組織及腫瘤生物標誌物進行評估。 受試者 The study consisted of once-daily (QD) or twice-daily (BID) oral administration of Compound 44-A fumarate after fasting > 2 hours. To manage adverse effects, the dose of Compound 44-A fumarate was delayed or reduced. Single daily dose levels include 20 mg, 40 mg, 80 mg, and 120 mg QD; the BID dose is 40 mg. Subjects were evaluated during a 28-day dosing restriction period. The safety of any subject receiving any dose was observed. Beginning on day 1 or week 1, safety was assessed every 4 weeks and included investigator-documented adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. A washout period on days 29-35 was used to determine the half-life and steady state of compound 44-A. Treatment extension period ≥ 36 days. Tumors were assessed with MRI or CT scans using RECIST v1.1 criteria at initial patient screening, every 8 weeks for the first 12 months, and every 12 weeks thereafter. The compound 44-A fumarate PK, peripheral blood biomarkers, tumor tissue and tumor biomarkers were evaluated. subjects
在資料截止日期，總共登記26名患有各種實體腫瘤之受試者，並在以下5個禁食劑量水平口服化合物44-A反丁烯二酸鹽進行治療：20 mg QD (n=3)；40 mg QD (n=3)；80 mg QD (n=7)；120 mg QD (n=4)；以及40 mg BID。受試者係經歷多種方案與治療之組，其中77%的受試者在轉移性環境中接受≥ 3線的全身抗癌療法。受試者納入或排除標准描述於實例1中。表4顯示基線人口統計資料及臨床特徵或登記之受試者。
表4：受試者基線人口統計、臨床疾病及既往療法之次數
化合物44-A之吸收迅速且Tmax為約1-3小時且消除半衰期為5-9小時。當單次每日劑量自40 mg增加至80 mg並未按比例增加血漿化合物44-A時，探索40 mg之BID劑量。在第28天，40 mg BID劑量之0-24小時曲線下面積(AUC
0-24)為40 mg QD劑量之兩倍。下表5顯示在第1天及第28天受試者體內各劑量化合物44-A之藥物動力學資料Tmax (h)、Cmax (ng/mL)及AUC0-24(h • ng/mL)。
表5：受試者體內化合物44-A之藥物動力學參數資料
圖6A中的圖標繪在第1天單次給藥後受試者之化合物44-A的血漿濃度-時間曲線。圖6B中的圖標繪在第28天重複每日給藥後化合物44-A的血漿濃度-時間曲線。X軸上的標記係給藥後的小時數，而Y軸上的數字係化合物44-A之血漿濃度，以ng/mL表示。注意，圖6A及圖6B中的虛線圖係BID化合物44-A之血漿濃度-時間曲線。該圖亦顯示自40 mg至80 mg化合物44-A的不成比例的血漿濃度-時間曲線。以下圖6A及圖6B曲線之水平虛線係定量下限(LLOQ)，估計為1 ng/mL。 按劑量呈現的目標佔有率概貌 The graph in Figure 6A plots the plasma concentration-time profiles of Compound 44-A in subjects following a single dose on Day 1. The graph in Figure 6B plots the plasma concentration-time profile of Compound 44-A following repeated daily dosing at day 28. The labels on the X-axis are hours after dosing, while the numbers on the Y-axis are the plasma concentrations of Compound 44-A expressed in ng/mL. Note that the dotted line graphs in Figures 6A and 6B are plasma concentration-time profiles of BID Compound 44-A. The figure also shows a disproportionate plasma concentration-time profile of Compound 44-A from 40 mg to 80 mg. The horizontal dotted line in the curves of Figure 6A and Figure 6B below is the lower limit of quantitation (LLOQ), which is estimated to be 1 ng/mL. Target Occupancy Profile by Dose
使用電化學發光單株捕捉抗體免疫分析偵測CDK7目標佔有率。在來自給藥前受試者的PBMC溶解產物中量測CDK7佔有率。用經鏈球菌親生物素蛋白塗覆之板捕獲與游離CDK7結合的生物素化之化合物44-A，且用單株抗體捕捉捕獲總CDK7。總經標記CDK7與在生物素化之化合物44-A存在下量測之CDK7之間的差異代表在各化合物44-A濃度下的總CDK7佔有率。各時間點之目標佔用率對應於由3個樣本得到的平均值，且誤差條表示平均值之1個標準差。佔有率百分比係藉由用1減去游離CDK7/總CDK7之比率來計算。CDK7 target occupancy was detected using an electrochemiluminescence monoclonal capture antibody immunoassay. CDK7 occupancy was measured in PBMC lysates from pre-dose subjects. Biotinylated Compound 44-A bound to free CDK7 was captured with streptavidin-coated plates, and total CDK7 was captured with monoclonal antibody capture. The difference between total labeled CDK7 and CDK7 measured in the presence of biotinylated Compound 44-A represents the total CDK7 occupancy at each Compound 44-A concentration. Target occupancy at each time point corresponds to the mean obtained from 3 samples, and error bars represent 1 standard deviation of the mean. Percent occupancy was calculated by subtracting the ratio of free CDK7/total CDK7 from 1.
圖7A顯示第1天(給藥前)在不同化合物44-A濃度下來自受試者之PBMC溶解產物中的CDK7目標佔有率。最高的化合物44-A劑量具有最高佔有率，且比較低的濃度晚達到峰值佔有率。40 mg BID劑量顯示2至8小時之持續佔有率。圖7B顯示第28天(給藥前)在不同化合物44-A濃度下來自受試者之PBMC溶解產物中的CDK7目標佔有率。Figure 7A shows the target occupancy of CDK7 in PBMC lysates from subjects at different concentrations of Compound 44-A on Day 1 (pre-dose). The highest Compound 44-A dose had the highest occupancy and peak occupancy was reached later than lower concentrations. The 40 mg BID dose showed a sustained occupancy of 2 to 8 hours. Figure 7B shows the target occupancy of CDK7 in PBMC lysates from subjects at different concentrations of Compound 44-A on day 28 (pre-dose).
