CN116916900A - 用于治疗膀胱癌的低氧诱导因子-2(α)抑制剂 - Google Patents
用于治疗膀胱癌的低氧诱导因子-2(α)抑制剂 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- A61P35/00—Antineoplastic agents
Abstract
本披露涉及用低氧诱导因子2α(HIF‑2α)抑制剂治疗膀胱癌的方法。还披露了包含该抑制剂的药物组合物。
Description
相关申请的交叉引用
本申请要求2021年10月18日提交的美国临时申请号63/257,069的权益,将其内容通过引用以其整体并入本文。
技术领域
本披露涉及用低氧诱导因子2α(HIF-2a)抑制剂治疗膀胱癌的方法。还披露了包含该抑制剂的药物组合物。
背景技术
膀胱癌(BC)是发病率和死亡率的主要来源,估计全世界每年有50万例新病例和20万人死亡(Lenis等人(2020)JAMA[美国医学会杂志]324(19):1980-1991;下文简称“Lenis等人”)。仅在美国,推断2021年就有超过8万例新病例和1.7万人死亡。
膀胱癌可能发生于膀胱的乳头状/管腔状和非乳头状/基底尿路上的不同细胞。根据世界卫生组织所描述的标准化组织病理学特征,它被分为非肌层浸润性膀胱癌(NMIBC,肿瘤局限于尿路上皮和固有层)和肌层浸润性膀胱癌(MIBC,肿瘤侵犯肌肉及膀胱外)。
NMIBC大约占器官局限性膀胱癌的70%至80%。NMIBC通常通过经尿道肿瘤切除(TUR)联合或不联合辅助膀胱内灌注来治疗(Babjuk等人(2019)Eur Urol[欧洲泌尿学]76(5):639-57)。尽管很少危及生命,但NMIBC有复发和进展为肌层浸润性疾病的倾向。因此,具有不同机制的更好的新颖型治疗剂可能会改善NMIBC的治疗结局。
相比之下,MIBC有很高的转移扩散趋势,最终导致最高的发病率和死亡率。虽然早期诊断和多模式治疗可改善非转移性MIBC患者的结局,但转移性疾病一般来说仍然无法治愈,其中相对5年总体存活(OS)率为15%(Nawaz和Webster(2016)Nat Rev Drug Discov[自然评论:药物发现]15(9):599-600)。全身联合化疗是不能手术的局部晚期或转移性MIBC患者进行初始治疗的标准方法。虽然初始反应率很高,但反应的持久性是可变的,多药化疗后的中值存活期大约为15个月,并且晚期疾病患者的预后仍然很差。
膀胱癌的高突变负荷使其容易受到免疫疗法(特别是使用靶向程序性细胞死亡蛋白-1(PD-1)及其配体PD-L1的检查点抑制剂)的影响。迄今已经批准了五种检查点抑制剂用于治疗不同阶段的膀胱癌,包括派姆单抗、阿特珠单抗、纳武单抗、德瓦鲁单抗和阿维鲁单抗。尽管免疫检查点抑制剂(ICI)单一疗法取得了成功,但长期持久反应率仍然很低,并且大多数患者会复发(Nadal和Bellmunt(2019)Cancer Treat Rev.[癌症治疗综述]76:10-21,下文简称“Nadal和Bellmunt”;Lenis等人;Nadal等人(2021)Hematol Oncol ClinNorth Am.[北美血液学/肿瘤学临床]35(3):469-93;下文简称“Nadal等人”)。
膀胱癌的病理生理学和分子生物学认识的最新进展也导致两种新型靶向治疗剂的批准,一种小分子FGFR抑制剂和一种抗体-药物缀合物。尽管FGFR改变在非MIBC中更为常见,但在高达21%的局部晚期或转移性膀胱癌中也发现了FGFR基因的扩增、突变和融合。厄达替尼(Erdafitinib)是一种泛FGFR抑制剂,被批准用于FGFR2和FGFR3改变的晚期膀胱癌患者,这是同时批准的检测患者组织中的FGFR改变的首款基于PCR的诊断伴侣(Alifrangis等人(2019) Nat Rev Urol[自然评论:泌尿学]16:465-83;Nadal和Bellmunt;Nadal等人)。抗体-药物缀合物利用高表达的粘连蛋白_4蛋白作为药物递送的靶标。恩弗妥单抗-维汀(Enfortumab vedotin)使用与微管破坏分子单甲基澳瑞他汀E连接的抗粘连蛋白-4抗体,在用化疗和免疫疗法治疗后仍进展的患者中显示出44%的客观反应率。这导致FDA批准了恩弗妥单抗-维汀在这种双重难治环境中的应用(Nadal和Bellmunt;Lenis等人)。
尽管最近批准了多种免疫疗法和靶向疗法,但在单一疗法和组合疗法环境下,对于膀胱癌的治疗仍然需要新型的治疗剂。
发明内容
本文披露了通过抑制HIF-2α治疗膀胱癌的方法。这些方法至少部分地基于用3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(下文称为化合物1)治疗某些膀胱癌异种移植模型(包括MIBC T24模型)后获得的结果。化合物1是一种有效的选择性HIF-2α小分子抑制剂,作为化合物编号5在PCT申请号公开号WO 2020/214853的表1中披露。
化合物1在膀胱癌异种移植模型,即NMIBC模型RT112和RT4以及MIBC T24模型中进行了测试。用20mg/kg的化合物1进行的治疗在RT4模型中产生了显著的抗肿瘤效果(TGI=44%)并在T24模型中导致肿瘤完全消退(图1)。化合物1在MIBC T24肿瘤模型中导致的完全肿瘤消退是出乎意料的,因为HIF-1α和HIF-2α在T24细胞中在常氧(20%O2)条件下均可检测到并且在低氧(1%O2)条件下均上调(图2(a))。
HIF-1α和HIF-2α是介导细胞对低氧有反应并促进肿瘤生长的转录因子。由于已经发现HIF-1α和HIF-2α在许多细胞环境中具有功能冗余,所以为了确定HIF-1α和HIF-2α中的一者或两者是否是T24细胞中肿瘤发生的驱动因素,我们确定了以下:血管内皮生长因子A(VEGFA)和葡萄糖转运蛋白1(GLUT1)基因的mRNA水平对低氧、HIF-1α和HIF-2α的siRNA敲低、以及化合物1的治疗的响应。VEGFA和GLUT1是关键的低氧下游基因,调节肿瘤血管生成和代谢重编程,从而促进肿瘤生长。据发现,HIF-1α和HIF-2α在T24细胞中在低氧条件下均上调(图2(a)),HIF-2α的siRNA敲低和用化合物1治疗T24细胞分别显著抑制了低氧诱导的VEGFA和GLUT1的上调(图2(b)和2(c))。相比之下,HIF-1α的敲低上调了VEGFA和GLUT1mRNA的水平(图2(a))。这些结果证实,在T24癌中,HIF-2α,而不是HIF-1α,调节对T24膀胱癌生长至关重要的低氧反应。因此,HIF-2α抑制剂有可能单独地或与其他抗癌剂和/或放射疗法组合有效治疗膀胱癌。
在第一方面,提供了一种治疗患者的膀胱癌的方法,该方法包括向有需要的患者以药物组合物施用治疗有效量的HIF-2α抑制剂或其药学上可接受的盐,该药物组合物包含HIF-2α抑制剂或其药学上可接受的盐以及药学上可接受的赋形剂。
在第一方面的第一实施例中,该HIF-2α抑制剂是:
(a)具有式(I)的化合物:
其中:
X1是CH或N;
R1是羟基、卤代、氨基、-OP(O)(OH)2、-OCH2OP(O)(OH)2、-OCOR10、-OCOOR11、-OCONR12R13、-OCHR14OCOR15或-OCHR14OCOOR15a,其中R10、R11、R15和R15a独立地是烷基或被氨基、羧基或羟基取代的烷基,R12和R13独立地是氢、烷基、或被氨基、羧基或羟基取代的烷基,或R12和R13与它们所附接的氮原子一起形成任选地取代的杂环基,并且每个R14是氢、烷基、或卤代烷基;
R2是氢、氘、烷基、卤代、卤代烷基、烯基、或炔基;
R2a是氢、卤代、或氘;
R3和R4独立地是氢、氘、烷基、环烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基;或
R3和R4与它们所附接的碳一起形成氧代、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;
R5是氢、氘、烷基、卤代、卤代烷基、羟基、或烷氧基;
R6是氢、氘、烷基、环烷基、或卤代;或
R5和R6与它们所附接的碳一起形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;条件是R5和R6以及R3和R4与它们所附接的碳一起不同时形成氧代、环亚烷基或任选地取代的4元至6元杂亚环基;
R7是氢、氘、烷基、烷氧基、氰基、卤代、卤代烷基、或卤代烷氧基;
L是键、S、SO、SO2、O、CO、或NR16,其中R16是氢或烷基;
R8是烷基、卤代烷基、羟基烷基、烷氧基烷基、氨基烷基、环烷基、环烯基、二环环烷基、稠合苯基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,杂环基本身或作为杂环基烷基和稠合苯基的一部分,被Ra、Rb、Rc、Rg和Rh取代,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;
R9是氢、烷基、环烷基、羟基、烷氧基、氰基、卤代、卤代烷基、卤代烷氧基、烷基亚砜、烷基磺酰基、或杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代:或
当R9和R2附接至同一碳原子时,它们可以组合形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元杂亚环基;并且
R9a是氢、卤代、或氘:
(b)3-(((1S,2S,3R)-2,3一二氟-1-羟基-7-(甲基磺酰基)-2,3-二氢-1H-茚-4-基)氧基)-5-氟苯甲腈;
(c)Novartis DFF332;或
(d)Arcus AB521;
或其药学上可接受的盐。
在第一方面的第二实施例中,该HiF-2抑制剂是具有式(II)或(III)的化合物:
其中式(II)和(III)分别对应于PCT申请公开号WO 2019/191227中编号为(I’)和(II)的式;并且其中式(II)中的X、Y、Z、R1b、RA1、RA2和R2b以及式(III)中的n’、Z、X’、R1、R15b、R16b、R17、R18和R19如PCT申请公开号WO 2019/191227的段落[008]、[024]、以及[033]至[049]所定义,并且将这些段落通过引用以其整体并入本文。具有式(II)的化合物和具有式(III)的化合物的实施例披露于PCT申请公开号WO 2019/191227的段落[009]至[023]、[025]至[026]以及[0125]至[0187]中并且披露为具体化合物1至833(表1)以及II-1至II-60(表2),并且将这些段落和具体化合物通过引用以其整体并入本文。
在第一方面的第三实施例中,该HIF-2抑制剂是具有式(IV)的化合物:
其中式(IV)对应于PCT申请公开号WO 2021/188769中的式(I);并且其中段落[0055]、[0058]、[0059]至[0089]中的式(IV)及其实施例(即,如WO 2021/188769中编号的具有式II、III、(IV-a)至(IV-f)、以及(V-a)至(V-g)的化合物)中的Y1、Y2、Y3、Y4、W1、W2、W3和R1以及段落[0012]至[0051]中此类式中使用的术语的定义披露于PCT申请公开号WO 2021/188769中,并且将这些式和段落通过引用以其整体并入本文。也将PCT申请公开号WO 2021/188769的表1、2和3中披露的具体化合物1至248通过引用以其整体并入本文。
在第一方面的第四实施例中,该HIF-2抑制剂是(S)-1′_氯-8-(二氟甲氧基)-8′,8′-二氟-6-(三氟甲基)-7′,8′-二氢-3H,6′H-螺[咪唑并[1,2-a]-吡啶-2,5′-异喹啉]或其药学上可接受的盐(DFF332)。
在第四方面,提供了具有式(I)、(II)、(III)、(IV)的化合物,包括Arcus AB521、或Novartis DFF332;(或本文所述的其任何实施例),或其药学上可接受的盐,用于在治疗膀胱癌中使用。
在第五方面,提供了具有式(I)、(II)、(III)、(IV)的化合物,包括Arcus AB521、或Novartis DFF332;(或本文所述的其任何实施例),或其药学上可接受的盐,用于制备用于在治疗膀胱癌中使用的药物。
