CN105189497B - 作为janus激酶抑制剂的n-(2-氰基杂环基)吡唑并吡啶酮 - Google Patents
作为janus激酶抑制剂的n-(2-氰基杂环基)吡唑并吡啶酮 Download PDFInfo
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- CN105189497B CN105189497B CN201480016754.4A CN201480016754A CN105189497B CN 105189497 B CN105189497 B CN 105189497B CN 201480016754 A CN201480016754 A CN 201480016754A CN 105189497 B CN105189497 B CN 105189497B
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- Prior art keywords
- alkyl
- base
- amino
- dihydro
- pyrazolo
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- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 121
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 76
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical compound C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 claims description 37
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- GELZFJXJHIPBLW-UHFFFAOYSA-N 3-(4-methylsulfonylanilino)-1,5-dihydropyrazolo[4,3-c]pyridin-4-one Chemical compound CS(=O)(=O)C1=CC=C(C=C1)NC1=NNC2=C1C(NC=C2)=O GELZFJXJHIPBLW-UHFFFAOYSA-N 0.000 claims description 2
- UHWMBVCJHNFUGC-UHFFFAOYSA-N 3-anilino-1,5-dihydropyrazolo[4,3-c]pyridin-4-one Chemical compound O=c1[nH]ccc2[nH]nc(Nc3ccccc3)c12 UHWMBVCJHNFUGC-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
本发明提供式I的化合物,其为JAK抑制剂,且这些化合物用于JAK介导的疾病、如类风湿性关节炎、哮喘、COPD和癌症的治疗。
Description
背景技术
蛋白激酶是通过向蛋白底物加入磷酸基团而调节其靶蛋白的活性的一组酶。激酶在许多生理过程包括细胞分裂,分化,细胞的自动调节和信号转导中发挥重要作用。激酶可根据其靶标细分为丝氨酸/苏氨酸激酶和酪氨酸激酶。酪氨酸激酶进一步细分为受体酪氨酸激酶和非受体酪氨酸激酶。哺乳动物Janus激酶(JAK)家族的成员是非受体酪氨酸激酶。
JAK家族有四个成员:JAK1,JAK2,JAK3和TYK2。JAK1,JAK2和TYK2是普遍表达的,而JAK3表达限于造血细胞。JAK家族参与来自于大于 70种不同的细胞因子的细胞内的信号转导。细胞因子结合在其细胞表面受体上,导致受体二聚化和随后的JAK酪氨酸激酶的激活/磷酸化。该JAKs组成上与受体相关联或在细胞因子结合时被恢复。受体上的特定的酪氨酸残基然后通过活化的JAKs磷酸化,并作为STAT蛋白的停泊位点起作用。STATs通过JAKs磷酸化,二聚化,然后移位到它们结合特定的DNA分子并激活基因转录的细胞核。JAK1以细胞因子依赖的方式连同所有JAK同工型发出信号。
JAKs对于多种生理功能是必不可少的。这通过使用缺乏特定JAKs的遗传工程小鼠模型已被证实。Jak1-/-小鼠围产期死亡,而Jak2-/-小鼠在红细胞生成方面存在缺陷并在约E12天死亡。Jak3-/-小鼠是存活的,但在T细胞、B细胞和NK细胞中有具有缺陷的SCID表型。TYK2-/-小鼠表现出高IgE综合征的特点。这些表型表明JAK活性在体内的必需和非冗余的作用(K. Ghoreschi,A. Laurence,J. J. O'Shea,Immunol. Rev. 228,273(2009))。
此外,在JAK酶中的突变已与人类疾病相关。JAK3(或同源的共同γ链细胞因子受体)中的失活性突变引起严重的SCID表型(J. J. O'Shea,M. Pesu,D. C. Borie,P. S.Changelian,Nat. Rev. Drug Discov. 3,555(2004))。TYK2的除去导致高IgG综合征和增加的感染风险(Y. Minegishi 等,Immunity. 25,745(2006))。对于JAK1或JAK2没有失活性突变的报道,与来自小鼠的数据相一致,所述来自小鼠的数据表明JAK1和JAK2缺陷小鼠不是存活的。然而,引起组成性地活性的JAK2的几个突变已经确定,导致骨髓增殖性疾病,确认JAK2在造血中的核心作用(O. bdel-Wahab,Curr. Opin. Hematol. 18,117(2011))。JAK2是涉及关键造血细胞因子IL-3、GMCSF、EPO和TPO的信号转导的唯一JAK家族成员。
表明JAK激酶活性在自身免疫性疾病、造血作用和肿瘤方面的核心作用的小鼠和人类基因的大量数据已经通过pan-JAK抑制剂在自体免疫疾病和肿瘤的临床试验中的使用而被支持(参见K. Ghoreschi,等,Immunol. Rev. 228,273(2009),和A. Quintas-Cardama,H. Kantarjian,J. Cortes,S. Verstovsek,Nat. Rev. Drug Discov. 10,127(2011))。
大量文献已经积累了下述认识:将Jak / STAT途径与各种疾病和障碍,包括过度增殖性障碍和癌症、例如白血病和淋巴瘤,免疫和炎性病症、如移植排斥,哮喘,慢性阻塞性肺病,过敏症,类风湿关节炎,I型糖尿病,肌萎缩性侧索硬化和多发性硬化联系在一起。
发明内容
本发明提供新的化合物,其是JAKs的抑制剂。本发明还提供用于JAK介导的疾病和障碍的治疗和预防的方法,其使用该新的化合物,以及含有该化合物的药物组合物。
具体实施方式
本发明提供式I的化合物或其药学上可接受的盐、或立体异构体:
A 选自芳基和杂芳基;
X 独立地选自 CH2,NH,S,和O,其中至少一个X 不同于CH2;
n为0、1、2、3或4;
m为0、1、2、3或4;
p 为1、2、3、4或5;
R1 选自:
卤素,
氧代(=O),
C0-10烷基亚氨基C0-10烷基,
C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C1-10杂烷基(氧基)0-1(羰基)0-1C0-10烷基,
芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
杂芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
(C1-10)杂烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
芳基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
杂芳基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
(C1-10)杂烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
芳基C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
杂芳基C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
(C3-12)杂环烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
C0-10烷基磺酰基C0-10烷基,
C1-10杂烷基磺酰基C0-10烷基,
(C3-12)环烷基C0-10烷基磺酰基C0-10烷基,
(C3-12)环杂烷基C0-10烷基磺酰基C0-10烷基,
杂芳基C0-10烷基磺酰基C0-10烷基,
芳基C0-10烷基磺酰基C0-10烷基,
C1-10烷基氨磺酰基C0-10烷基,
C1-10杂烷基氨磺酰基C0-10烷基,
(C3-12)环烷基C0-10烷基氨磺酰基C0-10烷基,
(C3-12)环杂烷基C0-10烷基氨磺酰基C0-10烷基,
杂芳基C0-10烷基氨磺酰基C0-10烷基,
芳基C0-10烷基氨磺酰基C0-10烷基,
(C0-10烷基)1-2 氨基,
-CO2(C0-10烷基),
-(C0-10烷基)CO2H,
-SO2NH2,
-SO2NH(C1-10烷基),
-SO2N(C1-10烷基)2,
-SO2CF3,
-SO2CF2H,
C1-10烷基亚磺酰基C0-10烷基,
C1-10杂烷基亚磺酰基C0-10烷基,
(C3-12)环烷基C0-10烷基亚磺酰基C0-10烷基,
(C3-12)环杂烷基C0-10烷基亚磺酰基C0-10烷基,
杂芳基C0-10烷基亚磺酰基C0-10烷基,
芳基C0-10烷基亚磺酰基C0-10烷基,
C0-10烷基亚磺酰基氨基C0-10烷基,
C1-4 酰基氨基 C0-10烷基,
硫基C1-10烷基,
羟基,
-(C1-10烷基)OH,
-C0-10烷基烷氧基,
氰基,
(C1-6烷基)氰基,和
C1-6卤代烷基;
R2 选自:
卤素,
氧代(=O),
C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C0-10烷基氨基C0-10烷基,
(C1-10)杂烷基氨基C0-10烷基,
C3-12环烷基C0-10烷基氨基C0-10烷基,
芳基C0-10烷基氨基C0-10烷基,
杂芳基C0-10烷基氨基C0-10烷基,
(C3-12)杂环烷基C0-10烷基氨基C0-10烷基,
C1-10烷基磺酰基,
(C3-12)环烷基C0-10烷基磺酰基,
(C3-12)环杂烷基C0-10烷基磺酰基,
(C0-10烷基)1-2 氨基,
-CO2(C0-10烷基),
-(C0-10烷基)CO2H,
-SO2CF3,
-SO2CF2H,
C1-10烷基亚磺酰基,
羟基,
-(C1-10烷基)OH,
-C0-10烷基烷氧基,
氰基,
(C1-6烷基)氰基,和
C1-6卤代烷基,和
其中R1和R2 各自任选地被1、2、3或4 个R3取代基取代;
R3 独立地选自:
卤素,
C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C1-10杂烷基(氧基)0-1(羰基)0-1C0-10烷基,
芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
杂芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
((C0-10)烷基)1-2氨基羰基氧基,
芳基(C0-10)烷基氨基羰基氧基,
-CO2(C0-10烷基),
-(C0-10烷基)CO2H,
氧代(=O),
-SO2NH2,
-SO2NH(C1-10烷基),
-SO2N(C1-10烷基)2,
-SO2CF3,
-SO2CF2H,
C1-10烷基亚磺酰基,
氨基,
(C0-10烷基)1-2 氨基,
-(氧基)0-1(羰基)0-1N(C0-10烷基)1-2
羟基,
(C1-10烷基)OH,
C1-10 烷氧基,
(C1-10烷基)氰基,
氰基,和
C1-6卤代烷基;和
R3 任选被1、2或3个R4取代基取代,所述R4取代基选自羟基,(C1-6)烷基,(C1-6)烷氧基,(C1-10烷基)OH,卤素,CO2H,-(C0-6)烷基CN,
-O(C=O)C1-C6烷基,NO2,三氟甲氧基,三氟乙氧基,三氟甲基,三氟乙基,
-N-C(O)O(C0-6)烷基,C1-10烷基磺酰基,氧代(O=),氨基磺酰基,-SO2NH2,
-SO2NH(C1-10烷基),-SO2N(C1-10烷基)2,-SO2C1-6烷基,-SO2CF3,-SO2CF2H,-C1-10烷基亚磺酰基,-O(0-1)(C1-10)卤代烷基,氨基(C1-6烷基)0-2和NH2。
本发明的代表性化合物包括、但不限于以下的化合物和它们的药学上可接受的盐和立体异构体:
3-(3-((4-(甲基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(4-氧代-3-(苯基氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-((2-甲基-1,1-二氧代-2,3-二氢苯并[d]异噻唑-5-基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-((2-(叔丁基)-1,1-二氧代-2,3-二氢苯并[d]异噻唑-5-基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
4-((1-(4-氰基四氢-2H-吡喃-3-基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基)氨基)-N,N-二甲基苯磺酰胺;
3-(3-((1,1-二氧代-2-(2,2,2-三氟乙基)-2,3-二氢苯并[d]异噻唑-5-基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-((4-(1-氨基-2,2,2-三氟乙基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
N-(叔丁基)-4-((1-(4-氰基四氢-2H-吡喃-3-基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基)氨基)苯磺酰胺;
3-(3-((4-(异丙基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