與第1天相比較，第28天之CDK7目標佔有率較高。此表明化合物44-A之每日治療係暴露量依賴性的且持續時間長，表明化合物44-A之重複暴露可具有下調的受試者體內之CDK7蛋白質表現。 暴露與安全性 The CDK7 target occupancy was higher on day 28 compared to day 1. This indicates that daily treatment of Compound 44-A is exposure-dependent and prolonged, suggesting that repeated exposures of Compound 44-A may have down-regulated CDK7 protein expression in subjects. Exposure and Safety
化合物44-A在所評價之劑量水平下具有良好耐受性。中值暴露持續時間為9.1週，其範圍為0-46週。在26名受試者中，有2名受試者(8%)具有劑量減少且9名受試者(35%)由於治療中出現之不良事件(TEAE)而具有劑量延遲。80 mg QD劑量具有最高的TEAE比率。中止治療之原因包括放射線攝影腫瘤進展跡象(42%)、不良事件(12%)、缺乏臨床效益(8%)及患者要求(8%)。治療相關不良事件(TRAE)之中止百分比僅為4%。表6提供受試者暴露之中值持續時間、平均每日劑量及導致劑量減少或延遲之TEAE百分比、由於TEAE及TRAE而中止治療以及劑量限制性毒性。
表6：處置、暴露及安全性匯總
對於QD及BID給藥時間表，化合物44-A反丁烯二酸鹽在可評價的劑量水平下具有可管理之安全概貌。表7顯示在各劑量水平下治療中出現之不良事件。在各劑量，事件被分級為任何等級以及3級或4級，參見各劑量欄。3級係嚴重的或有醫學意義的，而4級係危及生命的且需要緊急干預。沒有5級TEAE。
表7：受試者在各劑量水平的不良事件類型百分比
迄今為止，在劑量遞增階段未觀察到客觀反應。截至資料截止日期，兩名病情穩定之患者仍在接受治療。服用CDK4/6抑制劑仍進展的一名患有HR+BC之受試者已治療46週。既往亦有CDK4/6抑制劑暴露的另一名患有復發高分化性脂肪肉瘤(CDK4、CCND2及MDM2基因擴增)之受試者接受治療45週。一名乳癌受試者達到病情穩定作為最佳反應，但在25週時中止治療。 結論 To date, no objective responses have been observed during the dose escalation phase. As of the data cut-off date, two patients in stable condition are still receiving treatment. One subject with HR+BC who progressed on CDK4/6 inhibitors had been treated for 46 weeks. Another subject with recurrent well-differentiated liposarcoma (CDK4, CCND2, and MDM2 gene amplification) who was also previously exposed to a CDK4/6 inhibitor was treated for 45 weeks. One subject with breast cancer achieved stable disease as best response but discontinued treatment at 25 weeks. in conclusion
化合物44-A具有良好的耐受性且在所評價之劑量具有可管理之安全概貌。PK分析提供化合物44-A之血漿Tmax、Cmax及AUC0-24。40 mg化合物44-A BID之濃度-時間曲線係40 mg QD的兩倍，而40 mg至80 mg QD之濃度-時間曲線沒有按比例加倍。 實例 3 ：經由對掌性分離合成化合物 44A 及化合物 44B 步驟 -1 ： 2-(3- 溴苯基 )-3- 甲基丁酸之合成 Compound 44-A was well tolerated and had a manageable safety profile at the doses evaluated. PK analysis provided the plasma Tmax, Cmax and AUC0-24 of Compound 44-A. The concentration-time curve of 40 mg Compound 44-A BID was twice that of 40 mg QD, while the concentration-time curve of 40 mg to 80 mg QD was not Doubling proportionally. Example 3 : Synthesis of Compound 44A and Compound 44B via Chiral Separation Step -1 : Synthesis of 2-(3- bromophenyl )-3- methylbutanoic acid
在-78℃下，經30分鐘時段將2M LDA (698 mL，1.38 mol)添加至2-(3-溴苯基)乙酸(試劑-1，150 g，0.69 mol)於THF (700 mL)中之溶液中。將反應物質在-78℃攪拌2小時，隨後在-78℃經30分鐘時段逐滴添加異丙基溴(255 g，2.07 mol)。將反應物質在室溫下攪拌隔夜。將反應物質用1N HCl (pH 2)淬滅並將產物萃取至乙酸乙酯(500 mL × 3)中。將合併之有機層依次用水及鹽水洗滌，乾燥並減壓濃縮，得到標題粗化合物，將該粗化合物藉由二氧化矽管柱，利用0-10%乙酸乙酯-己烷系統溶析來純化，得到標題化合物2 (150 g，83%產率)。LCMS: m/z = 254.80 (M-2H)-。 步驟 -2 ： 3-(2-(3- 溴苯基 )-3- 甲基丁醯胺基 )-5- 環丙基 -1H- 吡唑 -1- 甲酸三級丁酯之合成 2M LDA (698 mL, 1.38 mol) was added to 2-(3-bromophenyl)acetic acid (reagent-1, 150 g, 0.69 mol) in THF (700 mL) over a period of 30 minutes at -78 °C in the solution. The reaction mass was stirred at -78°C for 2 hours, then isopropyl bromide (255 g, 2.07 mol) was added dropwise at -78°C over a period of 30 minutes. The reaction mass was stirred overnight at room temperature. The reaction mass was quenched with 1N HCl (pH 2) and the product was extracted into ethyl acetate (500 mL x 3). The combined organic layers were washed with water and brine successively, dried and concentrated under reduced pressure to obtain the title crude compound, which was purified by silica column and eluted with 0-10% ethyl acetate-hexane system , to obtain the title compound 2 (150 g, 83% yield). LCMS: m/z = 254.80 (M-2H)-. Step -2 : Synthesis of tertiary butyl 3-(2-(3- bromophenyl )-3- methylbutyrylamino )-5- cyclopropyl -1H - pyrazole -1- carboxylate