在第六方面,上述任何一个方面的方法是其中披露的化合物可以与本申请中披露的一种或多种抗癌剂组合施用,任选地与放疗和/或手术组合施用。在第五方面的一个实施例中,该一种或多种抗癌剂选自FGFR抑制剂(如沃凡妥单抗(vofatamab)、英菲格拉替尼(infigratinib)、LY2874455((R,E)一2-(4-(2-(5-(1-(3,5-二氯吡啶_4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙-1-醇)、培米替尼(pemigatinib)、罗加替尼(rogaratinib)、PRN1371(8-(3-(4-丙烯酰基哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯基)-2-(甲基氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮)、唑来替尼(zoligratinib)、德赞替尼(derazantinib)、唑来替尼[Debio-1347,(5-氨基-1-(2-甲基-1H-苯并[d]咪唑-6-基)-1H-吡唑_4-基)(1H-吲哚-2-基)甲酮]、以及厄达替尼(erdafitinib))、检查点抑制剂(如PD1、PDL1、或CTLA-4抑制剂(如纳武单抗、派姆单抗、匹地利珠单抗、MEDI-0680(人源化IgG4κ抗程序性细胞死亡蛋白-1抗体)、德瓦鲁单抗、BMS-936559(抗PD-L1单克隆抗体)、西利单抗(cetrelimab)、阿维鲁单抗、伊匹单抗、曲美木单抗、和阿特珠单抗))、阿法替尼、拉帕替尼、埃罗替尼、帕妥珠单抗、曲妥珠单抗、曲妥珠单抗-德鲁替康、贝伐单抗、雷莫芦单抗、索拉非尼、乐伐替尼、卡博替尼(carbonzanitib)、帕唑帕尼、奥拉帕尼、AZD1775(苏氨酰基苏氨酰基酪氨酰基丙氨酰基天冬氨酰基苯基丙氨酰基异亮氨酰基丙氨酰基丝氨酰基甘氨酰基精氨酰基苏氨酰基甘氨酰基精氨酰基精氨酰基天冬氨酰基丙氨酰基异亮氨酰基组氨酰基天冬氨酸)、维妥舍替(Vistusertib)、林罗司他(Linrodostat)、顺铂、卡铂、多柔比星、维汀-恩弗妥单抗-ejfv(Enfortumab Vedotin-ejfv)、丝裂霉素、戈沙妥珠单抗-hziy(Sacituzumab Govitecan-hziy)、RC48-ADC(维迪西妥单抗(disitamab vedotin))、噻替派、戊柔比星(valrubicin)、吉西他滨、甲氨蝶呤、长春花碱、多西他赛、紫杉醇、培美曲塞、卡介苗(Bacillus Calmette-Guerin)、以及干扰素。
在第七方面,提供了具有式(V)的化合物:
其中:
X1是CH或N;
R1是羟基、卤代、氨基、-OP(O)(OH)2、-OCH2OP(O)(OH)2、-OCOR10、-OCOOR11、-OCONR12R13、-OCHR14OCOR15或-OCHR14OCOOR15a,其中R10、R11、R15和R15a独立地是烷基或被氨基、羧基或羟基取代的烷基,R12和R13独立地是氢、烷基、或被氨基、羧基或羟基取代的烷基,或R12和R13与它们所附接的氮原子一起形成任选地取代的杂环基,并且每个R14是氢、烷基、或卤代烷基;
R2是氢、氘、烷基、卤代、卤代烷基、烯基、或炔基;
R2a是氢、卤代、或氘:
R3和R4独立地是氢、氘、烷基、环烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基;或
R3和R4与它们所附接的碳一起形成氧代、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;
R5是氢、氘、烷基、卤代、卤代烷基、羟基、或烷氧基;
R6是氢、氘、烷基、环烷基、或卤代;或
R5和R6与它们所附接的碳一起形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;条件是R5和R6以及R3和R4与它们所附接的碳一起不同时形成氧代、环亚烷基或任选地取代的4元至6元杂亚环基;
R7是氢、氘、烷基、烷氧基、氰基、卤代、卤代烷基、或卤代烷氧基;
L是键、S、SO、SO2、O、CO、或NR16,其中R16是氢或烷基;
R8是被Ra、Rb、Rc、Rg和Rh取代的稠合苯基,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;
R9是氢、烷基、环烷基、羟基、烷氧基、氰基、卤代、卤代烷基、卤代烷氧基、烷基亚砜、烷基磺酰基、或杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代:或
当R9和R2附接至同一碳原子时,它们可以组合形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元杂亚环基;并且
R9a是氢、卤代、或氘:
或其药学上可接受的盐。
在第七方面的某些实施例中,L是键并且基团R1、R2、R3、R4、R5、R6、R7、R9、R2a、R9a如下文实施例2a至25以及31至37中所定义。
附图说明
图1提供了HIF-2a抑制剂化合物1(A型多晶型物)在小鼠膀胱癌异种移植模型RT112、RT4和T24中的抗肿瘤作用。
图2(a)提供了72h的常氧和低氧条件对膀胱癌细胞T24中的HIF-1a和HIF-2a蛋白水平的诱导。
图2(b)示出了72h的常氧或低氧条件对用HIF-1α、HIF-2α或对照的siRNA处理的膀胱癌T24细胞中的低氧诱导的GLUT1和VEGFA上调的影响。
图2(c)示出了72h的常氧或低氧条件对用1μM化合物1或DMSO处理的膀胱癌T24细胞中的低氧诱导的GLUT1和VEGFA上调的影响。
图3描绘了化合物1的A型多晶型物的代表性XRPD衍射图。
具体实施方式
定义:
除非另有说明,否则本说明书和权利要求书中使用的以下术语,包括具有式(I)和(V)的化合物中的术语X1、R1、R2、R2a、R3、R4、R5、R6、R7、R8、R9、R9a,出于本申请的目的被定义并且具有以下含义,除非另有说明。
“烷基”是指具有一个至六个碳原子的直链饱和单价烃基或具有三个至六个碳原子的支链饱和单价烃基,例如,甲基、乙基、丙基、2-丙基、丁基、戊基等。本领域技术人员将认识到,术语“烷基”可包括“亚烷基”基团。
除非另有说明,否则“亚烷基”是指具有一个至六个碳原子的直链饱和二价烃基或具有三个至六个碳原子的支链饱和二价烃基,例如,亚甲基、亚乙基、亚丙基、1-甲基亚丙基、2-甲基亚丙基、亚丁基、亚戊基等。
“烯基”是指含有双键的具有两个至六个碳原子的直链单价烃基或具有三个至六个碳原子的支链单价烃基,例如,丙烯基、丁烯基等。
“烷基二烯基”是经由末端二价碳附接的如上所定义的烯基。例如,在以下的化合物中:
箭头所指示的方框内包围的是烷基二烯基基团。
“卤代烷基二烯基”是被一个或两个卤代取代的烷基二烯基,每个基团如本文所定义。
“炔基”是指含有三键的具有两个至六个碳原子的直链单价烃基或具有三个至六个碳原子的支链单价烃基,例如,丙炔基、丁炔基等。
“烷硫基”是指-SR基(其中R是如上所定义的烷基),例如甲硫基、乙硫基等。
“烷基磺酰基”是指-SO2R基(其中R是如上所定义的烷基),例如甲基磺酰基、乙基磺酰基等。
“烷基亚砜”是指-SOR基(其中R是如上所定义的烷基),例如甲基亚砜、乙基亚砜等。
“氨基”是指-NH2。
“烷基氨基”是指-NHR基(其中R是如上所定义的烷基),例如甲基氨基、乙基氨基、丙基氨基、或2-丙基氨基等。
“氨基烷基”是指被-NR’R”取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基(其中R’和R”独立地是各自如本文所定义的氢、烷基、卤代烷基、羟基烷基、烷氧基烷基、或烷基羰基),例如氨基甲基、氨基乙基、甲基氨基甲基等。
“烷氧基”是指-OR基(其中R是如上所定义的烷基),例如甲氧基、乙氧基、丙氧基或2-丙氧基、正丁氧基、异丁氧基、或叔丁氧基等。
“烷氧基烷基”是指被至少一个如上所定义的烷氧基基团(例如一个或两个烷氧基基团)取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基,例如2-甲氧基乙基,1-、2-、或3-甲氧基丙基,2-乙氧基乙基等。
“烷氧基羰基”是指-C(O)OR基(其中R是如上所定义的烷基),例如甲氧基羰基、乙氧基羰基等。
“烷基羰基”是指-C(O)R基(其中R是如本文所定义的烷基),例如甲基羰基、乙基羰基等。
“芳基”是指具有6个至10个环原子的单价单环或二环芳香族烃基,例如苯基或萘基。
“芳烷基”是指-(亚烷基)-R基(其中R是如上所定义的芳基),例如苄基、苯乙基等。
“二环环烷基”是指任选地被独立地选自烷基、卤代、烷氧基、羟基、和氰基的一个或两个取代基取代的具有六个至十个碳原子的稠合二环饱和单价烃基。实例包括但不限于十氢化萘、八氢-1H-茚等。
“环烷基”是指任选地被独立地选自烷基、烷基二烯基、卤代、烷氧基、羟基、氰基、卤代烷基二烯基和氰基烷基的一个或两个取代基取代的具有三个至十个碳原子的单环饱和单价烃基。实例包括但不限于环丙基、环丁基、环戊基、环己基、1-氰基环丙-1-基、1-氰基甲基环丙-1-基、3-氟环己基等。环烷基可以包括如本文所定义的环亚烷基。
“环烷基烷基”是指-(亚烷基)-R基(其中R是如上所定义的环烷基),例如环丙基甲基、环己基甲基等。
除非另有说明,否则“环亚烷基”是指如上所定义的二价环烷基。
“环烯基”是指任选地被独立地选自烷基、卤代、烷氧基、羟基、氰基、和氰基烷基的一个或两个取代基取代的含有一个或两个双键的具有三个至十个碳原子的单环单价烃基。实例包括但不限于环丙烯基、环丁烯基、环戊烯基、或环己烯基等。
“氧代环烯基”是指含有一个或两个双键和氧代基团的具有三个至十个碳原子的单环单价烃基,并且任选地被独立地选自烷基、卤代、烷氧基、羟基、氰基、和氰基烷基的一个或两个取代基取代。实例包括但不限于3-氧代环己-1-烯基等。
“氰基烷基”是指被氰基取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基,例如氰基甲基、氰基乙基等。
“羧基”是指-COOH。
“二烷基氨基”是指-NRR’基(其中R和R’是如上所定义的烷基),例如二甲基氨基、甲基乙基氨基等。
“二取代的氨基”是指-NRR’基(其中R和R’独立地是各自如本文所定义的烷基、卤代烷基、羟基烷基、烷氧基烷基、或烷基羰基),例如二甲基氨基、乙基甲基氨基、双羟基乙基氨基、双甲氧基乙基氨基、二乙基氨基乙基氨基等。
“稠合苯基”是指与环烷基、环烯基或杂环基(各自如本文所定义)稠合的苯基。该稠合苯基可以在任一环原子处附接至式(I)的-L-。
“卤代”是指氟、氯、溴或碘,优选氟或氯。
“卤代烷基”是指被一个或多个卤素原子(例如一个至五个卤素原子(如氟或氯))取代的如上所定义的烷基,包括被不同卤素取代的那些,例如-CH2Cl、-CF3、-CHF2、-CH2CF3、-CF2CF3、-CF(CH3)2等。当烷基仅被氟取代时,在本申请中其可以被称作氟烷基。
“卤代烷氧基”是指-OR基(其中R是如上所定义的卤代烷基),例如-OCF3、-OCHF2等。当R是卤代烷基(其中该烷基仅被氟取代)时,在本申请中其可被称作氟烷氧基。
“羟基烷基”是指被一个或两个羟基基团取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基,条件是如果存在两个羟基基团,则它们两个不在同一碳原子上。代表性实例包括但不限于羟基甲基、2-羟基-乙基、2-羟基丙基、3-羟基丙基、1-(羟基甲基)-2-甲基丙基、2-羟基丁基、3-羟基丁基、4-羟基丁基、2,3-二羟基丙基、1-(羟基甲基)-2-羟基乙基、2,3-二羟基丁基、3,4-二羟基丁基以及2-(羟基甲基)-3-羟基丙基,优选2-羟基乙基、2,3-二羟基丙基和1-(羟基甲基)-2-羟基乙基。
除非另有说明,否则“杂环基”是指具有4个至8个环原子的饱和或不饱和单价单环基团,其中一个或两个环原子是选自N、O或S(O)n(其中n是从0至2的整数)的杂原子,剩余的环原子是C。另外,在该杂环基环中的一个或两个环碳原子可以任选地被-CO-基团替代。更特别地,术语杂环基包括但不限于吡咯烷代、哌啶代、高哌啶代、2-氧代吡咯烷基、2-氧代哌啶基、吗啉代、哌嗪代、四氢-吡喃基、硫代吗啉代等。当该杂环基环不饱和时,其可以含有一个或两个环双键,条件是该环不是芳香族的。当该杂环基基团含有至少一个氮原子时,其在本文中也被称为杂环氨基并且其是杂环基基团的子集。
“杂环基烷基”或“杂环烷基”是指-(亚烷基)-R基(其中R是如上所定义的杂环基环),例如四氢呋喃基甲基、哌嗪基甲基、吗啉基乙基等。
除非另有说明,否则“杂亚环基”是指如上所定义的二价杂环基。当杂亚环基含有4个、5个或6个环原子时,其在本文中也被称为4元至6元杂亚环基。
除非另有说明,否则“杂芳基”是指具有5个至10个环原子的单价单环或二环芳香族基,其中一个或多个(在一个实施例中,一个、两个或三个)环原子是选自N、O或S的杂原子,剩余的环原子是碳。代表性实例包括但不限于吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、异吲哚基、噁唑基、异噁唑基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、四唑基等。如本文所定义,术语“杂芳基”和“芳基”是相互排斥的。当该杂芳基环含有5个或6个环原子时,其在本文中也被称为5元或6元杂芳基。
“杂亚芳基”是指如上所定义的二价杂芳基。
“杂芳烷基”是指-(亚烷基)-R基(其中R是如上所定义的杂芳基),例如吡啶基甲基等。当杂芳烷基中的杂芳基环含有5个或6个环原子时,其在本文中也被称为5元或6元杂芳烷基。
如本文单独或组合使用的,术语“氧代”是指=(O)。