N-(叔丁基)-4-((1-(4-氰基四氢-2H-吡喃-3-基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基)氨基)-N-甲基苯磺酰胺;
3-(3-((4-(叔丁基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-{[2-(2-甲基丙基)-2,3-二氢-1H-异吲哚-5-基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-{[2-(1-甲基乙基)-2,3-二氢-1H-异吲哚-5-基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
5-({1-[4-氰基四氢-2H-吡喃-3-基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基}氨基)-2-羟基苯甲亚胺酸甲酯;
3-{3-[(4-氟-3-甲氧基苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-[3-({4-[(1R或1S)-1-(二甲基氨基)-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
3-(3-{[4-(5,5-二甲基-3-氧代-2-氧杂双环[2.2.2]辛-1-基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-{[4-(叔丁基磺酰基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈;
3-(3-{[4-(叔丁基磺酰基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈;
5-(3-{[4-(叔丁基磺酰基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈;
5-(3-{[4-(叔丁基磺酰基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈;
3-{3-[(2-氟吡啶-4-基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-{3-[(4-氰基苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-{3-[(4-氰基-3-氟苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-(4-氧代-3-((4-(1,1,1-三氟-2-甲氧基丙烷-2-基)苯基)氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈 ;
3-(3-((2,3-二甲基-1,1-二氧代-2,3-二氢苯并[d]异噻唑-5-基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈 ;
3-(3-((4-(4,4-二氟哌啶-1-羰基)-3-甲基苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-[4-氧代-3-({4-[2,2,2-三氟-1-(4-甲基哌嗪-1-基)乙基]苯基}氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
3-[4-氧代-3-({4-[2,2,2-三氟-1-哌嗪-1-基乙基]苯基}氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
N-{1-[4-({1-[4-氰基四氢-2H-吡喃-3-基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基}氨基)苯基]-2,2,2-三氟乙基}甘氨酸叔丁酯;
3-[4-氧代-3-({4-[2,2,2-三氟-1-吡咯烷-1-基乙基]苯基}氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
3-[4-氧代-3-({4-[1-(2H-1,2,3-三唑-2-基)乙基]苯基}氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
3-{3-[{[(2,2-二甲基环丙基)氨基]-2,2,2-三氟乙基}苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-[3-({4-[1-(叔丁基氨基)-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-{4-氧代-3-[(4-{2,2,2-三氟-1-[(1-甲基乙基)氨基]乙基}苯基)氨基]-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈 ;
3-[3-({4-[1-(乙基氨基)-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
3-[3-({4-[1-氮杂环丁烷-1-基-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
3-[3-({4-[1-(二甲基氨基)-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈 ;
3-(3-{[4-(1-氨基-1-甲基乙基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-{3-[(4-{1-甲基-1-[(1-甲基乙基)氨基]乙基}苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-(3-{[1,1-二氧代-2-(2,2,2-三氟乙基)-2,3-二氢-1,2-苯并异噻唑-5-基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
N-(叔丁基)-4-({1-[4-氰基四氢-2H-吡喃-3-基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基}氨基)-N-甲基苯磺酰胺;
[5-({1-[4-氰基四氢-2H-吡喃-3-基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基}氨基)-1,1-二氧代-1,2-苯并异噻唑-2(3H)-基]乙酸叔丁酯;
3-[3-({4-[(1,1-二甲基丙基)磺酰基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-[4-氧代-3-({4-[(1,1,2-三甲基丙基)磺酰基]苯基}氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
5-({1-[4-氰基四氢-2H-吡喃-3-基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基}氨基)-N,N-二甲基吡啶-2-磺酰胺;