將2-(3-溴苯基)-3-甲基丁酸(中間物-2，70 g，0.0.27 mol)溶解於無水DCM (500 mL)中，並在0℃下逐滴添加草醯氯(68 mL，0.78 mol)，隨後添加催化量之DMF (0.8 mL)並將反應物質在相同溫度下維持30分鐘。使反應物質達到室溫並攪拌4小時，在真空下蒸出溶劑及過量的草醯氯。將殘餘物再溶解於DCM (250 mL)中並在0℃下，將其緩慢添加至3-胺基-5-環丙基-1H-吡唑-1-甲酸三級丁酯(中間物-3，49 g，0.218 mol)及TEA (55 mL，0.546 mol)於THF (250 mL)中的冷卻之溶液中，保持30分鐘。在室溫下攪拌反應12小時，接著將反應物質減壓濃縮並將殘餘物溶解於DCM中，用飽和NaHCO3溶液及鹽水洗滌。將有機層經無水硫酸鈉乾燥並減壓濃縮，將粗品藉由矽膠管柱層析法，利用15%乙酸乙酯-己烷溶析來純化，得到標題化合物4 (90 g，71%)。LCMS: m/z = 363.80(M-Boc+2)。 步驟 -3 ： 5- 環丙基 -3-(3- 甲基 -2-(3-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼雜環戊烷 -2- 基 ) 苯基 ) 丁醯胺基 )-1H- 吡唑 -1- 甲酸三級丁酯之合成 2-(3-Bromophenyl)-3-methylbutanoic acid (Intermediate-2, 70 g, 0.0.27 mol) was dissolved in anhydrous DCM (500 mL), and oxalate was added dropwise at 0 °C Acyl chloride (68 mL, 0.78 mol), then a catalytic amount of DMF (0.8 mL) was added and the reaction mass was maintained at the same temperature for 30 minutes. The reaction mass was allowed to reach room temperature and stirred for 4 hours, and the solvent and excess oxalyl chloride were distilled off in vacuo. The residue was redissolved in DCM (250 mL) and added slowly to tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (intermediate- 3, 49 g, 0.218 mol) and TEA (55 mL, 0.546 mol) in THF (250 mL) in a cooled solution for 30 minutes. The reaction was stirred at room temperature for 12 hours, then the reaction mass was concentrated under reduced pressure and the residue was dissolved in DCM, washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and eluted with 15% ethyl acetate-hexane to obtain the title compound 4 (90 g, 71%). LCMS: m/z = 363.80 (M-Boc+2). Step -3 : 5- cyclopropyl -3-(3- methyl -2-(3-(4,4,5,5 - tetramethyl -1,3,2- dioxaborolane Synthesis of -2- yl ) phenyl ) butyrylamino )-1H- pyrazole -1- carboxylic acid tertiary butyl ester
向3-(2-(3-溴苯基)-3-甲基丁醯胺基)-5-環丙基-1H-吡唑-1-甲酸三級丁酯(中間物-4，90 g，0.193 mol)及4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧雜硼雜環戊烷)(62 g，0.251 mol)於1,4-二噁烷(500 mL)中脫氣的溶液中添加乙酸鉀(37.80 g，0.386 mol)。在室溫下，在脫氣下將反應物質攪拌10分鐘，並添加PdCl2(dppf).DCM複合物(12.5 g, 0.015 mol)。將反應物質在100℃加熱3-4小時。將反應混合物冷卻至室溫並在矽藻土床上過濾，將濾液蒸發，得到深褐色液體。將粗物質藉由二氧化矽管柱層析法，利用己烷中之20%乙酸乙酯溶析來純化，得到化合物5 (90 g， 86%)。LCMS: m/z = 410 (M-Boc+1)+。 步驟 -4 ： (E)-N-(5-(3-(1-((5- 環丙基 -1H- 吡唑 -3- 基 ) 胺基 )-3- 甲基 -1- 側氧基丁 -2- 基 ) 苯基 ) 吡啶 -2- 基 )-4-(N- 𠰌 啉基 ) 丁 -2- 烯醯胺之合成 To 3-(2-(3-bromophenyl)-3-methylbutyrylamino)-5-cyclopropyl-1H-pyrazole-1-carboxylic acid tertiary butyl ester (intermediate-4, 90 g , 0.193 mol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane ) (62 g, 0.251 mol) in 1,4-dioxane (500 mL) degassed solution was added potassium acetate (37.80 g, 0.386 mol). The reaction mass was stirred under degassing for 10 min at room temperature and PdCl2(dppf).DCM complex (12.5 g, 0.015 mol) was added. The reaction mass was heated at 100°C for 3-4 hours. The reaction mixture was cooled to room temperature and filtered on a bed of celite, the filtrate was evaporated to give a dark brown liquid. The crude material was purified by silica column chromatography using 20% ethyl acetate in hexane to give compound 5 (90 g, 86%). LCMS: m/z = 410 (M-Boc+1)+. Step -4 : (E)-N-(5-(3-(1-((5- cyclopropyl -1H- pyrazol -3- yl ) amino )-3- methyl -1- oxo Synthesis of but -2- yl ) phenyl ) pyridin -2- yl )-4-(N- metholinyl ) but - 2- enamide
向5-環丙基-3-(3-甲基-2-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丁醯胺基)-1H-吡唑-1-甲酸三級丁酯5 (10 g，0.019 mol)及(E)-N-(5-溴吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺(7.7 g，0.023 mol)於1,4-二噁烷(100 mL)及水(40 mL)中之脫氣溶液中隨後添加Cs2CO3 (14.5 g，0.045 mol)。在脫氣下，將反應物質攪拌10分鐘，並添加Pd(PPh3)4 (1.1 g，0.00095 mol)，在密封管中將反應物質在100℃下加熱4小時。將反應物質冷卻並用鹽水溶液稀釋。將水層分離並用乙酸乙酯再萃取。將合併之有機層蒸發至乾並將粗物質藉由二氧化矽管柱層析法，利用10%-15%於DCM中之甲醇溶析，得到所希望之純化合物44 (4.5 g， 44%)。LCMS: m/z = 529.15 (M+H)+；HPLC: 95.17%，rt: 6.34 min。To 5-cyclopropyl-3-(3-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)phenyl)butyrylamino)-1H-pyrazole-1-carboxylic acid tertiary butyl ester 5 (10 g, 0.019 mol) and (E)-N-(5-bromopyridin-2-yl)-4 To a degassed solution of -(N-𠰌linyl)but-2-enamide (7.7 g, 0.023 mol) in 1,4-dioxane (100 mL) and water (40 mL) was added Cs2CO3 ( 14.5 g, 0.045 mol). Under degassing, the reaction mass was stirred for 10 minutes and Pd(PPh3)4 (1.1 g, 0.00095 mol) was added and the reaction mass was heated at 100 °C for 4 hours in a sealed tube. The reaction mass was cooled and diluted with brine solution. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layers were evaporated to dryness and the crude material was eluted by silica column chromatography using 10%-15% methanol in DCM to afford the desired pure compound 44 (4.5 g, 44% ). LCMS: m/z = 529.15 (M+H)+; HPLC: 95.17%, rt: 6.34 min.
