CN107001329B - 作为激酶抑制剂的化合物和组合物 - Google Patents
作为激酶抑制剂的化合物和组合物 Download PDFInfo
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- CN107001329B CN107001329B CN201580061305.6A CN201580061305A CN107001329B CN 107001329 B CN107001329 B CN 107001329B CN 201580061305 A CN201580061305 A CN 201580061305A CN 107001329 B CN107001329 B CN 107001329B
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 48
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明提供了本文所述的式(I)和(II)的化合物:
Description
发明领域
本发明提供了抑制Raf激酶、因此可用于治疗与过度Raf激酶活性相关的某些障碍的化合物,所述障碍包括细胞增殖性障碍例如癌症。本发明还提供了含有这些化合物的药物组合物以及使用这些化合物治疗包括癌症在内的病症的方法。
背景
蛋白激酶参与非常复杂的信号级联,所述信号级联调节大部分细胞功能,包括细胞存活和增殖。已经对这些信号传导通路进行了大量研究,特别是在细胞功能失调导致的障碍例如癌症的情况中。例如,已经对促***原-激活的蛋白激酶(MAPK)级联进行了深入地研究,该通路中的激酶(例如RAS、RAF、MEK和ERK)已经被开发利用为药物研发的靶点。在相当大一部分恶性病(所有肿瘤的30%以上,黑素瘤的40%)中发现了突变的B-Raf,已经报道了多种抑制常见B-Raf突变(V600E,在多种癌症中、特别是在皮肤恶性黑素瘤、甲状腺癌、结肠直肠癌和卵巢癌中发现的一种激活的突变)的候选药物,包括GDC-0879、PLX4032和PLX4720,而其它靶向于C-Raf或B-Raf(或这二者)的抑制剂包括索拉非尼(sorafenib)、XL281 RAF265和BAY43-9006。这些实例证明,抑制B-Raf或C-Raf的化合物能用于治疗各种癌症。
MAPK信号级联包括RAS、Raf、MEK和ERK激酶,实际上其各自是一组相关的蛋白质。这些蛋白作为信号转导级联共同发挥作用,其中不同激酶的数量及其多样化的底物特异性产生了复杂的、高度分枝的通路。例如,Raf由被称为A-Raf、B-Raf和C-Raf(也称为Raf-1)的单体组成,它们各自主要作为二聚体发挥作用。RAF复合物包括这三种类型的异源二聚体以及同源二聚体,从而使得Raf组的二聚体种类的总数多至6种,它们各自具有许多位点,其中在丝氨酸、苏氨酸或酪氨酸上的磷酸化会导致激活或抑制。由于通路及其调节的复杂性,已经报道,B-Raf的抑制剂可导致通路的反常激活(paradoxical activation),这显然是由于对影响二聚化、膜定位和与RAS-GTP相互作用的Raf激酶结构域的构象作用导致的。特别地,ATP-竞争性抑制剂能对信号传导通路表现出相反的作用,可以作为抑制剂或激活剂,这取决于细胞环境。因此,有效对抗具有激活B-Raf突变V600E的肿瘤的B-Raf抑制剂在具有野生型B-Raf或KRas突变的肿瘤中可能不如预期的那样有效。
本发明提供了新的Raf激酶抑制剂,所述Raf激酶包括A-Raf、B-Raf和/或C-Raf,以及这些化合物用于治疗与过度的或不期望的Raf活性水平相关的障碍例如一些癌症的用途。本发明的化合物最小化不期望的通路激活作用,因此会比导致反常通路激活的B-Raf抑制剂在体内更有效且更可预测,甚至当它们具有类似的体外效力时也是如此。本发明的化合物以DFG-out模式结合,从而使得它们为2型抑制剂,已有报道,2型抑制剂更不倾向于诱导反常的激活。这些化合物适合用于治疗Braf野生型和Kras突变型肿瘤以及B-Raf V600E突变型肿瘤。
发明概述
在一个方面,本发明提供了式I或II的化合物:
其中:
L选自–NHC(O)–和–C(O)NH–;
Y1选自N和CH;
R1选自H、卤素、异丙基、甲基-磺酰基、OR6、NR5R6、甲氧基-乙氧基、2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基、3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基、8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基、2-氧代-1,2-二氢吡啶-4-基、四氢-2H-吡喃基、4-氧代吡啶-1(4H)-基、吡唑基、哒嗪基和氮杂环丁烷基;其中所述氮杂环丁烷基、吡唑基或2-氧代-1,2-二氢吡啶-4-基是未被取代的或被1-3个独立地选自甲基和羟基的基团取代;
R2选自H和甲基;
R3选自H、甲基和氨基;
R4选自:
R5选自H和甲基;
R6选自H和甲基、乙基、丙基、异丙基、环丙基、甲氧基、羟基-乙基、甲氧基-乙基、四氢-2H-吡喃基、吡啶基、四氢呋喃基和氧杂环丁烷基;或者R5和R6与R5和R6所连接的氮一起形成选自吗啉代、2-氧代吡啶-1(2H)-基、1,1-二氧化硫吗啉代(1,1-dioxidothiomorpholino)、哌嗪基、吡咯烷基、咪唑基和吡唑基的基团;其中所述吗啉代、吡唑基或咪唑基可以是未被取代的或被1-2个甲基取代;
R7选自H、甲基、–CF3、–C(CH3)2CN、–C(CH3)2OH、–C(CH3)2F、–CF2CH3、–CF2H、异丙基、环丙基和甲基-磺酰基;其中所述环丙基是未被取代的或被氰基取代;
R8选自H、甲基、乙基、异丙基、–C(CH3)2OH和–C(CH3)2NH2;且R9选自H和乙基。
在第二个方面,本发明提供了药物组合物,其含有式I或II的化合物或者式I或II的N-氧化物衍生物、其单个异构体和异构体的混合物;或其药学上可接受的盐,以及与之混合的一种或多种适合的赋形剂。
在另一个方面,式I或II的化合物是Raf激酶的抑制剂,如本文的数据所证明的那样,因此可用于治疗病症,例如黑素瘤、乳腺癌、肉瘤、胃肠肿瘤如胃肠间质肿瘤(gastrointestinal stromal tumors)、卵巢癌、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、以及与过度Raf通路活性相关的恶性病,特别是由Ras突变驱动的癌症。此外,本发明的化合物表现出低水平的Raf通路反常激活。
在另一个方面,本发明提供了药物组合物,其包含式I或II的化合物以及与之混合的至少一种或药学上可接受的载体或赋形剂,任选包含与之混合的两种或更多种药学上可接受的载体或赋形剂。
此外,本发明提供了式I或II的化合物与共同治疗剂的组合产品(combination),其任选包含一种或多种药学上可接受的载体,还提供了使用式I或II的化合物与共同治疗剂的组合的治疗方法。本发明中使用的适合的共同治疗剂包括例如癌症化疗药,包括但不限于PI3K抑制剂、Raf通路的其它抑制剂、紫杉醇、多西他赛、替莫唑胺、铂类化合物(platins)、阿霉素类化合物、长春碱类化合物、环磷酰胺、拓扑替康、吉西他滨、异环磷酰胺、依托泊苷、伊立替康等。
另一方面,本发明提供了治疗以过度的或不希望的Raf、尤其是B-Raf和/或C-Raf活性水平为特征的病症的方法,该方法包括给需要所述治疗的个体施用有效量的本文所述的式I或II或其任意子式的化合物或者包含所述化合物的药物组合物。所述个体可以是哺乳动物,优选人。可通过本文所述的化合物和方法治疗的病症包括各种形式的癌症,例如实体瘤、黑素瘤、乳腺癌、肺癌(例如非小细胞肺癌)、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌。因此,本发明包括本文所公开的式I或II及其子式的化合物,包括本文所公开的每个具体化合物,它们用于进行治疗,特别是用于治疗癌症,例如黑素瘤、乳腺癌、肺癌、肝癌、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌。本发明还包括所述化合物在制备用于治疗这些病症的药剂中的用途。
本发明包括本文所述的式I或II的化合物和式I或II的子式的化合物、和所有立体异构体(包括非对映异构体和对映体)、互变异构体及其同位素富集的形式(包括氘取代物)、以及这些化合物的药学上可接受的盐。特定地,如果含有N作为杂环原子的杂芳基环任选地被羟基取代,例如2-羟基吡啶环,则包括其中羟基被描绘为羰基的互变异构体(例如2-吡啶酮)。本发明的化合物还包含式I(或其子式)的化合物及其盐的多晶型物。
发明详述
除非另有明确说明,否则施用下列定义。
本文所用的术语“卤素”(或卤代)是指氟、溴、氯或碘,特别是氟或氯。卤素-取代的基团和原子团例如被卤素取代的烷基(卤代烷基)可以是单-、多-或全-卤代的。
本文所用的术语“杂原子”是指氮(N)、氧(O)或硫(S)原子,特别是氮或氧,另有说明的除外。
本文所用的术语“烷基”是指具有至多20个碳原子的完全饱和的支链或无支链的烃原子团。除非另有说明,否则烷基是指具有1至10个碳原子、1至6个碳原子或者1至4个碳原子的烃原子团。典型地,烷基具有1-6个碳原子。“低级烷基”是指具有1-4个碳原子的烷基。烷基的代表性实例包括但不限于甲基、乙基、正-丙基、异-丙基、正-丁基、仲-丁基、异-丁基、叔-丁基、正-戊基、异戊基、新戊基、正-己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正-庚基、正-辛基、正-壬基、正-癸基等。
被取代的烷基是含有一个或多个替换氢的取代基的烷基,例如1、2或3个取代基,或者1-4个取代基,至多是未被取代的烷基上存在的氢的数量。如果没有另外规定,则烷基的适合的取代基可以选自卤素、CN、氧代、羟基、被取代的或未被取代的C1-4烷氧基、被取代的或未被取代的C3-6环烷基、被取代的或未被取代的C3-6杂环烷基、被取代的或未被取代的苯基、氨基、(C1-4烷基)氨基、二(C1-4烷基)氨基、C1-4烷基硫基、C1-4烷基磺酰基、-C(=O)-C1-4烷基、COOH、COO(C1-4烷基)、-O(C=O)-C1-4烷基、–NHC(=O)C1-4烷基和–NHC(=O)OC1-4烷基;其中被取代的C1-4烷氧基、被取代的C3-6环烷基、C3-6杂环烷基和被取代的苯基的取代基是至多3个选自卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、氨基、羟基和CN的基团。烷基的优选取代基包括卤素、CN、氧代、羟基、C1-4烷氧基、C3-6环烷基、苯基、氨基、(C1-4烷基)氨基、二(C1-4烷基)氨基、C1-4烷基硫基、C1-4烷基磺酰基、-C(=O)-C1-4烷基、COOH、-COO(C1-4烷基)、-O(C=O)-C1-4烷基、–NHC(=O)C1-4烷基和–NHC(=O)OC1-4烷基。
本文所用的术语“亚烷基”是指具有1至10个碳原子和与其它特征连接的两个开放化合价的二价烷基。除非另有说明,否则亚烷基是指具有1至10个碳原子、1至6个碳原子或者1至4个碳原子的原子团。亚烷基的代表性实例包括但不限于亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚仲丁基、亚异丁基、亚叔丁基、亚正戊基、亚异戊基、亚新戊基、亚正己基、3-甲基亚己基、2,2-二甲基亚戊基、2,3-二甲基亚戊基、亚正庚基、亚正辛基、亚正壬基、亚正癸基等。被取代的亚烷基是含有一个或多个、例如两个或三个取代基的亚烷基;除非另有规定,否则适合的和优选的取代基选自描述为对烷基而言适合的和优选的取代基。
本文所用的术语“卤代烷基”是指被一个或多个本文所定义的卤素基团取代的本文所定义的烷基。所述卤代烷基可以是单卤代烷基、二卤代烷基、三卤代烷基或多卤代烷基,包括全卤代烷基。单卤代烷基可以在烷基内具有一个碘、溴、氯或氟。在烷基或环烷基上优选氯和氟;在芳基或杂芳基上通常优选氟、氯和溴。二卤代烷基和多卤代烷基可以在烷基内具有两个或更多个相同的卤素原子或不同卤素基团的组合。典型地,多卤代烷基含有至多12个或10个或8个或6个或4个或3个或2个卤素基团。卤代烷基的非限制性实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。全卤代烷基是指所有氢原子均被卤原子替代的烷基,例如三氟甲基。
本文所用的术语“烷氧基”是指烷基-O-,其中烷基如上文所定义。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔-丁氧基、戊基氧基、己基氧基等。典型地,烷氧基具有1-10个或1-6个碳,更通常地为1-4个碳原子。
“被取代的烷氧基”是在烷氧基的烷基部分上含有一个或多个、例如1、2或3个取代基的烷氧基。除非另有规定,否则适合的和优选的取代基选自上文针对烷基所列出的取代基,不同之处在于羟基和氨基通常不存在于直接与被取代的‘烷基-O’基团的氧连接的碳上。
类似地,其它基团如“烷基氨基羰基”、“烷氧基烷基”、“烷氧基羰基”、“烷氧基-羰基烷基”、“烷基磺酰基”、“烷基亚磺酰基(sulfoxyl)”、“烷基氨基”、“卤代烷基”的各烷基部分具有与上述“烷基”的定义中所述的相同的含义。当以这种方式使用时,除非另有说明,否则烷基通常是1-4个碳的烷基且不被所命名的组成部分以外的基团进一步取代。当这类烷基被取代时,适合的取代基选自上文针对烷基所列出的适合的或优选的取代基,另有规定的除外。