“任选地取代的芳基”是指任选地被一个、两个、或三个取代基取代的芳基,这些取代基独立地选自烷基、羟基、环烷基、羧基、烷氧基羰基、羟基、烷氧基、烷硫基、烷基磺酰基、氨基、烷基氨基、二烷基氨基、卤代、卤代烷基、卤代烷氧基、和氰基。
“任选地取代的杂芳基”是指任选地被一个、两个、或三个取代基取代的如上所定义的杂芳基,这些取代基独立地选自烷基、烷硫基、烷基磺酰基、羟基、环烷基、羧基、烷氧基羰基、羟基、烷氧基、卤代、卤代烷基、卤代烷氧基、氨基、烷基氨基、二烷基氨基、和氰基。
除非另有说明,否则“任选地取代的杂环基”是指任选地被一个、两个、或三个取代基取代的如上所定义的杂环基,这些取代基独立地选自烷基、烷硫基、烷基磺酰基、羟基、环烷基、羧基、烷氧基羰基、羟基、羟基烷基、烷氧基、烷氧基烷基、氨基烷基、卤代、卤代烷基、卤代烷氧基、和氰基。
“任选地取代的杂亚环基”是二价任选地取代的如上所定义的杂环基。
“任选的”或“任选地”是指随后所描述的事件或情况可能发生或可能不发生,且该描述包括该事件或情况发生的例子和没有发生的例子。例如,“任选地取代的芳基”是指芳基基团可以被或可以不被取代,并且该描述包括经取代的芳基基团和没有取代的芳基基团两者。
“螺环烷基”是指具有6个至10个环碳原子的饱和二环,其中这些环仅通过一个原子连接,该连接原子也称为螺原子,最通常为季碳(“螺碳”)。螺环烷基环任选地被一个或两个取代基取代,这些取代基独立地选自烷基、卤代、烷氧基、羟基、和氰基。代表性实例包括但不限于螺[3.3]庚烷、螺[3.4]辛烷、螺[3.5]壬烷、螺[4.4]壬烷(1∶2∶1∶1)等。
“螺杂环基”是指具有6个至10个环原子的饱和二环,其中一个、两个或三个环原子是选自N、O或S(O)n(其中n是从0至2的整数)的杂原子,其余的环原子是C,并且这些环仅通过一个原子连接,该连接原子也称为螺原子,最通常为季碳(“螺碳”)。螺杂环基环任选地被一个、两个、或三个取代基取代,这些取代基独立地选自烷基、烷硫基、烷基磺酰基、羟基、环烷基、羧基、烷氧基羰基、羟基、羟基烷基、烷氧基、烷氧基烷基、氨基烷基、卤代、卤代烷基、卤代烷氧基、和氰基。代表性实例包括但不限于2,6-二氮杂螺[3.3]庚烷、2,6-二氮杂螺[3.4]辛烷、2-氮杂螺[3.4]辛烷、2-氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷等。
如本文使用的“基本上相同”是指在变化范围内,在值或数据追踪中是相当的、在峰位置和振幅或强度方面是相当的测量的物理特征,所述变化通常与样品定位或处理、或用于获取追踪或物理特征的仪器的身份相关,或由于通常在实验室环境或分析仪器内部或之间遇到的其他变化或变动。
当需要时,本文中的任何定义可以与任何其他定义组合使用以描述复合结构基团。按照惯例,任何这样的定义的后继元素是附接至母体部分的元素。例如,复合基团烷氧基烷基是指烷氧基基团通过烷基基团附接至母体分子。
本披露还包括具有式(I)的化合物的受保护的衍生物。例如,当具有式(I)的化合物含有基团(如羟基、羧基、硫醇或含有一个或多个氮原子的任何基团)时,这些基团可以被适合的保护基团保护。合适的保护基团的综合列表可以发现于T.W.Greene,ProtectiveGroups in Organic Synthesis[有机合成中的保护基团],第5版,John Wiley&Sons,Inc.[约翰·威利父子出版公司](2014)中,将该文献的披露内容通过引用以其整体并入本文。本披露的化合物的受保护的衍生物可以通过本领域熟知的方法制备。
本披露还包括具有式(I)的化合物或其药学上可接受的盐的多晶型形式。多晶型物是化合物的不同结晶形式,这些结晶形式在该化合物的分子在晶格中的排列方面不同。因此,单一化合物可产生多种多晶型形式。化合物的多晶型物通常具有不同的熔点、溶解度、密度和光学特性。化合物的多晶型形式可以通过几种技术来区分,例如X射线衍射法、IR或拉曼(Raman)光谱法。
术语“前药”是指在体内变得更具活性的化合物。具有式(I)的某些化合物也可以作为前药存在,如Hydrolysis in Drug and Prodrug Metabolism:Chemistry,Biochemistry,and Enzymology[药物和前药代谢中的水解作用:化学、生物化学和酶学](Testa,Bernard和Mayer,Joachim M.Wiley-VHCA,苏黎世,瑞士2003)中所述。具有式(I)的化合物的前药是在生理条件下容易进行化学变化以提供活性化合物的化合物的结构修饰形式。因为在一些情况下前药比化合物或母体药物更容易施用,所以它们经常是有用的。例如,它们可以通过口服施用而具有可生物利用性,然而母体药物却不行。本领域已知多种前药衍生物,例如依赖前药的水解切割或氧化激活的那些。前药的实例(但不限于)是作为酯(该“前药”)施用的化合物,但是然后代谢水解为羧酸,活性实体。另外的实例包括具有式(I)的化合物的肽基衍生物。
化合物的“药学上可接受的盐”意指药学上可接受的并且具有母体化合物的所希望的药理学活性的盐。此类盐包括:
与无机酸(如盐酸、氢溴酸、硫酸、硝酸、磷酸等)形成的酸加成盐;或与有机酸(如甲酸、乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、葡萄庚酸、4,4′-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、粘康酸等)形成的酸加成盐;或
当母体化合物中存在的酸性质子被金属离子(例如碱金属离子、碱土离子或铝离子)替代而形成的盐;或与有机碱(如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N_甲基葡糖胺等)配位形成的盐。应理解,药学上可接受的盐是无毒的。关于合适的药学上可接受的盐的另外的信息可以发现于Remington’s Pharmaceutical Sciences[雷明顿药物科学],第17版,Mack Publishing Company[马克出版公司],伊斯顿,宾夕法尼亚州,1985中,将其通过引用以其整体并入本文。
具有式(I)的化合物可以具有不对称中心。包含不对称取代的原子的具有式(I)的化合物能以光学活性形式或外消旋形式被分离。化合物的单独的立体异构体可以通过从含有手性中心的可商购的起始材料合成制备,或通过制备对映异构体产物的混合物随后分离(例如转化成非对映体的混合物随后分离或重结晶、色谱技术、在手性色谱柱上直接分离对映异构体、或本领域已知的任何其他适当的方法)来制备。除非确切地指出特定的立体化学形式或异构体形式,所有的手性形式、非对映异构体形式、手性或非对映异构体形式的所有混合物、以及外消旋形式都在本披露的范围之内。
某些具有式(I)的化合物能以互变异构体和/或几何异构体存在。所有可能的互变异构体以及顺式和反式异构体(作为单独的形式及其混合物)都在本披露的范围之内。另外,如本文使用的,虽然仅列出了几个实例,但是术语烷基包括所述烷基基团的所有可能的异构体形式。此外,当这些环基团(例如芳基、杂芳基、杂环基)被取代时,虽然仅列出了几个实例,但是它们包括所有可能的异构体。此外,具有式(I)的化合物的所有水合物都在本披露的范围之内。
具有式(I)的化合物还可以在构成此类化合物的一个或多个原子上包含非天然量的同位素。非天然量的同位素可经定义为从自然中发现的量至所讨论的原子的100%的量,仅在一或多种同位素富集原子的存在方面不同。可掺入具有式(I)的化合物(以及本文披露的其任何实施例,包括特定的化合物)中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,分别为例如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33p、35S、18F、36Cl、123I和125I。同位素标记的化合物(例如,用3H和14C标记的化合物)可用于化合物或基质组织分布测定中。氚化的(即3H)和碳-14(即14C)同位素因其容易制备和可检测性而是有用的。此外,较重的同位素如氘(即2H)的取代可以赋予由更好的代谢稳定性引起的某些治疗优势(例如,增加的体内半衰期或降低的剂量需求)。在一些实施例中,在本文披露的化合物中,包括在下表1中,一个或多个氢原子被2H或3H替代,或者一个或多个碳原子被13C-或14C-富集的碳替代。正电子发射同位素(例如15O、13N、11C和15F)可用于正电子发射断层扫描(PET)研究,以检查基质受体的占有率。通过用同位素标记的试剂取代非同位素标记的试剂,通常可以通过以下程序来制备同位素标记的化合物,这些程序类似于本文方案或实例中披露的那些。
本文提供的某些结构被绘制为具有一个或多个浮动的取代基。除非另外提供或另外从上下文清楚可见,否则在化学上可行且化合价规则允许的情况下,一个或多个取代基可以存在于其所附接的环的任何原子上。例如,在结构:中,R7取代基可以替代三环的苯并部分上的任何氢,包括CH的氢(当X1是CH时)。
“药学上可接受的载剂或赋形剂”意指在制备药物组合物中有用的载剂或赋形剂,其通常是安全、无毒的并且不是生物学上或其他方面不希望的,并且包括对于兽用连同人类药用是可接受的载剂或赋形剂。如在本说明书和权利要求书中使用的“药学上可接受的载剂/赋形剂”包括一种和超过一种此类赋形剂两者。
如本文使用的术语“肿瘤”是指所有赘生性细胞(无论是恶性还是良性)的生长和增殖,以及所有癌前和癌的细胞和组织。
术语“癌症”、“癌的”和“肿瘤”在本文提及时并不相互排斥。
本披露包括化合物1的多晶型形式。多晶型物是化合物的不同结晶形式,这些结晶形式在该化合物的分子在晶格中的排列方面不同。因此,单一化合物可产生多种多晶型形式。化合物的多晶型物通常具有不同的熔点、溶解度、密度和光学特性。化合物的多晶型形式可以通过本领域熟知的许多技术(如X-射线衍射法、IR或拉曼光谱)来区分。
“XRPD”意指X-射线粉末衍射,一种在固体组分的存在下测量X-射线的衍射的分析技术。结晶且具有原子的规则重复阵列的材料产生独特粉末图案。
如本文使用的,术语“约”旨在限定它所修饰的数值,表示这个值为在误差界限之内的变量。当没有列举出特定的误差范围(例如,数据图或表中给出的平均值的标准偏差)时,术语“约”应理解为表示涵盖±10%,优选为±5%的范围,包括所列举的值和范围。
在式(I)中R9的定义中,短语“杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代”(以及用于定义式(I)中其他基团的类似短语)旨在涵盖未被取代的杂芳基和被Rd、Re、和Rf中任一个取代的杂芳基。
如本文使用的,术语“疾病”旨在为一般同义的,并且可以与术语“障碍”、“综合征”和“病症”(在医学病症时)互换使用,其中所有这些都反映了人类或动物体的或者损害了其正常功能的部分之一的异常情况,典型表现为区别的体征和症状,并且使人或动物有减少的寿命期限或生活质量。
术语“组合疗法”或“与......组合施用”是指施用两种或更多种治疗剂来治疗本披露中描述的疾病或障碍。这种施用涵盖以同时的方式共同施用这些治疗剂,如以具有固定比率的活性成分的单个胶囊或片剂施用或以每种活性成分的多个分开的胶囊或片剂施用。此外,这种施用还涵盖以依次的方式使用每种类型的治疗剂。在任何一种情况下,治疗方案将在治疗本文所述的病症或障碍方面提供药物组合的有益作用。
术语“化疗”和“抗癌剂”在本文中可互换使用。
术语“患者”通常与术语“受试者”同义,并且包括所有哺乳动物,包括人。患者的实例包括人、牲畜(例如牛、山羊、绵羊、猪和兔)和宠物(例如狗、猫、兔和马)。优选地,患者是人。
术语“协同”或“协同的”用于意指HIF-2α抑制剂或其药学上可接受的盐与一种或多种抗癌剂的组合的结果大于单独每种化合物的总和。这种对所治疗的疾病、病症或障碍的改善是“协同”效应。
“协同量”是产生协同效应(如本文所定义的“协同的”)的HIF-2α抑制剂或其药学上可接受的盐与一种或多种抗癌剂的组合的量。
“治疗(treating或treatment)”疾病包括:
(1)预防该疾病,即,使疾病的临床症状在可能暴露于或易患该疾病但尚未经历或显示该疾病的症状的哺乳动物中不发展;
(2)抑制该疾病,即,阻滞(稳定)或减少该疾病或其临床症状的发展;或
(3)缓解该疾病,即,使该疾病或其临床症状消退。
“治疗有效量”是指当向患者施用以用于治疗疾病时,足以影响该疾病的此类治疗的本披露化合物或其药学上可接受的盐的量。“治疗有效量”将根据化合物、疾病和它的严重性以及所要治疗的哺乳动物的年龄、体重等变化。
与HIF-2α相关的术语“抑制”和“降低”或这些术语的任何变体包括任何可测量的减少或完全抑制以达到所需的结果。例如,减少可以是与正常活性相比,HIF-2α活性降低约、至多约或至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或更多,或其中可衍生的任何范围。
以下化合物表I披露了具有式(I)的代表性HIF-2α抑制剂:
表I
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实施例:
在以下另外的实施例1-55中,本披露包括:
1.在实施例1中,提供了一种如第一方面所述的治疗膀胱癌的方法。
2.在实施例2中,如实施例1所述的方法是其中该HIF-2α抑制剂是具有式(I)的化合物或其药学上可接受的盐。
2a.在实施例2a,如实施例1或2所述的方法是其中该HIF-2α抑制剂是具有式(I)的化合物或其药学上可接受的盐,其中只有R2、R2a、R9、和R9a中的R9可以是卤代。在实施例2a的一个子实施例中,R9是卤代。
2b.在实施例2b,如实施例1或2所述的方法是其中该HIF-2α抑制剂是具有式(I)的化合物或其药学上可接受的盐,其中只有R2、R2a、R9、和R9a中的R9和R2a可以是卤代。在实施例2b的一个子实施例中,R9是卤代。
3.在实施例3中,如实施例2、2a、或2b所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R3和R4独立地是卤代。
4.在实施例4中,如实施例2、2a、或2b所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R3是卤代并且R4是氢。
5.在实施例5中,如实施例2、2a、2b、3、或4所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R1是羟基。
6.在实施例6中,如实施例2至4中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R1是氨基。
7.在实施例7中,如实施例2至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是卤代。
8.在实施例8中,如实施例2至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是烷基,优选地R6是甲基。
9.在实施例9中,如实施例2至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是氢。
10.在实施例10中,如实施例3至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是环烷基,优选环丙基、环丁基、环戊基或环己基。
11.在实施例11中,如实施例2至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是卤代,优选氟。
12.在实施例12中,如实施例2至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是卤代烷基,优选地R5是二氟甲基或三氟甲基。
13.在实施例13中,如实施例2至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是烷基,优选地R5是甲基或乙基。
14.在实施例14中,如实施例2至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是氢或烷氧基。
15.在实施例15中,如实施例2至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5和R6与它们所附接的碳一起形成3元至6元环亚烷基,优选环亚丙基、环亚丁基或环亚戊基,其各自任选地被一个或两个氟取代。
16.在实施例16中,如实施例2至15中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中X1是CR7。
17.在实施例17中,如实施例2、2a、或2b所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIal)或(IIb1)的结构:
18.在实施例18中,如实施例2、2a、或2b所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIal’)或(IIb1’)的结构.
19.在实施例19中,如实施例2、2a、或2b所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIa)或(IIb)的结构:
20.在实施例20中,如实施例2、2a、2b、或19所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIa’)或(IIb’)的结构:
21.在实施例21中,如实施例2、2a、或2b所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IVa)的结构:
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其中R5和Rb与它们所附接的碳一起形成3元至6元环亚烷基,优选环亚丙基、环亚丁基或环亚戊基,其各自任选地被一或两个氟取代。
22.在实施例22中,如实施例17至21中任一项所述的方法是其中具有式(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R3是氟。
23.在实施例23中,如实施例17至21中任一项所述的方法是其中具有式(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R3和R4是氟。
24.在实施例24中,如实施例2至23中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIal’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中L是O、S、SO、SO2、或NH。
25.在实施例25中,如实施例24所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中L是O。
25a.在实施例25a,如实施例24所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中L是键并且R8是如本发明内容的第一方面所定义的经取代的稠合苯基。
26.在实施例26中,如实施例2至25以及其中含有的子实施例中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIbl’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R8是被Ra、Rb、Rc、Rg和Rh取代的苯基,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rhh独立地选自氢、氘、和卤代。
27.在实施例28中,如实施例26以及其中含有的子实施例所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R8是3-氯-5-氟苯基、3,5-二氟苯基、3-氟-5-甲氧基苯基、3-氰基-5-氟苯基、3-氯-5-氰基苯基、3-氰基-5-甲基苯基、3-氯-4-氟苯基、3-氯-5-氟苯基、3-氟-5-甲基苯基、3-氰基苯基、3-三氟甲基苯基、3,4-二氯苯基、3-氯-2-甲基苯基、3,5-二氯苯基、3,5-二甲基苯基、2-氯-6-甲基苯基、2,6-二氟苯基、3,4,5-三氟苯基、3,4-二氟苯基、4-氟-3-甲基苯基、3-氰基-4-氟苯基、3-氰基-5-二氟甲基苯基或3-氰基-5-氟-2,4,6-三氘苯基。在实施例27的第一子实施例中,R10是3-氰基-5-氟苯基或3-氰基-5-氟-2,4,6-三氘苯基。
28.在实施例28中,如实施例2至25中任一项以及其中含有的任何子实施例所述的方法是其中具有式(I)、(IIal)、(IIbl)、(IIal’)、(IIbl’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R8是各自任选地被独立地选自烷基、卤代、烷氧基、氰基、和羟基的一个或两个取代基取代的环烷基或环烷基烷基。
29.在实施例29中,如实施例2至25中任一项以及其中含有的任何子实施例所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R8是被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基的Ra、Rb、和Rc取代的杂芳基。
30.在实施例30中,如实施例2至25中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R8是吡啶-3-基、吡啶-2-基、哒嗪-3-基、哒嗪-4-基、嘧啶-5-基、嘧啶-2-基、噻吩-2-基、呋喃-2-基、噻唑-5-基、噁唑-5-基、咪唑-5-基、呋喃-3-基、噻吩-3-基、噻唑_4-基、吡啶_4-基、噁唑-2-基、咪唑-2-基、吡啶-2-基、吡嗪-2-基、或噻唑-2-基,并且R8被Ra、Rb、和Rc取代,其中Ra和Rb独立地选自氢、甲基、甲氧基、羟基、氯、氟、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基,并且Rc选自氢、甲基、氰基、氯、氟、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基。
31.在实施例32中,如实施例2至30中任一项所述的方法是其中具有式(I)、(IIal)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R7是氢、甲基、乙基、甲氧基、氟、三氟甲基、或三氟甲氧基,优选地R7是氢。
32.在实施例32中,如实施例2至31中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R2是氢、氟、甲基、或乙基。
33.在实施例33中,如实施例2至32中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIal’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIB’)和(IVa)的化合物或其药学上可接受的盐是其中R9是氢、烷基、卤代、羟基、或烷氧基。
34.在实施例34中,如实施例33所述的方法是其中具有式(I)、(IIal)、(IIb1)、(IIa1’)、(IIbl’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R9是氢、甲基、羟基、或氟。
35.在实施例35中,如实施例2所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(VIIIa)或(VIIIb)的结构:
优选具有式(VIIIb)的结构。
36.在实施例36中,如实施例1所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IXa)或(IXb)的结构:
其中R2a不是氢。
37.在实施例37中,如实施例35或36所述的方法是其中R7是氢,R8是3-氰基-5-氟苯基,R9和R2a是卤代。
38.在实施例38中,如实施例2所述的方法是其中具有式(I)的化合物选自:
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aS)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
1,3,3,4,4-五氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢螺[环戊[cd]-茚-1,1′_环丙烷]_7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-((2a-氨基-1,3,3,4,4-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈;
3-氟-5-((1,1,2a,3,3,4,4-七氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-((3,3-二氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-((3,3-二氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-((3,3-二氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-氟-5-((1,3,3-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈;
3-氟-5-((1,2,2,3,3,4,4-七氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]_茚-7-基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3;