藉由使用對掌性製備型HPLC管柱(方法：管柱：Chiral Pak IA (20mm × 250 mm，5微米)，溶析：等度溶析(50:50)，A=ACN，B=甲醇，流量：20 mL/min)分離外消旋(E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2 -基)-4-(N-𠰌啉基)丁-2-烯醯胺，得到純異構物-1及異構物-2。 異構物1 (化合物44-A)： By using a chiral preparative HPLC column (method: column: Chiral Pak IA (20mm × 250 mm, 5 microns), elution: isocratic elution (50:50), A=ACN, B=methanol , flow: 20 mL/min) to separate racemic (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3- Methyl-1-oxobut-2-yl)phenyl)pyridin-2-yl)-4-(N-alphalinyl)but-2-enamide to obtain pure isomer-1 and iso Construct-2. Isomer 1 (Compound 44-A):
1HNMR (DMSO-d6, 400MHz): δ 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.49 (d, 1H), 6.13 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.41-2.32 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.59 (m, 2H)；LCMS: m/z = 529.15 (M+H)+；HPLC: 96.72%，rt: 6.39 min；對掌性HPLC: 97.68%，rt: 14.47。 異構物2 (化合物44B)： 1HNMR (DMSO-d6, 400MHz): δ 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.05 (m , 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.49 (d, 1H), 6.13 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.41-2.32 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.59 (m, 2H); LCMS: m/z = 529.15 (M+H)+; HPLC: 96.72%, rt: 6.39 min; Chiral HPLC: 97.68%, rt: 14.47. Isomer 2 (Compound 44B):
1HNMR (DMSO-d6, 400MHz): δ 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.04 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.50 (d, 1H), 6.14 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.40-2.39 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H)；LCMS: m/z = 529.15 (M+H)+；HPLC: 96.24%，rt: 6.39 min；對掌性HPLC: 97.92%，rt: 8.80。 實例 4 ：經由對掌性合成製備化合物 44-AKRM-A (化合物44-A之化學前驅體)之製備 步驟 -1 ： 2-(3- 溴苯基 )-3- 甲基丁酸 (1) 之製備 1HNMR (DMSO-d6, 400MHz): δ 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.04 (m , 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.50 (d, 1H), 6.14 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.40-2.39 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H); LCMS: m/z = 529.15 (M+H)+; HPLC: 96.24%, rt: 6.39 min; Chiral HPLC: 97.92%, rt: 8.80. Example 4 : Preparation of Compound 44-A KRM-A (Chemical Precursor of Compound 44-A) via Chiral Synthesis Step -1 : Preparation of 2-(3- bromophenyl )-3- methylbutanoic acid (1)
在-78℃下，經30分鐘時段將2M LDA(698 mL，1.38 mol)添加至2-(3-溴苯基)乙酸(150 g，0.69 mol)於THF (700mL)中之溶液中。將反應混合物在-78℃攪拌2小時，隨後在-78℃下，經30分鐘時段逐滴添加異丙基溴(XB，255 g，2.07 mol)。將反應物質在室溫下攪拌隔夜。將反應物質用1N HCl (pH 2)淬滅並將所獲得的產物萃取至乙酸乙酯(500 mL × 3)中。將合併之有機層依次用水及鹽水洗滌，經無水硫酸鈉乾燥並減壓濃縮，得到標題粗化合物，將該粗化合物藉由二氧化矽管柱，利用0-10%乙酸乙酯-己烷系統溶析來純化，得到標題化合物(150 g，83%產率)，HPLC純度-96%。式(1)之化合物亦可藉由CN110590747中所描述之方法製備。 步驟 -2 ：化合物 3 之製備 To a solution of 2-(3-bromophenyl)acetic acid (150 g, 0.69 mol) in THF (700 mL) was added 2M LDA (698 mL, 1.38 mol) over a period of 30 minutes at -78 °C. The reaction mixture was stirred at -78°C for 2 hours, then isopropyl bromide (XB, 255 g, 2.07 mol) was added dropwise over a period of 30 minutes at -78°C. The reaction mass was stirred overnight at room temperature. The reaction mass was quenched with 1N HCl (pH 2) and the obtained product was extracted into ethyl acetate (500 mL x 3). The combined organic layers were washed with water and brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title crude compound, which was passed through a silica column using a 0-10% ethyl acetate-hexane system Purification by elusion afforded the title compound (150 g, 83% yield), HPLC purity - 96%. The compound of formula (1) can also be prepared by the method described in CN110590747. Step -2 : Preparation of compound 3
將2-(3-溴苯基)-3-甲基丁酸(1，510 g，1.98 mol)溶解於30% IPA水溶液(10.2 L；3.06 L IPA-7.14 L水)及(1R, 2R)-環己烷-1,2-二胺( 2，113 g，0.9 mol)中。將反應混合物在室溫下攪拌10分鐘直至觀察到沈澱，接著將其加熱至100℃直至溶液變澄清並在相同溫度下再攪拌30分鐘。使反應混合物緩慢達到室溫，保持8-12小時。將所獲得的固體過濾並用500 mL之30% IPA-水混合物洗滌，並在真空下乾燥以提供化合物 3(620 g，濕品)。 2-(3-Bromophenyl)-3-methylbutanoic acid (1,510 g, 1.98 mol) was dissolved in 30% aqueous IPA (10.2 L; 3.06 L IPA-7.14 L water) and (1R, 2R) - in cyclohexane-1,2-diamine ( 2 , 113 g, 0.9 mol). The reaction mixture was stirred at room temperature for 10 minutes until a precipitate was observed, then it was heated to 100° C. until the solution became clear and stirred at the same temperature for another 30 minutes. The reaction mixture was slowly brought to room temperature for 8-12 hours. The obtained solid was filtered and washed with 500 mL of 30% IPA-water mixture, and dried under vacuum to provide Compound 3 (620 g, wet).
