CN111454268B - 作为布鲁顿酪氨酸激酶抑制剂的环状分子 - Google Patents
作为布鲁顿酪氨酸激酶抑制剂的环状分子 Download PDFInfo
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- CN111454268B CN111454268B CN201910049183.9A CN201910049183A CN111454268B CN 111454268 B CN111454268 B CN 111454268B CN 201910049183 A CN201910049183 A CN 201910049183A CN 111454268 B CN111454268 B CN 111454268B
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Classifications
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明描述了具有蛋白酪氨酸激酶抑制活性的新型分子,以及该化合物的合成和使用方法。具体地,本发明描述了式(A)化合物或其药学上可接受的盐、水合物或溶剂合物,以及该化合物的合成和使用方法。
Description
技术领域
本发明涉及小分子药物领域,具体地,本发明提供了一种具有蛋白酪氨酸激酶抑制活性的新型分子,以及此类化合物的合成和使用方法。
背景技术
蛋白激酶是人类酶中的最大家族,涵盖超过500种蛋白质。布鲁顿酪氨酸激酶(BTK)是酪氨酸激酶Tec家族的成员,并且是早期B细胞发育和成熟B细胞活化、信号转导、和存活的调节剂。BTK已成为用于治疗B细胞淋巴瘤、白血病和自身免疫疾病的新分子靶标。因此,本领域迫切需要提供更多具有BTK抑制活性的小分子化合物。
发明内容
本发明的目的是提供一种具有BTK抑制活性的小分子化合物。
本发明的第一方面,提供了一种如下式(A)所示的化合物,或其药学上可接受的盐,
其中:
A环和B环互相并联,且各自独立地为取代或未取代的5-15元杂环或杂芳环;
Cyc1选自下组:取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的C2-C6烯基、取代或未取代的C3-C10环烯基、取代的或未取代的5-15元杂环基、取代的或未取代的5-15元杂芳基、取代或未取代的C6-C10芳基;
Cyc2选自下组:取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的C2-C6烯基、取代或未取代的C3-C10环烯基、取代的或未取代的5-15元杂环基、取代的或未取代的5-15元杂芳基、取代或未取代的C6-C10芳基;
L1、L2各自独立地选自下组:化学键、N、O、S、-S(=O)、-S(=O)2、C(=O)、-C(O)NH-;
Z为(CR2R3)n,n为0、1、2、3、4、5或6;
Y为(CR4R5)m,m为0、1、2、3、4、5或6;
U为(CR6R7)r,r为0、1、2或3;
且n、m和r不同时为0;
R2、R3、R4、R5、R6和R7各自独立地选自下组:H、NH2、OH、卤素、取代或未取代的C1-C6烷基;或R2、R3、R4、R5、R6、R7和R8中任意两个与其相连的碳原子以及间隔的环骨架原子共同形成C3-C8碳环,或4-8元的杂环,其中,所述杂环的杂原子选自:S、O、或NRf;Rf为H、C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基;且R2、R3、R4、R5、R6、R7、R8和R9中至少有一个是OH或-[C(R10)(R11)]k-OH;
W选自下组:N、O、S或化学键;
X为-C(R8R9)-;
R8选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C20芳基、或取代或未取代的C3-C14杂芳基、CO2H、C(O)NRf 2;
R9选自下组:H、OH或-[C(R10)(R11)]k-OH;
或R8和R9共同构成=O;
且当R8为H时,R9为OH或-[C(R10)(R11)]k-OH;
R10和R11各自独立地选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C10芳基、或取代或未取代的C3-C14杂芳基;或R10和R11与其相连的碳原子共同形成C3-C8碳环,或4-8元的杂环,其中杂原子可以是硫、氧、或NRf;
k为1、2、3、4、5或6;
除非特别说明,上述的杂芳环、杂芳基、杂环、杂环基各自独立地含有1-4个选自N,O和S的杂原子;
除非特别说明,所述的取代指基团被一个或多个(例如2个、3个、4个等)选自下组的取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、羟基-C1-C6烷基、氨基、羧基、C6-C10芳基、卤代的C6-C10芳基、未取代或被选自下组的取代基取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基:卤素、苯基。
在另一优选例中,L1-Cyc1-L2-Cyc2为:
其中,R12,R13,R14和R15分别独立为H,卤素,取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10的杂环烷基,杂原子选择N,O,S;
在另一优选例中,L1-Cyc1-L2-Cyc2为
V为N或-CR16-;其中,R16选自下组:H、卤素取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基。
在另一优选例中,所述的具有如下结构:
其中,虚线为化学键或无;各A1、A2、A3、A4、A5、A6、A7、A8和A9各自独立地为O、S、N、NH、CH或CH2;
波浪线表示连接位点;
且上述基团的各个可取代位点可以包括取代基,其中,取代基的定义如上文中所述。
在另一优选例中,所述的具有选自下组的结构:
在另一优选例中,所述的化合物具有如下式(B)所示的结构:
其中,
R12、R13、R14和R15各自独立地选自下组:H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的5-15元的杂环基。
在另一优选例中,所述的化合物具有如下式(C)所示的结构:
式(C)中,V为N或-CR16-;
R12、R13、R14和R15各自独立地选自下组:H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的5-15元的杂环基;
R16为H、卤素取代或非取代的C1-C6烷基、取代或非取代的C3-C10环烷基。
在另一优选例中,为选自下组的基团:
在另一优选例中,为/>
在另一优选例中,为/>
在另一优选例中,所述的为取代或未取代的环己基或环氧戊烷基。
在另一优选例中,所述的化合物具有如下式(D)、(E)或(F)所示的结构:
在另一优选例中,所述化合物选自下组:
1).(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)环己-1-醇(实施例1)
2)(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(实施例2)
3)(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇/(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇(实施例3)
4)3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-(三氟甲基)环己-1-醇(实施例4)
5)3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊醇(实施例5)
6)3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊醇;(实施例6)
7)3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-(三氟甲基)环戊醇(实施例7)
8)(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己烷-1-醇/(1r,4r)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己烷-1-醇
(实施例8)
9)(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇/(1r,4r)-4(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇(实施例9)
10)4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-环丙基环己烷-1-醇(实施例10)
11)(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇/(1r,4r)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(实施例11)
12)(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇和(1r,4R)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇(实施例12)
13)顺式-3-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇和反式-3-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(实施例13)
14)(±)顺式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇/(±)反式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇(实施例14)
15)(1R,3R)-3-(4-胺基-3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇;(实施例15)
16)(1R,3R)-3-(4-胺基-3-(2-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇;(实施例16)
17)(1R,3R)-3-(4-胺基-3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇;(实施例17)
18)(1R,3R)-3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(实施例18)
19)(1R,3R)-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(实施例19)
20)(1s,4s)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(实施例20)
21)(1r,4r)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(实施例21)
22)顺式-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(实施例22)
23)反式-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(实施例23)
24)5-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)四氢-2H-吡喃-3,4-二醇(实施例24)
25)3-(4-氨基-3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(实施例25)
26)(1S,3R)-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
本发明的第二方面,提供了一种药物组合物,其包含(1)本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物;和(2)药学上可接受的载体。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或如本发明第二方面所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗BTK的异常活性以及BTK突变体(如C481S)异常活性相关的疾病的药物。
在另一优选例中,所述的疾病或病症选自膀胱癌,脑肿瘤,乳腺癌,子宫癌,结肠直肠癌,食道癌,肝脏癌症,滤泡性淋巴瘤,黑色素瘤,恶性血液病,骨髓瘤,卵巢癌,非小细胞肺癌,***癌,小细胞肺癌,和B-细胞来源的淋巴恶性肿瘤,B细胞增殖性病症:弥漫性B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞幼淋巴细胞白血病、淋巴质浆细胞淋巴瘤/瓦尔登斯特伦氏巨球蛋白血症、脾脏边缘带淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘带B细胞淋巴瘤、结内边缘带B细胞淋巴瘤、外套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特氏淋巴瘤/白血病或淋巴瘤样肉芽肿病。
在另一优选例中,所述的疾病或病症选自自身免疫疾病和炎性疾病包括类风湿关节炎、银屑病关节炎、骨性关节炎和幼年型关节炎;所述肝炎包括自身免疫性肝炎;所述膀胱炎包括间质性膀胱炎;所述过敏反应包括过敏症、I型超敏反应、过敏性鼻炎;所述支气管炎包括细支气管炎;所述肠炎包括结肠炎、直肠炎;所述皮炎包括特异性皮炎、硬皮病、银屑病;所述脊髓炎包括急性播散性脑脊髓炎;所述胃炎包括胃肠炎;所述肾炎包括肾盂肾炎;所述鼻炎包括鼻窦炎。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1.给药期间溶剂对照及各给药组TMD8皮下异种移植瘤体积(平均值±标准误)
图2.给药期间溶剂对照及各给药组动物体重(平均值±标准误)。
具体实施方式
本发明人经过长期而深入的研究,意外地发现了一种如式A所示的化合物。所述的化合物对BTK,特别是BTK C481S突变体抑制具有出乎意料的抑制活性,可用于治疗由BTK介导的癌症,过敏性疾病、自身免疫疾病、炎性疾病等,以及用于B-细胞淋巴瘤和白血病,特别是针对现有药物产生耐药性的癌症病人具有优异的治疗效果。基于上述发现,发明人完成了本发明。
术语
本文所用的缩写具有化学和生物学领域中的常规含义。
除非另外说明,术语“烷基”本身或作为另一取代基的一部分是指直链(即无支链的)或支链、或环状烃基、或其组合,其可以是饱和的、单或多不饱和的,可包括二价或多价基团,具有指定数量的碳原子(即C1-C10是指一至十个碳原子)。饱和烃基的示例包括,但不限于,如甲基、乙基、n-丙基、异丙基、n-丁基、t-丁基、异丁基、仲丁基、环己基、环己基甲基、环丙基甲基等基团,如n-戊基、n-己基、n-庚基、n-辛基等同系物和异构体。不饱和烷基是具有一个或多个双键或三键的烷基。不饱和烷基的示例包括,但不限于,乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基,以及高级同系物和异构体。限定为烃基的烷基称为“同烷基(homoalkyl)”。所述烷基任选地被一个或多个卤素原子取代。
术语“氟代烷基”是指如上定义的烷基,其中一个或多个氢原子被氟原子取代。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷基的二价基团,例如,但不限于,-CH2CH2CH2CH2-、-CH2CH=CHCH2-、-CH2C≡CCH2-、-CH2CH2CH(CH2CH2CH3)CH2-。烷基(或亚烷基)通常具有1自24个碳原子,本发明优选具有10或更少碳原子的基团。“低级烷基”或“低级亚烷基”是指链更短的烷基或亚烷基,通常具有八个或更少的碳原子。所述亚烷基任选地被一个或多个卤素原子取代。
术语“炔基”是指含有至少一个碳碳三键的碳链,其可以是线性或支链的、或其组合。炔基的示例包括乙炔基、炔丙基、3-甲基-1-戊炔基、2-庚炔基等。所述炔基任选地被一个或多个卤素原子取代。
术语“环烷基”是指单环或双环饱和碳环,各自具有3至10碳原子。环烷基的“稠和类似物”是指单环与芳基或杂芳基稠和,其中,连接位点在非芳香部分。环烷基及其稠和类似物的示例包括环丙基、环丁基、环戊基、环己基、四氢萘基、十氢萘基、二氢茚基等。所述环烷基任选地被一个或多个卤素原子取代。
术语“烷氧基”是指具有示出碳原子数的直链或支链烷氧基团。C1-6烷氧基,例如,包括甲氧基、乙氧基、丙氧基、异丙氧基等。
除非另外说明,术语“杂烷基”本身或与另一术语组合是指由至少一个碳原子和至少一个选自O、N、P、Si、S的杂原子构成的稳定的直链或支链、或环烃基、或其组合,其中,氮原子、磷原子或硫原子可任选地被氧化以及氮原子可任选地被季胺化。杂原子O、N、P、S和Si可置于杂烷基内的任意位置或置于烷基与该分子的其余部分相连的位置。例如包括,但不限于,-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3和-CN。最多两个或三个杂原子可以是连续的。例如,-CH2-NH-OCH3和-CH2-O-Si(CH3)3。类似地,术语“杂亚烷基”本身或与其它术语组合是指衍生自杂烷基的二价基团,例如,但不限于,-CH2-CH2-S-CH2-CH2-和-CH2-S-CH2-CH2-NH-CH2-。对于杂亚烷基,杂原子可在链的任一端或两端(例如,亚烷基氧基、亚烷基二氧基、亚烷基胺基、亚烷基二氨基等)。此外,对于亚烷基和杂亚烷基连接基团,连接基团分子式的书写方向不表示连接基团的取向。例如,分子式-C(O)OR'-表示-C(O)OR'-和-R'OC(O)-。如上所述,本文所用的杂烷基包括通过杂原子连接在分子其余部分的那些基团,例如-C(O)R'、-C(O)NR'、-NR'R"、-OR'、-SR'和/或-SO2R'。在述及“杂烷基”,随后述及如-NR'R″等具体杂烷基之处,应理解,术语杂烷基和-NR'R″不重复且不互相排斥。相反,引用这些具体的杂烷基以便更清晰。因而,术语“杂烷基”不应该在本文中解释为排除如-NR'R″等特定杂烷基。