3-{3-[(3,4-二甲基苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-(3-{[4-(氮杂环丁烷-1-基磺酰基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-[3-({4-[(3-甲基氮杂环丁烷-1-基)磺酰基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-[3-({4-[(2,2-二甲基吗啉-4-基)磺酰基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-[3-({4-[(2,2-二甲基吡咯烷-1-基)磺酰基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-{3-[(4-{[ 2,6-二甲基吗啉-4-基]磺酰基}苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-{3-[(4-{[2-甲基吗啉-4-基]磺酰基}苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-{3-[(4-{[2,6-二甲基吗啉-4-基]磺酰基}苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-{3-[(4-{[2-甲基氮杂环丁烷-1-基]磺酰基}苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
N-(叔丁基)-4-((1-(4-氰基四氢-2H-吡喃-3-基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基)氨基)-N-乙基苯磺酰胺;
3-[3-({4-[1-(环丙基氨基)-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-{3-[(4-{1-[(2,2-二甲基丙基)氨基]-2,2,2-三氟乙基}苯基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-[3-({4-[1-(环戊基氨基)-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-{4-氧代-3-[(4-{2,2,2-三氟-1-[2-甲基吡咯烷-1-基]乙基}苯基)氨基]-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-{4-氧代-3-[(4-{(2,2,2-三氟-1-[(2-甲基丙基)氨基]乙基}苯基)氨基]-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-[3-({4-[1-(环丁基氨基)-2,2,2-三氟乙基]苯基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-(4-氧代-3-((4-(2,2,2-三氟-1-羟基-1-(吡啶-4-基)乙基)苯基)氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(4-氧代-3-((4-(2,2,2-三氟-1-羟基-1-(吡啶-2-基)乙基)苯基)氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(4-氧代-3-((4-(3-(三氟甲基)吡咯烷-3-基)苯基)氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-[3-({3-甲基-3-[(1-甲基乙基)氨基]-2-氧代-2,3-二氢-1H-吲哚-6-基}氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-{3-[(2-甲基-1,3-苯并噻唑-6-基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3- c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-{3-[(3,3-二甲基-2-氧代-2,3-二氢-1H-吲哚-6-基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈;
3-[4-氧代-3-({4-[(1R或1S)-2,2,2-三氟-1-羟基-1-甲基乙基]苯基}氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基]四氢-2H-吡喃-4-甲腈;
3-(3-((4-氯-3-(甲基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-((4-氟-3-(甲基亚磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈,和
3-(3-{[4-氯-3-(甲基亚磺酰基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈。
本发明还包括含有式I化合物的药物组合物,和使用式I化合物的、JAK介导的疾病的治疗或预防的方法。
本发明使用下列定义来记述,除非另有说明。
如本文所使用,除非另有说明,“烷基”意指包括支链和直链的饱和脂肪族烃基,包括所有异构体,具有特定数量的碳原子。烷基的常用缩写用于整个说明书中,如甲基可以通过“Me” 或CH3来表示,乙基可以由“Et”或CH2CH3表示,丙基可以通过“Pr” 或CH2CH2CH3来表示,丁基可以用“Bu”或CH2CH2CH2CH3表示等。例如“C1-6 烷基”(或“C1-C6烷基”)是指直链或支链烷基,包括所有异构体,具有特定数量的碳原子。C1-6 烷基包括所有的己基烷基和戊基烷基异构体以及正、异、仲和叔丁基、正和异丙基、乙基和甲基。“C1-4 烷基”是指正、异、仲和叔丁基、正和异丙基、乙基和甲基。
术语“亚烷基”是指支链和直链的饱和脂肪族烃基,包括所有异构体,具有特定数量的碳原子,以及具有两个末端链连接物。为了说明,“未取代的A-C4 亚烷基-B”是表示A-CH2-CH2-CH2-CH2-B。
术语“烷氧基”代表通过氧桥连接的指定碳原子数的直链或支链的烷基。
“酰基”指–C(O)R基团,其中R是任选取代的烷基,烯基,环烷基,杂环烷基,芳基杂芳基等。
“酰基氨基”是指-NRR'基团,其中R是H,OH或烷氧基,R'是酰基,如本文所定义。
术语“烷基”是指脂肪族烃基,其可以是直链或支链的,且具有指定数量的碳原子。烷基的非限制性实例包括甲基,乙基,丙基,异丙基,丁基,仲和叔丁基,戊基,己基等。
术语“杂烷基”是指其中1,2或3个碳原子被独立地选自N,O或S的杂原子代替的烷基。
“烯基”是指含有至少一个碳-碳双键的脂肪族烃基,其可以是直链或支链的,并具有指定数量的碳原子。优选的烯基包含一个碳-碳双键,以及多达四个非芳香族的碳-碳双键可以存在。烯基的实例包括乙烯基,丙烯基,正丁烯基,2-甲基-1-丁烯基,3-甲基丁-2-烯基,正戊烯基,辛烯基和癸烯基。