分析處理(對於對掌性純度)：將一小部分(100 mg)化合物3溶解於DCM (2-3 mL)中，並在0℃下添加1N HCl (pH 2)，直至觀察到澄清溶液。將化合物萃取至DCM中，經Na 2SO 4乾燥並蒸發溶劑，得到呈白色固體狀之標題化合物(20 mg)。記錄下此樣本之對掌性HPLC，並在對掌性HPLC中觀察到20.6%的不需要之異構物。 Analytical workup (for chiral purity): A small portion (100 mg) of compound 3 was dissolved in DCM (2-3 mL) and 1 N HCl (pH 2) was added at 0 °C until a clear solution was observed. The compound was extracted into DCM, dried over Na2SO4 and the solvent was evaporated to give the title compound (20 mg) as a white solid. The chiral HPLC of this sample was recorded and 20.6% of the undesired isomer was observed in the chiral HPLC.
為了提高標題化合物之對掌性純度，如下所描述執行再結晶方法。 步驟 -3 ：再結晶 To increase the chiral purity of the title compound, a recrystallization procedure was performed as described below. Step -3 : Recrystallization
將化合物3 (619.90 g)溶解於30%於水中之IPA (12.4 L)中，接著將混合物加熱至100℃，直至溶液變澄清，並在相同溫度下再攪拌30分鐘。使反應混合物緩慢達到室溫，保持8-12小時。將所獲得的固體過濾並用500mL之30% IPA-水洗滌並在真空下乾燥，得到所需化合物(360 g，濕品)。Compound 3 (619.90 g) was dissolved in 30% IPA in water (12.4 L), then the mixture was heated to 100 °C until the solution became clear, and stirred at the same temperature for another 30 minutes. The reaction mixture was slowly brought to room temperature for 8-12 hours. The obtained solid was filtered and washed with 500 mL of 30% IPA-water and dried under vacuum to obtain the desired compound (360 g, wet).
分析處理(對於對掌性純度)：將來自上述化合物的一小部分(100 mg)溶解於DCM (2-3 mL)中，在0℃下添加1N HCl (pH 2)直至觀察到澄清溶液，並將該化合物萃取至DCM中，經Na 2SO 4乾燥並蒸發溶劑，得到呈白色固體狀之標題化合物(35 mg)。記錄下此樣本之對掌性HPLC，並在對掌性HPLC中觀察到10.3%的不需要之異構物。 Analytical work-up (for chiral purity): A small portion (100 mg) from the above compound was dissolved in DCM (2-3 mL), 1 N HCl (pH 2) was added at 0 °C until a clear solution was observed, The compound was extracted into DCM, dried over Na2SO4 and the solvent was evaporated to give the title compound (35 mg) as a white solid. The chiral HPLC of this sample was recorded and 10.3% of the undesired isomer was observed in the chiral HPLC.
如上所描述，使用30％於水中之IPA將再結晶方法又重複三次，得到純度＞98.50% ee，以及0.27%的其他異構物，由此得到286 g化合物4。 步驟 -4 ： (S)-2-(3- 溴苯基 )-3- 甲基丁酸 (KRM-A) 之製備 The recrystallization process was repeated three more times using 30% IPA in water as described above to give a purity >98.50% ee, and 0.27% other isomers, thus yielding 286 g of compound 4. Step -4 : Preparation of (S)-2-(3- bromophenyl )-3- methylbutanoic acid (KRM-A)
將化合物4 (286 g)溶解於DCM (1.3 L)中，接著在0℃下添加1N HCl直至觀察到澄清溶液，並將該化合物萃取至DCM (500 mL × 2)中。將有機層分離並用鹽水溶液(500 mL)洗滌且經Na2SO4乾燥，蒸發溶劑，得到呈白色固體狀之標題化合物(148 g，60％產率)。對掌性HPLC：98.50%Compound 4 (286 g) was dissolved in DCM (1.3 L), then 1 N HCl was added at 0 °C until a clear solution was observed, and the compound was extracted into DCM (500 mL x 2). The organic layer was separated and washed with brine solution (500 mL) and dried over Na2SO4, the solvent was evaporated to give the title compound (148 g, 60% yield) as a white solid. Opposite chiral HPLC: 98.50%
1H NMR (400MHz, DMSO-d6): δ12.5 (s, 1H), 7.50-7.44 (m, 2H), 7.34-7.26 (m, 2H), 3.16 (d, 1H), 2.23-2.11 (m, 1H), 0.98 (d, 3H), 0.63 (d, 3H)；對掌性HPLC：98.50%，滯留時間：4.588 min。 化合物44-A之製備 步驟 -1 ： (S)-2-(3- 溴苯基 )-N-(5- 環丙基 -1H- 吡唑 -3- 基 )-3- 甲基丁醯胺之合成 步驟-1a：KRM-D之製備 1 H NMR (400MHz, DMSO-d6): δ 12.5 (s, 1H), 7.50-7.44 (m, 2H), 7.34-7.26 (m, 2H), 3.16 (d, 1H), 2.23-2.11 (m, 1H), 0.98 (d, 3H), 0.63 (d, 3H); chiral HPLC: 98.50%, retention time: 4.588 min. Preparation of Compound 44-A Step -1 : Synthesis of (S)-2-(3- bromophenyl )-N-(5 -cyclopropyl -1H- pyrazol -3- yl )-3- methylbutanamide Step-1a: Preparation of KRM-D
向KRM-A (100 g，0.388 mol)於無水DCM (600 mL， 6 vol)中之經攪拌溶液中添加催化量之DMF (10 mL)，隨後在0℃下經30分鐘時段逐滴添加草醯氯(45 mL，0.525 mol)。添加完成後，將反應混合物在相同溫度下攪拌15分鐘。使反應混合物升溫至室溫並攪拌2至4小時。反應完成(藉由TLC監測反應，藉由用MeOH淬滅反應混合物之等分試樣來檢查醯氯化物之形成)後，將反應混合物在40℃-45℃下真空濃縮，得到粗2-(3-溴苯基)-3-甲基丁醯氯(KRM-D)。將粗KRM-D溶解於甲苯(500 mL)中並用於下一步驟。 步驟-1b：式Z之化合物的製備 To a stirred solution of KRM-A (100 g, 0.388 mol) in anhydrous DCM (600 mL, 6 vol) was added a catalytic amount of DMF (10 mL), followed by the dropwise addition of grass at 0 °C over a period of 30 min. Acyl chloride (45 mL, 0.525 mol). After the addition was complete, the reaction mixture was stirred at the same temperature for 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 to 4 hours. After completion of the reaction (reaction monitored by TLC, formation of acyl chloride was checked by quenching an aliquot of the reaction mixture with MeOH), the reaction mixture was concentrated in vacuo at 40°C-45°C to afford crude 2-( 3-bromophenyl)-3-methylbutyryl chloride (KRM-D). Crude KRM-D was dissolved in toluene (500 mL) and used in the next step. Step-1b: Preparation of Compound of Formula Z