本文所用的术语“卤代烷氧基”是指卤代烷基-O-,其中卤代烷基如上文所定义。卤代烷氧基的代表性实例包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、三氯甲氧基、2-氯乙氧基、2,2,2-三氟乙氧基、1,1,1,3,3,3-六氟-2-丙氧基等。典型地,卤代烷基具有1-4个碳原子。
优选实施方案描述
本发明提供了用于治疗激酶相关疾病、特别是Raf激酶相关疾病的化合物、组合物和方法;所述疾病例如:各种形式的癌症,例如实体瘤、黑素瘤、乳腺癌、肺癌(例如非小细胞肺癌)、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌。本发明的各种实施方案如本文所述。应当理解的是,每个实施方案中列出的特征可以与其它列出的特征组合,从而提供本发明的另外的实施方案。下面的实施方案是本发明的代表。
在一个实施方案中,所述式I和II的化合物是式Ia的化合物:
其中:Y1选自N和CH;R1选自H、卤素、异丙基、甲基-磺酰基、OR6、NR5R6、甲氧基-乙氧基、2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基、3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基、8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基、2-氧代-1,2-二氢吡啶-4-基、四氢-2H-吡喃基、4-氧代吡啶-1(4H)-基、吡唑基、哒嗪基和氮杂环丁烷基;其中所述氮杂环丁烷基、吡唑基或2-氧代-1,2-二氢吡啶-4-基是未被取代的或被1-3个独立地选自甲基和羟基的基团取代;R2选自H和甲基;R3选自H、甲基和氨基;R7选自H、甲基、–CF3、–C(CH3)2CN、–C(CH3)2OH、–C(CH3)2F、–CF2CH3,–CF2H、异丙基、环丙基和甲基-磺酰基;其中所述环丙基是未被取代的或被氰基取代;R8选自H、甲基、乙基、异丙基、–C(CH3)2OH和–C(CH3)2NH2,
和其药学上可接受的盐。
在另一个实施方案中,是选自以下的化合物或其药学上可接受的盐:
在另一个实施方案中,是式Ib的化合物:
其中:Y1选自N和CH;R1选自H、卤素、异丙基、甲基-磺酰基、OR6、NR5R6、甲氧基-乙氧基、2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基、3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基、8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基、2-氧代-1,2-二氢吡啶-4-基、四氢-2H-吡喃基、4-氧代吡啶-1(4H)-基、吡唑基、哒嗪基和氮杂环丁烷基;其中所述氮杂环丁烷基、吡唑基或2-氧代-1,2-二氢吡啶-4-基是未被取代的或被1-3个独立地选自甲基和羟基的基团取代;R2选自H和甲基;R3选自H、甲基和氨基;R7选自H、甲基、–CF3、–C(CH3)2CN、–C(CH3)2OH、–C(CH3)2F、–CF2CH3、–CF2H、异丙基、环丙基和甲基-磺酰基;其中所述环丙基是未被取代的或被氰基取代,
和其药学上可接受的盐。
在另一个实施方案中,是选自以下的化合物或其药学上可接受的盐:
在另一个实施方案中,是选自以下的化合物或其药学上可接受的盐:
表9中所给出的测定的IC-50(B-Raf)小于或等于0.01μM和测定的IC-50(c-Raf)小于0.005μM的实施例化合物中的每一个是本发明的优选化合物。表9中所给出的测定的IC-50(B-Raf)小于或等于0.01μM和测定的IC-50(c-Raf)小于或等于0.002μM的实施例化合物是尤其优选的。因此,这些化合物中的任意一个化合物用于治疗选自黑素瘤、乳腺癌、肺癌(例如非小细胞肺癌、肺腺癌)、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌的病症的用途是本发明的一个实施方案。
本文所用的术语“旋光异构体”或“立体异构体”是指本发明的给定化合物可以存在的各种立体异构构型中的任意一种且包括几何异构体。应当理解的是,取代基可以连接在碳原子的手性中心上。术语“手性”是指在它们的镜像伙伴上具有非叠加性的分子,而术语“非手性”是指在它们的镜像伙伴上是可叠加的分子。因此,本发明包括所述化合物的对映体、非对映体或外消旋物。“对映体”是互为不可叠加镜像的一对立体异构体。一对对映体的1:1混合物是“外消旋”混合物。在适宜的情况下,该术语用于指外消旋混合物。“非对映异构体”是具有至少两个不对称原子、但是不互为镜像的立体异构体。绝对立体化学是根据Cahn-lngold-Prelog“R-S”***来规定的。当一种化合物是纯对映体时,每个手性碳上的立体化学可以用R或S来说明。拆分的其绝对构型不明的化合物可以根据它们在钠D线波长下旋转平面偏振光的方向(右旋-或左旋-)而被指定为(+)或(-)。本文所述的某些化合物含有一个或多个不对称中心或轴,因此可以产生对映体、非对映体和可以在绝对立体化学上被定义为(R)-或(S)-的其它立体异构形式。
取决于起始材料的选择和合成操作,所述化合物可以以可能的异构体之一的形式或以其混合物的形式、例如以纯旋光异构体的形式、或以异构体混合物例如外消旋物和非对映异构体混合物的形式存在,这取决于不对称碳原子的数量。本发明包括所有这类可能的立体异构体,包括外消旋混合物、非对映体混合物和旋光纯的形式。旋光活性的(R)-和(S)-异构体可以用手性合成子或手性试剂制备或者用常规技术进行拆分。如果化合物含有双键,则取代基可以是E或Z构型,另有说明的除外。如果化合物含有二取代的环烷基,则环烷基取代基可具有顺式-或反式-构型,另有说明的除外。还包括所有互变异构形式。
在许多情况下,由于存在氨基和/或羧基或者与其类似的基团,本发明的化合物能形成酸盐和/或碱盐。本文所用的术语“盐”是指本发明的化合物的酸加成盐或碱加成盐。“盐”特别是包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留了本发明的化合物的生物学有效性和性质并且典型地在生物学上或其它方面不具有不希望的性质的盐。
药学上可接受的酸加成盐可以用无机酸和有机酸形成,例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、chlortheophyllonate、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。另外的适合的盐的列表可以在例如“Remington'sPharmaceutical Sciences”,第20版,Mack Publishing Company,Easton,Pa.,(1985);和Stahl和Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection andUse”(Wiley-VCH,Weinheim,德国,2002)中找到。
可以自其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以自其衍生得到盐的有机酸包括例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。
药学上可接受的碱加成盐可以用无机碱和有机碱形成,可以具有无机或有机抗衡离子。
可以自其衍生得到盐的无机碱包括例如铵盐和来自元素周期表I-XII族的金属。在某些实施方案中,盐衍生自钠、钾、铵、具有1-4个C1-C4烷基的烷基铵、钙、镁、铁、银、锌和铜;特别适合的盐包括铵、钾、钠、钙和镁盐。
可以自其衍生得到盐的有机碱包括例如伯、仲和叔胺、被取代的胺,包括天然存在的被取代的胺、环状胺、碱性离子交换树脂等。适合的有机胺包括异丙基胺、苄星盐(benzathine)、胆碱酸盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨丁三醇。
本发明的药学上可接受的盐可以通过常规的化学方法由碱性或酸性原子团合成。一般而言,可以通过使这些化合物的游离酸形式与化学计量的适合的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或通过使这些化合物的游离碱形式与化学计量的适合的酸反应来制备这类盐。这类反应典型地在水中或在有机溶剂中或在两者的混合物中进行。一般而言,如果切实可行,则非水性介质例如***、乙酸乙酯、四氢呋喃、甲苯、氯仿、二氯甲烷、甲醇、乙醇、异丙醇或乙腈的使用是合乎需要的。
本文给出的任意结构式还旨在表示其中所有原子以天然同位素丰度存在、无同位素富集的未标记的形式的化合物以及同位素富集或标记的形式的化合物。同位素富集或标记的化合物具有本文给出的结构式所描绘的结构,不同之处在于化合物的至少一个原子被具有与天然存在的原子质量或原子质量分布不同的原子质量或质量数的原子代替。可掺入富集的或标记的本发明化合物的同位素的实例包括:氢、碳、氮、氧、磷、氟和氯的同位素,例如分别是2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I。本发明包括各种同位素标记的本文所定义的化合物,例如其中存在放射性同位素如3H和14C的那些或者其中存在非放射性同位素例如2H和13C的那些,所述放射性同位素或非放射性同位素以显著高于这些同位素的天然丰度的水平存在。这类同位素标记的化合物可用于代谢研究(使用14C)、反应动力学研究(例如使用2H或3H)、检测或成像技术,例如正电子发射断层成象术(PET)或单光子发射计算机断层成象术(SPECT),包括药物或底物组织分布测定,或用于患者的放射性治疗。特别地,对于PET或SPECT研究,18F标记的化合物可能是特别合乎需要的。一般而言,可以通过本领域技术人员已知的常规技术或通过与所附的实施例和制备例中所描述的那些类似的方法、用适宜的同位素标记的试剂替换之前使用的非标记的试剂来制备同位素标记的式I或II的化合物。
此外,被更重的同位素、特别是氘(即2H或D)取代可因更大的代谢稳定性而提供某些治疗优势,例如增加的体内半衰期或降低的剂量需求或治疗指数的改善。应当理解的是,在上下文中氘被视为式I或II的化合物的取代基。这类更重的同位素、特别是氘的浓度可以用同位素富集因子来定义。本文所用的术语“同位素富集因子”意指同位素丰度与具体给定的同位素的天然丰度之比。如果本发明的化合物中的取代基是所示的氘,则这种化合物对每个指定的氘原子而言具有至少3500(在每个指定的氘原子上52.5%氘掺入)、至少4000(60%氘掺入)、至少4500(67.5%氘掺入)、至少5000(75%氘掺入)、至少5500(82.5%氘掺入)、至少6000(90%氘掺入)、至少6333.3(95%氘掺入)、至少6466.7(97%氘掺入)、至少6600(99%氘掺入)或至少6633.3(99.5%氘掺入)的同位素富集因子。
本发明的药学上可接受的溶剂合物包括其中结晶的溶剂可以是同位素取代的、例如D2O、d6-丙酮、d6-DMSO的那些、以及具有非富集溶剂的溶剂合物。
含有能作为氢键供体和/或受体的基团的本发明的化合物、即式I或II的化合物可能能与适合的共晶(co-crystal)形成剂一起形成共晶。可以通过已知的共晶形成操作由式I或II的化合物制备这些共晶。这类操作包括将式I或II的化合物与共晶形成剂一起研磨、加热、共升华、共熔或使它们在结晶条件下在溶液中接触并分离由此形成的共晶。适合的共晶形成剂包括WO2004/078163中所述的那些。因此,本发明还提供了包含式I或II的化合物的共晶。
本文所用的术语“药学上可接受的载体”包括任何和所有的溶剂、分散介质、包衣、表面活性剂、抗氧剂、防腐剂(例如抗细菌剂、抗真菌剂)、等张剂(isotonic agent)、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料等及其组合,如本领域技术人员已知的那样(参见,例如Remington’s PharmaceuticalSciences,第18版,Mack Printing Company,1990,第1289-1329页)。除非与活性成分不相容,否则任何常规载体均可用在治疗或药物组合物中。
术语本发明的化合物的“治疗有效量”是指将引起个体的生物学或医学响应的本发明化合物的量,所述响应例如是降低或抑制酶或蛋白质活性,或者改善症状、缓解病症、减慢或延迟疾病进展,或者预防疾病等。在一个非限制性实施方案中,术语“治疗有效量”是指当施用于个体时有效地(1)至少部分缓解、抑制、预防和/或改善由Raf激酶例如B-Raf或C-Raf介导的或与激酶例如B-Raf或C-Raf活性相关的病症或障碍或疾病,或(2)降低或抑制激酶例如B-Raf或C-Raf体内活性的本发明的化合物的量。
在另一个非限制性实施方案中,术语“治疗有效量”是指当施用于细胞或组织或非细胞生物学材料或介质时有效地至少部分降低或抑制激酶例如B-Raf或C-Raf的活性、或者至少部分减轻或缓解与过度的Raf激酶活性相关的症状或病症的本发明的化合物的量。
本文所用的术语“个体”是指动物。典型地,所述动物是哺乳动物。个体还指例如灵长类动物(例如,人,男性或女性)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中,所述个体是灵长类动物。在特定的实施方案中,所述个体是人。
本文所用的术语“抑制”是指减轻或抑制给定的病症、症状、或障碍、或疾病,或者显著减少生物学活性或过程的基线活性。