(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
(S)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;和
3-氟-5-(((1R,2R,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
39.在实施例39中,如实施例1所述的方法是其中该HIF-2α抑制剂是:
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊-[cd]-茚-7-基)氧基)苯甲腈;
3-(((1S,2S,3R)-2,3-二氟-1-羟基-7-(甲基磺酰基)-2,3-二氢-1H-茚-4-基)-氧基)-5-氟苯甲腈;
Novartis DFF332;或
Arcus AB521;或
其药学上可接受的盐。
39a.在实施例39a,如实施例1所述的方法是其中该HIF-2α抑制剂是:
3-(((1S,2S,3R)-2,3-二氟-1-羟基-7-(甲基磺酰基)-2,3-二氢-1H-茚-4-基)-氧基)-5-氟苯甲腈;
(S)-1′-氯-8-(二氟甲氧基)-8′,8′-二氟-6-(三氟甲基)-7′,8′-二氢-3H,6′H-螺[咪唑并[1,2-a]吡啶-2,5′-异喹啉](Novartis DFF332);或
Arcus AB521;或
其药学上可接受的盐;
其中该膀胱癌是肌层浸润性膀胱癌。
40.在实施例40中,如实施例1、2、或38所述的方法是其中该HIF-2α抑制剂是3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
41.在实施例41中,如实施例1、2、或40所述的方法是其中该HIF-2α抑制剂是3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
42.在实施例42中,如实施例41所述的方法是其中该3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈是结晶固体,指定为A型多晶型物,具有包含在角位置15.8和18.6处的峰的X-射线粉末衍射图,其中这些角位置可变化±0.2°2θ,如通过X-射线粉末衍射使用(Cu Kα)的X-射线波长所测量的。
43.在实施例43中,如实施例42所述的方法是其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置20.1处的峰,其中该角位置可以变化±0.2°2θ。
44.在实施例44中,如实施例42所述的方法是其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置12.9和20.1处的峰,其中这些角位置可以变化±0.2°2θ。
45.在实施例45中,如实施例42所述的方法是其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置11.4、12.9、和20.1处的峰,其中这些角位置可以变化±0.2°2θ。
46.在实施例46中,如实施例42所述的方法是其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置10.1、11.4、12.9、和20.1处的峰,其中这些角位置可以变化±0.2°2θ。
47.在实施例47中,如实施例42所述的方法是其中该3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈是结晶固体,指定为A型多晶型物,具有包含在选自下表1的角位置处的至少两个、至少三个、至少四个、至少五个、至少六个峰、至少七个峰、或至少八个峰的X-射线粉末衍射图,其中这些角位置可以变化±0.2°2θ。
表1
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48.在实施例48中,如实施例47所述的方法是其中该至少两个、至少三个、至少四个、至少五个、或至少六个峰选自10.1、11.4、12.9、13.7、15.9、18.0、19.6、20.1、21.4、21.7、25.0、和26.0,其中这些角位置可以变化±0.2°2θ。
49.在实施例49中,如实施例41所述的方法是其中该3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈是结晶固体,指定为A型多晶型物,具有X-射线粉末衍射图,具有基本与图1所示相同的X-射线粉末衍射图。
50.在实施例50中,如实施例42至48中任一项所述的方法是其中本文所示的X-射线粉末衍射图峰的角位置可以变化±0.1°2θ。
51.在实施例51中,提供了第一方面的第三实施例的一个子实施例,其中该HIF-2抑制剂选自由以下组成的组:
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52.在实施例52中,如实施例1至51中任一项所述的方法是其中该膀胱癌选自由以下组成的组:转移性膀胱癌、非转移性膀胱癌、早期膀胱癌、非浸润性膀胱癌、肌层浸润性膀胱癌(MIBC)、非肌层浸润性膀胱癌(NMIBC)、原发性膀胱癌、晚期膀胱癌、局部晚期膀胱癌、缓解期膀胱癌、进行性膀胱癌、复发性膀胱癌和尿路上皮癌。
53.在实施例53中,如实施例52所述的方法是其中该膀胱癌是肌层浸润性膀胱癌。
54.在实施例54中,如实施例1至53中任一项所述的方法是其中该方法进一步包括施用该HIF-2α抑制剂与一种或多种另外的抗癌剂、放射疗法和/或手术的组合。
55.在实施例55中,如实施例1至54中任一项所述的方法是其中顺序地或同时施用该HIF-2α抑制剂和该一种或多种另外的抗癌剂。
56.在实施例56中,如实施例1至55中任一项所述的方法是其中该一种或多种抗癌剂选自由以下组成的组:沃凡妥单抗、英菲格拉替尼、LY2874455、培米替尼、罗加替尼、PRN1371、唑来替尼、德赞替尼、厄达替尼、纳武单抗、派姆单抗、匹地利珠单抗、MEDI-0680、德瓦鲁单抗、BMS-936559、西利单抗、阿维鲁单抗、阿特珠单抗、拉帕替尼、埃罗替尼、贝伐单抗、索拉非尼、卡博替尼、帕唑帕尼、奥拉帕尼、AZD1775、维妥舍替、林罗司他、顺铂、卡铂、多柔比星、维汀-恩弗妥单抗-ejfv、丝裂霉素、噻替派、戈沙妥珠单抗-hziy、戊柔比星、吉西他滨、甲氨蝶呤、长春花碱、多西他赛、紫杉醇、培美曲塞、卡介苗、以及干扰素。
药物组合物
通常,本披露的HIF-2α将以治疗有效量、通过用于类似效用的药剂的任何接受的施用方式进行施用。本文披露的HIF-2α抑制剂的治疗有效量的范围可以为约100mg至约500mg/天,优选200mg至500mg/天,其能以单剂量或多剂量施用。
HIF-2a抑制剂(即活性成分)的实际量将取决于多种因素,如待治疗的疾病的严重程度、患者的年龄和相对健康状况、所利用的化合物的效力、施用的途径和形式、以及其他因素。
通常,本披露的HIF-2α将通过以下途径中的任一种作为药物组合物施用:口服、全身(例如,经皮、鼻内或通过栓剂)、或肠胃外(例如,肌内、静脉内或皮下)施用。优选的施用方式是使用方便的日剂量方案口服,其可以根据患病程度进行调整。组合物可以采取片剂、丸剂、胶囊、半固体、粉末、缓释配制品、溶液、混悬液、酏剂、气溶胶或任何其他适当的组合物的形式。
配制品的选择取决于多种因素,如药物施用方式(例如,对于口服施用,优选呈片剂、丸剂或胶囊形式的配制品,包括肠溶包衣的或缓释的片剂、丸剂或胶囊)和原料药的生物利用度。
通常,组合物由本披露的HIF-2α抑制剂与至少一种药学上可接受的赋形剂组合构成。可接受的赋形剂是无毒的,有助于施用,并且不会不利地影响HIF-2α抑制剂的治疗益处。此类赋形剂可以是任何固体、液体、半固体或在气溶胶组合物的情况下是本领域的普通技术人员通常可用的气体赋形剂。
固体药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、氯化钠、脱脂乳粉等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇以及各种油,包括石油、动物、植物或合成来源的那些,例如,花生油、大豆油、矿物油、芝麻油等。优选的液体载剂,特别是用于可注射溶液的液体载剂,包括水、盐水、葡萄糖水溶液和二醇。
化合物可配制为用于通过注射(例如,通过推注或连续输注)进行肠胃外施用。注射用配制品可以以单位剂型提供,例如,在添加有防腐剂的安瓿中或在多剂量容器中。组合物可以采取例如处于油性或水性媒介物中的混悬液、溶液或乳液的形式,并且可以含有配制剂(如混悬剂、稳定剂和/或分散剂)。配制品可存在于单位剂量或多剂量容器(例如,密封的安瓿和小瓶)中,并且可以以粉末形式储存或在冷冻干燥(冻干)条件下储存,只需要在使用前即时添加无菌液体载剂(例如,盐水或无菌的无热原水)。临时的注射溶液和混悬液可由前述种类的无菌粉末、颗粒和片剂制备。
用于肠胃外施用的配制品包括活性化合物的水性和非水性(油性)无菌注射溶液,其可包含抗氧化剂、缓冲液、抑菌剂和使配制品与预期接受体的血液等渗的溶质;以及水性和非水性无菌混悬液,其可包括混悬剂和增稠剂。合适的亲脂性溶剂或媒介物包括脂肪油(如芝麻油)、或合成的脂肪酸酯(如油酸乙酯或甘油三酯)、或脂质体。水性注射混悬液可包含增加混悬液的粘度的物质,如羧甲基纤维素钠、山梨醇、或葡聚糖。任选地,混悬液还可含有合适的稳定剂或增加化合物的溶解度的药剂,以允许制备高度浓缩的溶液。
除了前述配制品之外,化合物还可配制成贮库(depot)制剂。此类长效型配制品可通过植入(例如,皮下或肌内)或通过肌内注射进行施用。因此,例如,化合物可以用合适的聚合或疏水性材料配制(例如配制成可接受的油中的乳液)或用离子交换树脂配制,或配制成难溶性衍生物,例如配制成难溶性盐。
对于口腔含化或舌下施用,组合物可以采取以常规方式配制的片剂、锭剂、糖果锭剂、或凝胶的形式。此类组合物可以包含调味基质(如蔗糖和阿拉伯胶或黄芪胶)中的活性成分。
化合物还可被配制成直肠组合物(如栓剂或保留灌肠剂),例如包含常规的栓剂基质(如可可脂、聚乙二醇、或其他甘油酯)。
配制品中化合物的水平可以在本领域技术人员所使用的全范围内变化。典型地,基于总配制品,该配制品将含有以重量百分比(wt.%)计的约0.01-99.99wt.%的HIF-2α抑制剂,其余的是一种或多种合适的药物赋形剂。例如,HIF-2α抑制剂以约1-80Wt.%的水平存在。
本文披露的HIF-2α抑制剂可以单独或与一种或多种其他抗癌药组合施用,这些抗癌药可用于治疗本披露的化合物对其具有效用的癌症。此类一种或多种其他药物可以通过一种途径以及其常用的量与HIF-2α抑制剂同时或顺序地施用。还预期,当与此类一种或多种其他活性成分组合使用时,HIF-2α抑制剂以及其他活性成分能以比各自单独使用时更低的剂量使用。
因此,除了一种或多种HIF-2α抑制剂之外,本披露的药物组合物还包括含有一种或多种其他药物的那些。本披露的化合物与此类其他活性成分的重量比可以变化,并将取决于每种成分的有效剂量。通常,将使用各自的有效剂量。
此类其他抗癌剂的实例包括但不限于棉子酚、根纳三思、多酚E、氯融蛋白、全反式维甲酸(all trans-retinoic acid,ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2’-脱氧胞苷、全反式维甲酸、多柔比星、长春新碱、依托泊苷、吉西他滨、伊马替尼(GleevecTM)、格尔德霉素、17-N-烯丙基氨基-17-去甲氧基格尔德霉素(17-AAG)、夫拉平度、LY294002、硼替佐米、曲妥珠单抗、BAY 11-7082、PKC412、或PD184352、TaxolTM(也称为“紫杉醇”,其是熟知的通过增强和稳定微管形成而起作用的抗癌药)、以及TaxolTM的类似物(如TaxotereTM)。