术语“环烷氧基”是指结合于氧原子的如上定义的环烷基,如环丙氧基。
术语“氟烷氧基”是指一个或多个氢原子被氟取代的如上定义的烷氧基。
术语“芳基”是指仅含有碳原子的单环或双环芳基。芳基的“稠和类似物”是指芳基和单环的环烷基或单环的杂环基稠和,其中连接点位于芳基部分。芳基及其稠环类似物的例子包括苯基、萘基、茚满基、茚基、四氢萘基、2,3-二氢苯并呋喃基、二氢苯并吡喃基、1,4-苯并二噁烷基等。
术语“杂芳基”是指含有至少一个选自N、O和S的杂原子的单环或双环芳基。杂芳基的“稠和类似物”是指杂芳基和单环的环烷基或单环的杂环基稠和,其中连接点位于芳基部分。杂芳基的例子包括吡咯基、异唑基、异噻唑基、吡唑基、吡啶基、噁唑基、噁二唑基、噻二唑基、噻唑基、咪唑基、***基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、哒嗪基、吡嗪基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、呋喃并(2,3-b)吡啶基、喹啉基、吲哚基、异喹啉基等。
所定义的烷基、芳基和杂芳基是未取代的或被至少一个选自取代基组成的组的取代基所取代。
所述取代基选自下组:卤原子、具有1至6个碳原子的烷基、具有1至6个碳原子的烷氧基、具有1至6个碳原子的卤代烷基、具有1至6个碳原子的卤代烷氧基、氰基、具有2至6个碳原子的炔基、具有1至6个碳原子的烷酰基、具有3至7个环原子的环烷基、杂芳基、芳基、具有7-10个碳原子的芳烷氧基、芳基羰基、氨基羰基、具有2至5个碳原子的烯基、具有1至6个碳原子的烷硫基、氨基亚磺酰基、氨基磺酰基、羟基、-SF5、具有1至4个碳原子的羟基烷基、硝基、氨基、羧基、具有2至5个碳原子的烷氧羰基、具有1至4个碳原子的烷氧基烷基、具有1-4个碳原子的烷基磺酰基、具有1至4个碳原子的烷酰基氨基、具有1至6个碳原子的烷酰基(烷基)氨基、在烷酰基和烷基部分均具有1至6个碳原子的烷酰基胺基烷基、在烷酰基和各烷基部分均具有1至6个碳原子的烷酰基(烷基)胺基烷基、具有1至4个碳原子的烷基磺酰基胺基、具有1至6个碳原子的单烷基胺基羰基或二烷基胺基羰基、具有1至6个碳原子的单烷基胺基亚磺酰基或双烷基胺基亚磺酰基、具有1至6个碳原子的单烷基胺基磺酰基或双烷基胺基磺酰基、具有1至4个碳原子的胺基烷基、具有1至6个碳原子的单烷基胺基或二烷基胺基、在各烷基部分均有1至6个碳原子的单烷基胺基烷基或二烷基胺基烷基、具有7至10个碳原子的芳烷基、在烷基部分具有1至4个碳原子的杂芳烷基、在烷氧基部分具有从1至4个碳原子的杂芳基烷氧基和具有1至4个碳原子的烷基磺酰胺基。
如本文所用,术语“杂环”或“杂环的”或“杂环烷基”或“杂环基”是指饱和的、部分饱和的或不饱和的基团(但不是芳香性的),具有单环或稠环(包括桥环体系和螺环体系,环内具有1至10个碳原子和1至4个选自氮、硫或氧的杂原子,在稠环体系中,一个或多个环可以是环烷基、芳基或杂芳基,只要连接点通过非芳香性环。在一实施例中,杂环基团的氮原子和/或硫原子任选地被氧化,以提供N-氧化物、亚磺酰基和磺酰基部分。“杂环基”及其稠和类似物的例子包括吡咯烷基、哌啶基、哌嗪基、咪唑烷基、2,3-二氢呋喃(2,3-b)并吡啶基、苯并噁嗪基、四氢喹啉基、四氢异喹啉基、二氢吲哚基等。该术语也包括非芳香性的部分不饱和的单环,如通过氮原子连接的2-或4-吡啶酮或N-取代的-(1H,3H)-嘧啶-2,4-二酮类(N-取代的尿嘧啶)。
如本文所用,术语“取代的杂环的”或“取代的杂环烷基”或“取代的杂环基”是指被1到5(如1至3)个取代基所取代的杂环基团,所述取代基与取代的环烷基所定义的取代基相同。
除非另外说明,术语“卤代的”或“卤素”本身或作为另一取代基的一部分是指氟、氯、溴或碘原子。另外,术语“卤代烷基”是指包括单卤代烷基和多卤代烷基。例如,术语“卤代(C1-C4)烷基”是指包括,但不限于,三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
“前药”是指在体内转化为母体药物物质。在某些状况下,由于前药比母体药物更容易施用,因此经常使用前药。例如,前药经口服可为生物可利用的而母体药物不能。在药物组合物中,前药也可具有较母体药物更高的溶解度。前药的例子,但不限于,可以是式I化合物中的任一化合物以酯(前药)的形式施用,以促进跨细胞膜传输,在细胞膜中水溶性对迁移有害,而一旦处于水溶性有益的细胞内,该酯随后代谢水解为活性物质羧酸。前药的另一例子可以是键合酸基的短肽(聚氨基酸),其中,肽经代谢以释放活性部分。
光学异构体、非对映体、几何异构体和互变异构体
由于本发明的化合物含有一个或多个不对称中心,因此可作为外消旋体和外消旋混合物,单一对映体,非对映体混合物和单一非对映体。当提及本发明化合物或式(A)化合物时,应当理解为包括所有这些异构形式。
一些本文所述的化合物含有烯属(olefinic)双键,除非另有说明,否则是指包括E和Z两种几何异构体。
一些式(A)化合物可包含一个或多于一个的环体系,因此可存在顺式-和反式-异构体。本发明旨在包含所有这些顺式-和反式-异构体。
本文描述的一些化合物可存在不同的与氢原子连接的位点,被称为互变异构体。这样的例子可以是称为酮-烯醇互变异构体的酮和其烯醇形式。单个互变异构体以及其混合物均包括在式(A)化合物中。
式(A)化合物可被分离成对映异构体的非对映体对(diastereoisomeric pairs),例如通过从合适的溶剂,如甲醇或乙酸乙酯或它们的混合物中分级结晶。一对如此得到的对映异构体可通过常规方法,例如使用光学活性的胺或酸作为拆分试剂或在手性HPLC柱中来分离成单独的立体异构体。
或者,通式(A)化合物的任何对映异构体可通过使用光学纯原料或已知构型的试剂立体定向合成获得。
此外,式(A)化合物还可以包括一系列稳定同位素标记的类似物。例如,式(A)化合物中的一个或一个以上的质子可以被替换为氘原子,从而可提供药理活性改善的氘代类似物。
盐与剂型
如本文所用,术语“药学上可接受的盐”是指通式I化合物的非毒性酸或碱土金属盐。这些盐可在最终分离和纯化通式I化合物时原位制得、或分别将合适的有机或无机酸或碱与碱性或酸性官能团反应制得。代表性的盐包括,但不限于:乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡萄糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘基磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、硫氰酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一烷酸盐。此外,含氮的碱性基团可被如下试剂季铵盐化:烷基卤化物,如甲基、乙基、丙基、丁基的氯化物、溴化物和碘化物;二烷基硫酸盐,如二甲基、二乙基、二丁基和二戊基硫酸酯;长链卤化物如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;芳烷基卤化物如苄基和苯乙基溴化物等。由此得到水溶性或油溶性或可分散产品。可被用于形成药学上可接受的酸加成盐的酸的例子包括如盐酸、硫酸、磷酸的无机酸,和如草酸、马来酸、甲磺酸、琥珀酸、柠檬酸的有机酸。碱加成盐可在最终分离和纯化通式I的化合物时原位制得、或使羧酸部分分别与合适的碱(如药学上可接受的金属阳离子的氢氧化物,碳酸盐或碳酸氢盐)或氨、或有机伯、仲或叔胺反应制得。药学上可接受的盐包括,但不限于,基于碱金属和碱土金属的阳离子,如钠、锂、钾、钙、镁、铝的盐等,以及无毒的铵、季铵和胺阳离子,包括,但不限于:铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。其它代表性的用于形成碱加成盐的有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。
应理解,如本文所用,提及式(A)化合物也包括药学上可接受的盐。
用于口服的制剂也可以为硬明胶胶囊,其中活性成分与惰性固体稀释剂混合,例如,碳酸钙,磷酸钙或高岭土,或者为软明胶胶囊,其中活性成分与水或油介质混合,例如花生油,液体石蜡或橄榄油。
水性悬浮液含有与适于制备水性悬浮液的赋形剂混合的活性物质。这样的赋形剂为悬浮剂,例如羧甲基纤维素钠,甲基纤维素,羟丙基甲基纤维素,藻酸钠,聚乙烯吡咯烷酮,黄蓍胶和***树胶;分散剂或润湿剂可以是天然存在的磷脂,例如卵磷脂,或环氧烷(alkylene oxide)与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂族醇,例如十七碳乙烯-氧鲸蜡醇(heptadecaethylene–oxycetanol)的缩合产物,或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如,聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,例如,聚乙烯脱水山梨醇单油酸酯。水性混悬剂也可含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种调味剂,以及一种或多种甜味剂,如蔗糖,糖精或阿斯巴甜。
油性悬浮液可将活性成分悬浮在植物油中,例如花生油,橄榄油,芝麻油或椰子油,或悬浮在矿物油,如液体石蜡中配制。油性悬浮液可含有增稠剂,例如蜂蜡,硬石蜡或鲸蜡醇。可加入上述的甜味剂,可加入矫味剂以提供可口的口服制剂。这些组合物可通过加入抗氧化剂如抗坏血酸来保存。
适合通过添加水来制备水性悬浮液的可分散粉剂和颗粒剂提供与分散剂或润湿剂,悬浮剂和一种或多种防腐剂混合的活性成分。合适的分散剂或润湿剂和助悬剂由上文已提及的例子示出。也可以存在额外的赋形剂,例如甜味剂,调味剂和着色剂。
本发明的药物组合物也可以是水包油的乳液形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡或这些的混合物。合适的乳化剂可以是天然存在的磷脂,例如大豆,卵磷脂以及衍生自脂肪酸和己糖醇酐的酯或偏酯,例如山梨糖醇单油酸酯,以及上述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯失水山梨醇单油酸酯。该乳剂也可含有甜味剂和矫味剂。
糖浆和酏剂(elixirs)可以用甜味剂配制,例如甘油,丙二醇,山梨醇或蔗糖。这样的制剂也可含有缓和剂,防腐剂,调味剂和着色剂。该药物组合物可以是无菌可注射的水性或油性悬浮液的形式。该悬浮液可通过已知技术,使用上述那些合适的分散剂或润湿剂和悬浮剂来配制。无菌注射制剂也可以是利用无毒的胃肠外可接受的稀释剂或溶剂配制的无菌注射溶液或悬浮液,例如1,3-丁二醇配制的溶液。可以使用的可接受载体和溶剂为水,林格氏溶液和等渗氯化钠溶液。此外,无菌,不挥发性油通常用作溶剂或悬浮介质。用于此目的的任何温和不挥发性油都可以使用,包括合成的单或双甘油酯。此外,脂肪酸如油酸可用在注射剂的制备中。
本发明的化合物也可以经鼻内或通过吸入给药,通常是来自干粉吸入器的干粉形式(单独,作为混合物,例如,含乳糖的干燥共混物,或作为混合组分颗粒,例如与磷脂如磷脂酰胆碱混合),或来自加压容器,泵,喷射器,雾化器(使用电流来产生细雾优选的I雾化器)或喷雾器的气溶胶喷雾器,使用或不使用合适的推进剂,如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷。对于鼻内使用,粉末可以包括生物粘附剂,例如壳聚糖或环糊精。
加压容器、泵、喷射器、雾化器或喷雾器包含本发明化合物的溶液或悬浮液,所述溶液或悬浮液包含例如,乙醇,含水乙醇,或用于分散,增溶,或延长释放活性的适宜替代试剂,作为溶剂的推进剂和可选的表面活性剂,如脱水山梨糖醇三油酸酯,油酸或低聚乳酸。
在以干粉或悬浮液制剂的形式使用前,将药物产品微粉化至适于吸入递送(通常小于5微米)的尺寸。
可以通过任何适当的粉碎方法实现,例如螺旋喷射研磨,流化床喷射研磨,超临界流体加工以形成纳米颗粒,高压均化,或喷雾干燥。
用于吸入器或吹入器的胶囊剂(例如由明胶或羟丙基甲基纤维素制备),泡罩和药盒可配制成含有本发明化合物的粉末,合适的粉质如乳糖或淀粉以及性能改性剂,如L-亮氨酸,甘露醇或硬脂酸镁。乳糖可以是无水的或单水合物形式,优选后者。其它合适的赋形剂包括葡聚糖,葡萄糖,麦芽糖,山梨醇,木糖醇,果糖,蔗糖和海藻糖。
在使用电流动力学方法产生细雾的雾化器中使用的合适溶液制剂可含有每次启动从10g到20mg的本发明化合物,启动体积可从11到1001变化。典型制剂可包含式(A)化合物,丙二醇,无菌水,乙醇和氯化钠。可被用于代替丙二醇的替代溶剂包括甘油和聚乙二醇。
合适的调味剂,如薄荷醇和左薄荷脑,或甜味剂,例如糖精或糖精钠,可以加入到本发明的用于吸入/鼻内给药的那些制剂中。
用于吸入/鼻内给药的制剂可以配制成即刻使用的和/或改进释放的,例如,使用聚(DL-乳酸-乙醇酸(PGLA)。改进释放制剂包括延迟释放,持续释放,脉冲释放,受控释放,靶向释放和程序释放。
在干粉吸入器和气雾剂的情况下,剂量单位是通过提供计量量的阀来确定。本发明的单位通常安排为施用含0.001至10毫克式(A)化合物的计量剂量或“喷雾”。每日总剂量通常从0.001至10毫克,可在一天内以单剂量或更通常作为分批剂量施用。
式(A)化合物也可以栓剂形式进行药物的直肠给药。这些组合物可以通过将药物与合适的无刺激性赋形剂混合制备,该赋形剂在常温下为固体,但在直肠温度下为液体,因此将在直肠中融化以释放药物。这类物质为可可脂和聚乙二醇。
对于局部使用,施用含式(A)化合物的霜剂,软膏剂,凝胶剂,溶液或悬浮液等。(对于本申请的目的,局部应用应包括漱口剂和含漱剂)。
每天约0.01毫克到约140毫克/千克体重的剂量水平在上述条件的治疗中是有用的,或每名患者每天约0.5mg至约7g是有用。例如,可通过每天每公斤体重施用约0.01至50毫克化合物,或每天对每名患者施用约0.5mg至3.5克,优选每人每天2.5毫克至1克化合物来有效治疗炎症。
可与载体材料组合产生单一剂型的活性成分的量将根据所治疗的宿主和具体给药模式变化。例如,用于人口服给药的制剂可含有0.5毫克至5g活性剂,活性剂与适当方便数量的载体材料复合,载体材料可在总的组合物的约5%到约95%范围变化。剂量单位形式一般含有约1毫克至约500毫克的活性成分,通常为25毫克,50毫克,100毫克,200毫克,300毫克,400毫克,500毫克,600毫克,800毫克或1000毫克。
然而,应当理解,对于任何特定患者的具体剂量水平取决于多种因素,包括年龄,体重,一般健康状况,性别,饮食,给药时间,给药途径,***速率,药物组合以及正在接受治疗的具体疾病的严重程度。
应用
本发明的化合物可用于治疗与BTK的异常活性以及BTK突变体(如C481S)相关的疾病。
本发明还包括使用对患者施用治疗有效量的式(A)化合物的方法来治疗患者疾病的方法。
更特别地,本发明的化合物对于治疗异常细胞生长和/或凋亡失调的疾病是有用的,如间皮瘤(mesothioloma),膀胱癌,胰腺癌,皮肤癌,头部或颈部癌症,皮肤或眼内黑色素瘤,卵巢癌,乳腺癌,子宫癌,子宫内膜输卵管癌,子***,***癌,外阴癌,骨癌,***,结肠癌,直肠癌,***区域癌,胃癌,胃肠道癌(胃,结直肠和十二指肠),慢性淋巴细胞性白血病,食管癌,小肠癌,内分泌***癌,甲状腺癌,甲状旁腺癌的癌腺,肾上腺癌,软组织癌,尿道癌,***癌,睾丸癌,肝细胞癌(肝癌和胆汁导管),原发性或继发性中枢神经***肿瘤,原发性或继发性脑肿瘤,霍奇金肉瘤,慢性或急性白血病,慢性髓细胞性白血病,淋巴细胞性淋巴瘤,成淋巴细胞性白血病,T-细胞或B-细胞来源的滤泡性淋巴瘤,黑色素瘤,多发性骨髓瘤,口腔癌,卵巢癌,非小细胞肺癌,***癌,小细胞肺癌,肾和输尿管癌,肾细胞癌,肾盂癌,中枢神经***肿瘤,原发性中枢神经***淋巴瘤,非何杰金氏淋巴瘤,脊轴肿瘤,脑干神经胶质瘤,垂体腺瘤,肾上腺皮质癌,胆囊癌,脾癌,胆管癌,纤维肉瘤,神经母细胞瘤,眼癌(retinoblasitoma),或其组合。另一实施方案包括对患者的间皮瘤(mesothioloma),膀胱癌,胰腺癌,皮肤癌,头部或颈部癌症,皮肤或眼内黑色素瘤,乳腺癌,子宫癌,输卵管癌,子宫内膜癌,子***,***,外阴癌,骨癌,卵巢癌,子***,结肠癌,直肠癌,肛区癌,胃癌,胃肠道癌(胃,结直肠和十二指肠),慢性淋巴细胞性白血病,食管癌,小肠癌,内分泌***癌,甲状腺癌,甲状旁腺癌,肾上腺癌,软组织肉瘤,尿道癌,***癌,睾丸癌,肝细胞癌(肝癌和胆汁导管),原发性或继发性中枢神经***肿瘤,原发性或继发性脑肿瘤,霍奇金病,慢性或者急性白血病,慢性髓细胞性白血病,淋巴细胞性淋巴瘤,成淋巴细胞性白血病,滤泡性淋巴瘤,T细胞或B-细胞来源的淋巴恶性肿瘤,黑色素瘤,多发性骨髓瘤,口腔癌,卵巢癌,非小细胞肺癌,***癌,小细胞肺癌,肾和输尿管癌,肾细胞癌,肾盂癌,在中枢神经***,原发性中枢神经***淋巴瘤,非何杰金氏淋巴瘤,脊轴肿瘤,脑干神经胶质瘤,垂体腺瘤,肾上腺皮质癌,胆囊癌,脾癌,胆管癌,纤维肉瘤,神经母细胞瘤,眼癌(retinoblasitoma)或上述一种或多种癌症组合的治疗方法,所述方法包括给予治疗有效量的式(A)化合物。