本文所用的术语“治疗”任何疾病或障碍或者任何疾病或障碍的“治疗”在一个实施方案中是指改善所述疾病或障碍(即,减慢或阻止或减轻疾病或其至少一种临床症状的发展)。在另一个实施方案中,“治疗”是指缓解或改善至少一种物理参数,包括可能不是患者可辨别的那些物理参数。在又一个实施方案中,“治疗”是指在身体上(例如可辨别的症状的稳定)、生理上(例如物理参数的稳定)或者这两个方面对所述疾病或障碍进行调节。在又一个实施方案中,“治疗”是指预防或延迟所述疾病或障碍的发生或进展。
如本文所用的那样,如果个体会在生物学上、医学上或生活质量方面从这类治疗中获益,那么该个体是“需要”治疗的。
除非本文另有说明或者上下文清楚地有相反含义,否则本文所用的术语“一个”、“一种”、“该/所述”以及本发明的上下文中(尤其是在权利要求书的上下文中)所使用的类似术语应理解为既包括单数,又包括复数。
除非本文另有说明或者上下文清楚地有相反含义,否则本文所述的所有方法可以以任意适合的顺序进行。本文提供的任意和所有实施例或举例性语言(例如,“例如”、“如”)的使用仅仅旨在更好地举例说明本发明,不对在另外部分请求保护的本发明的范围构成限制。
本发明的化合物的任何不对称碳原子(例如碳等)可以以外消旋或对映体富集的形式、例如(R)-、(S)-或(R,S)-构型存在。在某些实施方案中,每个不对称原子具有至少50%对映体过量、至少60%对映体过量、至少70%对映体过量、至少80%对映体过量、至少90%对映体过量、至少95%对映体过量或至少99%对映体过量的(R)-或(S)-构型;即,对于旋光化合物,经常优选使用一个对映体,基本上排除另一个对映体。如果可能,带有不饱和键的原子上的取代基可以以顺式-(Z)-或反式-(E)-形式存在。
因此,本文所用的本发明的化合物可以是可能的异构体、旋转异构体、阻转异构体、互变异构体或其混合物之一的形式,例如,为基本上纯的几何(顺式或反式)异构体、非对映体、旋光异构体(对映体)、外消旋物或其混合物。本文所用的“基本上纯的”或“基本上不含其它异构体”意指相对于优选的异构体的量而言所述产物含有以重量计低于5%、优选低于2%的其它异构体。
任何所得的异构体混合物可以根据组分的理化差异被分离成纯的或基本上纯的几何异构体或旋光异构体、非对映体、外消旋物,例如通过色谱法和/或分级结晶来分离。
任何所得的终产物或中间体的外消旋物可以用已知方法被拆分成旋光对映体,例如通过分离用旋光活性酸或碱获得的其非对映体盐并释放旋光活性的酸性或碱性化合物来拆分。特别地,因此碱性原子团可被用于将本发明的化合物拆分成其旋光对映体,例如通过分级结晶用旋光活性的酸例如酒石酸、二苯甲酰基酒石酸、二乙酰基酒石酸、二-O,O'-对-甲苯酰酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸形成的盐来拆分。外消旋产物也可以通过手性色谱法、例如使用手性吸附剂的高效液相色谱法(HPLC)或超临界流体色谱法(SFC)来拆分。
此外,包括它们的盐在内的本发明的化合物也可以以其水合物的形式被获得或者包括用于其结晶的其它溶剂。本发明的化合物可以固有地或经设计与药学上可接受的溶剂(包括水)形成溶剂合物;因此,本发明既包括溶剂化的形式,也包括非溶剂化的形式。术语“溶剂合物”是指本发明的化合物(包括其药学上可接受的盐)与一个或多个溶剂分子的分子复合物。这类溶剂分子是药物领域中常用的那些,其已知对接受者是无害的,例如水、乙醇等。术语“水合物”是指其中溶剂分子是水的所述复合物。
包括其盐、水合物和溶剂合物在内的本发明的化合物可以固有地或经设计形成多晶形物。
在另一个方面,本发明提供了包含本发明的化合物或其药学上可接受的盐和至少一种药学上可接受的载体的药物组合物。所述药物组合物可被配制用于特定的施用途径如口服施用、肠胃外施用和直肠施用等。另外,本发明的药物组合物可被配制成固体形式(包括但不限于胶囊剂、片剂、丸剂、颗粒剂、散剂或栓剂)或液体形式(包括但不限于溶液、混悬剂、乳剂)。药物组合物可经受常规药学操作如灭菌和/或可含有常规的惰性稀释剂、润滑剂或缓冲剂以及辅剂(adjuvant)如防腐剂、稳定剂、湿润剂、乳化剂和缓冲剂等。
典型地,式I或II的化合物的药物组合物是包含式I或II的活性成分以及下面的药学上可接受的赋形剂中的至少一种的片剂或明胶胶囊剂:
a)稀释剂,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;
b)润滑剂,例如二氧化硅、滑石粉、硬脂酸、硬脂酸镁或硬脂酸钙和/或聚乙二醇;对于片剂而言,还有
c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果需要的话,还有
d)崩解剂,例如淀粉类、琼脂、海藻酸或其钠盐、或泡腾混合物;和/或
e)吸收剂、着色剂、矫味剂和甜味剂。
可以按照本领域已知的方法给片剂包薄膜衣或肠溶衣。
用于口服施用的适合的组合物包括片剂、锭剂(lozenge)、水性或油性混悬剂、可分散的散剂或颗粒剂、乳剂、硬和软胶囊剂、或者糖浆剂或酏剂形式的有效量的本发明的化合物。用于口服使用的组合物是按照本领域已知的用于制备药物组合物的任何方法制备的,这类组合物可含有一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的物质以便提供药学上美观的和口味佳的制剂。片剂可以含有活性成分以及与其混合的适合用于制备片剂的无毒的药学上可接受的赋形剂。这些赋形剂有例如:惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或***胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂是无包衣的或者用已知技术进行包衣以延迟在胃肠道中的崩解和吸收并且从而在较长的一段时间中提供持续的作用。例如,可使用延时材料如甘油单硬脂酸酯或甘油二硬脂酸酯。用于口服使用的制剂可以是其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊或者其中活性成分与水或油媒介物例如花生油、液体石蜡或橄榄油混合的软明胶胶囊的形式。
某些可注射的组合物是等张的水性溶液或混悬液,栓剂有利地是由脂肪乳或混悬剂制备的。所述组合物可以被灭菌和/或含有辅剂,如防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、调节渗透压的盐和/或缓冲剂。另外,它们还可含有其它治疗上有价值的物质。所述组合物分别按照常规的混合、造粒或包衣方法制备,含有约0.1-75%或含有约1-50%活性成分。
用于透皮应用的适合的组合物包含有效量的本发明的化合物和适合的载体。适合用于透皮递送的载体包括帮助通过接受主体皮肤的可吸收的药理学上可接受的溶剂。例如,透皮装置是绷带的形式,其包括背衬层、含有化合物并任选含有载体的贮库,任选地包括在延长的一段时间中将化合物以控制的和预定的速度递送至接受主体皮肤的控速屏障,以及将该装置固定于皮肤的器具。
用于局部应用、例如局部应用于皮肤和眼的合适组合物包括水溶液、混悬剂、软膏剂、乳膏剂、凝胶剂或可喷雾制剂,例如用于通过气雾剂递送的可喷雾制剂等。这类局部递送***将特别适宜用于皮肤应用,例如用于治疗皮肤癌,例如在防晒霜、洗剂、喷雾剂等中用于预防性用途。因此,它们特别适合用于本领域公知的局部(包括美容)制剂中。这类局部递送***可含有增溶剂、稳定剂、张力促进剂(tonicity enhancing agent)、缓冲剂和防腐剂。
本文所用的局部应用还可涉及吸入或鼻内应用。它们可以方便地以干粉形式(单独的药物,混合物的形式,例如具有乳糖的干掺合物,或混合的组分颗粒,例如具有磷脂的混合的组分颗粒)从干粉吸入器中被递送或以气雾剂喷雾形式从加压的容器、泵、喷雾器、雾化器或喷洒器中被递送,使用或不使用适合的抛射剂。
本发明还提供了包含本发明的化合物作为活性成分的无水药物组合物和剂型,因为水可促进某些化合物降解。
本发明的无水药物组合物和剂型可用无水或含有低水分含量的成分和低水分或低湿度条件来制备。可以制备和储存无水药物组合物以便维持其无水性质。因此,可以用已知防止与水接触的材料来对无水组合物进行包装,以便它们能被包括在适合的制剂盒中。适合的包装的实例包括但不限于气密性密封的箔、塑料、单位剂量容器(例如,小瓶)、泡罩包装和窄条(strip)包装。
本发明还提供了包含一种或多种降低作为活性成分的本发明的化合物分解速度的物质的药物组合物和剂型。这类物质在本文中也称为“稳定剂”,其包括但不限于抗氧化剂如抗坏血酸、pH缓冲剂或盐缓冲剂等。
游离形式或盐形式的式I的化合物表现出有价值的药理学性质,例如,如接下来的部分中所提供的试验数据所显示的那样,它们调节或抑制A-Raf、B-Raf和/或C-Raf的活性,因此它们适用于治疗或者用作研究化学物质,例如作为工具化合物。这些化合物特别可用于治疗由Raf/Raf/MEK/ERK通路中的突变所驱动的癌症,包括以激活Raf突变例如RafV600E为特征的癌症,包括但不限于黑素瘤(例如恶性黑素瘤)、乳腺癌、肺癌(例如,非小细胞肺癌)、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌。
因此,作为另一个实施方案,本发明提供了本文所述的式I或II的化合物或者式I或II范围内的任何实施方案的化合物在治疗中的用途。在另一个实施方案中,所述治疗用于可通过抑制A-Raf、B-Raf或C-Raf被治疗的疾病。在另一个实施方案中,本发明的化合物用于治疗癌症,包括但不限于黑素瘤、乳腺癌、肺癌、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌。
在另一个实施方案中,本发明提供了治疗可通过抑制A-Raf、B-Raf或C-Raf或其组合被治疗的疾病的方法,该方法包括施用治疗有效量的本文所述的式I或II的化合物或者式I或II范围内的任何实施方案的化合物。在另一个实施方案中,所述疾病选自上文所述的列表,适当地是黑素瘤、乳腺癌、肺癌、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌。所述方法典型地包括给需要这类治疗的个体施用有效量的本文所述的化合物或包含所述化合物的药物组合物。所述化合物可以通过任何适合的方法、例如本文所述的那些方法施用,可以按照主治医师选择的时间间隔重复施用。
因此,作为另一个实施方案,本发明提供了本文所述的式I或II的化合物或者所述化合物的任何实施方案在制备药剂中的用途。在另一个实施方案中,所述药剂用于治疗可通过抑制A-Raf、B-Raf或C-Raf治疗的疾病。在另一个实施方案中,所述疾病是癌症,例如选自上文所述的列表的癌症,包括黑素瘤、乳腺癌、肺癌、肉瘤、胃肠肿瘤例如胃肠间质肿瘤、卵巢癌、结肠直肠癌、甲状腺癌和胰腺癌。
对于约50-70kg的个体,本发明的药物组合物或组合产品可以是约1-1000mg一种或多种活性成分、或约1-500mg或约1-250mg或约1-150mg或约0.5-100mg或约1-50mg活性成分的单位剂量。化合物、药物组合物或其组合产品的治疗有效剂量取决于个体的种属、体重、年龄和个体情况、待治疗的障碍或疾病或其严重程度。普通技术的医师、临床医师或兽医能容易地确定每种活性成分预防、治疗所述障碍或疾病或抑制所述障碍或疾病进展所需的有效量。
上述剂量性质可有利地使用哺乳动物例如小鼠、大鼠、狗、猴或离体的器官、组织和其制备物在体外和体内试验中证明。本发明的化合物可以以溶液(例如水溶液)的形式体外应用以及例如以混悬剂或以水溶液的形式肠内、肠胃外(有利地,静脉内)体内应用。体外剂量可以为约10-3至10-9摩尔浓度。根据施用途径,体内治疗有效量可以为约0.1-500mg/kg或约1-100mg/kg。
本发明的化合物可以与一种或多种治疗共用药物(共同治疗剂)同时施用或者在其施用之前或之后施用。本发明中使用的适合的共同治疗剂包括例如癌症化疗药,包括但不限于PI3K抑制剂、Raf通路的其它抑制剂、紫杉醇、多西他赛、替莫唑胺、铂类化合物、阿霉素类化合物、长春碱类化合物、环磷酰胺、拓扑替康、吉西他滨、异环磷酰胺、依托泊苷、伊立替康等。本发明的化合物与共同治疗剂可以通过相同或不同的施用途径分别施用或者在同一药物组合物中一起施用。
在一个实施方案中,本发明提供了包含式I或II的化合物和至少一种另外的治疗共用药物的产品,其是组合制剂的形式,在治疗中同时、分别或相继使用。在一个实施方案中,所述治疗是由B-Raf或C-Raf介导的疾病或病症例如癌症的治疗。以组合制剂的形式提供的产品包括在同一药物组合物中包含式I或II的化合物和另外一种或多种治疗共用药物的组合物或者分开的形式、例如药盒形式的式I或II的化合物和另外一种或多种治疗共用药物。
在一个实施方案中,本发明提供了包含式I或II的化合物和另外的一种或多种治疗共用药物的药物组合物。任选地,所述药物组合物可以包含上问所述的药学上可接受的载体。
在一个实施方案中,本发明提供了一种药盒,其包含两种或更多种分开的药物组合物,其中至少一种药物组合物包含式I或II的化合物。在一个实施方案中,所述药盒包含分别存放所述组合物的工具,例如容器、分开的瓶子或分开的铝箔袋。这类药盒的一个实例是泡罩包装,如典型地用于包装片剂、胶囊等的泡罩包装。
本发明的药盒可用于施用不同的剂型,例如口服和肠胃外剂型,用于以不同的给药间隔施用分开的组合物,或者用于逐步增加分开的组合物的彼此的剂量。为了增加顺应性,本发明的药盒典型地包含施用说明书。
在本发明的组合疗法中,本发明的化合物和另一种治疗共用药物可以由相同或不同的生产商生产和/或配制。此外,本发明的化合物和另一种治疗药物在组合疗法中可以如下汇集到一起使用:(i)将组合产品发放给医师之前汇集(例如,在包含本发明的化合物和另一种治疗药物的药盒的情况下);(ii)在施用前短时间内由医师自己(或者在医师的指导下)汇集;(iii)由患者自己汇集,例如在将本发明的化合物和另一种治疗药物相继施用过程中。