在0℃下，將在甲苯中之 (S)-2-(3-溴苯基)-3-甲基丁醯氯緩慢添加至3-胺基-5-環丙基-1H-吡唑-1-甲酸三級丁酯(KRM-B，95.5 g，0.427 mol)及N,N-二異丙基乙胺(100 mL，0.583 mol)於甲苯(1.2 L)中的預先冷卻之溶液(0至5℃)中，保持1-2小時之時段。使反應混合物達到室溫並攪拌隔夜。接著，將反應混合物冷卻至0-5℃並用冰冷的1.5N HCl (3×500 mL)洗滌。將有機層用碳酸氫鈉溶液(500 mL)、鹽水溶液(500 mL)洗滌，經無水 Na 2SO 4乾燥，過濾並在45-50℃下真空濃縮，得到呈淺褐色油狀之粗( S)- 5-(2-(3-溴苯基)-3-甲基丁醯胺基)-3-環丙基-1H-吡唑-1-甲酸三級丁酯(式Z之化合物) (約180 g，LCMS: m/z= 461.9 (M+H) +，HPLC: 80.80%，滯留時間：15.89 min)。將粗產物不經進一步純化即以原樣用於下一步驟。 步驟-1c：式Y之化合物的製備 (S) -2-(3-Bromophenyl)-3-methylbutyryl chloride in toluene was slowly added to 3-amino-5-cyclopropyl-1H-pyrazole- A precooled solution (0 to 5°C) for a period of 1-2 hours. The reaction mixture was allowed to reach room temperature and stirred overnight. Next, the reaction mixture was cooled to 0-5 °C and washed with ice-cold 1.5N HCl (3 x 500 mL). The organic layer was washed with sodium bicarbonate solution (500 mL), brine solution (500 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo at 45-50 °C to give crude ( S )-5-(2-(3-bromophenyl)-3-methylbutyrylamino)-3-cyclopropyl-1H-pyrazole-1-carboxylic acid tertiary butyl ester (compound of formula Z) ( About 180 g, LCMS: m/z= 461.9 (M+H) + , HPLC: 80.80%, retention time: 15.89 min). The crude product was used as such in the next step without further purification. Step-1c: Preparation of compound of formula Y
在0℃下，向 (S)-5-(2-(3-溴苯基)-3-甲基丁醯胺基)-3-環丙基-1H-吡唑-1-甲酸三級丁酯(180 g，1.731 mol)於二噁烷(360 mL)中之懸浮液中添加2N HCl水溶液(360 mL)。將反應混合物在室溫下攪拌隔夜。 At 0°C, to (S) -5-(2-(3-bromophenyl)-3-methylbutyrylamino)-3-cyclopropyl-1H-pyrazole-1-carboxylic acid tertiary butyl To a suspension of the ester (180 g, 1.731 mol) in dioxane (360 mL) was added 2N aqueous HCl (360 mL). The reaction mixture was stirred overnight at room temperature.
反應完成後，濃縮二噁烷，並將反應混合物用水(500 mL)稀釋並用固體碳酸氫鈉鹼化(直至pH-8)。將所得化合物用DCM (700 mL × 3)萃取。將合併之有機層用水(300 mL)及鹽水溶液(300 mL)洗滌，且經無水 Na 2SO 4乾燥。將有機層濃縮，得到呈半固體狀之粗( S)-2-(3-溴苯基)-N-(5-環丙基-1H-吡唑-3-基)-3-甲基丁醯胺(式Y之化合物)。將粗品溶解於甲苯(500 mL)中並將溶液攪拌18小時。將所形成之固體過濾並用甲苯(100 mL)及正庚烷(200 mL)洗滌。將固體在45-50℃下進一步真空乾燥6小時，得到標題化合物(110 g，產率：經兩步驟78%)。LCMS: m/z= 362 (M+H) +，HPLC: 97.66%，滯留時間：24.10 min。 步驟-2：(S, E)-N-(5-(3-(1-((5-環丙基-1H-吡唑-3-基)胺基)-3-甲基-1-側氧基丁-2-基)苯基)吡啶-2-基)-4-(N-𠰌啉基)丁-2-烯醯胺(化合物44A)之製備 After the reaction was complete, the dioxane was concentrated, and the reaction mixture was diluted with water (500 mL) and basified (until pH-8) with solid sodium bicarbonate. The resulting compound was extracted with DCM (700 mL x 3). The combined organic layers were washed with water (300 mL) and brine solution (300 mL), and dried over anhydrous Na 2 SO 4 . The organic layer was concentrated to give crude ( S )-2-(3-bromophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methylbutanol as a semisolid Amides (compounds of formula Y). The crude product was dissolved in toluene (500 mL) and the solution was stirred for 18 hours. The solid formed was filtered and washed with toluene (100 mL) and n-heptane (200 mL). The solid was further dried under vacuum at 45-50 °C for 6 hours to obtain the title compound (110 g, yield: 78% over two steps). LCMS: m/z= 362 (M+H) + , HPLC: 97.66%, retention time: 24.10 min. Step-2: (S, E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-side Preparation of oxybut-2-yl)phenyl)pyridin-2-yl)-4-(N-𠰌linyl)but-2-enamide (compound 44A)
在室溫下，向( S)-2-(3-溴苯基)-N-(5-環丙基-1H-吡唑-3-基)-3-甲基丁醯胺(50 g，0.138 mol)及( E)-4-(N-𠰌啉基)-N-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-2-基)丁-2-烯醯胺(KRM-C，56.6 g，0.151 mol，1.1 eq) (根據WO2020202001中所描述之程序製備)於1,4-二噁烷(500 mL，10 vol)及水(100 mL，2 vol)中之脫氣溶液中添加三鹼式K 3PO 4(73.2 g， 0.345 mol，2.5 eq)。在氬吹掃(脫氣)下，將反應物質攪拌20分鐘。添加Pd(dppf)Cl 2.DCM [1,1′-雙(二苯基膦基)二茂铁]二氯钯(II)與二氯甲烷之複合物] (3.38 g，0.0042 mol，及0.03 eq)，並將反應混合物加熱至90℃，保持1-2小時(使用含10%甲醇之DCM作為溶劑系統，藉由TLC監測反應)。 At room temperature, to ( S )-2-(3-bromophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methylbutanamide (50 g, 0.138 mol) and ( E )-4-(N-𠰌linyl)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)pyridin-2-yl)but-2-enamide (KRM-C, 56.6 g, 0.151 mol, 1.1 eq) (prepared according to the procedure described in WO2020202001) in 1,4-dioxane To a degassed solution in (500 mL, 10 vol) and water (100 mL, 2 vol) was added tribasic K 3 PO 4 (73.2 g, 0.345 mol, 2.5 eq). The reaction mass was stirred for 20 minutes under an argon purge (degassed). Add Pd(dppf)Cl 2 .DCM [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane] (3.38 g, 0.0042 mol, and 0.03 eq) and the reaction mixture was heated to 90° C. for 1-2 hours (10% methanol in DCM was used as solvent system, the reaction was monitored by TLC).