式(A)化合物也可用于治疗自身免疫疾病和炎性疾病,例如,炎性肠病,关节炎,狼疮,类风湿关节炎,银屑病关节炎,骨性关节炎和幼年型关节炎,斯蒂尔病,糖尿病,重症肌无力,桥本氏甲状腺炎,奥德氏甲状腺炎,格雷夫斯病,干燥综合征,多发性硬化,格林-巴利综合征(GuiUain-Barre syndrome)、急性播散性脑脊髓炎、阿狄森氏病(Addison'sdisease)、眼球斜视痉挛综合征(opsoclonus-myoclonus syndrome)、强直性脊柱炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、腹部疾病、古德帕斯彻氏综合征(Goodpasture's syndrome)、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔氏综合征(Reiter's syndrome)、高安动脉炎(Takayasu's arteritis)、颞动脉炎、温抗体型自身免疫性溶血性贫血(warm autoimmune hemolytic anemia)、韦格纳氏肉芽肿病(Wegener's granulomatosis)、银屑病、全身毛发脱失、贝切特氏病(Behcet'sdisease)、慢性疲劳、自律神经失调、子宫内膜异位症、间质性膀胱炎、神经性肌强直、硬皮病、外阴痛、移植、输血、过敏反应、过敏症、I型超敏反应、过敏性结膜炎、过敏性鼻炎、特应性皮炎、哮喘、阑尾炎、眼睑炎、细支气管炎、支气管炎、滑囊炎、***、胆管炎、胆囊炎、结肠炎、结膜炎、膀胱炎、泪腺炎、皮炎、皮肌炎、脑炎、心内膜炎、子***、肠炎、小肠结肠炎、上髁炎、***、筋膜炎、纤维组织炎、胃炎、胃肠炎、肝炎、化脓性汗腺炎、喉炎、乳腺炎、脑膜炎、脊髓炎、心肌炎、肌炎、肾炎、***、***、骨炎、耳炎、胰腺炎、腮腺炎、心包炎、腹膜炎、咽炎、肋膜炎、静脉炎、肺炎(pneumonitis)、肺炎(pneumonia)、直肠炎、***炎、肾盂肾炎、鼻炎、输卵管炎、鼻窦炎、口炎、滑膜炎、腱炎、扁桃体炎、葡萄膜炎、***炎、血管炎或外阴炎。
在一些实施例中,如果所述对象患有癌症,除了上述化合物之外,给该对象施用抗癌剂。在一实施例中,所述抗癌剂为丝裂原活化蛋白激酶信号通路抑制剂,例如U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素、或LY294002。
本发明还涉及包括至少一种式(A)化合物本身或至少一种式(A)化合物与一种或多种药学上可接受的赋形剂结合的药物组合物。
根据本发明的药物组合物,可以更特别地提及的是那些适合于口服、肠胃外、经鼻、经皮或穿皮、直肠、经舌、眼部或呼吸道给药,特别是片剂或糖锭剂、舌下片剂、香囊剂、药包(packets)、明胶胶囊剂、舌下剂(glossettes)、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶剂、可饮用或可注射的安瓿。
剂量可根据患者的性别,年龄和体重,给药途径,适应症的性质,或者任何相关的治疗而变化,在一次或多次施用中,剂量范围从每24小时0.01毫克至1克。
此外,本发明还涉及式(A)与一种或多种抗癌剂的组合,所述抗癌剂选自细胞毒性剂,有丝***毒素,抗代谢物,蛋白酶体抑制剂和激酶抑制剂,并且涉及该类型的组合在制备用于治疗癌症的药物中的用途。
本发明的化合物也可与治疗癌症的放疗联用。
式(A)化合物也可望用作与治疗剂相组合的化疗剂,治疗剂包括,但不限于,血管生成抑制剂,抗增殖剂,其他激酶抑制剂,其他受体酪氨酸激酶抑制剂,极光(aurora)激酶抑制剂,Polo样激酶抑制剂,bcr-abl激酶抑制剂,生长因子抑制剂,COX-2抑制剂,非甾体抗炎药(NSAIDS),抗有丝***剂,烷化剂,抗代谢物,嵌入抗生素,含铂试剂,生长因子抑制剂,电离辐射,细胞周期抑制剂,酶,拓扑异构酶抑制剂,生物反应调节剂,免疫调节剂,免疫制剂,抗体,激素疗法,类维生素A/三角肌植物生物碱,蛋白酶体抑制剂,HSP-90抑制剂,组蛋白脱乙酰酶抑制剂(HDAC)抑制剂,嘌呤类似物,嘧啶类似物,MEK抑制剂,CDK抑制剂,ERBB2受体抑制剂,mTOR抑制剂,BCL抑制剂,MCL抑制剂及其组合,PD1抗体,PDL1抗体,CTLA4抗体,IDO抑制剂,TDO抑制剂,A2a拮抗剂,精氨酸酶抑制剂,以及其它抗肿瘤剂。
血管生成抑制剂包括,但不限于,EGFR抑制剂,PDGFR抑制剂,VEGFR抑制剂,TTE2抑制剂,IGF1R抑制剂,基质金属蛋白酶-2(MMP-2)抑制剂,基质金属蛋白酶-9(MMP-9)抑制剂,血小板反应蛋白类似物,例如血小板反应蛋白-1和N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-IIe-Arg-Pro-NHCH2CH3或其盐和N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-PrO-NHCH2CH3类似物,如N-Ac-GlyVal-D-AIle-Ser-GIn-Ile-Arg-ProNHCH2CH3或其盐。
EGFR抑制剂的例子包括,但不限于,易瑞沙(吉非替尼),特罗凯(厄洛替尼或OSI-774),埃克替尼,西妥昔单抗(西妥昔单抗),EMD-7200,ABX-EGF,HR3,IgA抗体,TP-38(IVAX),EGFR融合蛋白,EGF-疫苗,AZD9291,CO1686,抗EGFr免疫脂质体和Tykerb(拉帕替尼)。
PDGFR抑制剂的例子包括,但不限于,CP-673,451和CP-868596。
VEGFR抑制剂的例子包括,但不限于,阿瓦斯丁(贝伐单抗),纾癌特(舒尼替尼,SUl1248),多吉美(索拉非尼,BAY43-9006),CP-547,632,阿西替尼(AG13736),阿帕替尼,卡博替尼,易瑞莎(凡德他尼,ZD-6474),AEE788,AZD-2171,VEGF trap,瓦他拉尼(PTK-787,ZK-222584),哌加他尼,M862,帕唑帕尼(GW786034),BC-00016,ABT-869和血管酶(angiozyme)。
血小板反应蛋白类似物的例子包括,但不限于,ABT-510。
BCL抑制剂的例子包括,但不限于,奥巴克拉(obatoclax)和那维克拉(navitoclax),ABT199。
极光激酶抑制剂的例子包括,但不限于,VX-680,AZD-1152和MLN-8054。polo样激酶抑制剂的例子包括,但不限于,BI-2536。
BCR-ABL激酶抑制剂的例子包括,但不限于,格列卫(伊马替尼),泼那替尼(ponatinib),尼洛替尼和达沙替尼(BMS354825)。
含铂试剂的例子包括,但不限于,顺铂,伯尔(卡铂),依铂,洛铂,奈达铂,乐沙定(奥沙利铂)或沙铂。
mTOR抑制剂的例子包括,但不限于,CCI-779,雷帕霉素,替西罗莫司,依维莫司,RAD001,INK-128和里达福洛莫司(ridaforolimus)。
HSP-90抑制剂的例子包括,但不限于,格尔德霉素,根赤壳菌素,17-AAG,KOS-953,17-DMAG,CNF-101,CNF-1010,17-AAG-nab,NCS-683664,迈考拉伯(Mycograb),CNF-2024,PU3,PU24FC1,VER49009,IPI-504,SNX-2112和STA-9090。
组蛋白脱乙酰酶抑制剂(HDAC)的例子包括,但不限于,辛二酰苯胺异羟肟酸(SAHA),MS-275,丙戊酸,TSA,LAQ-824,特拉泼星(Trapoxin),图拔星(tubacin),图拔他汀(tubastatin),ACY-1215和缩酚酸肽(Depsipeptide)。
MEK抑制剂的例子包括,但不限于,PD325901,ARRY-142886,ARRY-438162和PD98059。
CDK抑制剂的例子包括,但不限于,夫拉平度(flavopyridol),MCS-5A,CVT-2584,色立昔布(seliciclib)(CYC-202,R-洛扣瓦汀(roscovitine)),ZK-304709,PHA-690509,BMI-1040,GPC-286199,BMS-387,032,PD0332991和AZD-5438。
COX-2抑制剂的例子包括,但不限于,CELEBREXTM(塞来昔布),帕瑞考昔,地拉考昔,ABT-963,MK-663(依托考昔),COX-189(罗美昔布),BMS347070,RS57067,NS-398,伐地考昔,帕雷考昔,罗非昔布,SD-8381,4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基-苯基-1H-吡咯,T-614,JTE-522,S-2474,SVT-2016,CT-3,SC-58125和Arcoxia(依托考昔)。
非甾体类抗炎药(NSAID)的例子包括,但不限于,双水杨酯(Amigesic),二氟尼柳(Dolobid),布洛芬(布洛芬),酮洛芬(Orudis),萘丁美酮(Relafen),吡罗昔康(Feldene),萘普生(Aleve,萘普生),双氯芬酸(扶他林),吲哚美辛(消炎痛),舒林酸(Clinoril),托美丁(Tolectin),依托度酸(碘值),酮咯酸(Toradol)和奥沙普秦(Daypro)。
ERBB2受体抑制剂的例子包括,但不限于,CP-724-714,CI-1033,(卡奈替尼),赫赛汀(曲妥珠单抗),Omitarg(2C4,佩图珠单抗-petuzumab),TAK-165,GW-572016(Ionafarnib)GW-282974,EKB-569,PI-166,dHER2(HER2疫苗),APC8024(HER2疫苗),抗HER/2neu双特异性抗体,B7.her2IgG3,AS HER2的三功能双特异性抗体,单克隆抗体AR-209和单克隆抗体2B-1。
烷基化剂的例子包括,但不限于,氮芥N-氧化物,环磷酰胺,异环磷酰胺,氯乙环磷酰胺,苯丁酸氮芥,美法仑,白消安,二溴甘露醇,卡波醌,塞替派,雷莫司汀,尼莫司汀,替莫唑胺,AMD-473,六甲蜜胺,AP-5280,阿帕昆(apaziquone),布洛塔星(brostallicin),苯达莫司汀,卡莫司汀,雌莫司汀,福莫司汀,葡磷酰胺,KW-2170,马磷酰胺,二溴卫矛醇以及,卡莫司汀(BCNU),洛莫司汀(CCNU),白消安,曲奥舒凡,氮烯咪胺和替莫唑胺。
抗代谢物的例子包括,但不限于,甲氨蝶呤,6-巯基嘌呤核苷,巯基嘌呤,尿嘧啶类似物,如5-氟尿嘧啶(5-FU)单独或组合使用亚叶酸,替加氟,UFT,去氧氟尿苷,卡莫氟,阿糖胞苷,阿糖胞苷,依诺他滨,S-I,力比泰(培美曲塞二钠,LY231514,MTA),健择(吉西他滨),氟达拉滨,5-氮杂胞苷,卡培他滨,克拉屈滨,氯法拉滨,地西他滨,依氟鸟氨酸,ethnylcytidine,阿糖胞苷,羟基脲,TS-I,美法仑,奈拉滨,洛拉曲克,ocfosate,培美曲塞二钠(disodium premetrexed),喷司他丁,pelitrexol,雷替曲塞,triapine,三甲曲沙,阿糖腺苷,长春新碱,长春瑞滨,霉酚酸,噻唑呋林,利巴韦林,EICAR,羟基脲和去铁胺。
抗生素的实例包括嵌入抗生素,但不限于,阿柔比星,放线菌素(如放线菌素D),氨柔比星,阿那米星(annamycin),阿霉素,博莱霉素a,博来霉素b,柔红霉素,多柔比星,依沙芦星,表柔比星(epirbucin),格拉布星(glarbuicin),伊达比星,丝裂霉素C,奈莫柔比星,新制癌菌素,培洛霉素,吡柔比星,蝴蝶霉素,丁斯酯,链佐星,戊柔比星,净司他丁和其组合。
拓扑异构酶抑制剂的例子包括,但不限于,一种或多种选自下组的试剂:阿柔比星,氨萘非特(amonafide),贝洛替康(belotecan),喜树碱,10-羟基喜树碱,9-氨基喜树碱,氟替康(diflomotecan),伊立替康盐酸盐(Camptosar),edotecarin,表柔比星(Ellence),依托泊苷,依喜替康(exatecan),吉马替康,勒托替康,orathecin(Supergen),BN-80915,米托蒽醌,匹拉布星(pirarbucin),匹杉琼(pixantrone),卢比替康,索布佐生,SN-38,他弗泊苷(tafluposide)和托泊替康。
抗体的例子包括,但不限于,利妥昔单抗,西妥昔单抗,贝伐单抗,特拉图单抗(Trastuzimab),特异性CD40抗体和特异性IGF1R抗体。
激素疗法的实例包括,但不限于,依西美坦(阿诺新),醋酸亮丙瑞林,阿那曲唑(瑞宁得),福斯林(fosrelin,诺雷德),戈舍瑞林(goserelin),度骨化醇,法倔唑,福美坦,他莫昔芬柠檬酸盐(他莫昔芬),康士得,阿巴瑞克,TRELSTAR,非那雄胺,氟维司群,托瑞米芬,雷洛昔芬,拉索昔芬,来曲唑,氟他胺,比卡鲁胺,甲地孕酮(megesterol),米非司酮,尼鲁米特,***,强的松等皮质激素
类维生素A/三角肌(deltoids)的例子包括,但不限于,西奥骨化醇(seocalcitol)(EB1089,CB1093),来沙骨化醇(lexacalcitrol,KH 1060),芬维A胺,阿利微A酸(Aliretinoin),蓓萨罗丁和LGD-1550。
植物生物碱的实例包括,但不限于,长春新碱,长春碱,长春地辛和长春瑞滨。
蛋白酶体抑制剂的实例包括,但不限于,硼替佐米(万珂),MGL32,NPI-0052和PR-171。
免疫制剂的实例包括,但不限于,干扰素和许多其它免疫促进剂。干扰素包括干扰素α,干扰素α-2a,干扰素α-2b,干扰素β,干扰素γ-1a中,干扰素γ-1b(Actimmune)或干扰素γ-nl及其组合。其他促进剂包括非尔司亭(filgrastin),香菇多糖(lentinan),西佐喃(sizofilan),TheraCys,乌苯美司(ubenimex),WF-10,阿地白介素(aldesleukin),阿仑单抗,BAM-002,达卡巴嗪(decarbazine),赛尼哌(daclizumab),地尼白介素(denileukin),吉妥单抗(gemtuzumab ozogamicin),替伊莫(ibritumomab),咪喹莫特(imiquimod),来格司亭(lenograstim),香菇多糖(lentinan),黑色素瘤疫苗(melanoma vaccine)(Corixa公司),莫拉司亭(molgramostim),OncoVAC-CL,沙莫司亭(sargaramostim),他索纳明(tasonermin),tecleukin,thymalasin,托西莫单抗(tositumomab),维如利金(Virulizin),Z-100,依帕珠单抗(epratuzumab),米妥莫单抗(mitumomab),奥戈伏单抗(oregovomab),佩图莫单抗(pemtumomab,Y-muHMFGl),普罗文奇(Provenge)(Dendreon公司),STING激活剂,IDO抑制剂,精氨酸代谢酶抑制剂,CTLA4(细胞毒性淋巴细胞抗原4)抗体以及能阻断CTLA4的试剂,PD1抗体或PD-L1等免疫检查点蛋白抑制剂或抗体。
生物反应调节剂的例子是调节有生命的生物体的防御机制或生物反应(如组织细胞的存活、生长或分化)以引导其具有抗肿瘤活性的试剂。这样的药物包括云芝胞内多糖(Krestin),香菇多糖,西佐弗兰(sizofrran),溶链菌和乌苯美司。
嘧啶类似物的例子包括,但不限于,5-氟尿嘧啶,氟尿苷,去氧氟尿苷,拉地曲德(Ratitrexed),阿糖胞苷(阿糖胞苷C),阿糖胞苷,氟达拉滨和吉西他滨。
嘌呤类似物的例子包括,但不限于,巯基嘌呤和硫鸟嘌呤。
免疫调节剂的例子包括,但不限于,沙利度胺和来那度胺。
抗有丝***剂的例子包括,但不限于,紫杉醇,多西他赛,白蛋白紫杉醇(ABRAXANE),埃坡霉素D(KOS-862)和ZK-EPO。
合成
本发明的化合物可通过如下反应式制备:
合成流程
本发明的化合物可以通过化学合成的方法制备,其实例在下文示出。应理解的是,所述过程中的步骤的顺序可以改变,那些具体提及的试剂、溶剂和反应条件可以替换,如有必要,易反应的部位可被保护和脱保护。
下面的缩写具有如下所示的意义。DBU是指1,8-二氮杂双环[5.4.0]十一碳-7-烯;DIBAL表示二异丁基氢化铝;DIEA指二异丙基乙胺;DMAP是指N,N-二甲基氨基吡啶;DME指1,2-二甲氧基乙烷;DMF指N,N-二甲基甲酰胺;DMPE是指1,2-双(二甲基膦基)乙烷;DMSO表示二甲亚砜;DPPB指1,4-双(二苯基膦基)丁烷;dppe指1,2-双(二苯基膦基)乙烷;dppf指1,1′-双(二苯基膦基)二茂铁;dppm指1,1′-双(二苯基膦基)甲烷;DIAD指偶氮二甲酸二异丙酯;EDCI表示1-(3-二甲基氨基丙基)-3-乙基碳二亚胺;HATU表示2-(7-氮杂-1H-苯并***-1-基)-1,1,3,3-四甲基脲六氟磷酸盐;HMPA表示六甲基磷酰胺;IPA是指异丙醇;LDA是指二异丙基氨基锂;LHMDS是指二(三甲基硅基)氨基锂;LAH表示氢化铝锂;NCS指N-氯琥珀酰亚胺;PyBOP是指苯并***-1-基-氧基三吡咯烷基磷苯并***六氟磷酸盐;TDA-I是指三(2-(2-甲氧基乙氧基)乙基)胺;DCM指二氯甲烷;TEA是指三乙胺,TFA是指三氟乙酸;THF是指四氢呋喃;NCS指N-氯琥珀酰亚胺;NMM是指N-甲基吗啉;NMP是指N-甲基吡咯烷酮;PPh3指三苯基膦,rt是指室温。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1
(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:(1R,3S)-3-羟基环己基乙酸酯
氮气保护下,向一个烘干的100毫升二口烧瓶中,加入顺-1,3-环己二醇(1.00g,8.61mmol)和Candida Antarctica lipase B(CALB)(180mg)。另取一个50毫升二口烧瓶,向其中加入乙酸4-氯苯酯(2.20g,12.91mmol)以及30毫升甲苯溶液,用氮气脱气5分钟后,将该溶液加入到上述反应瓶中。室温搅拌过夜,TLC监测反应,8小时后反应结束,除去溶剂,粗产品经硅胶柱纯化(石油醚:乙酸乙酯=3:1),得到产品1.20g,产率为88%。
1H NMR(400MHz,CDCl3):δ4.78-4.71(m,1H),3.74-3.67(m,1H),2.25-2.21(m,1H),2.05(s,3H),1.92-1.89(m,2H),1.83-1.80(m,2H),1.44-1.23(m,4H).