因此,本发明提供了式I或II的化合物用于治疗由B-Raf或C-Raf介导的疾病或病症的用途,其中制备药剂用于与另一种治疗药物一起施用。本发明还提供了另一种治疗共用药物用于治疗疾病或病症的用途,其中药剂与式I或II的化合物一起施用。
本发明还提供了用在治疗由B-Raf或C-Raf介导的疾病或病症的方法中的式I或II的化合物,其中制备式I或II的化合物用于与另一种治疗药物一起施用。本发明还提供了用在治疗由B-Raf或C-Raf介导的疾病或病症的方法中的另一种治疗共用药物,其中制备另一种治疗共用药物用于与式I或II的化合物一起施用。本发明还提供了用在治疗由B-Raf或C-Raf介导的疾病或病症的方法中的式I或II的化合物,其中式I或II的化合物与另一种治疗共用药物一起施用。本发明还提供了用在治疗由B-Raf或C-Raf介导的疾病或病症的方法中的另一种治疗共用药物,其中另一种治疗共用药物与式I或II的化合物一起施用。
本发明还提供了式I或II的化合物用于治疗由B-Raf或C-Raf介导的疾病或病症的用途,其中患者之前(例如24小时内)已经用另一种治疗药物进行了治疗。本发明还提供了另一种治疗药物用于治疗由B-Raf或C-Raf介导的疾病或病症的用途,其中患者之前(例如24小时内)已经用式I或II的化合物进行了治疗。
制备本发明的化合物的方法
本发明还包括制备本发明的化合物的方法。在所述的反应中,当在终产物中需要这些基团时,可能需要保护反应性官能团例如羟基、氨基、亚氨基、巯基或羧基,以避免它们不希望地参与反应。可以根据标准实践使用常规保护基团,例如,参见T.W.Greene和P.G.M.Wuts,“Protective Groups in Organic Chemistry”,John Wiley and Sons,1991。
可以通过下面的反应方案I中所述的方法制备式I的化合物:
反应方案I
其中L、R1、R2、R3、R4和Y1如发明概述中所定义。通过使式2或3的化合物分别与式4的化合物反应制备式I或II的化合物。该反应在适合的催化剂(例如Pd(PPh3)4等)的存在下进行。该反应在约50℃-约150℃的温度下进行,可能需要4小时完成。
用于具体实施例的合成方案在下文中描述。
制备本发明的化合物的另外的方法
可以通过使游离碱形式的化合物与药学上可接受的无机酸或有机酸反应来制备药学上可接受的酸加成盐形式的本发明的化合物。或者,可以通过使游离酸形式的化合物与药学上可接受的无机碱或有机碱反应来制备药学上可接受的碱加成盐形式的本发明的化合物。
或者,可以采用起始材料或中间体的盐来制备盐形式的本发明的化合物。
可以分别由相应的碱加成盐或酸加成盐形式制备游离酸或游离碱形式的本发明的化合物。例如,可以通过用适合的碱(例如氢氧化铵溶液、氢氧化钠等)处理将酸加成盐形式的本发明的化合物转化成相应的游离碱。可以通过用适合的酸(例如盐酸等)处理将碱加成盐形式的本发明的化合物转化成相应的游离酸。
可以通过用还原剂(例如硫、二氧化硫、三苯膦、硼氢化锂、硼氢化钠、三氯化磷、三溴化物等)在适合的惰性有机溶剂(例如乙腈、乙醇、二烷水溶液等)中在0-80℃下处理由本发明的化合物的N-氧化物制备非氧化形式的本发明的化合物。
可以通过本领域技术人员公知的方法制备本发明的化合物的前药衍生物(例如,进一步的详细描述参见Saulnier等人,(1994),Bioorganic and Medicinal ChemistryLetters,第4卷,第1985页)。例如,可以通过使本发明的非衍生的化合物与适合的氨基甲酰化试剂(例如1,1-酰氧基烷基羰基氯(1,1-acyloxyalkylcarbanochloridate)、碳酸对-硝基苯酯等)反应来制备适合的前药。
可以通过本领域技术人员公知的方式制备本发明的化合物的被保护的衍生物。适用于生成保护基团及其除去的技术的详细描述可以在T.W.Greene,“Protecting Groupsin Organic Chemistry”,第3版,John Wiley and Sons,Inc.,1999中找到。
可以通过使所述化合物的外消旋混合物与旋光拆分试剂反应以形成一对非对映异构体化合物、分离所述非对映体并且回收光学纯的对映体来制备其各立体异构体形式的本发明的化合物。尽管可以使用本发明的化合物的共价非对映体衍生物进行对映体的拆分,但是优选可分离的复合物(例如结晶性非对映体盐)。非对映体具有不同的物理特性(例如熔点、沸点、溶解度、反应性等),可通过利用这些不同性容易地被分离。可以通过色谱法或优选通过基于溶解度差异的分离/拆分技术来分离非对映体,然后通过不会导致外消旋的任意实用的方式回收光学纯的对映体以及拆分试剂。适用于将化合物的立体异构体从其外消旋混合物中拆分的技术的更详细的描述可以在Jean Jacques,Andre Collet,SamuelH.Wilen,“Enantiomers,Racemates and Resolutions”,John Wiley and Sons,Inc.,1981中找到。
概括而言,式I的化合物可以通过包括以下步骤的方法制备:
(a)反应方案I的步骤;和
(b)任选地将本发明的化合物转化成药学上可接受的盐;
(c)任选地将本发明的化合物的盐形式转化成非盐形式;
(d)任选地将本发明的化合物的非氧化形式转化成药学上可接受的N-氧化物;
(e)任选地将本发明的化合物的N-氧化物形式转化成其非氧化的形式;
(f)任选地从异构体混合物中拆分本发明的化合物的各异构体,例如立体异构体;
(g)任选地将非衍生化的本发明的化合物转化成药学上可接受的前药衍生物;和
(h)任选地将本发明的化合物的前药衍生物转化成其非衍生化的形式。
对起始材料的制备没有特别描述的,则化合物是已知的或者可通过与本领域已知的方法或下文实施例中所公开的方法类似的方法制备。
本领域技术人员应当理解的是,上述转化仅是用于制备本发明的化合物的代表,可以类似地使用其它公知的方法。
实施例
下面的中间体和实施例阐述了本发明的式I的化合物的制备,它们进一步举例说明了本发明,但不限制本发明。
下面的缩写可用在本文中:
下面的实施例用于举例说明本发明,不应视为对本发明的限制。温度以摄氏度给出。如果没有另外说明,所有蒸发均在减压下进行,典型地在约15mm Hg至100mm Hg(=20-133mbar)下进行。终产物、中间体和起始材料的结构通过标准分析方法确证,例如微量分析和光谱表征,如MS、IR、NMR。所使用的缩写是本领域中常规的缩写。
质谱分析是采用LCMS仪器进行的:Waters System(Acuity UPLC和Micromass ZQ质谱仪;柱:Acuity HSS C18 1.8-微米,2.1×50mm;梯度:包含0.05%TFA的5-95%乙腈水溶液,1.8min周期;流速1.2mL/min;分子量范围200-1500;锥电压20V;柱温50℃)。所有质量均被报告为质子化的母离子的质量。
核磁共振(NMR)分析采用Varian 400MHz NMR(Palo Alto,CA)对一些化合物进行。光谱参比物是TMS或已知化学位移的溶剂。
用于合成本发明的化合物的所有起始材料、构建模块、试剂、酸、碱、脱水剂、溶剂和催化剂均是商业可获得的或者可通过本领域技术人员已知的有机合成方法制备(Houben-Weyl第4版,1952,Methods of Organic Synthesis,Thieme,第21卷)。另外,可以参考下面的实施例根据本领域技术人员已知的有机合成方法来制备本发明的化合物。
5-溴-2-(甲基氨基)烟腈的合成
方法1:向5-溴-2-氧代-1,2-二氢吡啶-3-甲腈在乙腈(0.1M)中的溶液中加入DBU(2.0当量)、BOP(1.3当量)和甲胺(2M溶液,4.0当量)。将该溶液在室温搅拌7小时,真空除去挥发性物质,将残余物溶于乙酸乙酯,用水(2×)、碳酸钠洗涤,用盐水洗涤,用硫酸镁干燥。过滤,浓缩,通过硅胶柱色谱法纯化,用在庚烷中的乙酸乙酯(25%-50%)洗脱。浓缩纯级分,得到5-溴-2-(甲基氨基)烟腈,收率54%,为白色固体。LCMS(m/z)(M+H)=211.9/213.9,Rt=0.72min.
根据方法1采用适合的起始材料合成了下面的中间体:
5-溴-2-((四氢-2H-吡喃-4-基)氨基)烟腈的合成
向5-溴-2-羟基烟腈(1.0当量)在乙腈(0.1M)中的溶液中加入2,3,4,6,7,8,9,10-八氢嘧啶并[1,2-a]氮杂(2.0当量)、四氢-2H-吡喃-4-胺(2.0当量)和六氟磷酸((1H-苯并[d][1,2,3]***-1-基)氧基)三(二甲基氨基)(V)(1.3当量),将该均匀的溶液在rt下搅拌过夜。真空除去挥发性物质,将残余物溶于乙酸乙酯,用水、碳酸钠、饱和NaCl洗涤,用MgSO4干燥,过滤,浓缩。将残余物在DCM中研磨,过滤出沉淀,得到5-溴-2-((四氢-2H-吡喃-4-基)氨基)烟腈,收率67%。LCMS(m/z)(M+H)=283.9 Rt=0.79min.
2-氨基-5-溴-4-甲基烟腈的合成
向2-氨基-4-甲基烟腈(1.0当量)在氯仿(0.3M)中的溶液中加入NBS(1.0当量)。将该不均匀的反应体系避光搅拌16小时。真空除去挥发性物质,使残余物在乙酸乙酯与水之间分配。分离各层,用1M NaOH、盐水洗涤,用MgSO4干燥,过滤,浓缩。得到2-氨基-5-溴-4-甲基烟腈,为棕色固体,收率88%。LCMS(m/z)(M+H)=211.9/213.9,Rt=0.62min.
2-氨基-5-溴-6-甲基烟腈的合成
向2-氨基-6-甲基烟腈(1.0当量)在氯仿(0.25M)中的溶液中加入NBS(1.0当量)。将该不均匀的反应体系避光搅拌16小时。真空除去挥发性物质,使残余物在乙酸乙酯与水之间分配。分离各层,用1M NaOH、盐水洗涤,用MgSO4干燥,过滤,浓缩。得到2-氨基-5-溴-6-甲基烟腈,为淡米黄色固体,收率94%。LCMS(m/z)(M+H)=211.9/213.9,Rt=0.61min.
5-溴-2-(甲基磺酰基)烟腈的合成
步骤1:在0℃向5-溴-2-氯烟腈(1.0当量)在DME(0.2M)中的溶液中加入甲硫醇钠(1.0当量)。将混合物在0℃搅拌2小时,然后在rt搅拌1小时。通过添加饱和氯化铵猝灭,用乙酸乙酯萃取。用硫酸钠干燥有机相,过滤,真空浓缩。将粗物质不经进一步纯化即用于下一步。LCMS(m/z)(M+H)=229.0/231.0,Rt=0.77min.
步骤2:在0℃向5-溴-2-(甲基硫基)烟腈(1.0当量)在乙醇(0.18M)中的溶液中加入m-CPBA(2.1当量),将混合物在0℃搅拌2小时,然后在rt搅拌过夜。用乙酸乙酯稀释反应,用饱和NaHCO3、然后用饱和NaCl洗涤。用硫酸钠干燥有机层,过滤,浓缩。通过硅胶柱色谱法(ISCO,用0-100%乙酸乙酯/庚烷洗脱)纯化粗物质,得到5-溴-2-(甲基磺酰基)烟腈,收率70%。LCMS(m/z)(M+H)=260.9/262.9,Rt=0.39min.
5-(5-氨基-2-甲基苯基)-2-(二甲基氨基)烟腈的合成
通过将5-溴-2-(二甲基氨基)烟腈(1.0当量)、4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.2当量)、PdCl2(dppf).CH2Cl2加合物(0.05当量)在DME和2M Na2CO3(2:1,0.2M)中的溶液用氩气鼓泡脱气15min。然后将搅拌的混合物加热至95℃达2小时。冷却至RT,然后通过Celite过滤,用EtOAc充分冲洗。用旋转蒸发器除去溶剂,然后在EtOAc与1M NaOH之间分配。分离有机层,然后用1M NaOH(×2)、饱和盐水(×4)洗涤,然后干燥(Na2SO4),过滤,减压蒸发,得到深棕色树胶状物。通过干荷载、然后用0-40%EtOAc/庚烷洗脱用Analogix SiO2纯化,得到5-(5-氨基-2-甲基苯基)-2-(二甲基氨基)烟腈,收率82%。LCMS(m/z)(M+H)=253.0,Rt=0.53min.
5'-氨基-6-(二甲基氨基)-2'-甲基-[3,3'-联吡啶]-5-甲腈的合成
通过将5-溴-2-(二甲基氨基)烟腈(1.0当量)、6-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-胺(1.2当量)、PdCl2(dppf).CH2Cl2加合物(0.05当量)在DME和2M Na2CO3(2:1,0.2M)中的溶液用氩气鼓泡脱气15min。然后将搅拌的混合物加热至95℃达3小时。冷却至RT,然后通过Celite过滤,用EtOAc充分冲洗。用旋转蒸发器除去溶剂,然后在EtOAc与1M NaOH之间分配。分离有机层,然后用1M NaOH(×2)、饱和盐水(×4)洗涤,然后干燥(Na2SO4),过滤,减压蒸发,得到深棕色树胶状物。通过干荷载、然后用0-15%甲醇/DCM洗脱用Analogix SiO2纯化,得到5'-氨基-6-(二甲基氨基)-2'-甲基-[3,3'-联吡啶]-5-甲腈,收率90%。LCMS(m/z)(M+H)=254.0,Rt=0.44min.
5-(5-氨基-2-甲基苯基)烟腈的合成
向脱气的4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.0当量)、5-溴烟腈(1.1当量)和Na2CO3(5当量,2M水溶液)中的溶液中加入PdCl2(dppf).CH2Cl2加合物(0.15当量)。将混合物在微波中加热至120℃达15min,冷却至室温。加入水,分离各相,用乙酸乙酯萃取水混合物。合并有机相,用MgSO4干燥,真空除去挥发性物质,得到5-(5-氨基-2-甲基苯基)烟腈,收率99%。LCMS(m/z)(M+H)=210.0,Rt=0.43min.