其他抗癌剂包括与细胞增殖性障碍相关的激酶的抑制剂。这些激酶包括但不限于Aurora-A、BTK、CDK1、CDK2、CDK3、CDK4、CDK6、CDK5、CDK7、CDK8、CDK9、肝配蛋白受体激酶、CHK1、CHK2、SRC、Yes、Fyn、Lck、Fer、Fes、Syk、Itk、Bmx、GSK3、JNK、MEK、PAK1、PAK2、PAK3、PAK4、PDK1、PKA、PKC、RAF、Rsk和SGK。特别地,CDK4/6的抑制剂(包括阿贝西尼(Verzenio)、帕博西尼(Ibrance)和瑞博西尼(Kisqali))具有与如下协同作用的潜力:HIF-2α抑制剂并逆转对HIF-2α抑制的抗性;丝裂原激活的蛋白激酶信号传导,例如,U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素(wortmannin)、或LY294002;Syk抑制剂;抗体(例如,利妥昔单抗);MET抑制剂(如福瑞替尼(foretinib)、卡博替尼(carbozantinib)、或克唑替尼(crizotinib));VEGFR抑制剂(如舒尼替尼(sunitinib)、索拉非尼、瑞戈非尼(regorafinib)、乐伐替尼、凡德他尼(vandetanib)、卡博替尼、阿西替尼(axitinib));EGFR抑制剂(如阿法替尼、布立尼布(brivanib)、卡扎替尼(carbozatinib)、埃罗替尼、吉非替尼(gefitinib)、来那替尼(neratinib)、拉帕替尼);PI3K抑制剂(如XL147、XL765、BKM120(布帕昔布(buparlisib))、GDC-0941、BYL719、IPI145、BAY80-6946、BEX235(达托昔布(dactolisib))、CAL101(艾代拉里斯(idelalisib))、GSK2636771、TG100-115);MTOR抑制剂(如雷帕霉素(rapamycin)(西罗莫司(sirolimus))、坦罗莫司(temsirolimus)、依维莫司(everolimus)、XL388、XL765、AZD2013、PF04691502、PKI-587、BEZ235、GDC0349);MEK抑制剂(如AZD6244、曲美替尼(trametinib)、PD184352、皮马替尼(pimasertinib)、GDC-0973、AZD8330);CSF1R抑制剂(PLX3397、LY3022855等)和CSF1R抗体(IMC-054、RG7155等);TGFβ受体激酶抑制剂(如LY2157299);BTK抑制剂(如依鲁替尼)。
其他抗癌剂包括蛋白酶体抑制剂(如卡非佐米(carfilzomib)、MLN9708、德兰佐米(delanzomib)、或硼替佐米);BET抑制剂(如INCB054329、OTX015、CPI-0610);LSD1抑制剂(如GSK2979552、INCB059872);HDAC抑制剂(如帕比司他(panobinostat)、伏立诺他(vorinostat));DNA甲基转移酶抑制剂(如氮杂胞苷、地西他滨)和其他表观遗传调节剂;SHP-2抑制剂(如TNO155);Bcl2抑制剂ABT-199和其他Bcl-2家族蛋白抑制剂;HIF-2α抑制剂(如PT2977和PT2385);β连环蛋白途径抑制剂、notch途径抑制剂和hedgehog途径抑制剂;针对VEGF的抗体或其他治疗性蛋白包括贝伐单抗和阿柏西普(aflibercept)。
可以与本发明的化合物组合使用的其他抗癌剂/药物包括但不限于肝X受体(LXR)调节剂(包括LXR激动剂和LXRβ-选择性激动剂);芳烃受体(AhR)抑制剂。
可以与本披露的化合物组合使用的其他抗癌剂包括阿霉素、更生霉素、博来霉素、长春花碱、顺铂、阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;醋酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;天冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸比生群;二甲磺酸双奈法德;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素;卡普睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗霉素;克拉屈滨;甲磺酸克立那托(crisnatol mesylate);环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;甲磺酸地扎胍宁;地吖醌;多柔比星;盐酸多柔比星;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸伊索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;氯苯乙嘧胺;盐酸法屈唑;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;白介素II(包括重组白介素II、或Ril2)、干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-1a;干扰素γ-1b;异丙铂;盐酸伊立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;美坦辛;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔;巯基嘌呤;甲氨喋呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托克星;丝裂红素;米托洁林;米托马星;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;诺拉霉素;奥马铂;奥昔舒仑;培门冬酶;培利霉素;戊氮芥;硫酸培洛霉素;培磷酰胺;哌泊溴烷;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;甲基丝裂霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋林;利波腺苷;罗谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;司泊索非钠(sparfosate sodium);司帕霉素;盐酸锗螺胺;螺莫司汀;螺铂;链黑霉素;链脲菌素;磺氯苯脲;他利霉素;替可加兰钠;喃氟啶;盐酸替洛蒽醌;替莫泊芬;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;噻替派;噻唑呋林;替拉扎明;柠檬酸托瑞米芬;醋酸曲托龙;磷酸曲西立滨;三甲曲沙;葡萄糖醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸长春罗辛;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星。
可以与本披露的化合物组合使用的其他抗癌剂包括:20-表-1,25二羟基维生素D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;酰基富烯(acylfulvene);腺环戊醇;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;阿米多克斯(amidox);氨磷汀;氨基乙酰丙酸;氨柔比星;安吖啶;阿那格雷;阿那曲唑;穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯(antarelix);抗背部化形态发生蛋白-1;抗雄激素,前列腺癌;抗雌激素;抗瘤酮;反义寡核苷酸;甘氨酸阿非迪霉素;细胞凋亡基因调节剂;细胞凋亡调节剂;脱嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨酶;阿苏莱克林(asulacrine);阿他美坦;阿莫司汀;阿耐司汀1;阿耐司汀2;阿耐司汀3;阿扎司琼;阿扎毒素;重氮酪氨酸;巴卡亭III衍生物;巴拉诺(balanol);巴马司他;BCR/ABL拮抗剂;苯并二氢卟酚;苯甲酰星状孢菌素(benzoylstaurosporine);β内酰胺衍生物;β-阿立辛(beta-alethine);亚阿克拉霉素B;桦木酸;Bfgf抑制剂;比卡鲁胺;比生群;双吖丙啶基精胺;双奈法德;双崔特(Bistratene)A;比折来新;布瑞弗莱特(breflate);溴匹立明;布度钛;丁胱亚磺酰亚胺;卡泊三醇;卡弗他丁C;喜树碱衍生物;金丝雀痘IL-2;卡培他滨(capecitabine);甲酰胺-氨基-三唑;羧基酰氨基三唑;卡思特(CaRest)M3;CARN 700;软骨衍生的抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);粟树精胺;天蚕素B;西曲瑞克;绿素类(chlorlns);氯喹喔啉磺酰胺;西卡前列素;顺卟啉;克拉屈滨;氯米芬类似物;克霉唑;柯林斯霉菌素(collismycin)A;柯林斯霉菌素B;康普瑞汀A4;康普瑞汀类似物;康那格林(conagenin);康伯西汀(crambescidin)816;克立那托;念珠藻环肽8;念珠藻环肽A衍生物;库拉素A;环戊蒽醌;赛克普拉特(cycloplatam);赛普米新(cypemycin);阿糖胞苷十八烷基磷酸酯;溶细胞因子;磷酸己烷雌酚;达昔单抗;地西他滨;脱氢膜海鞘素B;地洛瑞林;地塞米松;右异环磷酰胺;右雷佐生;右维拉帕米;地吖醌;膜海鞘素B;迪多克斯(didox);二乙基去甲精胺;二氢-5-氮杂胞苷;9-二氧杂霉菌素;联苯螺莫司汀;二十二醇;多拉司琼;脱氧氟尿苷;屈洛昔芬;屈大麻酚;多卡米新SA;依布硒;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表柔比星;依立雄胺;雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;磷酸依托泊苷;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;非那雄胺;夫拉平度;氟卓斯汀;弗拉斯特伦(fluasterone);氟达拉滨;盐酸氟柔红霉素(fluorodaunorunicin hydrochloride);福酚美克;福美斯坦;福司曲星;福莫司汀;钆替沙林;硝酸镓;加洛他滨;加尼瑞克;明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;海普撒凡(hepsulfam);调蛋白;六甲撑二乙酰胺;金丝桃素;伊班膦酸;伊达比星;艾多昔芬;伊决孟酮;伊莫福新;伊洛马司他;咪唑并吖啶酮;咪喹莫特;免疫刺激剂肽;胰岛素样生长因子-1受体抑制剂;干扰素激动剂;干扰素;白介素;碘苄胍;碘多柔比星;甘薯苦醇(ipomeano1),4-;伊罗普拉(iroplact);伊索拉定;异本伽唑(isobengazole);异高软海绵素(isohomohalicondrin)B;伊他司琼;jasplakinolide;海蛞蝓提取物(kahalalide)F;三乙酸片螺素N(lamellarin-N triacetate);兰瑞肽;来那米新(leinamycin);来格司亭;硫酸香菇多糖;莱普妥斯新(leptolstatin);来曲唑;白血病抑制因子;白细胞α干扰素;亮丙瑞林+雌激素+孕酮;亮丙瑞林;左旋咪唑;利罗唑;线性多胺类似物;亲脂性二糖肽;亲脂性铂化合物;利沙克里那米得(lissoclinamide)7;洛铂;蚯蚓磷脂;洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;替沙林镥;利索茶碱;裂解肽;美坦新;制甘糖酶素(mannostatin)A;马立马司他;马索罗酚;乳腺丝抑蛋白;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;美巴龙;美替瑞林;甲硫氨酸酶;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;错配的双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;迈托毒素成纤维细胞生长因子-皂角素;米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体,人绒毛膜促性腺激素;莫哌达醇;多重抗药性基因抑制剂;基于多肿瘤抑制因子1的疗法;芥末抗癌剂;印度洋海绵(mycaperoxide)B;分枝杆菌细胞壁提取物;米利亚普隆(myriaporone);N-乙酰基地那林;N-取代的苯甲酰胺;那法瑞林;那瑞替喷;纳洛酮+喷他佐辛;纳帕因(napavin);纳福特平(naphterpin);那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性内肽酶;尼鲁米特;尼萨霉素(nisamycin);一氧化氮调节剂;氮氧化物抗氧化剂;尼图林(nitrullyn);O6-苄基鸟嘌呤;奥曲肽;奥琪森酮(okicenone);寡核苷酸;奥那司酮;昂丹司琼;奥罗新(oracin);口服细胞因子诱导剂;奥马铂;奥沙特隆;奥沙利铂;奥克萨霉素(oxaunomycin);帕劳霉素(palauamine);棕榈酰根霉菌素(palmitoylrhizoxin);帕米膦酸;人参炔三醇;帕诺米芬;副球菌素;帕折普汀;培门冬酶;培得星;木聚硫钠;喷司他丁;泮托唑(pentrozole);全氟溴烷;培磷酰胺;紫苏醇;苯连氮霉素;苯乙酸酯;磷酸酯酶抑制剂;沙培林;盐酸毛果芸香碱;吡柔比星;吡曲克辛;普拉斯汀(placetin)A;普拉斯汀B;纤溶酶原激活物抑制剂;铂复合物;铂化合物;铂-三胺复合物;卟吩姆钠;甲基丝裂霉素;强的松;丙基双-吖啶酮;前列腺素J2;蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂、微藻;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;羟基茜草素;吡唑啉吖啶;吡哆醛化血红蛋白聚氧乙烯缀合物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法呢基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;去甲基化瑞替普汀;依替膦酸铼Re 