步骤2:光学活性测试:(1S,3R)-3-乙酰氧基环己基(R)-3,3,3-三氟-2-甲氧基-2-苯基丙酸酯
在一个25毫升烧瓶中,加入(1R,3S)-3-羟基环己基乙酸酯(15mg,0.10mmol),吡啶(15mg,0.19mmol)以及5毫升二氯甲烷。在冰水浴冷却下,向体系中加入(S)-3,3,3-三氟-2-甲氧基-2-苯基丙酰氯(24mg,0.10mmol)的2毫升二氯甲烷溶液,TLC监测反应,原料消失后,制备TLC纯化(石油醚:乙酸乙酯=3:1),得35mg产品,产率:99%。
1H NMR(400MHz,Acetone-d6):δ7.56-7.54(m,2H),7.49-7.46(m,3H),5.13-5.06(m,1H),4.81-4.73(m,1H),3.57(s,3H),2.30-2.25(m,1H),2.08(m,1H),1.93(s,3H),1.90-1.84(m,2H),1.54-1.42(m,3H),1.40-1.29(m,1H).
19F NMR(400MHz,Acetone-d6):δ-72.71(s).
步骤3:(1R,3R)-3-(3-(4-苯氧基苯基)-4-((三苯基-5-亚膦基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯和(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯
氮气保护下,向一充分烘干的250毫升三口烧瓶中,加入三苯基膦(12.44g,47.41mmol),150毫升超干四氢呋喃溶剂,并把烧瓶置于冰浴中。冷却至0摄氏度后,向体系中逐滴加入偶氮二甲酸二异丙酯(9.59g,47.41mmol)。滴加完后,继续搅拌40分钟,有白色沉淀析出,继续搅拌10分钟。向体系中依次加入3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(6.04g,19.91mmol)和(1R,3S)-3-羟基环己基乙酸酯(3.00g,18.96mmol),加完之后,体系变为澄清浅黄色体系。室温搅拌过夜,TLC监测反应结束。向体系中加入5毫升饱和氯化铵溶液淬灭反应。除去四氢呋喃,加入100毫升二氯甲烷,50毫升饱和食盐水,分液,二氯甲烷萃取(50mL×2),合并有机相,无水硫酸钠干燥。过滤,滤液中加入硅胶旋干,硅胶柱纯化(石油醚(含10%二氯甲烷):乙酸乙酯=100:1~100:2),得到化合物(1R,3R)-3-(3-(4-苯氧基苯基)-4-((三苯基-5-亚膦基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯3.00g,产率:20%;用二氯甲烷:甲醇=100:1~100:2,得到产物(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯3.40g,产率:40%。
(1R,3R)-3-(3-(4-苯氧基苯基)-4-((三苯基-5-亚膦基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基):
1H NMR(400MHz,CDCl3):δ8.43-8.40(d,2H),8.07(s,1H),7.81-7.78(m,6H),7.52-7.50(m,3H),7.43-7.37(m,8H),7.13-7.07(m,5H),5.35(m,1H),5.12-5.08(m,1H),2.57-2.50(m,1H),2.19-2.15(m,1H),2.19(s,3H),1.9-1.98(m,1H),1.93-1.90(m,1H),1.84-1.74(m,1H),1.66-1.61(m,1H),1.43-1.40(m,1H).
MS ESI:m/z=704,[M+H]+.
(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯:
1H NMR(400MHz,CDCl3):δ8.39(s,1H),7.67-7.64(m,2H),7.41-7.37(m,2H),7.17-7.14(m,3H),7.09-7.07(m,2H),5.52(br-s,2H),5.35-5.30(m,1H),5.18-5.10(m,1H),2.51-2.44(m,1H),2.23-2.20(m,1H),2.13(s,3H),2.11-2.08(m,2H),1.97-1.77(m,4H),1.66-1.58(m,1H).
MS ESI:m/z=444,[M+H]+.
步骤4:(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯
在一烘干的25毫升烧瓶中,加入(1R,3R)-3-(3-(4-苯氧基苯基)-4-((三苯基-5-亚膦基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基)(0.30g,0.43mmol),再加入5毫升(乙酸/水v/v=1/1)混合溶剂,加热回流。TLC监测反应,待原料反应完毕,加入二氯甲烷萃取(10mL×3),合并有机相,经硅胶柱纯化(二氯甲烷:甲醇=100:1~100:2)得到产品180mg,产率:95%。
1H NMR(400MHz,CDCl3):δ8.39(s,1H),7.67-7.64(m,2H),7.41-7.37(m,2H),7.17-7.14(m,3H),7.09-7.07(m,2H),5.52(br-s,2H),5.35-5.30(m,1H),5.18-5.10(m,1H),2.51-2.44(m,1H),2.23-2.20(m,1H),2.13(s,3H),2.11-2.08(m,2H),1.97-1.77(m,4H),1.66-1.58(m,1H).
MS ESI:m/z=444,[M+H]+.
步骤5:(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)环己-1-醇
在一50毫升单口烧瓶中,加入(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯(1.50g,3.38mmol),30毫升甲醇。搅拌下,向其中加入无水LiOH(0.25g,10.28mmol),室温搅拌过夜。TLC监测反应结束。过滤除去LiOH,加入硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1~100:3)纯化,得到产品1.30g,产率:96%。
1H NMR(400MHz,CDCl3):δ8.36(s,1H),7.67-7.63(m,2H),7.41-7.37(m,2H),7.19-7.14(m,3H),7.09-7.07(m,2H),5.67(br-s,2H),5.28-5.23(m,1H),4.40(m,1H),2.41-2.34(m,1H),2.15-2.07(m,4H),1.84-1.73(m,2H),1.69-1.61(m,1H).
MS ESI:m/z=402,[M+H]+.
实施例2
(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯甲酸环己酯
在一25毫升烘干的烧瓶中,加入三苯基膦(131mg,0.50mmol),10毫升四氢呋喃,搅拌至澄清。在冰水浴冷却下,向烧瓶中慢慢滴加偶氮二甲酸二异丙酯(101mg,0.50mmol),保持5摄氏度以下反应1小时,析出白色沉淀。继续搅拌10分钟后,向体系中加入苯甲酸(61mg,0.50mmol)和(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)环己-1-醇(100mg,0.25mmol)的四氢呋喃混合溶液,滴加完毕,撤去冰浴,使反应液自然升至室温。反应2个小时后TLC监测反应结束,加入硅胶,旋干,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品110mg,产率:87%。
1H NMR(400MHz,Acetone-d6):δ8.27(s,1H),8.05-8.03(m,2H),7.78-7.74(m,2H),7.64-7.61(m,1H),7.52-7.48(m,2H),7.46-7.42(m,2H),7.21-7.17(m,3H),7.13-7.11(m,2H),6.38(br-s,2H),5.25-5.17(m,1H),5.04-4.96(m,1H),2.50-2.45(m,1H),2.42-2.30(m,1H),2.28-2.20(m,1H),2.18-2.11(m,1H),1.76-1.66(m,4H).
MS ESI:m/z=506,[M+H]+.
步骤2:(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一25毫升烧瓶中,加入(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)苯甲酸环己酯(100mg,0.20mmol),5毫升甲醇,向其中分批加入无水氢氧化锂(14mg,0.59mmol),室温搅拌过夜。TLC监测反应结束。过滤除去氢氧化锂,加入硅胶,旋干,经硅胶柱(二氯甲烷:甲醇=100:2~100:3)纯化,得到产品75mg,产率:94%。
1H NMR(400MHz,CDCl3):δ8.38(s,1H),7.67-7.64(m,2H),7.41-7.37(m,2H),7.17-7.14(m,3H),7.09-7.07(m,2H),5.47(br-s,2H),4.94-4.87(m,1H),3.91-3.86(m,1H),2.37-2.33(m,1H),2.21-2.12(m,2H),2.03-1.6(m,4H),1.52-1.44(m,1H).
MS ESI:m/z=402,[M+H]+.
实施例3
(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇和(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇
步骤1:(R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-酮
在一25毫升烧瓶中,加入(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)环己-1-醇(0.30g,0.68mmol),5毫升超干二氯甲烷,置于冰水浴中,然后加入Dess-Martin试剂(0.43g,1.02mmol),室温搅拌过夜,TLC监测反应,若原料还未反应完毕,补加0.5当量的Dess-Martin试剂。反应结束后,过滤除去白色不溶物,加入硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品230mg,产率:85%。
1H NMR(400MHz,Acetone-d6):δ8.26(s,1H),7.76-7.74(m,2H),7.46-7.42(m,2H),7.21-7.11(m,5H),6.40(br-s,2H),5.28-5.21(m,1H),3.18-3.09(m,1H),2.76-2.72(m,1H),2.57-2.49(m,1H),2.42-2.33(m,2H),2.25-2.08(m,2H),1.91-1.80(m,1H).
MS ESI:m/z=400,[M+H]+.
步骤2:(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇和(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇
氮气保护下,向一充分烘干的25毫升烧瓶中,加入无水三氯化铈(0.35g,1.41mmol),5毫升超干四氢呋喃。室温下搅拌2小时后,将烧瓶放入干冰-乙醇浴中,待体系温度降至零下七十摄氏度附近,向体系中慢慢加入甲基锂的1M***溶液(1.41mL,1.41mmol)。反应液在此温度下反应90分钟后,向体系中加入(R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-酮(0.12g,0.35mmol)的2毫升超干四氢呋喃溶液,并继续反应6个小时。TLC监测反应结束。加入硅胶,旋干,经硅胶柱(二氯甲烷:甲醇=100:2~100:3)纯化,依次得到实施例3A:(1S,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇50mg;实施例3B:(1R,3R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己烷-1-醇,50mg,总产率:68%。
实施例3A:
1H NMR(400MHz,Acetone-d6):δ8.25(s,1H),7.76-7.74(m,2H),7.46-7.42(m,2H),7.21-7.16(m,3H),7.13-7.11(m,2H),6.36(br-s,2H),4.97-4.89(m,1H),3.96(br-s,1H),2.29-2.23(m,1H),2.01-1.86(m,4H),1.74-1.71(m,1H),1.62-1.56(m,2H),1.35(s,3H).
MS ESI:m/z=416.2,[M+H]+.
实施例3B:
1H NMR(400MHz,Acetone-d6):δ8.24(s,1H),7.76-7.74(m,2H),7.46-7.42(m,2H),7.21-7.15(m,3H),7.13-7.11(m,2H),6.32(br-s,2H),5.27-5.19(m,1H),3.49(br-s,1H),2.18-2.12(m,1H),1.98-1.91(m,4H),1.72-1.69(m,2H),1.49-1.41(m,1H),1.29(s,3H).
MS ESI:m/z=416.2,[M+H]+.
实施例4
3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-(三氟甲基)环己-1-醇
在一25毫升烘干的烧瓶中,加入(R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-酮(30mg,0.09mmol),三氟甲基三甲基硅烷(13mg,0.09mmol),2毫升四氢呋喃。室温搅拌下,向体系中加入3mg氟化铯,室温搅拌3小时后,加入2毫升4N盐酸溶液,再搅拌2小时后,加入5毫升水,二氯甲烷萃取(5mL×2),合并有机相,无水硫酸钠干燥,加入硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品10mg,产率:21%。
1H NMR(400MHz,CDCl3):δ8.47(s,1H),8.08(br-s,1H),7.71-7.70(m,2H),7.47-7.38(m,2H),7.21-7.08(m,5H),5.66(br-s,2H),5.47(s,1H),2.42-2.41(m,2H),2.1-2.0(m,3H),1.9-1.85(m,2H),1.75-1.72(m,1H).
MS ESI:m/z=470.17,[M+H]+.