5'-(5-氨基-2-甲基苯基)-4-氧代-4H-[1,2'-联吡啶]-3'-甲腈的合成
步骤1:向2-氯-5-(2-甲基-5-硝基苯基)烟腈(1.0当量)在水和NMP(1:1,0.3M)中的溶液中加入吡啶-4-醇(2.0当量)和碳酸钾(2.0当量),将反应在油浴中于100℃加热30min。冷却至室温后,向混合物中加入水,过滤出沉淀,得到5'-(2-甲基-5-硝基苯基)-4-氧代-4H-[1,2'-联吡啶]-3'-甲腈,收率70%。LCMS(m/z)(M+H)=333.0,Rt=0.67min.
步骤2:向5'-(2-甲基-5-硝基苯基)-4-氧代-4H-[1,2'-联吡啶]-3'-甲腈(1.0当量)在AcOH(0.1M)中的溶液中加入铁(10当量)。将混合物在rt搅拌1小时。浓缩,用EtOAc和饱和NaHCO3溶液后处理。用盐水洗涤有机层,用Na2SO4干燥,浓缩,得到5'-(5-氨基-2-甲基苯基)-4-氧代-4H-[1,2'-联吡啶]-3'-甲腈,收率100%。LCMS(m/z)(M+H)=303.0,Rt=0.39min.
5-(5-氨基-2-甲基苯基)-2-异丙基烟腈的合成
步骤1:将2-氯-5-(2-甲基-5-硝基苯基)烟腈(1.0当量)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(3.0当量)、碳酸钾(3.0当量)和Pd(PPh3)4(0.03当量)在乙醇和甲苯(1:2.5,0.065M)中的溶液在微波中于120℃加热20分钟。将反应在乙酸乙酯与水之间分配,混合各层,然后分离。用饱和NaCl洗涤有机层,用MgSO4干燥,过滤,浓缩。通过硅胶柱色谱法(ISCO,用0-100%在庚烷中的乙酸乙酯洗脱)纯化粗产物,得到5-(2-甲基-5-硝基苯基)-2-(丙-1-烯-2-基)烟腈,收率80%。LCMS(m/z)(M+H)=280.1,Rt=1.00min.
步骤2:将5-(2-甲基-5-硝基苯基)-2-(丙-1-烯-2-基)烟腈(1.0当量)在MeOH(0.07M)中的不均匀溶液用氩气脱气和净化。加入Pd/C(Degussa型,0.1当量),对不均匀的溶液抽室内真空(house vacuum),将其用H2气囊换气。将真空/净化重复三次,将反应保持在H2气氛下搅拌8小时。将溶液抽真空,用氩气净化,通过1μM HPLC过滤器过滤,用EtOAc冲洗,浓缩,抽出(pump on),得到5-(5-氨基-2-甲基苯基)-2-异丙基烟腈,收率100%。LCMS(m/z)(M+H)=252.1,Rt=0.63min.
5-(5-氨基-2-甲基苯基)-2-(1-甲基-1H-吡唑-4-基)烟腈的合成
步骤1:向脱气的4,4,5,5-四甲基-2-(2-甲基-5-硝基苯基)-1,3,2-二氧杂硼杂环戊烷(1.0当量)、5-溴-2-氯烟腈(1.0当量)和Na2CO3(3.0当量,2M水溶液)在甲苯(0.19M)中的溶液中加入PdCl2(dppf).CH2Cl2加合物(0.1当量)。将混合物加热至90℃达3h,再加入0.05当量催化剂,在90℃搅拌1h,冷却至室温。加入水,分离各相,用乙酸乙酯萃取水混合物。合并有机相,用MgSO4干燥,真空除去挥发性物质。通过ISCO(20%EtOAc/庚烷)纯化,得到2-氯-5-(2-甲基-5-硝基苯基)烟腈,收率65%。LCMS(m/z)(M+H)=274.0,Rt=0.98min.
步骤2:向2-氯-5-(2-甲基-5-硝基苯基)烟腈(1.0当量)在AcOH(0.15M)中的溶液中加入铁(10当量)。将混合物在rt搅拌1小时。浓缩,用EtOAc和饱和NaHCO3溶液后处理。用盐水洗涤有机层,用Na2SO4干燥,浓缩,得到5-(5-氨基-2-甲基苯基)-2-氯烟腈,定量收率。LCMS(m/z)(M+H)=244.0,Rt=0.55min.
步骤3:向脱气的1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(2.0当量)、5-(5-氨基-2-甲基苯基)-2-氯烟腈(1.0当量)和Na2CO3(5当量,2M溶液)在DME(0.2M)中的溶液中加入PdCl2(dppf).CH2Cl2加合物(0.18当量)。将该混合物在微波中加热至110℃达15min,冷却至室温。加入水,分离各相,用乙酸乙酯萃取水混合物。合并有机相,用MgSO4干燥。真空除去挥发性物质。通过ISCO(65%EtOAc/庚烷)纯化该物质,得到5-(5-氨基-2-甲基苯基)-2-(1-甲基-1H-吡唑-4-基)烟腈,收率77%。LCMS(m/z)(M+H)=290.0,Rt=0.53min.
5-(5-氨基-2-甲基苯基)-2-氯烟腈的合成
向5-溴-2-氯烟腈(1.0当量)在THF和水(4:1,0.2M)中的溶液中加入碳酸钾(3.0当量)和4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.0当量),用氩气将溶液脱气。加入PdCl2(dppf)-DCM(0.1当量),将溶液在90℃回流24小时。冷却至室温后,将反应在1:1EtOAc/正-庚烷与H2O之间分配,混合,分离,用NaCl(饱和)洗涤,用MgSO4干燥,过滤,浓缩,通过ISCO SiO2色谱法(0-80%EtOAc/正-庚烷)纯化,得到5-(5-氨基-2-甲基苯基)-2-氯烟腈,收率82%。LCMS(m/z)(M+H)=243.9,Rt=0.56min.
4-(5-(5-氨基-2-甲基苯基)-3-氰基吡啶-2-基)哌嗪-1-甲酸叔丁酯的合成
将哌嗪-1-甲酸叔丁酯(1.4当量)、5-(5-氨基-2-甲基苯基)-2-氯烟腈(1.0当量)和碳酸钾(3.0当量)在DMF(0.4M)中的溶液在75℃加热5小时。冷却至rt后,将反应在乙酸乙酯与水之间分配,用水、然后用饱和NaCl洗涤有机相,用MgSO4干燥,过滤,浓缩至干。通过硅胶色谱法(ISCO,用0-80%乙酸乙酯/正-庚烷洗脱)纯化粗物质,得到4-(5-(5-氨基-2-甲基苯基)-3-氰基吡啶-2-基)哌嗪-1-甲酸叔丁酯,收率62%。LCMS(m/z)(M+H)=338.2,Rt=0.73min.
5-(5-氨基-2-甲基苯基)-2-吗啉代烟腈的合成
将吗啉(1.4当量)、5-(5-氨基-2-甲基苯基)-2-氯烟腈(1.0当量)和碳酸钾(3.0当量)在DMF(0.4M)中的溶液在75℃加热5小时。冷却至rt后,将反应在乙酸乙酯与水之间分配,用水、然后用饱和NaCl洗涤有机相,用MgSO4干燥,过滤,浓缩至干。通过硅胶色谱法(ISCO,用0-80%乙酸乙酯/正-庚烷洗脱)纯化粗物质,得到5-(5-氨基-2-甲基苯基)-2-吗啉代烟腈,收率67%。LCMS(m/z)(M+H)=295.1,Rt=0.55min.
5'-氨基-2'-甲基-6-吗啉代-[3,3'-联吡啶]-5-甲腈的合成
将5'-氨基-6-氯-2'-甲基-[3,3'-联吡啶]-5-甲腈(1.0当量)、吗啉(1.2当量)和碳酸钠(3.0当量)在DMSO中的溶液在rt搅拌48小时。用乙酸乙酯稀释混合物,用水、然后用饱和NaCl洗涤,用Na2SO4干燥,过滤,浓缩。通过硅胶色谱法(ISCO,用0-100%乙酸乙酯/庚烷洗脱)纯化残余物,得到5'-氨基-2'-甲基-6-吗啉代-[3,3'-联吡啶]-5-甲腈,收率91%。LCMS(m/z)(M+H)=295.1,Rt=0.42min.
5-(5-氨基-2-甲基苯基)-2-((四氢-2H-吡喃-4-基)氨基)烟腈的合成
将5-溴-2-((四氢-2H-吡喃-4-基)氨基)烟腈(1.0当量)、4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.0当量)、碳酸钠(3.0当量,2M水溶液)和PdCl2(dppf)-DCM(0.03当量)在DME(0.13M)中的溶液在微波中于130℃加热30min。将溶液在乙酸乙酯与水之间分配,用饱和NaCl洗涤有机相,用MgSO4干燥,过滤,浓缩至干。通过硅胶色谱法(ISCO,用0-100%乙酸乙酯/庚烷洗脱)纯化,得到5-(5-氨基-2-甲基苯基)-2-((四氢-2H-吡喃-4-基)氨基)烟腈,收率65%。LCMS(m/z)(M+H)=309.1 Rt=0.53min.
5'-氨基-2'-甲基-6-((四氢-2H-吡喃-4-基)氨基)-[3,3'-联吡啶]-5-甲腈的合
成
将5-溴-2-((四氢-2H-吡喃-4-基)氨基)烟腈(1.0当量)、6-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-胺(1.4当量)、碳酸钠(3.0当量,2M水溶液)和PdCl2(dppf)-DCM(0.03当量)在DME(0.12M)中的溶液在微波中于130℃加热30min。将溶液在乙酸乙酯与水之间分配,用饱和NaCl洗涤有机相,用MgSO4干燥,过滤,浓缩至干。通过硅胶色谱法(ISCO,用含有0.1%DIEA的0-5%甲醇/DCM―含有0.1%DIEA的25%甲醇/DCM洗脱)纯化,得到5'-氨基-2'-甲基-6-((四氢-2H-吡喃-4-基)氨基)-[3,3'-联吡啶]-5-甲腈,收率59%。LCMS(m/z)(M+H)=310.0 Rt=0.44min.
5-(5-氨基-2-甲基苯基)-2-((2-甲氧基乙基)氨基)烟腈的合成
将5-溴-2-((2-甲氧基乙基)氨基)烟腈(1.0当量)、4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.0当量)、碳酸钠(3.0当量,2M溶液)和PdCl2(dppf)-DCM(0.03当量)在DME(0.13M)中的溶液在微波中于130℃加热30min。将溶液在乙酸乙酯与水之间分配,用饱和NaCl洗涤有机相,用MgSO4干燥,过滤,浓缩至干。通过硅胶色谱法(ISCO,用0-100%乙酸乙酯/庚烷洗脱)纯化,得到5-(5-氨基-2-甲基苯基)-2-((2-甲氧基乙基)氨基)烟腈,收率88%。LCMS(m/z)(M+H)=283.0 Rt=0.51min.
5'-氨基-6-((2-甲氧基乙基)氨基)-2'-甲基-[3,3'-联吡啶]-5-甲腈的合成
将5-溴-2-((2-甲氧基乙基)氨基)烟腈(1.0当量)、6-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-胺(1.4当量)、碳酸钠(3.0当量,2M溶液)和PdCl2(dppf)-DCM(0.03当量)在DME(0.15M)中的溶液在微波中于130℃加热30min。将溶液在乙酸乙酯与水之间分配,用饱和NaCl洗涤有机相,用MgSO4干燥,过滤,浓缩至干。通过硅胶色谱法(ISCO,用含有0.1%DIEA的0-5%甲醇/DCM―含有0.1%DIEA的25%甲醇/DCM洗脱)纯化,得到5'-氨基-6-((2-甲氧基乙基)氨基)-2'-甲基-[3,3'-联吡啶]-5-甲腈,收率63%。LCMS(m/z)(M+H)=284.0 Rt=0.42min.
5-(5-氨基-2-甲基苯基)-2-(3-羟基-3-甲基氮杂环丁烷-1-基)烟腈的合成
将5-溴-2-(3-羟基-3-甲基氮杂环丁烷-1-基)烟腈(1.0当量)、4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(1.4当量)、碳酸钠(3.0当量,2M水溶液)和PdCl2(dppf)-DCM(0.03当量)在DME(0.22M)中的溶液在微波中于110℃加热15min。将溶液在乙酸乙酯与水之间分配,用Na2SO4干燥有机相,过滤,浓缩至干。通过硅胶色谱法(ISCO,用0-100%乙酸乙酯/庚烷洗脱)纯化,得到5-(5-氨基-2-甲基苯基)-2-(3-羟基-3-甲基氮杂环丁烷-1-基)烟腈,收率90%。LCMS(m/z)(M+H)=295.0 Rt=0.48min.
5'-氨基-6-(3-羟基-3-甲基氮杂环丁烷-1-基)-2'-甲基-[3,3'-联吡啶]-5-甲腈
的合成
将5-溴-2-(3-羟基-3-甲基氮杂环丁烷-1-基)烟腈(1.0当量)、6-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-胺(1.4当量)、碳酸钠(3.0当量,2M水溶液)和PdCl2(dppf)-DCM(0.15当量)在DME(0.22 M)中的溶液在微波中于110℃加热15 min。将溶液在乙酸乙酯与水之间分配,用Na2SO4干燥有机相,过滤,浓缩至干。通过硅胶色谱法(ISCO,用0-8%甲醇/DCM洗脱)纯化,得到5'-氨基-6-(3-羟基-3-甲基氮杂环丁烷-1-基)-2'-甲基-[3,3'-联吡啶]-5-甲腈,收率91%。LCMS(m/z)(M+H)=296.0 Rt=0.40min.