186;根霉素;核酶;R.sub.11维甲酰胺;罗谷亚胺;罗希吐碱;罗莫肽;罗喹美克;鲁滨吉隆(rubiginone)B1;如波希尔(ruboxyl);沙芬戈;辛妥平(saintopin);SarCNU;肌肉叶绿醇A;沙格司亭;Sdi1模拟物;司莫司汀;衰老衍生的1;正义寡核苷酸;信号转导抑制剂;信号转导调节剂;单链抗原结合蛋白;西佐喃;索布佐生;硼卡钠;苯乙酸钠;索沃绕(solverol);生长介素结合蛋白;索纳明;膦门冬酸;穗霉素D;螺莫司汀;斯耐潘定;海绵素1;角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;斯蒂匹酰胺(stipiamide);基质分解素抑制剂;萨菲诺辛(sulfinosine);强效血管活性肠肽拮抗剂;苏拉蒂斯塔(suradista);苏拉明;苦马豆素;合成的糖胺聚糖;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;喃氟啶;替鲁里姆(tellurapyrylium);端粒酶抑制剂;替莫泊芬;替莫唑胺;替尼泊苷;四氯十氧化物;四唑胺(tetrazomine);白蓬达亭(thaliblastine);噻可拉林;血小板生成素;血小板生成素模拟物;胸腺法新;胸腺生成素受体激动剂;胸腺曲南;促甲状腺激素;乙基初卟啉锡(tin ethyletiopurpurin);替拉扎明;二茂基二氯化钛;妥普森汀(topsentin);托瑞米芬;全能干细胞因子;翻译抑制剂;维甲酸;三乙酰尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂;UBC抑制剂;乌苯美司;泌尿生殖窦来源的生长抑制因子;尿激酶受体拮抗剂;伐普肽;维瑞尔林(variolin)B;载体系统,红细胞基因疗法;维拉雷琐;藜芦胺;维尔丁斯(verdins);维替泊芬;长春瑞滨;维撒丁(vinxaltine);维他星(vitaxin);伏氯唑;扎诺特隆;折尼铂;亚苄维C(zilascorb);和净司他丁斯酯。
可以与本披露的化合物组合使用的还其他抗癌剂包括烷化剂、抗代谢物、天然产物、或激素,例如,氮芥(例如,二氯甲基二乙胺(mechloroethamine)、环磷酰胺、苯丁酸氮芥等)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀、洛莫司汀等)、或三氮烯(鸨烯咪胺(decarbazine)等)。抗代谢物的实例包括但不限于叶酸类似物(例如,甲氨蝶呤)、或嘧啶类似物(例如,阿糖胞苷)、嘌呤类似物(例如,巯基嘌呤、硫鸟嘌呤、喷司他丁)。
可以与本披露的化合物组合使用的天然产物的实例包括但不限于长春花生物碱(例如,长春新碱)、表鬼臼毒素(例如,依托泊苷)、抗生素(例如,柔红霉素、多柔比星、博来霉素)、酶(例如,L-天冬酰胺酶)、或生物应答调节剂(例如,干扰素α)。
可以与本披露的化合物组合使用的烷化剂的实例包括但不限于氮芥(例如,二氯甲基二乙胺、环磷酰胺、苯丁酸氮芥、美法仑等)、乙烯亚胺和甲基三聚氰胺(例如,六甲基三聚氰胺、噻替派)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀、洛莫司汀、司莫司汀、链脲菌素等)、或三氮烯(鸨烯咪胺等)。抗代谢物的实例包括但不限于叶酸类似物(例如,甲氨蝶呤)、或嘧啶类似物(例如,氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤类似物(例如,巯基嘌呤、硫鸟嘌呤、喷司他丁)。
可以与本披露的化合物组合使用的激素和拮抗剂的实例包括但不限于肾上腺皮质类固醇(例如,强的松)、孕酮(例如,己酸羟孕酮、醋酸甲地孕酮和醋酸甲羟孕酮)、雌激素(例如,己烯雌酚、乙炔雌二醇)、抗雌激素(例如,他莫昔芬)、雄激素(例如,丙酸睾酮、氟甲睾酮)、抗雄激素(例如,氟他胺)、促性腺激素释放激素类似物(例如,亮丙瑞林)。可以用于本文描述的方法和组合物中的用于治疗或预防癌症的其他药剂包括铂配位复合物(例如,顺铂、卡铂)、蒽二酮(例如,米托蒽醌)、经取代的脲(例如,羟基脲)、甲基肼衍生物(例如,丙卡巴肼)、肾上腺皮质抑制药(例如,米托坦、氨鲁米特)。
可以与本披露的化合物组合使用的其他抗癌剂包括:由于稳定化的微管通过使细胞停留在G2-M期而起作用的抗癌剂包括厄布洛唑(也称为R-55104)、尾海兔素10(也称为DLS-10和NSC-376128)、羟乙磺酸米伏布林(Mivobulin isethionate)(也称为CI-980)、长春新碱、NSC-639829、圆皮海绵内酯(Discodermolide)(也称为NVP-XX-A-296)、ABT-751(雅培公司(Abbott),也称为E-7010)、阿托海汀(Altorhyrtin)(如阿托海汀A和阿托海汀C)、海绵毒素(Spongistatin)(如海绵毒素1、海绵毒素2、海绵毒素3、海绵毒素4、海绵毒素5、海绵毒素6、海绵毒素7、海绵毒素8、和海绵毒素9)、盐酸西马多丁(也称为LU-103793和NSC-D-669356)、埃博霉素(如埃博霉素A、埃博霉素B、埃博霉素C(也称为脱氧埃博霉素A或dEpoA)、埃博霉素D(也称为KOS-862、dEpoB、和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素BN-氧化物、埃博霉素AN-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(也称为BMS-310705)、21-羟基埃博霉素D(也称为脱氧埃博霉素F和dEpoF)、26-氟埃博霉素)、澳瑞他汀PE(也称为NSC-654663)、索利多亭(Soblidotin)(也称为TZT-1027)、LS_4559-P(法玛西亚公司(Pharmacia),也称为LS_4577)、LS_4578(法玛西亚公司,也称为LS_477-P)、LS_4477(法玛西亚公司)、LS_4559(法玛西亚公司)、RPR-112378(安内特公司(Aventis))、硫酸长春新碱、DZ-3358(第一实业公司(Daiichi))、FR-182877(藤泽公司(Fujisawa),也称为WS-9885B)、GS-164(武田制药公司(Takeda))、GS-198(武田制药公司)、KAR-2(匈牙利科学院(Hungarian Academy of Sciences))、BSF-223651(BASF公司,也称为ILX-651和LU-223651)、SAH_49960(礼来制药公司(Lilly)/诺华公司(Novartis))、SDZ-268970(礼来制药公司/诺华公司)、AM-97(阿曼达公司(Armad)/协和发酵工业株式会社(Kyowa Hakko))、AM-132(阿曼达公司)、AM-138(阿曼达公司/协和发酵工业株式会社)、IDN-5005(印第纳公司(Indena))、念珠藻素52(也称为LY-355703)、AC-7739(味之素公司(Ajinomoto),也称为AVE-8063A和CS-39.HCl)、AC-7700(味之素公司,也称为AVE-8062、AVE-8062A、CS-39-L-Ser.HCl、和RPR-258062A)、维提酰胺(Vitilevuamide)、微管蛋白抑制剂(Tubulysin)A、加纳单索(Canadensol)、矢车菊黄素(Centaureidin)(也称为NSC-106969)、T-138067(杜拉瑞克公司(Tularik),也称为T-67、TL-138067和TI-138067)、COBRA-1(帕克休斯研究院(Parker Hughes Institute),也称为DDE-261和WHI-261)、H10(堪萨斯州立大学(KansasState University))、H16(堪萨斯州立大学)、Oncocidin A1(也称为BTO-956和DIME)、DDE-313(帕克休斯研究院)、Fijianolide B.莱利霉素(Laulimalide)、SPA-2(帕克休斯研究院)、SPA-1(帕克休斯研究院,也称为SPIKET-P)、3-IAABU(细胞骨架公司(Cytoskeleton)/西奈山医学院(Mt.Sinai School of Medicine),也称为MF-569)、乐咳平(Narcosine)(也称为NSC-5366)、那卡平(Nascapine)、D-24851(爱斯达制药公司(Asta Medica))、A-105972(雅培公司)、哈米特林(Hemiasterlin)、3-BAABU(细胞骨架公司/西奈山医学院,也称为MF-191)、TMPN(亚利桑那州立大学(Arizona State University))、乙酰丙酮双钒(Vanadoceneacetylacetonate)、T-138026(杜拉瑞克公司(Tularik))、莫那撒尔(Monsatrol)、Inanocine(也称为NSC-698666)、3-1AABE(细胞骨架公司/西奈山医学院)、A-204197(雅培公司)、T-607(杜拉瑞克公司,也称为T-900607)、RPR-115781(安内特公司)、艾榴塞洛素(Eleutherobins)(如去甲基艾榴塞洛素、去乙酰基艾榴塞洛素、异艾榴塞洛素A、和Z-艾榴塞洛素)、Caribaeoside、Caribaeolin、软海绵素B、D-64131(爱斯达制药公司)、D-68144(爱斯达制药公司)、含氯环肽A(Diazonamide A)、A-293620(雅培公司)、NPI-2350(纳鲁斯公司(Nereus))、根薯酮内酯A(Taccalonolide A)、TUB-245(安内特公司)、A-259754(雅培公司)、Diozostatin、(-)-Phenylahistin(也称为NSCL-96F037)、D-68838(爱斯达制药公司)、D-68836(爱斯达制药公司)、肌基质蛋白B(Myoseverin B)、D-43411(Zentaris公司,也称为D-81862)、A-289099(雅培公司)、A-318315(雅培公司)、HTI-286(也称为SPA-110,三氟乙酸盐)(惠氏公司(Wyeth))、D-82317(Zentaris公司)、D-82318(Zentaris公司)、SC-12983(NCI)、Resverastatin磷酸钠、BPR-OY-007(国立卫生研究院(National Health ResearchInstitutes))、以及SSR-250411(赛诺菲公司(Sanofi))。
一种或多种另外的免疫检查点抑制剂可与本披露的化合物组合使用。示例性免疫检查点抑制剂包括针对免疫检查点分子(如CD27、CD28、CD40、CD122、CU96、CD73、CD39、CU47、OX40、GITR、CSF1R、JAK、PI3Kδ、PI3Kγ、TAM、精氨酸酶、CD137(也称为4-1BB)、ICOS、A2AR、A2BR、SHP-2、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、CD96、TIGIT、PD-1、PD-L1和PD-L2)的抑制剂(打击(smack)分子或生物制品)。在一些实施例中,免疫检查点分子是刺激性检查点分子,该刺激性检查点分子选自CD27、CD28、CD40、ICOS、OX40、GITR、CD137和STING。在一些实施例中,免疫检查点分子是抑制性检查点分子,该抑制性检查点分子选自B7-H3、B7-H4、BTLA、CTLA-4、IDO、TDO、精氨酸酶、KIR、LAG3、PD-1、TIM3、CD96、TIGIT和VISTA。在一些实施例中,本文提供的化合物可以与一种或多种药剂组合使用,这些药剂选自KIR抑制剂、TIGIT抑制剂、LAIR1抑制剂、CD160抑制剂、2B4抑制剂和TGFRβ抑制剂。
在一些实施例中,免疫检查点分子的抑制剂是PD-1的抑制剂,例如,抗PD-1单克隆抗体。在一些实施例中,抗PD-1单克隆抗体是纳武单抗、派姆单抗(也称为MK-3475)、匹地利珠单抗(pidilizumab)、SHR-1210、PDR001、或AMP-224。在一些实施例中,抗PD-1单克隆抗体是纳武单抗、或派姆单抗或PDR001。在一些实施例中,抗PD1抗体是派姆单抗。
在一些实施例中,免疫检查点分子的抑制剂是PD-L1的抑制剂,例如,抗PD-L1单克隆抗体。在一些实施例中,抗PD-L1单克隆抗体是BMS-935559、MEDI4736、MPDL3280A(也称为RG7446)、或MSB0010718C。在一些实施例中,抗PD-L1单克隆抗体是MPDL3280A(阿特珠单抗)或MEDI4736(德瓦鲁单抗)。