实施例5
3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊醇
3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(600mg,2.00mmol)和1,3-环戊二醇(200mg,2.00mmol),三苯基膦(924mg,3.50mmol)溶于20毫升无水四氢呋喃中,放置于冰水浴中搅拌,滴加偶氮二甲酸异丙酯(712mg,3.50mmol)。滴加完毕后,溶液在冰水浴下继续搅拌1小时,TLC显示原料消失。反应液直接浓缩后经硅胶柱(二氯甲烷:甲醇=20:1)纯化,得到产品500mg,收率:64%。
1H NMR(400MHz,DMSO-d6):δ8.24(s,1H),7.68-7.66(m,2H),7.46-7.42(m,2H),7.21-7.12(m,5H),5.22-5.14(m,1H),4.94(d,1H),4.24-4.20(m,1H),2.43-2.36(m,1H),2.21-2.14(m,1H),2.08-2.00(m,2H),1.92-1.84(m,1H),1.82-1.74(m,1H).
MS ESI:m/z=388.1,[M+H]+.
实施例6
3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊醇
步骤1:3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊酮
将实施例5(500mg,1.29mmol)溶于二氯甲烷15毫升中。在冰水浴冷却下,向体系中加入Dess-Martin氧化剂(548mg,1.29mmol),搅拌2小时后,再补加Dess-Martin氧化剂(273mg,0.64mmol)。TLC监测反应,待原料消失后,向体系中加入5毫升饱和碳酸氢钠溶液淬灭反应,分液,二氯甲烷萃取(20mL×1),合并有机相,干燥,过滤,浓缩后经硅胶柱(二氯甲烷:甲醇=20:1)纯化,得到产品500mg,收率:100%。
MS ESI:m/z=386.1,[M+H]+.
步骤2:3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊醇
氩气保护下,向一个25毫升两口反应瓶中加入无水三氯化铈(153mg,0.62mmol)以及10毫升超干四氢呋喃。在室温下搅拌1小时后,将反应体系置于干冰-乙醇浴中冷却。待冷却到零下75摄氏度后,向反应体系中逐滴加入甲基锂的***溶液(1.33M,0.48mL,0.62mmol)。所得溶液在此温度下继续搅拌1小时后,向反应体系中逐滴加入3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊酮的四氢呋喃溶液(40mg,0.1mmol/0.5mL THF)。滴加完毕后,此温度下继续反应1.5小时,TLC显示有新点生成。用10毫升饱和氯化铵溶液淬灭反应,乙酸乙酯(20mL×1),有机相经无水硫酸钠干燥,过滤,浓缩后经硅胶柱(二氯甲烷:甲醇=20:1)纯化,得到产品6mg,收率:15%。
1H NMR(400MHz,CDCl3):δ8.36(s,1H),7.65(m,2H),7.41-7.37(m,2H),7.19-7.14(m,3H),7.08(m,2H),5.71-5.63(m,1H),5.60(br-s,2H),2.52-2.45(m,1H),2.42-2.37(m,1H),2.28-2.11(m,4H),1.52(s,3H).
MS ESI:m/z=402.1,[M+H]+.
实施例7
3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-(三氟甲基)环戊醇
3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊酮(39mg,0.10mmol)、氟化铯(0.15mg)和三氟甲基三甲基硅烷(15mg,0.10mmol)加入到反应瓶中,然后加入1毫升超干四氢呋喃。溶液由无色变成橘色,室温下搅拌3小时。加入4N盐酸水溶液(0.06mL),继续搅拌2小时。TLC和LCMS监测反应完毕。向反应液中加入2毫升水淬灭反应,乙酸乙酯萃取(5mL×3),合并有机相,用无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=20:1)纯化,得到产品10mg,收率:22%。
1H NMR(400MHz,CDCl3):δ8.36(s,1H),7.63(m,2H),7.42-7.37(m,2H),7.20-7.17(m,1H),7.16-7.13(m,2H),7.10-7.07(m,2H),5.70(br-s,2H),5.55-5.50(m,1H),2.76-2.69(m,1H),2.56-2.49(m,1H),2.40(m,1H),2.36-2.30(m,1H),2.15-2.11(m,2H).
MS ESI:m/z=456.1,[M+H]+.
实施例8
(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己烷-1-醇和(1r,4r)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己烷-1-醇
在一个充分烘干的50毫升二口烧瓶中,加入三苯基膦(0.52g,1.98mmol),15毫升超干四氢呋喃溶剂,并置于冰乙醇浴中冷却。然后,向体系中滴入偶氮二甲酸二异丙酯(0.40g,0.39mL,1.98mmol),继续在此温下搅拌约30分钟,此时可以看到体系变为白色沉淀状。向上述反应液中加3-(4-苯氧苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(0.30g,0.99mmol)和1,4-环己二醇(顺式:反式=1:0.7,核磁含量)(114mg,0.99mmol)的10毫升四氢呋喃溶液。反应30分钟后,TLC监测反应,原料1,4-环己二醇已经消失。向反应体系中加入20毫升饱和氯化铵溶液,除去绝大部分四氢呋喃,二氯甲烷萃取(20mL×3),合并有机相,饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,加入硅胶拌样,经硅胶柱(二氯甲醇/甲醇体系)甲醇含量为1%时,得到产品实施例8A:(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己烷-1-醇100mg,产率:26%;甲醇含量为2%时,得到产品实施例8B:(1r,4r)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己烷-1-醇30mg,产率:10%。
实施例8A:
1H NMR(400MHz,CDCl3):δ8.38(s,1H),7.67-7.63(m,2H),7.40-7.39(m,2H),7.19-7.07(m,5H),5.46(br-s,2H),4.84-4.76(m,1H),3.86-3.79(m,1H),2.28-2.05(m,6H),1.57-1.56(m,2H).
MS ESI:m/z=402,[M+H]+.
实施例8B:
1H NMR(400MHz,CDCl3):δ8.43(s,1H),7.48-7.41(m,2H),7.40-7.39(m,2H),7.28-7.27(m,1H),7.24-7.16(m,4H),5.24(br-s,2H),4.22-4.16(m,1H),3.91-3.86(m,1H),2.45-2.35(m,2H),2.14-2.11(m,2H),1.95-1.92(m,2H),1.40-1.31(m,2H).
MS ESI:m/z=402,[M+H]+.
实施例9
(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇和(1r,4r)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇
步骤1:4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]环己酮-1-酮
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氩气保护下,在一个烘干的25毫升烧瓶中,加入化合物(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己烷-1-醇(0.20g,0.45mmol),3毫升无水二氯甲烷溶剂,并将其置于冰-乙醇浴中。搅拌下,向其中滴入Dess-Martin试剂(0.23g,0.53mmol)的3毫升二氯甲烷溶液,加完之后,继续搅拌5小时。TLC监测反应结束,向体系中加入适量硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品150mg,产率:83%。
1H NMR(400MHz,CDCl3):δ8.32(s,1H),7.59-7.57(m,2H),7.34-7.30(m,2H),7.12-7.06(m,3H),7.03-7.00(d,2H),5.53(br-s,2H),5.23-5.20(m,1H),2.62-2.49(m,6H),2.34-2.30(m,2H).
MS ESI:m/z=400,[M+H]+.
步骤2:(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇和(1r,4r)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇
在氩气保护下,在一个充分烘干的25毫升二口烧瓶中,加入无水三氯化铈(0.29g,1.18mmol),2毫升无水四氢呋喃溶剂,室温下搅拌1小时。将此反应液置于干冰-乙醇浴中冷却,待至零下75摄氏度左右时,向体系中逐滴加入1M甲基锂(1.18mL,1.18mmol)的***溶液,并保持零下75摄氏度反应2小时后,向其中加入中间体4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]环己酮-1-酮(100mg,0.30mmol)的5毫升四氢呋喃溶液。加完之后继续在此温度下反应15分钟,撤去干冰-乙醇浴,继续反应1小时(自然升温),TLC显示反应结束。向体系中加入15毫升0.5N盐酸水溶液,二氯甲烷萃取(10mL×3),合并有机相,饱和碳酸氢钠水溶液(10mL×2)洗涤,水洗(20mL×2),饱和食盐水洗涤(20mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品实施例9A:(1s,4s)-4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇50mg,产率:42%;实施例9B:(1r,4r)-4(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-甲基环己烷-1-醇50mg,产率:42%。
实施例9A:
1H NMR(400MHz,CDCl3):δ8.37(s,1H),7.66(d,J=8.6Hz,2H),7.39(t,J=8.0Hz,2H),7.16(dd,J=12.2Hz,8.0Hz,3H),7.08(d,J=7.7Hz,2H),5.49(br-s,2H),4.79-4.72(m,1H),2.55-2.45(m,2H),1.94-1.79(m,4H),1.75-1.67(m,2H),1.32(s,3H).
MS ESI:m/z=416,[M+H]+.
实施例9B:
1H NMR(400MHz,CDCl3):δ8.37(s,1H),7.65(d,J=8.7Hz,2H),7.39(dd,J=8.5,7.5Hz,2H),7.21-7.12(m,3H),7.08(dd,J=8.6,1.0Hz,2H),5.53(s,2H),4.91-4.76(m,1H),2.33–2.18(m,2H),2.09-2.01(m,2H),1.92(d,J=12.8Hz,2H),1.77(dd,J=13.1,3.8Hz,2H),1.43(s,3H).
MS ESI:m/z=416,[M+H]+.
实施例10
4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-环丙基环己烷-1-醇
氩气保护下,在一充分烘干的50毫升二口烧瓶中,加入中间体4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]环己-1-酮(0.30g,0.75mmol),30毫升无水四氢呋喃,并将反应瓶置于冰-乙醇浴中。待冷至负十度左右时,向体系中逐滴加入1M环丙基溴化镁的四氢呋喃溶液(7.51mL,7.51mmol)。滴加完后,撤去冰-乙醇浴,使之自然升至室温。室温下继续反应过夜。TLC监测反应结束。向体系中加入10毫升0.5N稀盐酸水溶液,二氯甲烷萃取(10mL×3),合并有机相,碳酸氢钠水溶液洗涤(10mL×3),水洗(10mL×3),饱和氯化钠溶液洗涤(20mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品250mg,产率:76%。
1H NMR(400MHz,CDCl3):δ8.35(s,1H),7.65(m,2H),7.45-7.32(m,2H),7.19-7.04(m,5H),5.70(br-s,2H),4.98-4.84(m,0.3H),4.77(m,0.7H),2.67-2.44(m,1.6H),2.44-2.32(m,0.75H),2.18-1.53(m,6H),1.06-0.84(m,1H),0.40(d,J=6.9Hz,4H).
MS ESI:m/z=442,[M+H]+.
实施例11
(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇和(1r,4r)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:1-溴-4-(4-氟苯氧基)苯
氩气保护下,向一个充分烘干的500毫升三口烧瓶内依次加入对溴碘苯(30.00g,106.04mmol),4-氟苯酚(17.83g,159.06mmol),碳酸铯(69.10g,212.08mmol),二甲氨基乙酸(0.82g,7.95mmol),碘化亚铜(0.40g,2.12mmol)和350毫升1,4-二氧六环。升温至90摄氏度。保持该温度反应8小时后,TLC显示原料已反应完全。向体系中加入200毫升水,分液,乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤(300mL×1),无水硫酸钠干燥,过滤,加入硅胶拌样,经硅胶柱(石油醚)纯化,得到产品21.00g,产率:73%。
1H NMR(400MHz,CDCl3):δ7.42(d,J=9.0Hz,2H),7.08-7.00(m,2H),7.00-6.93(m,2H),6.84(d,J=9.0Hz,2H).
步骤2:(4-(4-氟苯氧基)苯基)硼酸
氩气保护下,向一250毫升二口烧瓶中,加入中间体1-溴-4-(4-氟苯氧基)苯(2.00g,7.49mmol),100毫升无水四氢呋喃,并将反应瓶置于干冰-乙醇浴中冷却。向体系中逐滴加入2.4M的正丁基锂的正己烷溶液(4.06mL,9.73mmol),继续搅拌40分钟后,向体系中滴入三异丙氧硼。TLC监测反应完全后,将反应体系缓慢倒入100毫升饱和氯化铵溶液中,乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤(100mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(石油醚:乙酸乙酯=97:3~55:45)纯化,得到产品1.50g,产率:86%。
1H NMR(400MHz,CDCl3):δ8.16(d,J=8.6Hz,2H),7.10-6.94(m,8H).
步骤3:3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺
在一个烘干的25毫升二口烧瓶中,加入3-碘代-1H-吡唑并[3,4-d]嘧啶-4-胺(5.00g,19.16mmol),中间体(4-(4-氟苯氧基)苯基)硼酸(8.89g,38.31mmol),和磷酸钾(12.20g,57.47mmol)以及150毫升1,4-二氧六环和50毫升水,抽换氩气三次,然后加入四三苯基膦钯(3.32g,2.87mmol),再抽换氩气三次。升温至回流。约三小时后,TLC显示反应结束。向体系中加入150毫升水,搅拌10分钟后,过滤。粗产品用甲醇和乙酸乙酯(甲醇:乙酸乙酯=1:5,10mL)打浆,得到产品4.31g,产率:70%。
1H NMR(400MHz,DMSO-d6):δ13.45(s,1H),8.21(s,1H),7.66(d,J=8.5Hz,2H),7.27(t,J=8.7Hz,2H),7.21-7.16(m,2H),7.13(d,J=8.5Hz,2H),6.74(br-s,2H).
MS ESI:m/z=322,[M+H]+.
步骤4:(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇和(1r,4r)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
氩气保护下,在一个充分干燥的100毫升二口烧瓶中,加入中间体3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1.00g,3.11mmol),1,4-环己二醇(顺式:反式=1:0.7,核磁含量)(0.72g,6.22mmol),三苯基膦(1.63g,6.22mmol)和40毫升无水四氢呋喃,并将反应液置于冰乙醇浴中冷却。向反应液中慢慢滴加偶氮二甲酸二异丙酯(1.26g,6.22mmol),滴加完后反应液搅拌过夜。TLC和LCMS监测反应结束。然后加入20毫升饱和氯化铵溶液,除去大部分四氢呋喃,加入20毫升水,二氯甲烷萃取(30mL×3),合并有机相,饱和食盐水洗涤(50mL×1),无水硫酸钠干燥,过滤,加入硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1.2~100:10)纯化,得到产品实施例11A:(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇700mg,产率:53%;实施例11B:(1r,4r)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇100mg,产率:8%。
实施例11A:
1H NMR(400MHz,CDCl3):δ8.34(s,1H),7.66(d,J=8.7Hz,2H),7.10-7.06(m,6H),5.90(br-s,2H),4.83-4.78(m,1H),4.12(m,1H),2.55-2.49(m,2H),2.01(m,2H),2.42-2.41(m,2H),2.04-1.99(m,2H).
MS ESI:m/z=420,[M+H]+.
实施例11B:
1H NMR(400MHz,CDCl3):δ8.38(s,1H),7.64(d,J=8.7Hz,2H),7.12-7.05(m,6H),5.45(br-s,2H),4.82-4.76(m,1H),3.86–3.75(m,2H),2.27-2.05(m,7H).
MS ESI:m/z=420,[M+H]+.
实施例12
(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇和(1r,4r)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇
步骤1:4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基环己-1-酮
氩气保护下,在一干燥的50毫升的二口烧瓶中加入化合物(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(0.60g,1.43mmol),15毫升超干二氯甲烷。将反应液置于冰乙醇浴中冷却,然后逐滴加入Dess-Martin试剂(0.72g,1.69mmol)的15毫升二氯甲烷溶液。加完继续搅拌约4小时后,LCMS显示原料反应已完全。故向体系中加入10毫升饱和氯化铵溶液,用二氯甲烷萃取(15mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤(30mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1.2~100:4)纯化,得到产品500mg,产率:83%。
MS ESI:m/z=418,[M+H]+.