反應完成後，將反應物質冷卻至室溫並經由Celite ®床過濾。將該床用1,4-二噁烷(200 mL)洗滌並將濾液濃縮，得到粗化合物。將粗化合物溶解於含5%甲醇之DCM(400 mL)中並用水(200 mL × 2)洗滌。將有機層分離並用DCM (100 mL × 2)萃取。將合併之有機層用鹽水溶液洗滌，過濾並用硫酸鈉乾燥。將有機層在35-40℃下真空濃縮，得到粗標題化合物(約80 g)。 After the reaction was complete, the reaction mass was cooled to room temperature and filtered through a bed of Celite® . The bed was washed with 1,4-dioxane (200 mL) and the filtrate was concentrated to give crude compound. The crude compound was dissolved in 5% methanol in DCM (400 mL) and washed with water (200 mL x 2). The organic layer was separated and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine solution, filtered and dried over sodium sulfate. The organic layer was concentrated in vacuo at 35-40 °C to afford the crude title compound (ca. 80 g).
將粗化合物44A (80 g)溶解於700 mL乙酸乙酯中。將反應混合物冷卻至15℃並緩慢添加2N HCl (直至約pH 1)。接著，將反應混合物在室溫下攪拌20分鐘並分離各層。將水層(含有產物)用乙酸乙酯(300 mL × 3)洗滌。將水層冷卻至0℃並使用20% Na 2CO 3水溶液將pH值調至約8。用含10%甲醇之DCM (300 mL × 3)萃取產物。將合併之有機層用水(300 mL)洗滌，經硫酸鈉乾燥並過濾。將濾液用活性炭(16 g，20% w/w相對於80 g之粗品輸入量)處理，在室溫下攪拌隔夜並經由Celite ®床過濾。將該床用含5%甲醇之DCM (約20個體積，脂質藉由TLC確定無產物)洗滌。將濾液在35℃-40℃下真空濃縮，得到化合物44A (70 g，HPLC純度：92.70%，滯留時間：15.65 min)。 Crude compound 44A (80 g) was dissolved in 700 mL of ethyl acetate. The reaction mixture was cooled to 15 °C and 2N HCl was added slowly (up to about pH 1). Next, the reaction mixture was stirred at room temperature for 20 minutes and the layers were separated. The aqueous layer (containing the product) was washed with ethyl acetate (300 mL x 3). The aqueous layer was cooled to 0° C. and the pH was adjusted to about 8 using 20% aqueous Na 2 CO 3 . The product was extracted with 10% methanol in DCM (300 mL x 3). The combined organic layers were washed with water (300 mL), dried over sodium sulfate and filtered. The filtrate was treated with activated charcoal (16 g, 20% w/w relative to a crude input of 80 g), stirred overnight at room temperature and filtered through a bed of Celite® . The bed was washed with 5% methanol in DCM (approximately 20 vol, lipid free by TLC). The filtrate was concentrated in vacuo at 35°C-40°C to obtain compound 44A (70 g, HPLC purity: 92.70%, retention time: 15.65 min).
1H NMR (400MHz, DMSO- d 6 ): δ : 10.79 (s, 1H), 10.46 (s, 1H), 8.61 (d, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.39 (m, 2H), 6.84-6.77 (m, 1H), 6.62 (s, 2H), 6.51 (d, 1H), 6.13 (s, 1H), 3.62-3.59 (m, 4H), 3.35 (d, 1H), 3.15-3.13 (m, 2H), 2.42-2.39 (m, 5H), 1.80-1.77 (m, 1H), 0.98 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H)；LCMS: m/z= 529.25-游離鹼(M+H) +，HPLC：98.98%，滯留時間：15.40 min。 其他實施例 1 H NMR (400MHz, DMSO- d 6 ): δ : 10.79 (s, 1H), 10.46 (s, 1H), 8.61 (d, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H) , 7.69 (s, 1H), 7.56 (d, 1H), 7.39 (m, 2H), 6.84-6.77 (m, 1H), 6.62 (s, 2H), 6.51 (d, 1H), 6.13 (s, 1H ), 3.62-3.59 (m, 4H), 3.35 (d, 1H), 3.15-3.13 (m, 2H), 2.42-2.39 (m, 5H), 1.80-1.77 (m, 1H), 0.98 (d, 3H ), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H); LCMS: m/z= 529.25-free base (M+H) + , HPLC: 98.98%, retention Time: 15.40 min. other embodiments
出於清晰及理解之目的，已藉助說明及實例相當詳細地闡述前述揭示內容。已經參考各種特定且較佳之實施例及技術描述本發明。然而，應理解，在保持在本發明之精神及範圍內的同時可以進行許多變化及修改。熟習此項技術者應顯而易見，可以在所附申請專利範圍之範圍內進行改變及修改。因此，應理解，以上描述意欲為說明性的而非限制性的。因此，本發明之範圍不應參照上述說明來確定，而是應參照以下隨附申請專利範圍以及此等申請專利範圍所授權之全部等效內容範圍來確定。The foregoing disclosure has been set forth in some detail by way of illustration and examples for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many changes and modifications can be made while remaining within the spirit and scope of the invention. It should be obvious to those skilled in the art that changes and modifications can be made within the scope of the appended patent scope. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive. Accordingly, the scope of the present invention should be determined not with reference to the above description, but should be determined with reference to the following appended claims and all equivalents to which such claims are entitled.