“炔基”是指含有至少一个碳-碳三键的脂肪族烃基,其可以是直链或支链的,并具有指定数量的碳原子。合适的炔基的非限制性实例包括乙炔基,丙炔基,2-丁炔基和3-甲基丁炔基。
“烷氧基”是指烷基-O-基,其中烷基如上所述。例如 C1-6烷氧基包括甲氧基,乙氧基,丙氧基,异丙氧基等。
“烷氧基烷基”是指其中一个或多个(特别是1至3个)氢原子已被烷氧基取代的如上所述的烷基。实例包括CH2OCH3,CH2CH2OCH3和CH(OCH3)CH3。
“氨基烷基”是指其中一个氢原子已被氨基,单烷基氨基或二烷基氨基取代的如上所述的烷基。实例包括CH2NH2,CH2CH2NHCH3和CH(N(CH3)2)CH3。
在例如“C0-6烷基”的表达中采用的术语“C0”是指直接的共价键;或当该术语出现于取代基的末端时,C0-6 烷基是指氢或C1-6烷基。类似地,当定义在基团中的一定数目的原子的存在的整数等于零时,这意味着与其相邻的原子直接通过键连接。例如,在结构中,其中s为等于零、1或2的整数,当s为零时,该结构为 。
术语“C3-8 环烷基”(或“C3-C8 环烷基”)是指具有3至8个总碳原子的烷烃的环状环(即,环丙基,环丁基,环戊基,环己基,环庚基或环辛基)。术语 “C3-7 环烷基”,“C3-6 环烷基”,“C5-7 环烷基”等具有类似的意思。
术语“卤素”(或“卤代”)是指氟,氯,溴和碘(可选地称为氟代(F),氯代(Cl),溴代(溴),和碘代(I))。
术语“芳基”是指芳族的单碳环和多碳环的环系,其中在多环系中的各个碳环稠合或通过单键彼此连接。合适的芳基包括苯基,萘基,2,3-二氢-1H-茚基和联苯基。
本文中所使用的术语“碳环”(及其变型,例如“碳环的”或“碳环基”),除非另有说明,指的是(ⅰ)C3至C8单环的、饱和或不饱和环或(ii)C7至C12双环的、饱和或不饱和环系。(ii)中的每个环与其它环是独立的或稠合的,每个环是饱和或不饱和的。该碳环可以以任何产生稳定的化合物的碳原子连接到分子中的的其余部分。稠合双环的碳环是碳环的子集;即,术语“稠合双环的碳环”通常是指C 7至C10双环的环系,其中每个环是饱和或不饱和的,两个相邻碳原子在环系中被各环所共享。其中一个环是饱和的且另一个是饱和的稠合双环的碳环是饱和双环的环系。其中一个环是苯、且另一个是饱和的稠合双环的碳环是不饱和双环的环系。其中一个环是苯、且另一个是不饱和的稠合双环的碳环是不饱和环系。饱和碳环也称为环烷基环,例如环丙基,环丁基等。除非另有说明,碳环是未取代的或被C1-6烷基,C1-6烯基,C1-6炔基,芳基,卤素,NH2或OH取代。稠合双环的不饱和碳环的子集是其中一个环是苯环、另一个环是饱和或不饱和的、具有经由导致稳定化合物的任何碳原子的连接的那些双环的碳环。该子集的代表性实例包括以下:
。
“氰基烷基”是指其中一个氢原子已被氰基取代的如上所述的烷基。实例包括CH2CN,CH2CH2CN和CH(CN)CH3。
“环烷基”是指具有3至12个环碳原子的碳环环系;所述环系可以是(a)任选稠合到苯或部分不饱和碳环上的单环饱和碳环,或(b)双环的饱和碳环。对于双环体系,在(a)或(b)中,所述环是横跨两个相邻的环碳原子而被稠合(例如,萘烷),在一个环碳原子上(例如,螺[2.2]戊烷),或为桥接基团(例如,降冰片烷)。在上述含义的范围内的其它实例包括,但不限于,环丙烷,环丁烷,环戊烷,环己烷,全氢茚满,萘烷,螺[4.5]癸烷,双环[2.2.2]辛烷等。
“卤代烷基”是指其中一个或多个(特别是1至5个)氢原子已被卤原子取代的如上所述的烷基,具有多达所有的氢原子完全被卤素基团取代的情况。例如,C1-6卤代烷基,包括-CF3,-CF2CF3,-CH2CF3,CHFCH3等。
“杂环”,“杂环的”或“杂环基”表示单环或双环的3-12元环系,其中至少一个环是非芳族(饱和或部分不饱和),并含有至少一个选自O,S和N的杂原子。在双环环系中,第二环可以是杂芳基,杂环或饱和、部分不饱和或芳族的碳环,与分子的其余部分的连接点可以在任一环上。因此“杂环基”包括杂芳基,以及其二氢和四氢类似物。杂环基取代基的连接可以通过碳原子或通过杂原子存在。
杂环(杂环基)的实例包括,但不限于,氮杂环丁烷基,吡咯烷基,哌啶基,哌嗪基,吗啉基,硫吗啉基,四氢呋喃基,二氢呋喃基,四氢噻吩基,四氢吡喃基,二氢吡喃基,二氢咪唑基,二氢吲哚基,1、2、3、4-四氢异喹啉基,5,6,7,8-四氢咪唑并[1,2-a]吡嗪,2,3-二氢苯并呋喃基,苯并-1,4-二氧六环基,苯并咪唑基,苯并呋喃基,苯并呋咱基,苯并吡唑基,苯并三唑基,苯并噻吩基,苯并噁唑基,咔唑基,咔啉基,噌啉基,呋喃基,咪唑基,二氢吲哚基,吲哚基,吲嗪基(indolazinyl),吲唑基,异苯并呋喃基,异吲哚基,异喹啉基,异噻唑基,异噁唑基,萘并吡啶基,噁二唑基,噁唑基,噁唑啉,异噁唑啉,环氧丙烷基,吡喃基,吡嗪基,吡唑基,哒嗪基,吡啶并吡啶基,哒嗪基,吡啶基,嘧啶基,吡咯基,喹唑啉基,喹啉基,喹喔啉基,四氢吡喃基,四唑基,四唑并吡啶基,噻二唑基,噻唑基,噻吩基,三唑基,氮杂环丁烷基,氮丙啶基,1,4-二氧六环基,六氢吖庚因基,哌嗪基,哌啶基,吡咯烷基,吗啉基,硫代吗啉基,二氢苯并咪唑基,二氢苯并呋喃基,二氢苯并噻吩基,二氢苯并噁唑基,二氢呋喃基,二氢咪唑基,二氢吲哚基,二氢异噁唑基,二氢异噻唑基,二氢噁二唑基,二氢噁唑基,二氢吡嗪基,二氢吡唑基,二氢吡啶基,二氢嘧啶基,二氢吡咯基,二氢喹啉基,二氢四唑基,二氢噻二唑基,二氢噻唑基,二氢噻吩基,二氢三唑基,二氢氮杂环丁烷基,亚甲基二氧基苯甲酰基,四氢呋喃基,和四氢噻吩基,和其N-氧化物。
饱和杂环形成杂环的子集;即,术语“饱和杂环和(C3-12)杂环烷基”一般是指其中整个环系(无论单或多环)是饱和的如上述定义的杂环。术语“饱和杂环”是指4-至8-元饱和单环或稳定的7-至12-元双环的环系,其由碳原子和一个或多个选自N,O和S的杂原子构成。代表性的实例包括哌啶基、哌嗪基、氮杂环庚烷基,吡咯烷基,吡唑烷基,咪唑烷基,噁唑烷基,异噁唑烷基,吗啉基,硫代吗啉基,噻唑烷基,异噻唑烷基,和四氢呋喃基(或四氢呋喃基)。
杂芳族形成杂环的另一子集;即术语“杂芳族”(或者“杂芳基”)通常是指其中整个环系(无用论单或多环)是芳族环系的如上文所定义的杂环。术语“杂芳环”是指5-或6-元单环芳香环或7-至12-元双环,其由碳原子和一个或多个选自N,O和S中的杂原子构成。对于仅一个的环需要是杂芳族的双环的杂芳基,所述第二环可以是杂芳族或芳族的、饱和、或部分不饱和的碳环,与分子的其余部分的连接点可以在任一环上。在含有至少一个氮原子的取代的杂芳基环(例如,吡啶)的情况下,这样的取代可以是那些导致N-氧化物形成的取代。杂芳基的实例包括,但不限于,呋喃基,噻吩基(或噻吩基),吡咯基,咪唑基,吡唑基,噁唑基,噻唑基,异噁唑基,异噻唑基,三唑基,噁二唑基,噻二唑基,四唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,三嗪基,喹啉基,异喹啉基,萘啶基,苯并噻吩基,苯并呋喃基,苯并咪唑,苯并吡唑基,吲哚基,异吲哚基,吲嗪基,吲唑基,嘌呤基,喹嗪基,酞嗪基,喹喔啉基,喹唑啉基,苯并噁唑基,苯并异噁唑基,5,6,7,8-四氢喹啉基,咪唑并[1,2-a]吡啶基,咪唑并[1,2-a]嘧啶基,5,6-二氢吡咯并 [1,2-b]吡唑基,吡咯并[3,2-c]吡啶基,吡咯并[2,3-b]吡啶基,噻吩并 [2,3-b]吡咯基,呋喃并吡啶和噻吩并吡啶。