步骤2:(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇和(1r,4r)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇
氩气保护下,在一个充分干燥的25毫升二口烧瓶中,加入无水三氯化铈(0.24g,0.96mmol),3毫升无水四氢呋喃,室温搅拌1小时。然后将反应液置于干冰-乙醇浴中冷却至零下70摄氏度左右,向其中逐滴加入1.6M甲基锂的***溶液(0.60mL,0.96mmol)。所得反应液继续在此温度下搅拌1小时。然后向反应液中滴加4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基环己-1-酮(0.10g,0.24mmol)的3毫升四氢呋喃溶液。加完后继续搅拌1.5小时后,TLC显示原料已反应完全。向体系中加入3毫升饱和氯化铵溶液淬灭反应,除去四氢呋喃。乙酸乙酯萃取(5mL×3),合并有机相,有机相用饱和氯化钠溶液洗涤(5mL×3),无水硫酸钠干燥,过滤,加入硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1.2~100:5~100:10)纯化,得到产品实施例12A:(1s,4s)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇25mg,产率:25%;实施例12B:(1r,4r)-4-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环己-1-醇23mg,产率:23%。
实施例12A:
1H NMR(400MHz,CDCl3):δ8.34(s,1H),7.66-7.64(d,2H),7.12-7.05(m,6H),5.73(br-s,2H),4.79-4.71(m,1H),2.54-2.44(m,2H),1.91-1.84(m,4H),1.72-1.66(m,2H),1.32(s,3H).
MS ESI:m/z=434,[M+H]+.
实施例12B:
1H NMR(400MHz,CDCl3):δ8.37(s,1H),7.66-7.64(d,2H),7.13-7.06(m,6H),5.58(br-s,2H),4.88-4.80(m,1H),2.30-2.20(m,2H),2.07-2.03(m,2H),1.93-1.90(m,2H),1.79-1.72(m,2H),1.43(s,3H).
MS ESI:m/z=434,[M+H]+.
实施例13
(±)顺式-3-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇和(±)反式-3-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇
氩气保护下,在一干燥的100毫升三口烧瓶中,加入中间体3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(3.10g,9.65mmol),三苯基膦(2.56g,9.74mmol),抽换氩气三次,并将体系置于冰-乙醇浴中。向体系中加入1,3-环戊二醇(0.99g,9.65mmol)的10毫升超干四氢呋喃溶液,然后向体系中慢慢滴加偶氮二甲酸二异丙酯(1.95g,9.65mmol),滴加完毕,继续反应3小时。LCMS监测反应完全。将反应液倒入130毫升水中,乙酸乙酯萃取(100mL×3),合并有机相,有机相用饱和食盐水洗涤(200mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱纯化,得到实施例13A:(±)顺式-3-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇1.80g,产率:46%;实施例13B:(±)反式-3-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇200mg,产率:5%。
实施例13A:
1H NMR(400MHz,CDCl3):δ8.38(s,1H),7.63(m,2H),7.15-6.97(m,6H),5.56(br-s,2H),5.47(m,1H),4.44(s,1H),2.52-2.34(m,2H),2.32-2.16(m,1H),2.20(m,1H),2.12-2.00(m,1H),1.92-1.81(m,1H).
MS ESI:m/z=406,[M+H]+.
实施例13B:
MS ESI:m/z=406,[M+H]+.
实施例14
(±)顺式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇和(±)反式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇
步骤1:3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-酮
氩气保护下,在一干燥的50毫升的二口烧瓶中,加入(±)顺式-3-(4-胺基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(0.50g,1.23mmol),加入15毫升超干二氯甲烷,并将反应液置于冰乙醇浴中冷却。然后向反应液中逐滴加入Dess-Martin试剂(0.62g,1.46mmol)的15毫升二氯甲烷溶液。加完继续搅拌反应,LCMS监测反应,待原料反应完全后,向体系中加入10毫升饱和氯化铵溶液,二氯甲烷萃取(15mL×3),合并有机相,饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,过滤,加入硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1.2~100:5)纯化,得到产品430mg,产率:86%。
1H NMR(400MHz,CDCl3):δ8.38(s,1H),7.63(m,2H),7.14-7.01(m,6H),5.69-5.62(m,1H),5.58(br-s,2H),3.02-2.96(m,1H),2.82-2.68(m,2H),2.60-2.54(m,2H),2.45-2.32(m,1H).
19F NMR(376MHz,CDCl3):δ-118.79(s).
MS ESI:m/z=404,[M+H]+.
步骤2:(±)顺式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇和(±)反式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇
氩气保护下,在一个充分干燥的25毫升二口烧瓶中,加入无水三氯化铈(0.49g,1.98mmol),3毫升无水四氢呋喃,室温搅拌1小时。将反应液置于干冰-乙醇浴中冷却至零下70摄氏度左右时,向其中逐滴加入1.6M甲基锂的***溶液(1.24mL,1.98mmol),滴加完毕后继续在此温度下搅拌1小时。然后向反应液中滴加中间体3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-酮(0.20g,0.50mmol)的3毫升四氢呋喃溶液。加完后继续搅拌1.5小时。TLC显示原料已反应完全。向体系中加入3毫升饱和氯化铵水溶液淬灭反应,除去大部分四氢呋喃。乙酸乙酯萃取(5mL×3),合并有机相,饱和氯化钠溶液洗涤(5mL×3),无水硫酸钠干燥,过滤,加入硅胶拌样,经硅胶柱(二氯甲烷:甲醇=100:1.2~100:10)纯化,得到产品实施例14A:(±)顺式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇80mg,产率:40%;实施例14B:(±)反式-3-(4-氨基-3-(4-(4-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-1-甲基环戊-1-醇70mg,产率:35%。
实施例14A:
1H NMR(400MHz,CDCl3):δ8.39(s,1H),7.67-7.65(m,2H),7.13-7.05(m,6H),5.64(br-s,2H),5.54-5.48(m,1H),2.49-2.41(m,1H),2.39-2.33(m,2H),2.22-2.18(m,1H),2.08-2.02(m,1H),1.80-1.69(m,1H),1.45(s,3H).
19F NMR(376MHz,CDCl3):δ-118.82(s).
MS ESI:m/z=420,[M+H]+.
实施例14B
1H NMR(400MHz,CDCl3):δ8.37(s,1H),7.66-7.64(m,2H),7.13-7.03(m,6H),5.71-5.63(m,1H),5.49(br-s,2H),2.52-2.37(m,1H),2.29-2.26(m,1H),2.25-2.13(m,3H),1.88-1.83(m,1H),1.52(s,3H).
19F NMR(376MHz,CDCl3):δ-118.90(s).
MS ESI:m/z=420,[M+H]+.
实施例15
(1R,3R)-3-(4-胺基-3-(4-(3-氟苯氧基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:(1R,3R)-3-(3-碘-4-((三苯基-5-磷亚烷基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基]环己基乙酸酯
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在冰乙醇浴冷却下,向一干燥的250毫升三口烧瓶中,加入(1R,3S)-3-羟基环己基乙酸酯(1.00g,6.32mmol),3-碘代-1H-吡唑并[3,4-d]嘧啶-4-胺(3.30g,12.64mmol),Ph3P(4.97g,18.96mmol),100毫升超干四氢呋喃。然后向反应液中滴加DIAD(3.84g,18.96mmol)。继续在此温度下搅拌5小时,TLC显示原料反应完毕。向反应液中加入100毫升水,乙酸乙酯萃取(100mL×2),合并有机相。有机相用饱和食盐水洗涤(100mL×1),无水硫酸钠干燥。过滤,浓缩,经硅胶柱(石油醚:乙酸乙酯=5:1)纯化,得到产品1.20g,产率:60%。
MS ESI:m/z=662,[M+H]+.
步骤2:(1R,3R)-3-(4-胺基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯
氩气保护下,向一25毫升圆底烧瓶中,加入(1R,3R)-3-(3-碘-4-((三苯基-5-磷亚烷基)氨基)-1H-吡唑并[3,4-d]嘧啶-1-基]环己基乙酸酯(100mg,0.15mmol),乙酸和水各15毫升。将反应液加热回流2小时,LCMS检测反应完毕。用饱和碳酸氢钠水溶液50毫升中和反应体系,乙酸乙酯萃取(20mL×3),合并有机相。有机相用饱和氯化钠溶液洗涤(30mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品58mg,产率:99%。
1H NMR(400MHz,DMSO-d6):δ8.20(s,1H),6.57(s,2H),5.17(s,1H),4.97-4.79(m,1H),2.28-2.17(m,1H),2.07(s,3H),1.99(d,J=13.6Hz,1H),1.89(dd,J=13.4,8.4Hz,2H),1.79(d,J=13.3Hz,1H),1.70(d,J=3.3Hz,2H),1.64-1.55(m,1H).
MS ESI:m/z=402,[M+H]+.
步骤3:1-(4-溴苯氧基)-3-氟苯
在一烘干的1000毫升三口烧瓶中,加入对溴碘苯(36.80g,130.08mmol),间氟苯酚(15.31g,136.58mmol),N,N-二([1,1’-联苯]-2-基)草酰胺(2.55g,6.50mmol),碘化亚铜(1.24g,6.50mmol),磷酸钾(55.22g,260.15mmol)以及500毫升超干二甲基亚砜。抽换氩气三次,升温至100℃反应10小时后,TLC显示反应结束。将此反应液加入到1000毫升水中,乙酸乙酯萃取(1000mL×3),合并有机相,经硅胶过滤,石油醚洗涤,饱和氯化钠溶液洗涤(200mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(石油醚)纯化,得到产品18.00g,产率:60%。
1H NMR(400MHz,CDCl3):δ7.65(d,J=8.9Hz,0.4H),7.46(d,J=8.9Hz,1.6H),7.28(td,J=8.3,6.7Hz,1H),6.92(d,J=8.9Hz,1.6H),6.85-6.74(m,2.4H),6.70(dt,J=10.1,2.3Hz,1H).
步骤4:(4-(3-氟苯氧基)苯基)硼酸
氩气保护下,向一充分烘干的250毫升三口烧瓶中,加入100毫升超干四氢呋喃,1-(4-溴苯氧基)-3-氟苯(2.00g,7.49mmol),并将反应液置于干冰-乙醇浴冷却至零下70摄氏度。向反应液中缓慢滴加正丁基锂***溶液(1.6M,9.73mmol),加完之后,继续保持在此温度反应2小时。然后向反应液中加入三异丙基氧硼(1.69g,8.99mmol)。反应5小时后,TLC板显示原料几乎全部转化为产物。向反应液中加入100毫升1N稀盐酸,二氯甲烷萃取(100mL×3),合并有机相,饱和食盐水洗涤(50mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(石油醚:乙酸乙酯=3:1)纯化,得到产品700mg,产率:50%。
1H NMR(400MHz,CDCl3):δ8.21(d,J=8.6Hz,2H),7.33(td,J=8.3,6.7Hz,1H),7.13(d,J=8.6Hz,2H),6.87(dtd,J=7.6,5.0,2.5Hz,2H),6.80(dt,J=10.0,2.3Hz,1H).
步骤5:(1R,3R)-3-(4-胺基-3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯
在一充分烘干的25毫升二口烧瓶中,依次加入(1R,3R)-3-(4-胺基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯(0.10g,0.25mmol),(4-(3-氟苯氧基)苯基)硼酸(0.12g,0.50mmol)和磷酸钾(0.16g,0.75mmol),10毫升1,4-二氧六环和5毫升水。将反应液置换氩气三次后,升温至回流,向体系中迅速加入四三苯基膦钯(0.10g,0.05mmol)。反应2个小时,LCMS显示反应结束。将反应液冷却,向体系中加入10毫升水,二氯甲烷萃取(8mL×3),合并有机相,饱和食盐水洗涤(8mL×3),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品50mg,产率:40%。
MS ESI:m/z=462,[M+H]+.
步骤6:(1R,3R)-3-(4-胺基-3-(4-(3-氟苯氧基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一25毫升烧瓶中,加入(1R,3R)-3-(4-胺基-3-(3-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯(50mg,0.11mmol),LiOH(13mg,0.54mmol)以及5毫升甲醇。室温下搅拌过夜,LCMS监测反应结束。过滤除去LiOH,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品48mg,产率:99%。
1H NMR(400MHz,CDCl3):δ8.30(s,1H),7.62(d,J=8.6Hz,2H),7.25(td,J=8.3,6.7Hz,1H),7.11(d,J=8.6Hz,2H),6.79(ddd,J=8.3,6.3,2.2Hz,2H),6.70(dt,J=10.1,2.3Hz,1H),5.54(br-s,2H),5.28-5.08(m,1H),4.34(m,1H),2.37-2.23(m,1H),2.18-1.85(m,4H),1.76-1.66(m,2H),1.61-1.54(m,1H).
MS ESI:m/z=420,[M+H]+.
实施例16
(1R,3R)-3-(4-胺基-3-(2-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:1-溴-2-氟-4-苯氧基苯
在一个500毫升三口烧瓶中,加入4-溴-3-氟苯酚(10.00g,52.36mmol),苯硼酸(12.77g,104.71mmol),三乙胺(10.60g,104.71mmol),无水醋酸铜(4.754g,52.356mmol)和20g分子筛,300mL二氯甲烷。所得反应液置于氧气氛围中反应过夜,TLC监测反应结束。反应液经硅藻土过滤,用去500毫升二氯甲烷洗涤,浓缩,经硅胶柱(石油醚)纯化,得到产品6.00g,产率:50%。
1H NMR(400MHz,CDCl3):δ7.45(dd,J=8.7,8.0Hz,1H),7.38(dd,J=8.5,7.5Hz,2H),7.18(t,J=7.4Hz,1H),7.03(dd,J=8.6,1.0Hz,2H),6.76(dd,J=9.8,2.7Hz,1H),6.69(ddd,J=8.8,2.7,1.1Hz,1H).
步骤2:(2-氟-4-苯氧基苯基)硼酸
在一充分干燥的100毫升烧瓶中,加入1-(4-溴苯氧基)-3-氟苯(1.00g,3.74mmol),50毫升超干四氢呋喃,并将反应液置于干冰-乙醇浴冷却至零下70摄氏度。向反应液中缓缓滴加正丁基锂的正己烷溶液(1.6M,4.87mmol)。滴加完后继续保持该反应下反应2小时后,向反应液中加入三异丙氧硼(0.85g,4.49mmol)。TLC监测反应结束,向体系中缓缓加入100毫升0.5N的盐酸水溶液,二氯甲烷萃取(30mL×3)合并有机相,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,浓缩,粗产品直接投下步。
步骤3:(1R,3R)-3-(4-胺基-3-(2-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯
在一25毫升二口烧瓶中加入(1R,3R)-3-(4-胺基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯(0.25g,0.62mmol),(2-氟-4-苯氧基苯基)硼酸(0.19g,0.81mmol)和磷酸钾(0.30g,1.87mmol),10毫升1,4-二氧六环和5毫升水。置换氩气三次后,向体系中加入四三苯基膦钯(144mg,0.13mmol),并升温至回流。反应2小时后结束。向反应体系中加入15毫升水,二氯甲烷萃取(20mL×3),合并有机相,饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品150mg,产率:52%。
1H NMR(400MHz,CDCl3):δ8.38(s,1H),7.52(t,J=8.5Hz,1H),7.42(dd,J=8.4,7.6Hz,2H),7.22(t,J=7.4Hz,1H),7.10(d,J=7.6Hz,2H),6.94(dd,J=8.5,2.3Hz,1H),6.86(dd,J=11.2,2.4Hz,1H),5.35(br-s,3H),5.15(ddd,J=16.0,11.3,4.4Hz,1H),2.51-2.40(m,1H),2.22(d,J=13.7Hz,1H),2.13(s,3H),2.11-2.08(m,1H),2.08-1.99(m,1H),1.99-1.71(m,4H).
MS ESI:m/z=462,[M+H]+.
步骤4:(1R,3R)-3-(4-胺基-3-(2-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一25毫升烧瓶中,加入(1R,3R)-3-(4-胺基-3-(2-氟-4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯(100mg,0.22mmol),LiOH(20mg,0.87mmol)以及5毫升甲醇,室温搅拌过夜。TLC监测反应完毕后,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品80mg,产率:80%。
1H NMR(400MHz,CDCl3):δ8.33(s,1H),7.51(t,J=8.5Hz,1H),7.41(t,J=7.9Hz,2H),7.21(t,J=7.4Hz,1H),7.09(d,J=7.9Hz,2H),6.92(dd,J=8.5,2.0Hz,1H),6.88-6.80(m,1H),5.60(br-s,2H),5.33-5.19(m,1H),4.39(m,1H),2.35-2.28(m,1H),2.17-2.12(m,1H),2.10-2.03(m,2H),2.03-1.93(m,1H),1.89-1.70(m,2H),1.65-1.58(m,1H).