圖 1係顯示CDK7在細胞週期進程及轉錄中之作用的示意圖。在圖1中，(A)描繪化合物44-A藉由防止其他CDK之磷酸化來停止細胞週期進程；(B)描繪化合物44-A抑制類固醇激素受體之磷酸化；及(C)描繪化合物44-A使致癌及抗凋亡基因之轉錄起始及延伸失調。 圖 2係實例1之臨床研究的概略圖。該試驗以確定安全的起始單藥化合物44-A劑量開始，進行至晚期腫瘤之單藥劑量遞增階段，且接著在腫瘤特異性單藥隊列擴展階段中確定最大耐受劑量(MTD)及推薦劑量(RD)。組合劑量遞增階段根據腫瘤類型確定化合物44-A與組合之標準化學治療劑的安全起始劑量。接著，擴展組合隊列以確定在組合劑存在下之MTD及RD。 圖 3係實例1之單藥療法隊列之研究方案。擴展隊列按腫瘤類型分開，其包括上皮性卵巢癌(EOC)、三陰性乳癌(TNBC)、激素受體陽性乳癌(HR+BC)及轉移性去勢抵抗性***癌(mCRPC)。 圖 4係實例1之組合療法隊列的研究方案。該等組合療法隊列包括患有HR+BC及患有mCRPC之受試者。該等HR+BC隊列接受遞增劑量之化合物44-A加上標準劑量之氟維司群，以確定在組合療法情況下化合物44-A之最大耐受劑量(MTD)及推薦劑量(RD)。mCRPC隊列接受遞增劑量之化合物44-A加上標準劑量之阿比特龍(Abi)及普賴松(d)，以確定在組合療法情況下化合物44-A之最大耐受劑量(MTD)及推薦劑量(RD)。 圖 5顯示單藥(化合物44-A)劑量遞增階段之研究設計。 圖 6A顯示在第1天投與各種單次劑量之量後化合物44-A之化合物I血漿濃度-時間曲線。 圖 6B顯示在第28天重複給藥後化合物44-A之化合物I血漿濃度-時間曲線。 圖 7A顯示在第1天投與各種單次劑量之量後化合物44-A之CDK7目標佔有率。 圖 7B顯示在第28天投與各種重複每日給藥後化合物44-A之CDK7目標佔有率。 Figure 1 is a schematic diagram showing the role of CDK7 in cell cycle progression and transcription. In Figure 1, (A) depicts compound 44-A arresting cell cycle progression by preventing phosphorylation of other CDKs; (B) depicts compound 44-A inhibiting phosphorylation of steroid hormone receptors; and (C) depicts compound 44-A deregulates transcription initiation and elongation of oncogenic and anti-apoptotic genes. Figure 2 is a schematic diagram of the clinical study of Example 1. The trial began with the establishment of a safe initial single-agent compound 44-A dose, proceeded to a single-agent dose-escalation phase in advanced tumors, and then in a tumor-specific single-agent cohort expansion phase to determine the maximum tolerated dose (MTD) and recommended dose (RD). Combination dose escalation phase Determine safe starting doses of Compound 44-A and standard chemotherapeutic agents in combination according to tumor type. Next, the combination cohort was expanded to determine the MTD and RD in the presence of the combination agent. Figure 3 is the study protocol for the monotherapy cohort of Example 1. The expansion cohort was separated by tumor type, which included epithelial ovarian cancer (EOC), triple-negative breast cancer (TNBC), hormone receptor-positive breast cancer (HR+BC), and metastatic castration-resistant prostate cancer (mCRPC). Figure 4 is the study protocol for the combination therapy cohort of Example 1. These combination therapy cohorts included subjects with HR+BC and with mCRPC. These HR+BC cohorts received escalating doses of Compound 44-A plus standard doses of fulvestrant to determine the maximum tolerated dose (MTD) and recommended dose (RD) of Compound 44-A in the context of combination therapy. The mCRPC cohort received escalating doses of compound 44-A plus standard doses of abiraterone (Abi) and presone (d) to determine the maximum tolerated dose (MTD) and recommendations for compound 44-A in the context of combination therapy. dose (RD). Figure 5 shows the study design for the dose escalation phase of single agent (compound 44-A). Figure 6A shows Compound I plasma concentration-time profiles of Compound 44-A following administration of various single dose amounts on Day 1. Figure 6B shows the Compound I plasma concentration-time profile of Compound 44-A after repeated dosing on day 28. Figure 7A shows the CDK7 target occupancy of Compound 44-A following administration of various single dose amounts on Day 1. Figure 7B shows the CDK7 target occupancy of Compound 44-A after administration of various repeated daily doses at day 28.
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| TW (1) | TW202327583A (en) |
| WO (1) | WO2023107861A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023224961A1 (en) * | 2022-05-16 | 2023-11-23 | Exelixis, Inc. | Cancer therapy using a combination of a cdk7 inhibitor with an oral serd |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY190459A (en) * | 2015-06-04 | 2022-04-21 | Aurigene Discovery Tech Ltd | Substituted heterocyclyl derivatives as cdk inhibitors |
| AU2019247885B2 (en) * | 2018-04-04 | 2023-09-07 | Aurigene Oncology Limited | Substituted pyrazole derivatives as selective CDK12/13 inhibitors |
| WO2020202001A1 (en) * | 2019-04-01 | 2020-10-08 | Aurigene Discovery Technologies Limited | Substituted 5-cyclopropyl-1h-pyrazol-3-yl-amine derivatives as selective cdk12/13 inhibitors |
| EP4232010A2 (en) * | 2020-10-22 | 2023-08-30 | Aurigene Oncology Limited | Cancer therapy using a combination of cdk7 inhibitor with an anti-microtubule agent |
| WO2022249141A2 (en) * | 2021-05-28 | 2022-12-01 | Aurigene Discovery Technologies Limited | Cancer therapy using a combination of cdk7 inhibitor with an anti-cancer agent |
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2022
- 2022-12-02 WO PCT/US2022/080811 patent/WO2023107861A1/en unknown
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| Publication number | Publication date |
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| WO2023107861A1 (en) | 2023-06-15 |
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