双环杂环的代表性例子包括苯并三唑基,吲哚基,异吲哚基,吲唑基,二氢吲哚基,异二氢吲哚基,喹喔啉基,喹唑啉基,噌啉基,苯并二氢吡喃基,异苯并二氢吡喃基,四氢喹啉基,喹啉基,四氢异喹啉基,异喹啉基,2,3-二氢苯并呋喃基,2,3-二氢苯并-1,4-二噁烯基(即,),咪唑并(2,1-b)(1,3)噻唑,(即,),和苯并-1,3-间二氧杂环戊烯基(即, )。在本文中的某些情况下,可选地被称为具有连接至两个相邻的碳原子的亚甲基二氧基作为取代基的苯基。
取代的杂芳基的非限制性例子包括:异吲哚啉酮,异二氢吲哚-1-酮,2,3-二氢-1H-吡唑并[4,3-c]吡啶-4(5H)-酮,2,3,4,5-四氢苯并[d]异噻唑 1,1-二氧化物,和2,3,4,5-四氢苯并[b]噻吩 1,1-二氧化物。
"羟基烷基" 是指一个或多个(特别地1至3个)氢原子被羟基取代了的上述的烷基。例子包括CH2OH,CH2CHOH和CHOHCH3。
术语“亚氨基”是指与烷基或其它的非酸性基团联合的二价基团 =NH,例如,亚氨基甲基( .HC=NH)。
“亚烷基”、“亚烯基”、“亚炔基”、“亚环烷基”、“亚芳基”、“亚杂芳基”和“亚杂环基”是指通过分别从各自如上述定义的烷基、烯基、炔基、环烷基、芳基、杂芳基和杂环基中除去一个氢原子而得到的二价基团。
除非明确说明与此相反,“不饱和”环是部分或完全不饱和的环。例如,“不饱和单环C6碳环”是指环己烯、环己二烯和苯。
除非明确说明与此相反,本文引用的全部范围都是包含的。例如,描述为含有“1至4个杂原子”的杂环是指杂环可以含有1、2、3或4个杂原子。
当任何变量(variables)在任何组分或任何描绘和描述本发明的化合物的式子中出现超过一次时,其在每次出现时的定义独立于其在所有其它出现时的定义。此外,取代基和/或变量的组合是允许的,只要这样的组合产生稳定的化合物。
术语“氨磺酰基”是表示由磺酰胺、例如–SO2NH2,-–SO2NHR和-SO2N(RR1)衍生的基团的后缀(suffix)。
术语“取代的”(例如,如在“任选被一个或多个取代基取代的芳基...”中)包括利用指定的取代基进行的单和多取代,只要该单和多个取代(包括在同一位点的多个取代)是化学允许的。
术语“氧基”是指氧(O)原子。术语“硫基(thio)”是指硫(S)原子。术语“氧代”是指“= O”。术语“羰基”是指“C= O”。
当任何变量(例如,R2,R3等)在任何取代基或式I中出现多于一次时,其在每次出现时的定义独立于其在所有其它出现时的定义。此外,取代基和/或变量的组合是允许的,只要这样的组合产生稳定的化合物。
根据本文通篇的公开中所用的标准命名法,所指定的侧链的末端部分首先被描述,然后描述朝向连接点的相邻官能(functionality)。例如,C1-5 烷基羰基氨基 C1-6 烷基取代基等于。
在选择本发明的化合物中,本领域技术人员会认识到各取代基,即R1,R2,R3等,将以符合公知的化学结构连接原理的方式被选择。
从取代基画到环系中的线表明所示的键可以连接到任何可取代的环原子上。如果该环系是多环的,其意指该键被连接到仅仅近侧环上的任何合适的碳原子上。
应该理解本发明的化合物上的取代基和取代方式可由本领域技术人员进行选择,以提供化学上稳定的、且可以通过本领域中已知的技术、以及那些如下所述的方法由容易获得的起始物质容易地合成的化合物。如果取代基本身被多于一个基团取代,应该理解这些多个基团可以位于相同的碳或不同的碳上,只要产生稳定的结构结果。措辞“任选被一个或多个取代基取代”应理解为等价于“任选被至少一个取代基取代”,在这种情况下,一个实施方案将具有0至3个取代基。
具有用甲基终结的取代基的化合物的结构表示可以使用字符“CH3”、例如 “-CH3”或使用表示甲基的存在的直线、例如显示终端的甲基,即,
具有等同的意思。
对于包含具有重复术语的术语的变量定义,例如(CRiRj)r,其中r是整数2,Ri 是被定义的变量,和Rj 是被定义的变量,Ri 的值可以在其出现的每个实例中不同,和Rj 的值可以在其出现的每个实例中不同。例如,如果Ri和Rj独立地选自甲基、乙基、丙基和丁基,则(CRiRj)2 可以是
。
“患者”包括人类和动物。
“哺乳动物”是指人类和其它哺乳类动物。
“治疗有效量”是指正在由研究者、兽医、医师或其它临床医生寻求的、会引起组织、系统、动物或人的生物或医学的反应的药物或药剂的量。
术语“治疗”或“处理”包括减轻、改善、缓解或以其它方式减少与疾病或障碍相关的迹象和症状。
术语“组合物”,如在药物组合物中,意指包括一种产品,其包含活性成分和构成载体的惰性成分(药学上可接受的赋形剂),以及任何的产品,其直接或间接地由任何两种以上的成分的组合、复合或聚集产生,或由一种以上的成分的解离产生,或由其它类型的反应或一种以上的成分的相互作用产生。因此,本发明的药物组合物包括通过混合式I的化合物及其药学上可接受的赋形剂制造的任何组合物。
术语“任选取代的”是指“未取代的或取代的”,因此,本文中描述的一般的结构式涵盖含有规定的可选取代基的化合物以及不包含可选的取代基的化合物。
各个变量每次在一般结构式定义的范围内发生时独立地被定义。例如,当对于芳基/杂芳基存在多于一个取代基时,各个取代基每次出现时独立地被选择,并且各个取代基可以与其它相同或不同。作为另一个例子,对于基团-(CR3R3)2-,两个R3基团的每次出现可以相同或不同。如本文中所使用,除非明确说明与此相反,每次提及本发明的特定化合物或本发明化合物的通式时,意指包括化合物以及其药学上可接受的盐。
在本发明的一个实施方案中,本发明提供式I的化合物或其药学上可接受的盐、或立体异构体:
A 选自芳基和杂芳基;
X 独立地选自 CH2,NH,S,和O,其中至少一个X 不同于CH2;
n为0、1、2、3或4;
m为0、1、2、3或4;
p 为1、2、3、4或5;
R1 选自:
卤素,
氧代(=O),
C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C1-10杂烷基(氧基)0-1(羰基)0-1C0-10烷基,
芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
杂芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
(C1-10)杂烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
芳基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
杂芳基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,
C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
(C1-10)杂烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
芳基C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
杂芳基C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
(C3-12)杂环烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,