MS ESI:m/z=420,[M+H]+.
实施例17
(1R,3R)-3-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:1-(4-溴苯氧基)-2-氟苯
在一250毫升单口烧瓶中,加入邻氟苯酚(2.00g,17.84mmol),对溴苯硼酸(7.17g,35.68mmol),醋酸铜(4.75g,17.84mmol)和150毫升超干二氯甲烷和20克4A分子筛,并将反应液置于氧气氛围下。在室温搅拌下,向反应体系中逐滴加入三乙胺(3.61g,35.68mmol)。反应约10小时后,TLC显示反应结束。将反应液直接硅藻土过滤,150毫升石油醚洗涤,浓缩,经硅胶柱(石油醚)纯化,得到产品2.30g,产率:48%。
1H NMR(400MHz,CDCl3):δ7.41(d,J=8.9Hz,2H),7.22-7.01(m,4H),6.85(d,J=8.9Hz,2H).
步骤2:
氩气保护下,向一干燥的50毫升二口烧瓶中,加入1-(4-溴苯氧基)-2-氟苯(0.50g,1.87mmol)以及20毫升超干四氢呋喃。所得反应液经干冰-乙醇浴冷却后,向其中逐滴加入正丁基锂的正己烷溶液(1.6M,1.52mL,2.43mmol)。滴加完毕后继续搅拌30分钟。然后慢慢向反应液中加入三异丙氧基硼酸酯(0.42g,2.25mmol)。继续反应2小时,TLC显示反应结束。向反应液中加入15毫升饱和氯化铵水溶液,乙酸乙酯萃取(15mL×3),合并有机相,饱和食盐水洗涤(20mL×1),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(石油醚:乙酸乙酯=3:1)纯化,得到产品200mg,产率:46%。
步骤3:(1R,3R)-3-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯
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氩气保护下,向一25毫升二口烧瓶中加入(1R,3R)-3-(4-胺基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯(0.50g,1.25mmol),(4-(2-氟苯氧基)苯基)硼酸(0.38g,1.62mmol),磷酸钾(0.79g,3.74mmol),四三苯基膦钯(0.29g,0.25mmol),20毫升1,4-二氧六环和10毫升水。所得反应液加热至回流反应1.5小时,TLC显示反应已完毕。向反应体系中加入15毫升水,二氯甲烷萃取(10mL×3),合并有机相,饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1过出)纯化,得到产品390mg,产率:69%。
MS ESI:m/z=462,[M+H]+.
步骤4:(1R,3R)-3-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一25毫升单口烧瓶中,加入(1R,3R)-3-(4-氨基-3-(4-(2-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯(0.30g,0.65mmol),氢氧化锂(0.05g,1.95mmol),3毫升甲醇。反应液室温搅拌过夜。TLC显示反应完毕。向反应体系中加入5毫升水,二氯甲烷萃取(5mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:2)纯化,得到产品250mg,产率:90%。
1H NMR(400MHz,CDCl3):δ8.36(s,1H),7.64(d,J=8.7Hz,1H),7.40-7.32(m,0.5H),7.23(m,1H),7.21-7.14(m,3H),7.13-7.10(m,2H),7.05(d,J=7.7Hz,0.5H),5.59(br-s,2H),5.29-5.22(m,1H),4.40(m,1H),2.39-2.32(m,1H),2.21-1.97(m,4H),1.81-1.73(m,2H),1.68-1.61(m,1H).
19F NMR(376MHz,CDCl3):δ-130.18(s).
MS ESI:m/z=420,[M+H]+.
实施例18
(1R,3R)-3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:2-(4-溴苯氧基)-1,3-二氟苯
在一250毫升烧瓶中,加入2,6-二氟苯酚(2.00g,15.37mmol),对溴苯硼酸(6.18g,30.75mmol),20克分子筛,醋酸铜(4.75g,15.37mmol)和150毫升超干二氯甲烷,并将反应液置于氧气氛围下。室温搅拌下,向上述反应液中逐滴加入三乙胺(3.11g,30.75mmol)。继续在室温反应3小时,TLC显示反应结束。反应液经硅藻土过滤,浓缩,经硅胶柱(石油醚)纯化,得到产品2.40g,产率:55%。
步骤2:(4-(2,6-二氟苯氧基)苯基)硼酸
在一干燥的25毫升二口烧瓶中,加入2-(4-溴苯氧基)-1,3-二氟苯(0.50g,1.75mmol),15毫升超干四氢呋喃,并置于干冰-乙醇浴中冷至零下70摄氏度。向反应体系中逐滴加入正丁基锂的正己烷溶液(1.6M,1.43mL,2.28mmol)。滴加完毕后继续搅拌30分钟,然后向反应体系中加入三异丙氧基硼酸酯(0.40g,2.11mmol)。继续反应约2小时后,TLC显示反应完全后,向反应体系中加入15毫升饱和氯化铵溶液,用乙酸乙酯萃取(15mL×3),合并有机相,并用饱和食盐水洗涤(20mL×3),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(石油醚:乙酸乙酯=3:1)纯化,得到产品350mg,产率:80%。
1H NMR(400MHz,CDCl3):δ7.40(d,J=9.1Hz,2H),7.21-7.10(m,1H),7.08-6.95(m,2H),6.83(d,J=9.0Hz,2H).
步骤3:(1R,3R)-3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯
在氩气保护下,向一个50毫升的二口烧瓶中,加入(1R,3R)-3-(4-胺基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯(0.25g,0.62mmol),(4-(2,6-二氟苯氧基)苯基)硼酸(0.20g,0.81mmol),磷酸钾(0.40g,1.87mmol),四三苯基膦钯(144mg,0.13mmol),20毫升1,4-二氧六环和10毫升水。将反应液温度升至100摄氏度,反应1.5小时。LCMS显示反应结束。向反应体系中加入15毫升0.1N盐酸水溶液,乙酸乙酯洗涤(15mL×3),合并有机相,并用饱和氯化钠溶液洗涤(15mL×3),无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品240mg,产率:80%。
MS ESI:m/z=480,[M+H]+.
步骤4:(1R,3R)-3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一25毫升单口烧瓶中,加入(1R,3R)-3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)乙酸环己酯(0.20g,0.42mmol),LiOH(30mg,1.25mmol),3毫升甲醇。反应液在室温搅拌过夜。TLC监测反应结束。向反应瓶中加入10毫升水,乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品170mg,产率:93%。
1H NMR(400MHz,CDCl3):δ8.37(d,J=1.5Hz,1H),7.63(d,J=8.6Hz,1H),7.49-7.38(m,1H),7.34-7.29(m,1H),7.23-7.14(m,1H),7.11-6.99(m,3H),5.51(br-s,1H),5.35(br-s,1H),5.31-5.20(m,1H),4.40(s,1H),2.50-2.24(m,1H),2.14-1.97(m,4H),1.82(m,2H),1.68-1.54(m,1H).
MS ESI:m/z=438,[M+H]+.
实施例19
(1R,3R)-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:1-(4-碘苯氧基)-2-氟-3-甲氧基苯
在一干燥的100毫升单口烧瓶中,加入2-氟-3-甲氧基苯酚(1.00g,7.04mmol),4-碘苯硼酸(3.49g,14.07mmol),醋酸铜(4.75g,7.04mmol),4A分子筛10克和超干二氯甲烷50毫升,逐滴加入三乙胺(1.42g,14.07mmol)。将上述反应液置于氧气氛围下,室温搅拌过夜。TLC监测反应结束。反应液经硅藻土过滤,经硅胶柱(石油醚:乙酸乙酯=9:1)纯化,得到产品1.50g,产率:62%。
1H NMR(400MHz,CDCl3):δ7.59(d,J=8.9Hz,2H),7.02(td,J=8.4,2.2Hz,1H),6.80(dd,J=11.5,4.3Hz,1H),6.75(d,J=8.8Hz,2H),6.64(ddd,J=8.3,6.9,1.4Hz,1H),3.92(s,3H).
步骤2:2-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
氮气保护下,在一干燥的25毫升二口烧瓶中,依次加入PdCl2(dppf)(6mg,0.01mmol),醋酸钾(85mg,0.87mmol)和频哪硼酸酯(148mg,0.58mmol),1-(4-碘苯氧基)-2-氟-3-甲氧基苯(100mg,0.29mmol)和10毫升DMSO。将反应液升温至85摄氏度并保持此温度反应约1.5小时后,TLC显示反应结束。将反应液冷却至室温,加入15毫升水,二氯甲烷萃取(10mL×3),合并有机相,饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(石油醚:乙酸乙酯=3:1)纯化,得到产品44mg,产率:45%。
1H NMR(400MHz,CDCl3):δ7.81-7.70(m,2H),7.01(td,J=8.4,2.2Hz,1H),6.96(d,J=8.5Hz,2H),6.81-6.76(m,1H),6.66(ddd,J=8.3,6.9,1.4Hz,1H),3.92(s,3H),1.33(s,12H).
步骤3:(1R,3R)-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯
在一50毫升二口烧瓶中,加入(1R,3R)-3-(4-胺基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯(0.30g,0.75mmol),2-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(0.30g,0.90mmol),碳酸钾(0.40g,2.24mmol),四三苯基膦钯(173mg,0.15mmol)。抽换氩气三次后,向反应体系中加入1,4-二氧六环20毫升和水10毫升,并升温至回流。继续反应1小时后,LCMS监测反应结束。将反应液冷却至室温,加入10毫升水,二氯甲烷萃取(10mL×3),合并有机相,饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品250mg,产率:70%。
MS ESI:m/z=492,[M+H]+.
步骤4:(1R,3R)-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一25毫升单口烧瓶中,加入(1R,3R)-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基乙酸酯(0.25g,0.51mmol),氢氧化锂(37mg,1.53mmol)和5毫升甲醇。所得反应液室温下搅拌过夜。TLC监测反应结束。向反应体系中加入5毫升水,二氯甲烷萃取(5mL×3),合并有机相,饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品200mg,产率88%。
1H NMR(400MHz,CDCl3):δ8.35(s,1H),7.63(d,J=8.7Hz,2H),7.13(d,J=8.6Hz,2H),7.07(td,J=8.4,2.1Hz,1H),6.89-6.81(m,1H),6.73(ddd,J=8.3,6.9,1.5Hz,1H),5.60(br-s,2H),5.26(m,1H),4.44-4.36(m,1H),3.94(s,3H),2.52-2.24(m,1H),2.29-1.95(m,5H),1.84-1.80(m,1H),1.65-1.60(m,1H).
19F NMR(376MHz,CDCl3):δ-152.86(s).
MS ESI:m/z=450,[M+H]+.
实施例20
(1s,4s)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:(1s,4s)-4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
氩气保护下,向一干燥的500毫升二口烧瓶中,加入3-碘代-1H-吡唑并[3,4-d]嘧啶-4-胺(5.00g,19.16mmol),1,4-环己二醇(顺式:反式=1:0.7,核磁含量)(4.45g,38.3mmol),三苯基膦(10.05g,38.31mmol)以及超干四氢呋喃200毫升。将所得反应液置于冰-乙醇浴中冷却后,向其中逐滴加入偶氮二甲酸二异丙酯(7.75g,38.31mmol),加完后,继续反应5小时。LCMS监测完全反应后,过滤反应液中淡黄色固体,得到4.50g。所得母液浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品0.80g,总产率:73%。
MS ESI:m/z=360,[M+H]+.
步骤2:(1s,4s)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一50毫升二口烧瓶中,加入(1s,4s)-4-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(80mg,0.22mmol),2-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(97mg,0.29mmol),碳酸钾(118mg,0.67mmol),四三苯基膦钯(51mg,0.05mmol)。抽换氩气三次后,再依次加入1,4-二氧六环5毫升和水2.5毫升,并升温至回流。反应液反应1小时后,LCMS监测反应结束。将反应液冷却至室温,向其中加入5毫升水,二氯甲烷萃取(5mL×3),合并有机相,饱和食盐水(5mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品65mg,产率:65%。
1H NMR(400MHz,CDCl3):δ8.37(s,1H),7.63(d,J=8.7Hz,2H),7.13(d,J=8.6Hz,2H),7.07(td,J=8.4,2.1Hz,1H),6.84(t,J=7.2Hz,1H),6.77-6.69(m,1H),5.44(br-s,2H),4.87-4.74(m,1H),3.94(s,3H),3.82(m,1H),2.30-1.96(m,6H),1.55(m,2H).
19F NMR(376MHz,CDCl3):δ-152.83(s).
MS ESI:m/z=450,[M+H]+.
实施例21
(1r,4r)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
步骤1:(1R,4R)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基4-硝基苯甲酸酯
在一个烘干的25毫升二口烧瓶中,加入(1s,4s)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇(80mg,0.18mmol),4-硝基苯甲酸(59mg,0.36mmol),三苯基膦(93mg,0.36mmol)和5毫升超干四氢呋喃,并将反应液置于冰-乙醇浴中冷却。然后慢慢滴加偶氮二甲酸二异丙酯(72mg,0.36mmol)。滴加完,继续反应3小时。LCMS显示反应结束,向反应液中加入5毫升水,二氯甲烷萃取(5mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品80mg,产率:78%。
MS ESI:m/z=599,[M+H]+.
步骤2:(1R,4R)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己-1-醇
在一25毫升单口烧瓶中,加入(1r,4r)-4-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基4-硝基苯甲酸酯(80mg,0.13mmol),LiOH(13mg,0.54mmol),甲醇5毫升。反应液在室温下反应3小时,TLC和LCMS监测反应结束。向反应液中加入5毫升水,二氯甲烷萃取(5mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(展开剂:二氯甲烷:甲醇=100:1-100:2)纯化,得到产品50mg,产率:83%。
1H NMR(400MHz,CDCl3):δ8.29(s,1H),7.57(d,J=8.5Hz,2H),7.05(d,J=8.5Hz,2H),6.99(td,J=8.4,2.0Hz,1H),6.76(t,J=7.9Hz,1H),6.66(dd,J=8.2,7.0Hz,1H),5.52(br-s,2H),4.76-4.70(m,1H),4.07-4.05(m,1H),3.86(s,3H),2.45(qd,J=12.8,3.5Hz,2H),1.94(d,J=9.8Hz,2H),1.81-1.76(m,2H),1.74-1.68(m,2H).
MS ESI:m/z=450,[M+H]+.
实施例22
3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇
步骤1:3-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇
氩气保护下,向一干燥的500毫升二口烧瓶中,加入3-碘代-1H-吡唑并[3,4-d]嘧啶-4-胺(5.00g,19.16mmol),1,3-环戊二醇(顺式和反式的混合物)(3.91g,38.10mmol),三苯基膦(10.05g,38.31mmol)和超干四氢呋喃200毫升。将上述反应液置于冰-乙醇浴中冷却后,向其中逐滴加入偶氮二甲酸二异丙酯(7.75g,38.31mmol),滴加完后,继续反应5小时。LCMS监测反应结束。将反应液中产生的淡黄色沉淀过滤,得到3.80g。滤液浓缩,经硅胶柱(二氯甲烷:甲醇=100:1~100:2)纯化,得到产品200mg,总产率:60%。
MS ESI:m/z=346,[M+H]+.
步骤2:3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇
氩气保护下,向一50毫升二口烧瓶中依次加入3-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(0.25g,0.72mmol),2-(4-(2-氟-3-甲氧基苯氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(0.32g,0.94mmol),碳酸钾(0.30g,2.17mmol),四三苯基膦钯(0.17g,0.15mmol),1,4-二氧六环20毫升和水10毫升。将所得反应液升温至回流并反应1小时。LCMS监测反应结束。将反应液冷却至室温,向其中加入10毫升水,二氯甲烷萃取(10mL×3),合并有机相,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品200mg,产率:63%。
1H NMR(400MHz,CDCl3):δ8.38(s,1H),7.62(d,J=8.8Hz,2H),7.12(d,J=8.6Hz,2H),7.08(td,J=8.4,2.1Hz,1H),6.84(ddd,J=8.3,6.9,1.4Hz,1H),6.74(ddd,J=8.3,6.9,1.4Hz,1H),5.75(d,J=10.2Hz,1H),5.55(br-s,2H),5.46(dd,J=14.2,8.4Hz,1H),4.46-4.45(m,1H),3.94(s,3H),2.50-2.35(m,2H),2.32-2.23(m,1H),2.24-2.17(m,1H),2.10-2.01(m,1H),1.94-1.78(m,1H).