5-(5-氨基-2-甲基苯基)-2-(四氢-2H-吡喃-4-基)烟腈的合成
步骤1:将5-(5-氨基-2-甲基苯基)-2-氯烟腈(1.0当量)、2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1.4当量)、PdCl2(dppf)-DCM(0.1当量)和碳酸钠(3.8当量,2M溶液)在DME(0.18M)中的溶液在微波中于120℃加热40min。在水与乙酸乙酯之间分配,用饱和NaCl洗涤有机相,用MgSO4干燥,过滤,浓缩至干。通过硅胶色谱法(ISCO,用0-100%乙酸乙酯/庚烷洗脱)纯化残余物,得到5-(5-氨基-2-甲基苯基)-2-(3,6-二氢-2H-吡喃-4-基)烟腈,收率91%。LCMS(m/z)(M+H)=292.0 Rt=0.55min.
步骤2:向5-(5-氨基-2-甲基苯基)-2-(3,6-二氢-2H-吡喃-4-基)烟腈(1.0当量)在乙醇/DCM(5:1)中的溶液中加入Pd(OH)2(0.7当量),用氢气净化混合物,搅拌3小时。过滤溶液,浓缩滤液至干,得到5-(5-氨基-2-甲基苯基)-2-(四氢-2H-吡喃-4-基)烟腈,收率72%。LCMS(m/z)(M+H)=294.0 Rt=0.55min.
5'-氨基-6-(3,6-二氢-2H-吡喃-4-基)-2'-甲基-[3,3'-联吡啶]-5-甲腈的合成
步骤1:向6-氯-2'-甲基-5'-硝基-[3,3'-联吡啶]-5-甲腈(1.0当量)在DME(0.18M)中的溶液中加入2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(2.0当量)、碳酸钠(1.0当,2M水溶液)和PdCl2(dppf)-DCM(0.15当量),将反应在微波中于110℃加热15min。用乙酸乙酯稀释该溶液,用水、然后用饱和NaCl洗涤。用Na2SO4干燥有机层,过滤,浓缩。通过硅胶色谱法(ISCO,用0-30%乙酸乙酯/庚烷洗脱)纯化粗残余物,得到6-(3,6-二氢-2H-吡喃-4-基)-2'-甲基-5'-硝基-[3,3'-联吡啶]-5-甲腈,收率100%。LCMS(m/z)(M+H)=323.2 Rt=0.68min.
步骤2:向6-(3,6-二氢-2H-吡喃-4-基)-2'-甲基-5'-硝基-[3,3'-联吡啶]-5-甲腈(1.0当量)在EtOH/DCM(1:1,0.03M)中的混悬液中加入Pd(OH)2(1.0当量)。用H2净化混合物,在H2气氛下搅拌3小时。过滤出催化剂,浓缩,得到5'-氨基-6-(3,6-二氢-2H-吡喃-4-基)-2'-甲基-[3,3'-联吡啶]-5-甲腈,收率79%。LCMS(m/z)(M+H)=295.2 Rt=0.47min.
3-(6-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氰基吡啶-3-基)-4-甲基苯甲酸的合成
步骤1:向4-(5-溴-3-氰基吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.0当量)、4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(1.1当量)和PdCl2(dppf).CH2Cl2加合物(0.08当量)在DME(0.36M)中的混合物中加入Na2CO3(3.0当量,2M水溶液)。将混合物于120℃在微波中搅拌15min。LC-MS显示完全转化。加入盐水和EtOAc,用硫酸钠干燥有机层,浓缩,通过ISCO(0-100%EtOAc/庚烷)纯化,得到4-(3-氰基-5-(5-(甲氧基羰基)-2-甲基苯基)吡啶-2-基)哌嗪-1-甲酸叔丁酯,收率74%。LCMS(m/z)(M+H)=381.2,Rt=1.13min.
步骤2:向4-(3-氰基-5-(5-(甲氧基羰基)-2-甲基苯基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.0当量)在THF(0.13M)中的溶液中加入LiOH(5.5当量)。将混合物在rt搅拌4h。浓缩以除去大部分THF,用6N HCl将残余物中和至pH=3,用EtOAc萃取。用盐水洗涤有机层,用硫酸钠干燥,浓缩,得到3-(6-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氰基吡啶-3-基)-4-甲基苯甲酸,收率22%。LCMS(m/z)(M+H)=367.1,Rt=0.99min.
实施例1
N-(3-(6-氨基-5-氰基吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺
方法2:向2-氨基-5-溴烟腈(1.4当量)在甲苯和乙醇(2.5:1)中的溶液中加入N-(4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-3-(三氟甲基)苯甲酰胺(1.0当量)、Pd(PPh3)4(0.1当量)和碳酸钾水溶液(3M,3.0当量)。将反应于120℃在微波中加热40min。分离有机层,真空浓缩至干。将残余物溶于DMSO,通过反相HPLC纯化。冻干纯级分,得到N-(3-(6-氨基-5-氰基吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺,为TFA盐,收率48%。1H NMR(400MHz,DMSOd6)δ10.45(s,1H),8.30(s,1H),8.25(d,J=2.0,1H),8.23(d,J=2.0,1H),7.97(d,J=8.0,1H),7.95(d,J=4.0,1H),7.79(t,J=8.0,1H),7.72(dd,J=8.0,2.0,1H),7.61(d,J=4.0,1H),7.30(d,J=12.0,1H),2.23(s,3H).LCMS(m/z)(M+H)=397.1,Rt=0.91min.
使用与针对制备实施例1所述的方法(方法2)类似的方法用适合的起始材料制备了下面的表1中列出的化合物。
表1
实施例31
N-(3-(2-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺
方法3:向脱气的5-溴-6-氯烟腈(1.0当量)中的溶液中加入2-(2-氰基丙烷-2-基)-N-(4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)异烟酰胺(1.1当量),然后加入碳酸钠(5.0当量,2M溶液)和PdCl2(dppf)-DCM加合物(0.15当量)。将混合物加热至90℃达1小时,然后冷却至室温。加入水,分离各相,用乙酸乙酯萃取水混合物。合并有机相,用硫酸镁干燥,过滤,真空浓缩。通过硅胶色谱法纯化该物质,用40%在庚烷中的乙酸乙酯洗脱。浓缩纯级分,再通过反相HPLC纯化。冻干纯级分,得到N-(3-(2-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺,为TFA盐,收率23%。1H NMR(400MHz,<cd3od>)δppm 1.80(s,6H)2.12(s,3H)7.34-7.41(m,1H)7.55-7.62(m,1H)7.69-7.76(m,1H)7.77-7.83(m,1H)8.02-8.08(m,1H)8.19(s,1H)8.73-8.78(m,1H)8.80(s,1H).LCMS(m/z)(M+H)=416.1,Rt=0.94min.
实施例32
N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺
将EDC(2.0当量)加入到5-(5-氨基-2-甲基苯基)-2-氯烟腈(1.0当量)、2-(2-氰基丙烷-2-基)异烟酸(1.1当量)、HOAt(2.0当量)在DMF(0.2M)中的溶液中。将混合物在环境温度下搅拌3h。用水稀释反应混合物,用乙酸乙酯萃取。依次用1M氢氧化钠水溶液和盐水洗涤合并的萃取物,用硫酸钠干燥,过滤,浓缩。通过ISCO(26%EtOAc/庚烷)纯化,得到N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺,收率76%。LCMS(m/z)(M+H)=416.0,Rt=0.93min.
实施例33
N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺
将EDC(1.3当量)加入到5-(5-氨基-2-甲基苯基)-2-氯烟腈(1.0当量)、3-(三氟甲基)苯甲酸(1.1当量)、HOAt(1.3当量)在DMF(0.2M)中的溶液中。将该混合物在环境温度下搅拌3h。LC-MS显示100%转化率。用水稀释反应混合物,用乙酸乙酯萃取。依次用1M氢氧化钠水溶液和盐水洗涤合并的萃取物,用硫酸钠干燥,过滤,浓缩。通过ISCO(26%EtOAc/庚烷)纯化,得到N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺,收率78%。LCMS(m/z)(M+H)=416.0,Rt=1.06min.
使用与针对制备实施例31所述的方法(方法3)类似的方法用适合的起始材料制备了下面的表2中列出的化合物。
表2
实施例47
N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺
将EDC(2.0当量)加入到5-(5-氨基-2-甲基苯基)-2-氯烟腈(1.0当量)、2-(三氟甲基)异烟酸(1.1当量)、HOAt(2.0当量)在DMF(0.2M)中的溶液中。将混合物在环境温度下搅拌3h。用水稀释反应混合物,用乙酸乙酯萃取。依次用1M氢氧化钠水溶液和盐水洗涤合并的萃取物,用硫酸钠干燥,过滤,浓缩。通过ISCO(26%EtOAc/庚烷)纯化,得到N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺,收率100%。LCMS(m/z)(M+H)=417.0,Rt=1.03min.
实施例48
N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰
胺
向脱气的2-(2-氰基丙烷-2-基)-N-(6-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-基)异烟酰胺(1.0当量)、5-溴-2-氯烟腈(1.05当量)和碳酸钠(3.0当量,2M水溶液)中的溶液中加入PdCl2(dppf)-DCM加合物(0.15当量),将混合物加热至90℃达2小时。冷却至rt后,加入水,分离各相,用乙酸乙酯萃取水相。用MgSO4干燥合并的有机相,过滤,浓缩。通过硅胶色谱法(ISCO,0-100%在庚烷中的乙酸乙酯)纯化粗物质,浓缩纯级分,得到N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺,收率63%。LCMS(m/z)(M+H)=417.0,Rt=0.69min.
实施例49
N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(三氟甲基)异烟酰胺
步骤1:将5-溴-6-甲基吡啶-3-胺(1.0当量),2-(三氟甲基)异烟酸(1.05当量)、N1-((乙基亚氨基)亚甲基)-N3,N3-二甲基丙烷-1,3-二胺盐酸盐(1.2当量)和3H-[1,2,3]***并[4,5-b]吡啶-3-醇(1.2当量)在DMF(0.35M)中的溶液在rt搅拌过夜。将反应在乙酸乙酯与水之间分配,混合,分离有机层,用水、1N NaOH、NaCl(饱和)洗涤,用MgSO4干燥,过滤,浓缩,真空干燥,得到N-(5-溴-6-甲基吡啶-3-基)-2-(三氟甲基)异烟酰胺,定量收率。LCMS(m/z)(M+H)=361.9,Rt=0.78min.
步骤2:向N-(5-溴-6-甲基吡啶-3-基)-2-(三氟甲基)异烟酰胺(1.0当量)、4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二氧杂硼杂环戊烷)(1.1当量)和碳酸钾(3.0当量)中的溶液中加入PdCl2(dppf)-DCM加合物(0.05当量),将溶液加热至125℃达3小时。冷却至rt后,用乙酸乙酯稀释该溶液,过滤,再用乙酸乙酯冲洗固体。用水、饱和氯化钠洗涤合并的有机层,用MgSO4干燥,过滤,浓缩,得到棕色油状物。将该油状物在正-庚烷中研磨,超声处理30min。过滤得到的棕色固体,在高度真空下干燥,得到N-(6-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-基)-2-(三氟甲基)异烟酰胺,收率94%,为米黄色固体。LCMS(m/z)(M+H)=326.0,Rt=0.48min.
步骤3:向N-(6-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-基)-2-(三氟甲基)异烟酰胺(1.0当量)和5-溴-2-氯烟腈(1.5当量)在甲苯(0.1M)中的溶液中加入2M Na2CO3(3.0当量),用氩气鼓泡5分钟。加入PdCl2(dppf)-DCM加合物(0.1当量),将反应加热至90℃达3小时。冷却至rt后,将溶液在乙酸乙酯与水之间分配,分离有机层,用饱和氯化钠洗涤,用MgSO4干燥,过滤,浓缩。通过硅胶色谱法(ISCO,0-100%在庚烷中的乙酸乙酯)纯化粗物质,得到N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(三氟甲基)异烟酰胺,收率69%。LCMS(m/z)(M+H)=418.0,Rt=0.72min.
实施例50
N-(3-(5-氰基-6-((四氢-2H-吡喃-4-基)氨基)吡啶-3-基)-4-甲基苯基)-3-(三
氟甲基)苯甲酰胺
方法4:向N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(1.0当量)在DMSO(0.07M)中的溶液中加入Cs2CO3(3.0当量)、Huenig碱(3.0当量)和四氢-2H-吡喃-4-胺(2.0当量)。将反应在油浴中于50℃加热过夜。冷却至室温后,通过制备型-HPLC纯化该溶液。冻干后,得到N-(3-(5-氰基-6-((四氢-2H-吡喃-4-基)氨基)吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺,收率23%,为TFA盐。LCMS(m/z)(M+H)=481.1,Rt=1.04min.
使用与针对制备实施例50所述的方法(方法4)类似的方法用适合的起始材料制备了下面的表3中列出的化合物。
表3
实施例56
N-(3-(5-氰基-6-吗啉代吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰
胺
向N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺(1.0当量)在DMSO(0.07M)中的溶液中加入碳酸钠(3.0当量)和吗啉(2.0当量),将溶液在油浴中于50℃搅拌1小时。通过制备型-HPLC纯化混合物,将纯级分冻干2天,得到N-(3-(5-氰基-6-吗啉代吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺,为TFA盐,收率30%。1H NMR(400MHz,<dmso>)δppm 1.75(s,6H)2.23(s,3H)3.60-3.70(m,4H)3.71-3.80(m,4H)7.32(d,J=8.61Hz,1H)7.59-7.74(m,2H)7.84(d,J=5.09Hz,1H)7.99(s,1H)8.14(d,J=2.35Hz,1H)8.44(d,J=2.35Hz,1H)8.79(d,J=5.09Hz,1H)10.55(s,1H).LCMS(m/z)(M+H)=467.2,Rt=0.97min.