C0-10烷基磺酰基C0-10烷基,
C1-10杂烷基磺酰基C0-10烷基,
(C3-12)环烷基C0-10烷基磺酰基C0-10烷基,
(C3-12)环杂烷基C0-10烷基磺酰基C0-10烷基,
杂芳基C0-10烷基磺酰基C0-10烷基,
芳基C0-10烷基磺酰基C0-10烷基,
C1-10烷基氨磺酰基C0-10烷基,
C1-10杂烷基氨磺酰基C0-10烷基,
(C3-12)环烷基C0-10烷基氨磺酰基C0-10烷基,
(C3-12)环杂烷基C0-10烷基氨磺酰基C0-10烷基,
杂芳基C0-10烷基氨磺酰基C0-10烷基,
芳基C0-10烷基氨磺酰基C0-10烷基,
(C0-10烷基)1-2 氨基,
-CO2(C0-10烷基),
-(C0-10烷基)CO2H,
-SO2NH2,
-SO2NH(C1-10烷基),
-SO2N(C1-10烷基)2,
-SO2CF3,
-SO2CF2H,
C1-10烷基亚磺酰基C0-10烷基,
C1-10杂烷基亚磺酰基C0-10烷基,
(C3-12)环烷基C0-10烷基亚磺酰基C0-10烷基,
(C3-12)环杂烷基C0-10烷基亚磺酰基C0-10烷基,
杂芳基C0-10烷基亚磺酰基C0-10烷基,
芳基C0-10烷基亚磺酰基C0-10烷基,
C0-10烷基亚磺酰基氨基C0-10烷基,
C1-4 酰基氨基 C0-10烷基,
羟基,
-(C1-10烷基)OH,
-C0-10烷基烷氧基,
氰基,
(C1-6烷基)氰基,和
C1-6卤代烷基;
R2 选自
卤素,
氧代(=O),
C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C0-10烷基氨基C0-10烷基,
(C1-10)杂烷基氨基C0-10烷基,
C3-12环烷基C0-10烷基氨基C0-10烷基,
芳基C0-10烷基氨基C0-10烷基,
杂芳基C0-10烷基氨基C0-10烷基,
(C3-12)杂环烷基C0-10烷基氨基C0-10烷基,
C1-10烷基磺酰基,
(C3-12)环烷基C0-10烷基磺酰基,
(C3-12)环杂烷基C0-10烷基磺酰基,
(C0-10烷基)1-2 氨基,
-CO2(C0-10烷基),
-(C0-10烷基)CO2H,
-SO2CF3,
-SO2CF2H,
C1-10烷基亚磺酰基,
羟基,
-(C1-10烷基)OH,
-C0-10烷基烷氧基,
氰基,
(C1-6烷基)氰基,和
C1-6卤代烷基,和
其中R1和R2 各自任选地被1、2、3或4 个R3取代基取代;
R3 独立地选自:
卤素,
C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C1-10杂烷基(氧基)0-1(羰基)0-1C0-10烷基,
芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
杂芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,
((C0-10)烷基)1-2氨基羰基氧基,
芳基(C0-10)烷基氨基羰基氧基,
-CO2(C0-10烷基),
-(C0-10烷基)CO2H,
氧代(=O),
-SO2NH2,
-SO2NH(C1-10烷基),
-SO2N(C1-10烷基)2,
-SO2CF3,
-SO2CF2H,
C1-10烷基亚磺酰基,
氨基,
(C0-10烷基)1-2 氨基,
-(氧基)0-1(羰基)0-1N(C0-10烷基)1-2
羟基,
(C1-10烷基)OH,
C1-10 烷氧基,
(C1-10烷基)氰基,
氰基,和
C1-6卤代烷基; 和
R3 任选被1、2或3个R4取代基取代,所述R4取代基选自羟基,(C1-6)烷基,(C1-6)烷氧基,(C1-10烷基)OH,卤素,CO2H,-(C0-6)烷基CN,
-O(C=O)C1-C6烷基,NO2,三氟甲氧基,三氟乙氧基,三氟甲基,三氟乙基,
-N-C(O)O(C0-6)烷基,C1-10烷基磺酰基,氧代(O=),氨基磺酰基,-SO2NH2,
-SO2NH(C1-10烷基),-SO2N(C1-10烷基)2,-SO2C1-6烷基,-SO2CF3,-SO2CF2H,-C1-10烷基亚磺酰基,-O(0-1)(C1-10)卤代烷基,氨基(C1-6烷基)1-2和NH2。
在本发明的一个实施方案中,A 选自苯基,吡啶基,异二氢吲哚基,6,7-二氢苯并[d]噻唑基,2,3-二氢-1H-吲哚基,二氢苯并[d]噻唑基,吲哚基,1,3-苯并噻唑基,苯并间二氧杂环戊烯基,苯并[d][1,3]间二氧杂环戊烯基,2,3-二氢异吲哚基,喹啉基,喹喔啉基,二氢苯并异噻唑基,2,3-二氢苯并[d]异噻唑基,二氢茚基,二氢苯并呋喃基,2,3-二氢苯并呋喃基,2,3-二氢-1H-茚基,异吲哚基,二氢苯并[b]噻吩基,2,3-二氢苯并[b]噻吩基,和。
在另一实施方案中,A 选自苯基,吡啶基,异二氢吲哚基,吲哚基,1,3-苯并th偶氮lyl,苯并间二氧杂环戊烯基,苯并[d][1,3]间二氧杂环戊烯基,二氢异吲哚基,喹啉基,喹喔啉基,二氢苯并异噻唑基,2,3-二氢苯并[d]异噻唑基,二氢茚基,二氢苯并呋喃基,2,3-二氢苯并呋喃基,2,3-二氢-1H-茚基,异吲哚基,二氢苯并[b]噻吩基,2,3-二氢苯并[b]噻吩基 和。
在本发明的一个实施方案中,A 选自苯基,吡啶基,苯并间二氧杂环戊烯基,苯并[d][1,3]间二氧杂环戊烯基,二氢异吲哚基,喹啉基,喹喔啉基,二氢苯并异噻唑基,2,3-二氢苯并[d]异噻唑基,二氢茚基,二氢苯并呋喃基,2,3-二氢苯并呋喃基,2,3-二氢-1H-茚基,异吲哚基,和二氢苯并[b]噻吩基,2,3-二氢苯并[b]噻吩基。
在本发明的另一个实施方案中,A 选自苯基,吡啶基,2,3-二氢-1H-吲哚基,1,3-苯并噻唑基,2,3-二氢异吲哚基,二氢苯并异噻唑基,2,3-二氢苯并[d]异噻唑基,和。
在本发明的另一实施方案中,A 选自苯基,二氢苯并异噻唑基,和2,3-二氢苯并[d]异噻唑基。
在一个实施方案中,p为2,3,4,或5。 在本实施方案的变形中,p 为3,4,或5。在另一个变形中,p 为4,或5。
在一个实施方案中,m为0。 在本发明的另一实施方案中,m 为1,2,或3。
在一个实施方案中,n为0。 在本发明的另一实施方案中,n 为1,2,或3。
在一个实施方案中,X 选自CH2和O,其中至少一个X 不同于CH2。在本实施方案的变形中,仅一个X 为O。
在一个实施方案中,X 选自CH2,NH,和S,其中至少一个X 不同于CH2。
在一个实施方案中,由形成的式I中发现的环系选自四氢吡喃基,哌啶基,和氮杂环丁烷基。在本实施方案的变形中,环系为四氢吡喃基。
在一个实施方案中,由形成的式I中发现的环系选自四氢吡喃基,氧杂环庚烷基,哌啶基,和氮杂环丁烷基.在本实施方案的变形中,该环系是氧杂环庚烷基或四氢吡喃基。