19F NMR(376MHz,CDCl3):δ-152.82(s).
MS ESI:m/z=436,[M+H]+.
实施例23
(±)反式-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇
步骤1:3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊基4-硝基苯甲酸酯
在一个烘干的25毫升二口烧瓶中,加入(±)顺式-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(50mg,0.12mmol),4-硝基苯甲酸(38mg,0.23mmol),三苯基膦(60mg,0.23mmol)以及5毫升超干四氢呋喃。将反应液置于冰-乙醇浴中冷却。然后慢慢滴加偶氮二甲酸二异丙酯(46mg,0.23mmol)。滴加完毕后,继续反应3小时。LCMS显示反应结束。向反应液中加入5毫升水,二氯甲烷萃取(5mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品56mg,产率:80%。
MS ESI:m/z=585,[M+H]+.
步骤2:(±)反式-3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇
在一25毫升单口烧瓶中,加入3-(4-氨基-3-(4-(2-氟-3-甲氧基苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊基4-硝基苯甲酸酯(56mg,0.10mmol),LiOH(7mg,0.29mmol),甲醇3毫升。所得反应液在室温反应3小时。TLC和LCMS检测反应结束。向反应液中加入3毫升水,二氯甲烷萃取(3mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1-100:2)纯化,得到产品30mg,产率:90%。
1H NMR(400MHz,CDCl3):δ8.34(s,1H),7.62(d,J=8.6Hz,2H),7.12(d,J=8.6Hz,2H),7.07(td,J=8.4,2.0Hz,1H),6.84(t,J=7.4Hz,1H),6.74(t,J=7.6Hz,1H),5.82(br-s,2H),5.65–5.57(m,1H),4.76–4.63(m,1H),3.94(s,3H),2.56-2.09(m,6H).
19F NMR(376MHz,CDCl3):δ-152.83(s).
MS ESI:m/z=436,[M+H]+.
实施例24
5-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)四氢-2H-吡喃-3,4-二醇
步骤1:2-(烯丙氧基)乙醛
向一100毫升烧瓶中加入3-(烯丙氧基)丙烷-1,2-二醇(1.00g,7.57mmol),二氯甲烷30毫升,水15毫升。然后向反应液中加入高碘酸钠(1.94g,9.08mmol),室温搅拌。TLC监测反应结束。加入20毫升水,分液,二氯甲烷萃取(50mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩后直接投下一步。
步骤2:1-(烯丙氧基)丁-3-烯-2-醇
在一充分烘干的2000毫升三口烧瓶内,加入2-(烯丙氧基)乙醛(15.00g,粗品),超干THF 1000毫升,并将反应液置于冰-乙醇浴内冷却。在此温度下,向反应液中滴加乙烯基溴化镁的四氢呋喃溶液(1M,179.78mL,179.78mmol),1小时后滴完。继续搅拌4小时,TLC显示反应完毕。向反应体系中加入100毫升水淬灭反应,旋去大部分四氢呋喃。向反应瓶中加入300毫升二氯甲烷,100毫升水,分液,二氯甲烷萃取(150mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(石油醚:乙酸乙酯=7:3)纯化,得到产品7.20g,产率:35%。
1H NMR(400MHz,CDCl3):δ5.99-5.74(m,2H),5.41-5.24(m,2H),5.20(dd,J=10.7,1.3Hz,2H),4.39-4.27(m,1H),4.04(dt,J=5.7,1.3Hz,2H),3.51(dd,J=9.7,3.4Hz,1H),3.34(dd,J=9.6,8.0Hz,1H),2.49(d,J=3.4Hz,1H).
步骤3:3,6-二氢-2H-吡喃-3-醇
氩气保护下,向一干燥的500毫升三口烧瓶中,加入1-(烯丙氧基)丁-3-烯-2-醇(7.20g,56.18mmol),350毫升超干二氯甲烷,Grubbs二代催化剂(1.19g,1.40mmol)。反应液于室温下反应9小时。TLC监测反应结束,反应液直接经硅胶柱(石油醚:乙酸乙酯=4:1)纯化,得到产品5.00g,产率:90%。
1H NMR(400MHz,CDCl3):δ6.04-5.96(m,1H),5.96-5.90(m,1H),4.28-4.04(m,2H),3.98(dd,J=5.5,2.5Hz,1H),3.85(ddd,J=11.8,2.8,0.7Hz,1H),3.75(dd,J=11.8,3.0Hz,1H),1.97(d,J=9.3Hz,1H).
步骤4:1-(3,6-二氢-2H-吡喃-3-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺
在一烘干的25毫升二口烧瓶内,加入3,6-二氢-2H-吡喃-3-醇(0.14g,1.40mmol),3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(0.42g,1.40mmol),三苯基膦(0.73g,2.80mmol),10毫升超干四氢呋喃,并将反应液置于冰-乙醇浴内冷却。然后缓慢向瓶中滴加偶氮二甲酸二异丙酯(0.57g,2.80mmol)。反应1小时后,LCMS监测反应结束。向反应瓶中加入10毫升水,二氯甲烷萃取(20mL×3),合并有机相,饱和食盐水(30mL×1)洗涤,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=40:1)纯化,得到产品50mg,产率:95%。
1H NMR(400MHz,CDCl3):δ8.39(s,1H),7.64(d,J=8.7Hz,2H),7.39(dd,J=8.5,7.5Hz,2H),7.22-7.10(m,3H),7.09-7.04(m,2H),6.13(ddd,J=10.4,4.8,2.2Hz,1H),6.05(dd,J=10.4,2.1Hz,1H),5.63(ddd,J=10.1,5.1,2.5Hz,1H),5.52(br-s,2H),4.36(ddd,J=16.8,5.2,2.4Hz,1H),4.29-4.15(m,2H),4.08(dd,J=11.0,7.4Hz,1H).
MS ESI:m/z=386,[M+H]+.
步骤5:5-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)四氢-2H-吡喃-3,4-二醇
向一个25毫升二口烧瓶中加入5毫升去离子水,5毫升叔丁醇,K3Fe(CN)6(0.13g,0.39mmol),K2CO3(54mg,0.39mmol),K2OsO2(OH)4(24mg,0.07mmol)和1-(3,6-二氢-2H-吡喃-3-基)-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(50mg,0.13mmol),剧烈搅拌。反应4小时后经LCMS监测反应结束。向反应体系中加入10毫升乙酸乙酯,过滤,向滤液中加入15毫升水,分液,乙酸乙酯萃取(15mL×2),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=20:1)纯化,得到产品18mg,产率:36%。
1H NMR(400MHz,DMSO-d6):δ8.24(s,1H),7.66(d,J=8.7Hz,2H),7.51-7.37(m,2H),7.15(ddd,J=11.1,9.7,4.2Hz,5H),5.00(td,J=10.6,4.8Hz,1H),4.90(d,J=3.8Hz,1H),4.85(d,J=6.6Hz,1H),4.33-4.20(m,1H),3.86(d,J=8.5Hz,3H),3.65(t,J=11.0Hz,1H),3.57(d,J=11.8Hz,1H).
MS ESI:m/z=420,[M+H]+.
实施例25
3-(4-氨基-3-(4-(3-氟苯氧基)苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇
氩气保护下,向一25毫升二口烧瓶中依次加入3-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)环戊烷-1-醇(0.50g,1.45mmol),(4-(3-氟苯氧基)苯基)硼酸(0.40g,1.74mmol),磷酸钾(0.92g,4.35mmol),四三苯基膦钯(72mg,0.22mmol),10毫升1,4-二氧六环和5毫升水。反应液升温至回流并反应1小时,LCMS显示反应结束。向反应体系中加入10毫升水,二氯甲烷萃取(10mL×3),合并有机相,无水硫酸钠干燥,过滤,浓缩,经硅胶柱(二氯甲烷:甲醇=100:1)纯化,得到产品360mg,产率:62%。
1H NMR(400MHz,CDCl3):δ8.39(s,1H),7.68(d,J=8.7Hz,2H),7.33(td,J=8.3,6.7Hz,1H),7.21-7.14(m,2H),6.87(td,J=8.4,2.4Hz,2H),6.79(dt,J=10.0,2.4Hz,1H),5.75(d,J=10.2Hz,1H),5.56(s,2H),5.47(ddd,J=16.4,7.3,3.1Hz,1H),4.52-4.39(m,1H),2.58-2.35(m,2H),2.32-2.19(m,2H),2.09-2.04(m,1H),1.95-1.82(m,1H).
19F NMR(376MHz,CDCl3):δ-110.43(s).
MS ESI:m/z=406,[M+H]+.
生物化学评价
式A化合物的BTK/BTK(C481S)抑制活性在美国宾夕法尼亚州马尔文市大峡谷干道的反应生物公司(Reaction Biology Corporation,One Great Valley Parkway,Malvern,PA,USA)测定。使用人全长的BTK/BTK(C481S)酶,底物为20μM的肽底物[KVEKIGEGTYGVVYK]。测定用的ATP浓度为10μM,星形孢菌素用作标准品,IC50为3.94nM。
如下表1为诸实施例化合物对BTK/BTK(C481S)酶的抑制活性
其中,一些实施例在BTK/BTK(C481S)酶上的IC50值如下表2所示:
(a)标记的实施例中ATP的浓度为30uM;(b)标记的实施例中ATP的浓度为100uM;(c)标记的实施例中ATP的浓度为10uM。
采用CellTiter-Glo方法检测实施例对体外培养的人弥漫大B淋巴瘤细胞TMD8的抑制活性,IC50值如下表3所示。
如下表3为诸实施例化合物对TMD8细胞的抑制活性
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体内药效学评价
在人弥漫大B淋巴瘤TMD8细胞NOD/SCID小鼠皮下移植瘤模型中,检测实施例1对肿瘤生长的抑制作用,肿瘤体积及动物体重如下图1及图2所示。实施例1在30mg/kg剂量下每天口服给药一次,或在10→5mg/kg剂量下每天口服给药两次,对TMD8皮下移植瘤的生长具有明显抑制作用,给药22天后对肿瘤生长的抑制率(TGI)分别为49.6%和52.7%。实施例1在30mg/kg剂量下每天口服给药一次对动物体重无明显影响,在10mg/kg剂量下每天口服给药两次、连续给药8天后,动物体重有所下降,故调整剂量至5mg/kg,继续给药14天。
图1显示了给药期间溶剂对照及各给药组TMD8皮下异种移植瘤体积(平均值±标准差)。结果显示,在初次给药22天后,本发明化合物表现出了显著的治疗效果,且其治疗效果与阳性药物依鲁替尼相当。
图2显示了给药期间溶剂对照及各给药组动物体重(平均值±标准差)的变化。结果显示,本发明实施例1化合物在表现出显著的抗肿瘤效果同时,并没有对动物体重产生明显影响。
根据实验结果,本发明实施例1具有显著的抗肿瘤效果,显著的抑制了肿瘤的生长而没有对动物体重产生明显影响。
Claims (12)
1.一种如下式(B)所示的化合物,或其药学上可接受的盐,
其中:
R12、R13、R14和R15各自独立地选自下组:H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C10环烷基;
Z为(CR2R3)n,n为1或2;
Y为(CR4R5)m,m为1或2;
U为(CR6R7)r,r为1或2;
R2、R3、R4、R5、R6和R7各自独立地选自下组:H、NH2、OH、卤素、取代或未取代的C1-C6烷基;
W选自下组:O、S或化学键;
X为-C(R8R9)-;
除非特别说明,所述的R2、R3、R4、R5、R6、R7、R12、R13、R14和R15的取代指基团被一个或多个选自下组的取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、羟基-C1-C6烷基、氨基、羧基;
R8选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、CO2H、C(O)NRf 2;Rf为H、C1-C10烷基;且所述的取代指基团被一个或多个选自下组的取代基取代:卤素、C1-C6烷基、C3-C8环烷基、羟基;
R9选自下组:OH。
2.如权利要求1所述的化合物,其特征在于,所述的化合物具有如下式(B)所示的结构:
其中,
R12、R13、R14和R15各自独立地选自下组:H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基。
3.如权利要求1或2所述的化合物,其特征在于,为选自下组的基团:
4.如权利要求1或2所述的化合物,其特征在于,所述的化合物具有如下式(D)或式(E)所示的结构:
5.如权利要求1或2所述的化合物,其特征在于,为/>
6.如权利要求1或2所述的化合物,其特征在于,为/>
7.一种如下式(B)所示的化合物,或其药学上可接受的盐,
其中:
R12、R13、R14和R15各自独立地选自下组:H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C10环烷基;
Z为(CR2R3)n,n为1或2;
Y为(CR4R5)m,m为1或2;
U为(CR6R7)r,r为1或2;
R2、R3、R4、R5、R6和R7各自独立地选自下组:H、NH2、OH、卤素、取代或未取代的C1-C6烷基;
W选自下组:O或化学键;
X为-C(R8R9)-;
除非特别说明,所述的取代指基团被一个或多个选自下组的取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、羟基-C1-C6烷基、氨基、羧基;
R8选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基、CO2H、C(O)NRf 2;Rf为H、C1-C10烷基;且所述的取代指基团被一个或多个选自下组的取代基取代:卤素、C1-C6烷基、C3-C8环烷基、羟基;
R9选自下组:-[C(R10)(R11)]k-OH;其中R10和R11各自独立地为H;
k为1或2。
8.一种药物组合物,其包含(1)权利要求1-7任一所述的化合物、或其立体异构体、或其药学上可接受的盐;和(2)药学上可接受的载体。
9.如权利要求1-7任一所述的化合物、或其立体异构体、或其药学上可接受的盐或如权利要求8所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗BTK的异常活性以及BTK突变体异常活性相关的疾病的药物。
10.如权利要求9所述的用途,其特征在于,所述的BTK突变体为C481 S。
11.如权利要求9所述的用途,其特征在于,所述的疾病或病症选自膀胱癌,脑肿瘤,乳腺癌,子宫癌,结肠直肠癌,食道癌,肝脏癌症,滤泡性淋巴瘤,黑色素瘤,恶性血液病,骨髓瘤,卵巢癌,非小细胞肺癌,***癌,小细胞肺癌,和B-细胞来源的淋巴恶性肿瘤,B细胞增殖性病症。
12.如权利要求9所述的用途,其特征在于,所述的疾病或病症选自弥漫性B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞幼淋巴细胞白血病、淋巴质浆细胞淋巴瘤/瓦尔登斯特伦氏巨球蛋白血症、脾脏边缘带淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘带B细胞淋巴瘤、结内边缘带B细胞淋巴瘤、外套细胞淋巴瘤、纵隔大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特氏淋巴瘤/白血病或淋巴瘤样肉芽肿病。
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CA3129841C (en) | 2023-09-26 |
CN113710671A (zh) | 2021-11-26 |
EA202191995A1 (ru) | 2021-11-18 |
MX2021008632A (es) | 2021-10-26 |
KR20210135497A (ko) | 2021-11-15 |
CN111454268A (zh) | 2020-07-28 |
CN113710671B (zh) | 2023-04-28 |
AU2020208128A1 (en) | 2021-09-09 |
AU2020208128B2 (en) | 2023-05-25 |
SG11202107886RA (en) | 2021-08-30 |
JP7436994B2 (ja) | 2024-02-22 |
EP3912980A4 (en) | 2022-12-07 |
JP2023179562A (ja) | 2023-12-19 |
EP3912980A1 (en) | 2021-11-24 |
CN116589465A (zh) | 2023-08-15 |
IL284916A (en) | 2021-09-30 |
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US20220081445A1 (en) | 2022-03-17 |
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