在一些实施例中,免疫检查点分子的抑制剂是CTLA-4的抑制剂,例如,抗CTLA-4抗体。在一些实施例中,抗CTLA-4抗体是伊匹单抗或曲美木单抗。在一些实施例中,免疫检查点分子的抑制剂是LAG3的抑制剂,例如,抗LAG3抗体。在一些实施例中,抗LAG3抗体是BMS-986016或LAG525。在一些实施例中,免疫检查点分子的抑制剂是GITR的抑制剂,例如,抗GITR抗体。在一些实施例中,抗GITR抗体是TRX518、或MK-4166、INCAGN01876或MK-1248。在一些实施例中,免疫检查点分子的抑制剂是OX40的抑制剂,例如,抗OX40抗体或OX40L融合蛋白。在一些实施例中,抗OX40抗体是MEDI0562或INCAGN01949、GSK2831781、GSK-3174998、MOXR-0916、PF-04518600或LAG525。在一些实施例中,OX40L融合蛋白是MEDI6383。
此外,本文披露的组合疗法可以与放射一起施用。
实例
实例1
化合物1在小鼠膀胱癌异种移植模型中的抗肿瘤作用
将化合物1用0.5%甲基纤维素配制。在6-7周龄的每只Balb/c裸小鼠的右腹皮下接种在PBS和基质胶(体积1:1)中的4-10×106个肿瘤细胞,用于肿瘤生成。当肿瘤大小为100-200mm3时,将荷瘤小鼠随机分为2组(n=8),并分别以20mg/kg的媒介物(bid)和化合物1(bid)开始治疗,持续17-30天。每周两次使用卡尺测量二维肿瘤大小,并且体积使用公式V=0.5x a x b2以mm3表示,其中a和b分别为肿瘤的长直径和短直径。所有数据均显示为平均值和平均值的标准误差(SEM)。如图1所示,化合物1治疗后,RT112异种移植模型中有微小的抗肿瘤作用,RT4异种移植模型中有明显的肿瘤生长抑制,T24异种移植模型中肿瘤完全消退。
实例2
低氧条件对HIF-1α和HIF-2α蛋白水平的诱导
将T24细胞在含20%O2(常氧)或1%O2(低氧)的细胞培养箱中培养72小时。然后将细胞用PBS冲洗并在含有Pierce蛋白酶和磷酸酶抑制剂的RIPA缓冲液(赛默科技公司(Thermo Scientific);目录A32959)中裂解。用Pierce BCA蛋白测定试剂盒(赛默科技公司;目录23225)定量蛋白质浓度。将分离出的蛋白质通过SDS-PAGE凝胶分解,转移到硝化纤维素膜(赛默科技公司;目录IB23001)上,并使用以下抗体通过免疫印迹法检测:抗HIF-1α抗体(细胞信号传导技术公司(Cell signaling Technology);目录36169)、抗HIF-2α抗体(细胞信号传导技术公司;目录7096)和抗微管蛋白抗体(细胞信号传导技术公司;目录15115)。HIF-1α和HIF-2α在T24细胞中在常氧条件(20%O2)下均可检测到并且在低氧条件(1%O2)下均上调(图2(a))。
实例3
由复合物1或siRNA敲低产生的对HIF-2α的抑制阻抑了低氧诱导的VEGFA和GLUT1的mRNA上调
将T24细胞用DMSO或1.0μM化合物1、对照siRNA或HIF-1α、HIF-2α所特有的siRNA在常氧(20%O2)或低氧(1%O2)条件下处理72h。使用RNeasy迷你试剂盒(凯杰公司(Qiagen),目录号74104)和QIAshredder(凯杰公司,目录号79654)提取总RNA。然后使用AppliedBiosystemsTM高容量cDNA逆转录试剂盒(Applied BiosystemsTM目录号4368814)将RNA逆转录为cDNA。使用cDNA作为模板,通过定量聚合酶链式反应(PCR)测定(PowerUp SYBR Green预混液,Applied BiosystemsTM,目录号A25742)来检测VEGFA和GLUT1的mRNA表达,使用GAPDH作为对照进行归一化。HIF-2α的敲低和化合物1治疗阻抑低氧条件诱导的VEGFA和GLUT1 mRNA水平(图2(b)和(c))。相比之下,HIF-1α的敲低上调了VEGFA和GLUT1 mRNA的水平(图2(b))。
Claims (24)
1.一种治疗患者的膀胱癌的方法,该方法包括向有需要的患者施用治疗有效量的具有式(I)的HIF-2α抑制剂:
其中:
X1是CH或N;
R1是羟基、卤代、氨基、-OP(O)(OH)2、-OCH2OP(O)(OH)2、-OCOR10、-OCOOR11、-OCONR12R13、-OCHR14OCOR15或-OCHR14OCOOR15a,其中R10、R11、和R15以及R15a独立地是烷基或被氨基、羧基或羟基取代的烷基,R12和R13独立地是氢,烷基,或被氨基、羧基或羟基取代的烷基,或R12和R13与它们所附接的氮原子一起形成任选地取代的杂环基,并且每个R14是氢、烷基、或卤代烷基;
R2是氢、氘、烷基、卤代烷基、烯基、或炔基;
R2a是氢或氘;
R3和R4独立地是氢、氘、烷基、环烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基;或
R3和R4与它们所附接的碳一起形成氧代、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;
R5是氢、氘、烷基、卤代、卤代烷基、羟基、或烷氧基;
R6是氢、氘、烷基、环烷基、或卤代;或
R5和R6与它们所附接的碳一起形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;条件是R5和R6以及R3和R4与它们所附接的碳一起不同时形成氧代、环亚烷基或任选地取代的4元至6元杂亚环基;
R7是氢、氘、烷基、烷氧基、氰基、卤代、卤代烷基、或卤代烷氧基;
L是键、S、SO、SO2、O、CO、或NR16,其中R16是氢或烷基;
R8是烷基、卤代烷基、羟基烷基、烷氧基烷基、氨基烷基、环烷基、环烯基、二环环烷基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,或杂环基,本身或作为杂环基烷基的一部分,被Ra、Rb、Rc、Rg和Rh取代,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;
R9是氢、烷基、环烷基、羟基、烷氧基、氰基、卤代、卤代烷基、卤代烷氧基、烷基亚砜、烷基磺酰基、或杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代;或
当R9和R2附接至同一碳原子时,它们可以组合形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元杂亚环基;并且
R9a是氢或氘;
或其药学上可接受的盐。
2.如权利要求1所述的方法,其中该具有式(I)的化合物或其药学上可接受的盐具有式(IIa)或(IIb)的结构:
3.如权利要求1所述的方法,其中该具有式(I)的化合物或其药学上可接受的盐具有式(IIa’)或(IIb’)的结构:
4.如权利要求1-3中任一项所述的方法,其中R3是氟。
5.如权利要求1-3中任一项所述的方法,其中R3和R4是氟。
6.如权利要求1至5中任一项所述的方法,其中L是O。
7.如权利要求1至6中任一项所述的方法,其中R8是被Ra、Rb、Rc、Rg和Rh取代的苯基,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代。
8.如权利要求7所述的方法,其中R8是3-氯-5-氟苯基、3,5-二氟苯基、3-氟-5-甲氧基苯基、3-氰基-5-氟苯基、3-氯-5-氰基苯基、3-氰基-5-甲基苯基、3-氯-4-氟苯基、3-氯-5-氟苯基、3-氟-5-甲基苯基、3-氰基苯基、3-三氟甲基苯基、3,4-二氯苯基、3-氯-2-甲基苯基、3,5-二氯苯基、3,5-二甲基苯基、2-氯-6-甲基苯基、2,6-二氟苯基、3,4,5-三氟苯基、3,4-二氟苯基、4-氟-3-甲基苯基、3-氰基-4-氟苯基、3-氰基-5-二氟甲基苯基、或3-氰基-5-氟-2,4,6-三氘苯基。
9.如权利要求1至8中任一项所述的方法,其中
R7是氢;
R2是氢、甲基、或乙基;并且
R9是氢、烷基、氟、羟基、或烷氧基。
10.如权利要求1所述的方法,其中该具有式(I)的HIF-2α抑制剂选自:
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aS)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
1,3,3,4,4-五氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢螺[环戊[cd]-茚-1,1′-环丙烷]-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-((2a-氨基-1,3,3,4,4-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3;
(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;和
(S)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
11.如权利要求1所述的方法,其中该具有式(I)的HIF-2α抑制剂是3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
12.如权利要求1所述的方法,其中该具有式(I)的HIF-2α抑制剂是3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
13.如权利要求12所述的方法,其中该3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈是结晶固体,指定为A型多晶型物,具有包含在角位置15.8和18.6处的峰的X-射线粉末衍射图,其中这些角位置可变化±0.2°2θ,如通过X-射线粉末衍射使用(Cu Kα)的X-射线波长所测量的。
14.如权利要求13所述的方法,其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置20.1处的峰,其中该角位置可以变化±0.2°2θ。
15.如权利要求13所述的方法,其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置12.9和20.1处的峰,其中这些角位置可以变化±0.2°2θ。
16.如权利要求13所述的方法,其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置11.4、12.9、和20.1处的峰,其中这些角位置可以变化±0.2°2θ。
17.如权利要求13所述的方法,其中该A型多晶型物X-射线粉末衍射图进一步包含在角位置10.1、11.4、12.9、和20.1处的峰,其中这些角位置可以变化±0.2°2θ。
18.如权利要求12所述的方法,其中该3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈是结晶固体,指定为A型多晶型物,具有X-射线粉末衍射图,具有基本与图1所示相同的X-射线粉末衍射图。
19.如权利要求13至17中任一项所述的方法,其中本文所示的X-射线粉末衍射图峰的角位置可以变化±0.1°2θ。
20.如权利要求1至19中任一项所述的方法,其中该膀胱癌选自由以下组成的组:转移性膀胱癌、非转移性膀胱癌、早期膀胱癌、非浸润性膀胱癌、肌层浸润性膀胱癌(MIBC)、非肌层浸润性膀胱癌(NMIBC)、原发性膀胱癌、晚期膀胱癌、局部晚期膀胱癌、缓解期膀胱癌、进行性膀胱癌、复发性膀胱癌和尿路上皮癌。
21.如权利要求20所述的方法,其中该膀胱癌是肌层浸润性膀胱癌。
22.如权利要求1至21中任一项所述的方法,其中该方法进一步包括施用该HIF-2α抑制剂与一种或多种另外的抗癌剂、放射疗法和/或手术的组合。
23.如权利要求1至22中任一项所述的方法,其中顺序地或同时施用该HIF-2α抑制剂和该一种或多种另外的抗癌剂。
24.如权利要求22或23所述的方法,其中该一种或多种抗癌剂选自由以下组成的组:沃凡妥单抗、英菲格拉替尼、LY2874455、培米替尼、罗加替尼、PRN1371、唑来替尼、德赞替尼、厄达替尼、Debio-1347、纳武单抗、派姆单抗、匹地利珠单抗、MEDI-0680、德瓦鲁单抗、BMS-936559、西利单抗、阿维鲁单抗、阿特珠单抗、阿法替尼、拉帕替尼、埃罗替尼、帕妥珠单抗、曲妥珠单抗、曲妥珠单抗-德鲁替康、贝伐单抗、雷莫芦单抗、索拉非尼、卡博替尼、乐伐替尼、帕唑帕尼、奥拉帕尼、AZD1775、维妥舍替、林罗司他、顺铂、卡铂、多柔比星、维汀-恩弗妥单抗-ejfv、丝裂霉素、RC48-ADC、噻替派、戈沙妥珠单抗-hziy、戊柔比星、吉西他滨、甲氨蝶呤、长春花碱、多西他赛、紫杉醇、培美曲塞、卡介苗、以及干扰素。
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