实施例57
N-(3-(5-氰基-6-(3-羟基氮杂环丁烷-1-基)吡啶-3-基)-4-甲基苯基)-2-(2-氰
基丙烷-2-基)异烟酰胺
向N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺(1.0当量)在DMSO(0.07M)中的溶液中加入碳酸钠(2.0当量)和氮杂环丁烷-3-醇(2.0当量),将该溶液在油浴中于50℃搅拌1小时。通过制备型-HPLC纯化混合物,将纯级分冻干2天,得到N-(3-(5-氰基-6-(3-羟基氮杂环丁烷-1-基)吡啶-3-基)-4-甲基苯基)-2-(2-氰基丙烷-2-基)异烟酰胺,为TFA盐,收率40%。1H NMR(400MHz,<dmso>)δppm 1.75(s,6H)2.21(s,3H)3.99(dd,J=9.39,4.30Hz,2H)4.42-4.65(m,3H)7.30(d,J=8.61Hz,1H)7.59(d,J=1.57Hz,1H)7.67(d,J=8.61Hz,1H)7.84(d,J=4.70Hz,1H)7.94-8.03(m,2H)8.32(d,J=1.96Hz,1H)8.79(d,J=4.70Hz,1H)10.53(s,1H).LCMS(m/z)(M+H)=453.1,Rt=0.77min.
实施例58
N-(3-(5-氰基-6-(3-羟基氮杂环丁烷-1-基)吡啶-3-基)-4-甲基苯基)-3-(三氟
甲基)苯甲酰胺
向N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(1.0当量)在DMSO(0.07M)中的溶液中加入碳酸钾(2.0当量)和氮杂环丁烷-3-醇(2.0当量),将溶液在rt搅拌18小时。通过制备型-HPLC纯化混合物,将纯级分冻干2天,得到N-(3-(5-氰基-6-(3-羟基氮杂环丁烷-1-基)吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺,为TFA盐,收率37%。1H NMR(400MHz,<dmso>)δppm 2.21(s,3H)3.93-4.06(m,2H)4.47(s,2H)4.53-4.64(m,1H)7.30(s,1H)7.61(d,J=2.35Hz,1H)7.66-7.82(m,2H)7.99(d,J=2.35Hz,2H)8.19-8.38(m,3H)10.44(s,1H).LCMS(m/z)(M+H)=453.1,Rt=0.88min.
实施例59
N-(3-(5-氰基-6-吗啉代吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺
方法5:向N-(3-(6-氯-5-氰基吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(1.0当量)在DMSO(0.07M)中的溶液中加入碳酸钠(3.0当量)和吗啉(2.0当量),将溶液在油浴中于50℃搅拌1小时。通过制备型-HPLC纯化混合物,将纯级分冻干2天,得到N-(3-(5-氰基-6-吗啉代吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺,为TFA盐,收率42%。1HNMR(400MHz,<dmso>)δppm 2.23(s,3H)3.58-3.69(m,4H)3.72-3.80(m,4H)7.31(d,J=8.61Hz,1H)7.63-7.84(m,3H)7.95(d,J=7.83Hz,1H)8.14(d,J=2.35Hz,1H)8.20-8.34(m,2H)8.45(d,J=2.35Hz,1H)10.46(s,1H).LCMS(m/z)(M+H)=467.0,Rt=1.05min.
使用与针对制备实施例59所述的方法(方法5)类似的方法用适合的起始材料制备了下面的表4中列出的化合物。如果存在BOC保护基团,则通过将粗物质在TFA和DCM(1:2)中搅拌脱保护,直至脱保护完全,然后通过真空浓缩纯化,并且通过反相制备型-HPLC纯化。将纯级分冻干,得到所需的产物,为TFA盐。
表4
实施例92
N (5'-氰基-6'-(2-甲氧基乙氧基)-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙
烷-2-基)异烟酰胺
方法6:向2-甲氧基乙醇(1.2当量)在THF(0.12M)中的溶液中加入氢化钠(2.5当量),将溶液在室温搅拌1小时。将N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺(1.0当量)加入混合物中,将溶液在rt搅拌2小时。用水猝灭和真空浓缩后,通过反相制备型-HPLC纯化粗残余物。将纯级分冻干,得到N-(5'-氰基-6'-(2-甲氧基乙氧基)-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺,收率38%,为TFA盐。1H NMR(400MHz,<dmso>)δppm 1.75(s,6H)2.45(s,3H)3.33(s,3H)3.68-3.80(m,2H)4.52-4.65(m,2H)7.87(d,J=5.09Hz,1H)8.02(s,1H)8.12(d,J=1.96Hz,1H)8.45(d,J=2.35Hz,1H)8.53(d,J=2.35Hz,1H)8.79-8.94(m,2H)10.87(s,1H).LCMS(m/z)(M+H)=457.1,Rt=0.65min.
使用与针对制备实施例92所述的方法(方法6)类似的方法用适合的起始材料制备了下面的表5中列出的化合物。
表5
实施例100
N-(5'-氰基-6'-乙氧基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异
烟酰胺
向N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺(1.0当量)在THF(0.12M)中的溶液中加入乙醇钠(2.5当量,30%在乙醇中的溶液),将反应在rt搅拌2小时。用水猝灭和真空浓缩后,通过反相制备型-HPLC纯化粗残余物。将纯级分冻干,得到N-(5'-氰基-6'-乙氧基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺,收率35%。1H NMR(400MHz,<dmso>)δppm 1.39(t,J=7.04Hz,3H)1.75(s,6H)2.44(s,3H)4.52(q,J=7.04Hz,2H)7.87(d,J=5.09Hz,1H)8.02(s,1H)8.11(d,J=1.57Hz,1H)8.43(d,J=2.35Hz,1H)8.53(d,J=2.74Hz,1H)8.79-8.91(m,2H)10.86(s,1H).LCMS(m/z)(M+H)=427.1,Rt=0.72min.
实施例101
N-(5'-氰基-2-甲基-[3,3':6',4”-三联吡啶]-5-基)-2-(三氟甲基)异烟酰胺
方法7:向脱气的4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶(1.3当量)在DME(0.03M)中的溶液中加入N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(三氟甲基)异烟酰胺(1.0当量)、碳酸钠(5.0当量,2M水溶液)和PdCl2(dppf)-DCM加合物(0.15当量)。将该混合物在微波中加热至110℃达15min,冷却至rt。用乙酸乙酯稀释,真空浓缩有机层至干。通过反相制备型-HPLC纯化残余物,将纯级分冻干,得到N-(5'-氰基-2-甲基-[3,3':6',4”-三联吡啶]-5-基)-2-(三氟甲基)异烟酰胺,为TFA盐,收率72%。1H NMR(400MHz,<dmso>)δppm 2.46-2.48(m,3H)7.98(d,J=5.87Hz,2H)8.13-8.23(m,2H)8.34(s,1H)8.67(d,J=1.96Hz,1H)8.82-8.90(m,3H)8.97(d,J=4.70Hz,1H)9.05(d,J=1.96Hz,1H)10.98(s,1H).LCMS(m/z)(M+H)=461.0,Rt=0.53min.
使用与针对制备实施例101所述的方法(方法7)类似的方法用适合的起始材料制备了下面的表6中列出的化合物。
表6
实施例110
N-(5'-氰基-2-甲基-6'-(1-甲基-1H-吡唑-4-基)-[3,3'-联吡啶]-5-基)-2-(2-
氰基丙烷-2-基)异烟酰胺
方法8:将N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺(1.0当量)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(2.0当量)、碳酸钾(3.5当量,3M水溶液)和Pd(PPh3)4(0.05当量)在甲苯和乙醇(2.5:1,0.06M)中的溶液在微波中于120℃加热20分钟。分离有机层,浓缩至干。将残余物溶于DMSO,通过反相HPLC纯化。将纯级分冻干,得到N-(5'-氰基-2-甲基-6'-(1-甲基-1H-吡唑-4-基)-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺,为TFA盐,收率55%。1HNMR(400MHz,DMSOd6)δ10.91(s,1H),8.94(d,J=4.0,1H),8.90(d,J=2.0,1H),8.84(d,J=4.0,1H),8.54(s,1H),8.48(d,J=2.0,1H),8.22(s,1H),8.19(d,J=2.0,1H),8.04(s,1H),7.89(dd,J=8.0,2.0,1H),3.98(s,3H),2.51(s,3H),1.77(s,6H).LCMS(m/z)(M+H)=463.1,Rt=0.64min.
使用与针对制备实施例110所述的方法(方法8)类似的方法用适合的起始材料制备了下面的表7中列出的化合物。
表7
实施例117
N-(3-(5-氰基-6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-4-甲基苯基)-2-(1,1-二
氟乙基)异烟酰胺
方法9:在室温下向5-(5-氨基-2-甲基苯基)-2-(1-甲基-1H-吡唑-4-基)烟腈(1.0当量)在DMF(0.2M)中的溶液中加入EDC(1.3当量)、HOAt(1.3当量)和2-(1,1-二氟乙基)异烟酸(1.2当量),将混合物搅拌3小时。用水稀释,用乙酸乙酯萃取。用1MNaOH水溶液和饱和NaCl洗涤有机相,然后用硫酸钠干燥,过滤,浓缩。通过反相制备型-HPLC纯化粗物质,将纯级分冻干,得到N-(3-(5-氰基-6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-4-甲基苯基)-2-(1,1-二氟乙基)异烟酰胺,收率21%,为TFA盐。1H NMR(400MHz,<dmso>)δppm 1.99(t,J=19.17Hz,3H)2.21(s,3H)3.91(s,3H)7.33(s,1H)7.67(d,J=1.96Hz,2H)7.92-8.01(m,1H)8.14(d,J=9.00Hz,2H)8.31(d,J=1.96Hz,1H)8.46(s,1H)8.77(d,J=1.96Hz,2H)10.63(s,1H).LCMS(m/z)(M+H)=459.1,Rt=0.98min.
使用与针对制备实施例117所述的方法(方法9)类似的方法用适合的起始材料制备了下面的表8中列出的化合物。如果存在BOC保护基团,则通过将粗物质在TFA和DCM(1:2)中搅拌脱保护,直至脱保护完全,然后通过真空浓缩纯化,并且通过反相制备型-HPLC纯化。将纯级分冻干,得到所需的产物,为TFA盐。
表8
实施例274
N-(5'-氰基-6'-异丙基-2-甲基-[3,3'-联吡啶]-5-基)-2-(三氟甲基)异烟酰胺
向N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(三氟甲基)异烟酰胺(1.0当量)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(3.0当量)在甲苯和乙醇(2.5:1,0.07M)中的溶液中加入Pd(PPh3)4和碳酸钾(3.0当量,3M水溶液)。将反应在微波中于120℃加热20min。在水与饱和NaCl之间分配,混合,分离各层,用MgSO4干燥有机相,过滤,浓缩,高度真空干燥过夜。将粗物质溶于甲醇,通过抽室内真空将均匀的溶液脱气,用氩气净化。加入Pd/C(Degussa型,0.1当量),然后连氢气气囊。将反应在氢气下搅拌过夜、通过1μM HPLC过滤器过滤,用乙酸乙酯冲洗,浓缩滤液,溶于DMSO,通过反相-HPLC纯化。将纯级分冻干,得到N-(5'-氰基-6'-异丙基-2-甲基-[3,3'-联吡啶]-5-基)-2-(三氟甲基)异烟酰胺,收率45%。1H NMR(400MHz,DMSOd6)δ11.02(s,1H),9.04(d,J=4.0,1H),8.92(d,J=2.0,1H),8.90(d,J=2.0,1H),8.44(d,J=2.0,1H),8.39(s,1H),8.22(d,J=4.0,1H),8.19(d,J=2.0,1H),3.40(七重峰,J=8.0,1H),2.47(s,3H),1.34(d,J=8.0,6H).LCMS(m/z)(M+H)=426.1,Rt=0.78min.
实施例275
N-(5'-氰基-6'-异丙基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异
烟酰胺
向N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺(1.0当量)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(3.0当量)在甲苯和乙醇(2.5:1,0.07M)中的溶液中加入Pd(PPh3)4和碳酸钾(3.0当量,3M水溶液)。将反应在微波中于120℃加热20min。在水与饱和NaCl之间分配,混合,分离各层,用MgSO4干燥有机相,过滤,浓缩,高度真空干燥过夜。将粗物质溶于甲醇,通过抽室内真空将均匀的溶液脱气,用氩气净化。加入Pd/C(Degussa型,0.1当量),然后连氢气气囊。将反应在氢气下搅拌过夜。通过1μM HPLC过滤器过滤,用乙酸乙酯冲洗,浓缩滤液,溶于DMSO,通过反相-HPLC纯化。将纯级分冻干,得到N-(5'-氰基-6'-异丙基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺,收率43%。1H NMR(400MHz,DMSOd6)δppm 10.90(s,1H),8.92(d,J=4.0,1H),8.90(d,J=4.0,1H),8.85(d,J=8.0,1H),8.44(d,J=2.0,1H),8.18(d,J=2.0,1H),8.04(s,1H),7.89(d,J=8.0,1H),3.50(七重峰,J=8.0,1H),2.47(s,3H),1.77(s,6H),1.34(d,J=8.0,6H).LCMS(m/z)(M+H)=425.1,Rt=0.74min.
实施例276
N-(5'-氰基-2-甲基-6'-(四氢-2H-吡喃-4-基)-[3,3'-联吡啶]-5-基)-2-(2-氰
基丙烷-2-基)异烟酰胺
向N-(6'-氯-5'-氰基-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺(1.0当量)、2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(2.0当量)和碳酸钠(1.0当量,2M水溶液)在DME(0.2M)中的溶液中加入PdCl2(dppf)-DCM加合物(0.2当量),将反应在微波中于110℃加热15min。用乙酸乙酯稀释反应混合物,用水、然后用饱和NaCl洗涤。用硫酸钠干燥有机层,过滤,浓缩。通过硅胶色谱法(ISCO,0-100%乙酸乙酯/庚烷)纯化残余物,得到N-(5'-氰基-6'-(3,6-二氢-2H-吡喃-4-基)-2-甲基-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺。将该产物溶于MeOH/乙酸乙酯(3:1),加入Pd/C(0.8当量)。将反应于rt在氢气气囊下搅拌16小时。通过Celite过滤溶液,用乙酸乙酯洗涤,浓缩。通过反相制备型-HPLC纯化粗产物,将纯级分冻干,得到N-(5'-氰基-2-甲基-6'-(四氢-2H-吡喃-4-基)-[3,3'-联吡啶]-5-基)-2-(2-氰基丙烷-2-基)异烟酰胺,收率5%,为TFA盐。1H NMR(400MHz,<dmso>)δppm 1.73-1.81(m,8H)1.86-2.02(m,2H)2.44(s,3H)3.34-3.44(m,1H)3.45-3.57(m,2H)3.95-4.04(m,2H)7.76-7.91(m,1H)8.02(s,1H)8.08-8.16(m,1H)8.45(d,J=2.35Hz,1H)8.90(d,J=1.96Hz,3H)10.84(s,1H).LCMS(m/z)(M+H)=467.2,Rt=0.67min.
实施例277
4-(氨基甲基)-N-(3-(5-氰基-6-(二甲基氨基)吡啶-3-基)-4-甲基苯基)-3-(三
氟甲基)苯甲酰胺
将5-(5-氨基-2-甲基苯基)-2-(二甲基氨基)烟腈(1.0当量)、4-(溴甲基)-3-(三氟甲基)苯甲酸(1.1当量)、EDC(1.0当量)和HOAt(1.0当量)在DMF(0.15M)中的溶液在rt搅拌过夜。向反应中加入氨的甲醇溶液(24当量,7M溶液),加热至50℃。完成后,通过反相制备型-HPLC纯化反应,将纯级分冻干,得到4-(氨基甲基)-N-(3-(5-氰基-6-(二甲基氨基)吡啶-3-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺,收率3%,TFA盐。LCMS(m/z)(M+H)=454.3,Rt=0.78min.
实施例278
3-(5-氰基-6-(哌嗪-1-基)吡啶-3-基)-4-甲基-N-(2-(三氟甲基)吡啶-4-基)苯
甲酰胺
在0℃向搅拌着的3-(6-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氰基吡啶-3-基)-4-甲基苯甲酸(1.0当量)在DCM(0.06M)中的溶液中加入1-氯-N,N,2-三甲基-1-丙烯基胺(1.6当量),将混合物在0℃搅拌1h。随后将溶液加入到4-氨基-2-(三氟甲基)吡啶(1.7当量)和Et3N(2.0当量)在DCM中的溶液中,将反应温热至rt,搅拌1h。浓缩,溶于DCM,用饱和NaHCO3洗涤。用盐水洗涤有机层,用硫酸钠干燥,浓缩。再溶于DCM和TFA(2:1),在rt搅拌2h。浓缩反应,通过制备型HPLC纯化。冻干后,得到3-(5-氰基-6-(哌嗪-1-基)吡啶-3-基)-4-甲基-N-(2-(三氟甲基)吡啶-4-基)苯甲酰胺,收率17%。LCMS(m/z)(M+H)=467.2,Rt=0.77min.1HNMR(400MHz,<dmso>δppm 2.34(s,3H)3.29(br.s.,4H)3.81-3.86(m,4H)7.49-7.58(m,1H)7.88(d,J=1.96Hz,1H)7.92-8.00(m,1H)8.03-8.08(m,1H)8.27(d,J=1.57Hz,1H)8.32(d,J=2.35Hz,1H)8.56(d,J=2.35Hz,1H)8.63-8.70(m,1H)8.74-8.89(m,2H)10.84(s,1H).
实施例279
3-(5-氰基-6-(哌嗪-1-基)吡啶-3-基)-4-甲基-N-(2-(甲基磺酰基)吡啶-4-基)
苯甲酰胺
在0℃向搅拌着的3-(6-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氰基吡啶-3-基)-4-甲基苯甲酸(1.0当量)在DCM(0.06M)中的溶液中加入1-氯-N,N,2-三甲基-1-丙烯基胺(1.6当量),将该混合物在0℃搅拌1h。随后将溶液加入到2-(甲基磺酰基)吡啶-4-胺(1.7当量)和Et3N(2.0当量)在DCM中的溶液中,将反应温热至rt,搅拌1h。浓缩,溶于DCM,用饱和NaHCO3洗涤。用盐水洗涤有机层,用硫酸钠干燥,浓缩。重新溶于DCM和TFA(2:1),在rt搅拌2h。浓缩反应,通过制备型HPLC纯化。冻干后,得到3-(5-氰基-6-(哌嗪-1-基)吡啶-3-基)-4-甲基-N-(2-(甲基磺酰基)吡啶-4-基)苯甲酰胺,收率16%。LCMS(m/z)(M+H)=477.1,Rt=0.63min.1H NMR(400MHz,<dmso>)δppm 2.35(s,3H)3.25-3.31(m,7H)3.82-3.87(m,4H)7.55(s,1H)7.90(d,J=1.96Hz,1H)7.94-7.98(m,1H)8.11(dd,J=5.48,1.96Hz,1H)8.32(d,J=2.74Hz,1H)8.47(d,J=1.57Hz,1H)8.56(d,J=2.35Hz,1H)8.67(d,J=5.48Hz,1H)8.77-8.84(m,2H)10.90(s,1H).
测定法
可以通过公知的体外和体内方法评价本发明的化合物的活性。使用下面的操作获得了本文提供的Raf抑制数据。
体外Raf活性测定:RAF酶以及无催化活性的MEK1蛋白底物均是采用常规方法自己制备的。将CRAF cDNA以全长蛋白(具有Y340E和Y341E激活突变)亚克隆入杆状病毒载体中进行Sf9昆虫细胞表达。将h14-3-3ζcDNA亚克隆入杆状病毒表达载体中进行Sf9昆虫细胞表达。将共表达两种蛋白的Sf9细胞裂解,进行固定镍色谱(immobilized nickelchematography)处理,用咪唑洗脱。采用第二根柱子(Strepll结合柱),用脱硫生物素(desthiobiotin)洗脱。采用Prescission酶除去蛋白标记,采用除去标记的流转步骤进一步纯化蛋白质。
C-Raf TR是指修剪的C-Raf蛋白,其是一种Δ1-324删除突变体。C-Raf FL是指全长C-Raf蛋白。
采用具有失活K97R ATP结合位点突变的全长MEK1作为RAF底物。将MEK1cDNA采用N-末端(his)6标记亚克隆入载体中以进行大肠杆菌(E.Coli)表达。通过镍亲和色谱、然后是阴离子交换纯化来自大肠杆菌裂解物的MEK1底物。将最后的MEK1制备物生物素化(Pierce EZ-Link Sulfo-NHS-LC-生物素)并浓缩。
测定法材料:测定缓冲液是50mM Tris,pH 7.5,15mM MgCl2,0.01%牛血清白蛋白(BSA)和1mM二硫苏糖醇(DTT);终止缓冲液是60mM乙二胺四乙酸(EDTA)和0.01%20;b-Raf(V600E),活性的;生物素化的Mek,激酶为死的;Alpha Screen检测试剂盒(得自PerkinElmerTM,#6760617R);抗磷酸-MEK1/2(得自Cell Signaling Technology,Inc.#9121);384孔小体积测定板(White 板)。
测定条件:b-Raf(V600E)约4pM;c-Raf约4nM;生物素化的Mek,激酶为死的,约10nM;ATP 10μM用于BRAF(V600E),1uM用于CRAF;与化合物一起于室温预孵育60分钟;在室温下反应1或3小时。
测定方案:Raf和生物素化的Mek(激酶为死的)以2X终浓度在测定缓冲液(50mMTris,pH 7.5,15mM MgCl2,0.01%BSA和1mM DTT)中合并,在测定板(Greiner白色384孔测定板#781207)中每孔分配5ml,含有0.25ml 40X Raf激酶抑制剂测试化合物(稀释在100%DMSO中)。将板于室温孵育60分钟。通过每孔加入5mL 2X ATP(稀释在测定缓冲液中)启动Raf激酶活性反应。3小时(b-Raf(V600E))或1小时(c-Raf)后,终止反应并用兔抗-p-MEK(Cell Signaling,#9121)抗体和Alpha Screen IgG(ProteinA)检测试剂盒(PerkinElmer#6760617R)测定磷酸化产物,方法是将10mL加入到包含抗体(1:2000稀释)和检测珠(1:2000稀释的两种珠)在终止/珠缓冲液(25mM EDTA,50mM Tris,pH 7.5,0.01%Tween20)中的混合物的孔中。该加入在避光条件下进行以防止检测珠暴露于光。将盖子置于板的顶部,于室温孵育1小时,然后在PerkinElmer Envision仪器上读取发光。使用XL Fit数据分析软件通过非线性回归计算每个化合物的50%抑制浓度(IC50)。
使用上述测定法,本发明的化合物对C-Raf和B-Raf表现出抑制功效。表9详细描述了本发明的化合物的IC50数据。
表9
Claims (9)
1.式I或II的化合物:
其中:
L选自–NHC(O)–和–C(O)NH–;
Y1选自N和CH;
R1选自H、卤素、异丙基、甲基-磺酰基、OR6、NR5R6、甲氧基-乙氧基、2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基、3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基、8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基、2-氧代-1,2-二氢吡啶-4-基、四氢-2H-吡喃基、4-氧代吡啶-1(4H)-基、吡唑基、哒嗪基和氮杂环丁烷基;其中所述的氮杂环丁烷基、吡唑基或2-氧代-1,2-二氢吡啶-4-基是未被取代的或被1-3个独立地选自甲基和羟基的基团取代;
R2选自H和甲基;
R3选自H、甲基和氨基;
R4选自:
R5选自H和甲基;
R6选自H以及甲基、乙基、丙基、异丙基、环丙基、甲氧基、羟基-乙基、甲氧基-乙基、四氢-2H-吡喃基、吡啶基、四氢呋喃基和氧杂环丁烷基;或者R5和R6与R5和R6所连接的氮一起形成选自吗啉代、2-氧代吡啶-1(2H)-基、1,1-二氧化硫吗啉代、哌嗪基、吡咯烷基、咪唑基和吡唑基的基团;其中所述的吗啉代、吡唑基或咪唑基是未被取代的或被1-2个甲基取代;
R7选自H、甲基、–CF3、–C(CH3)2CN、–C(CH3)2OH、–C(CH3)2F、–CF2CH3、–CF2H、异丙基、环丙基和甲基-磺酰基;其中所述的环丙基是未被取代的或被氰基取代;
R8选自H、甲基、乙基、异丙基、–C(CH3)2OH和–C(CH3)2NH2;
R9选自H和乙基;
或其药学上可接受的盐。
2.权利要求1的化合物,其是式Ia的化合物:
其中:
Y1选自N和CH;
R1选自H、卤素、异丙基、甲基-磺酰基、OR6、NR5R6、甲氧基-乙氧基、2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基、3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基、8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基、2-氧代-1,2-二氢吡啶-4-基、四氢-2H-吡喃基、4-氧代吡啶-1(4H)-基、吡唑基、哒嗪基和氮杂环丁烷基;其中所述的氮杂环丁烷基、吡唑基或2-氧代-1,2-二氢吡啶-4-基是未被取代的或被1-3个独立地选自甲基和羟基的基团取代;
R2选自H和甲基;
R3选自H、甲基和氨基;
R7选自H、甲基、–CF3、–C(CH3)2CN、–C(CH3)2OH、–C(CH3)2F、–CF2CH3、–CF2H、异丙基、环丙基和甲基-磺酰基;其中所述的环丙基是未被取代的或被氰基取代;
R8选自H、甲基、乙基、异丙基、–C(CH3)2OH和–C(CH3)2NH2;
或其药学上可接受的盐。
4.权利要求1的化合物,其是式Ib的化合物:
其中:
Y1选自N和CH;
R1选自H、卤素、异丙基、甲基-磺酰基、OR6、NR5R6、甲氧基-乙氧基、2-氧杂-5-氮杂二环[2.2.1]庚烷-5-基、3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基、8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基、2-氧代-1,2-二氢吡啶-4-基、四氢-2H-吡喃基、4-氧代吡啶-1(4H)-基、吡唑基、哒嗪基和氮杂环丁烷基;其中所述的氮杂环丁烷基、吡唑基或2-氧代-1,2-二氢吡啶-4-基是未被取代的或被1-3个独立地选自甲基和羟基的基团取代;
R2选自H和甲基;
R3选自H、甲基和氨基;
R7选自H、甲基、–CF3、–C(CH3)2CN、–C(CH3)2OH、–C(CH3)2F、–CF2CH3、–CF2H、异丙基、环丙基和甲基-磺酰基;其中所述的环丙基是未被取代的或被氰基取代,
或其药学上可接受的盐。
7.药物组合物,其包含权利要求1-6中任意一项的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体。
8.权利要求1-6中任意一项的化合物或其药学上可接受的盐在制备用于治疗增殖性疾病的药物中的用途。
9.权利要求8的用途,其中所述增殖性疾病选自黑素瘤。
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WO2005058832A1 (en) * | 2003-12-10 | 2005-06-30 | Merck Patent Gmbh | Diacylhydrazine derivatives |
WO2013171640A1 (en) * | 2012-05-15 | 2013-11-21 | Novartis Ag | Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1 |
WO2013171641A1 (en) * | 2012-05-15 | 2013-11-21 | Novartis Ag | Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1 |
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JP6646044B2 (ja) | 2020-02-14 |
US20170260200A1 (en) | 2017-09-14 |
EP3191467A1 (en) | 2017-07-19 |
US10392404B2 (en) | 2019-08-27 |
ES2844211T3 (es) | 2021-07-21 |
CN107001329A (zh) | 2017-08-01 |
WO2016038583A1 (en) | 2016-03-17 |
JP2017526720A (ja) | 2017-09-14 |
EP3191467B1 (en) | 2020-10-21 |
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