在一个实施方案中,R1 选自:卤素,氧代(=O),C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C1-10杂烷基(氧基)0-1(羰基)0-1C0-10烷基,芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,杂芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,芳基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,杂芳基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,芳基C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,杂芳基C0-10烷基氨基(氧基)0-1(羰基)0-1C0-10烷基,C0-10烷基磺酰基C0-10烷基,C1-10杂烷基磺酰基C0-10烷基,(C3-12)环烷基C0-10烷基磺酰基C0-10烷基,(C3-12)环杂烷基C0-10烷基磺酰基C0-10烷基,杂芳基C0-10烷基磺酰基C0-10烷基,芳基C0-10烷基磺酰基C0-10烷基,C1-10烷基氨磺酰基C0-10烷基,C1-10杂烷基氨磺酰基C0-10烷基,(C3-12)环烷基C0-10烷基氨磺酰基C0-10烷基,(C3-12)环杂烷基C0-10烷基氨磺酰基C0-10烷基,杂芳基C0-10烷基氨磺酰基C0-10烷基,芳基C0-10烷基氨磺酰基C0-10烷基,(C0-10烷基)1-2 氨基,-SO2NH2,-SO2NH(C1-10烷基),
-SO2N(C1-10烷基)2,-SO2CF3,-SO2CF2H,C1-4 酰基氨基 C0-10烷基,羟基,-(C1-10烷基)OH,-C0-10烷基烷氧基,氰基,(C1-6烷基)氰基,和C1-6卤代烷基;其中R1 任选被1、2、3或4 个R3取代基取代。
在另一实施方案中,R1选自:卤素,氧代(=O),C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C1-10杂烷基(氧基)0-1(羰基)0-1C0-10烷基,芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,杂芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C0-10烷基磺酰基C0-10烷基,C1-10杂烷基磺酰基C0-10烷基,(C3-12)环烷基C0-10烷基磺酰基C0-10烷基,(C3-12)环杂烷基C0-10烷基磺酰基C0-10烷基,杂芳基C0-10烷基磺酰基C0-10烷基,芳基C0-10烷基磺酰基C0-10烷基,(C0-10烷基)1-2氨基,-SO2NH2,-SO2NH(C1-10烷基),-SO2N(C1-10烷基)2,-SO2CF3,-SO2CF2H,C1-4 酰基氨基 C0-10烷基,羟基,
-(C1-10烷基)OH,-C0-10烷基烷氧基,氰基,(C1-6烷基)氰基,和C1-6卤代烷基;其中R1任选被1、2、3或4个R3取代基取代。
在另一个实施方案中,R1 选自: 卤素,氧代(=O),C0-10烷基亚氨基C0-10烷基,C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,杂芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1氨基C0-10烷基,C0-10烷基磺酰基C0-10烷基,(C3-12)环杂烷基C0-10烷基磺酰基C0-10烷基,C1-10烷基氨磺酰基C0-10烷基,-SO2NH2,-SO2NH(C1-10烷基),-SO2N(C1-10烷基)2,C1-10烷基亚磺酰基C0-10烷基,硫基C1-10烷基,羟基,-(C1-10烷基)OH,-C0-10烷基烷氧基,氰基,和C1-6卤代烷基。
在另一实施方案中,R1 选自: 氧代(=O),C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C0-10烷基磺酰基C0-10烷基,(C0-10烷基)1-2 氨基,-SO2NH(C1-10烷基),-SO2N(C1-10烷基)2,和C1-6卤代烷基;其中R1 任选被1、2、3或4个 R3取代基取代。
在另一实施方案中,R1 选自:甲基磺酰基,甲基,氧代,叔丁基,--SO2N(CH3)2,三氟乙基,氨基,-SO2NH(叔丁基),异丙基磺酰基,和-SO2N((甲基)(叔丁基)),其中R1 任选被1、2、3或4个R3取代基取代。
在另一个实施方案中,R1 选自:三氟乙基,亚氨基甲基,氧代,叔丁基氨磺酰基,异丁基,氰基,甲硫基,氟代,甲氧基,叔丁基氧基羰基甲基,氯代,甲基磺酰基,甲基亚磺酰基,羟基,叔丁基氨基甲基,异丁基氨基甲基,环戊基氨基甲基,二甲基丙基氨基甲基,环丁基氨基甲基,吡啶基甲基,二甲基氨基磺酰基,甲基,三氟甲基,甲基氨基甲基,哌嗪基甲基,叔丁基,2,2,2-三氟乙基,氧杂双环[2.2.2]辛基,三唑基甲基,叔丁基氨基磺酰基,(1,1-二甲基丙基)磺酰基,(1,1,2-三甲基丙基)磺酰基,二甲基氨基甲基,吡咯烷基甲基,环丙基氨基甲基,异丙基氨基甲基,乙基氨基甲基,氮杂环丁烷基磺酰基,吗啉基磺酰基,吡咯烷基磺酰基,甲氧基乙-2-基,叔丁基磺酰基,氨基甲基,异丙基羰基,异丙基磺酰基,异丙基,吡咯烷基,哌啶基,硫代吗啉基甲基,哌啶基羰基,氮杂环丁烷基甲基,1-羟基-1-甲基乙基,1-甲基乙基氨基,和羟基甲基,其中R1 任选被1、2、3或4 个R3取代基取代。
在一个实施方案中,R2 选自:卤素,C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C3-12环烷基,C0-10烷基氨基C0-10烷基,C1-10烷基磺酰基,(C0-10烷基)1-2 氨基,-CO2(C0-10烷基),-(C0-10烷基)CO2H,-SO2CF3,-SO2CF2H,羟基,-(C1-10烷基)OH,-C0-10烷基烷氧基,氰基,(C1-6烷基)氰基,和C1-6卤代烷基,和其中R2 任选被1、2、3或4个 R3取代基取代。
在本发明的一个实施方案中,R3 独立地选自: 卤素,C1-10烷基(氧基)0-1(羰基)0- 1C0-10烷基,C1-10杂烷基(氧基)0-1(羰基)0-1C0-10烷基,芳基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,C3-12环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,杂芳基C0-10烷基(氧基)0-1(羰基)0- 1C0-10烷基,
(C3-12)杂环烷基C0-10烷基(氧基)0-1(羰基)0-1C0-10烷基,((C0-10)烷基)1-2氨基羰基氧基,-CO2(C0-10烷基),-(C0-10烷基)CO2H,氧代(=O),-SO2NH2,
-SO2NH(C1-10烷基),-SO2N(C1-10烷基)2,-SO2CF3,-SO2CF2H,氨基,羟基,(C1-10烷基)OH,C1-10 烷氧基,(C1-10烷基)氰基,氰基,和C1-6卤代烷基,其中R1 任选被1、2、3或4个 R3取代基取代。
在本发明的一个实施方案中,R3 独立地选自: 卤素,C1-10烷基(氧基)0-1(羰基)0- 1C0-10烷基,氧代(=O),氨基,羟基,(C1-10烷基)OH,C1-10烷氧基,和C1-6卤代烷基;其中R3 任选被1、2或3个R4取代基取代。
在一个实施方案中,R3 独立地选自: 卤素,
C1-10烷基(氧基)0-1(羰基)0-1C0-10烷基,氨基,和C1-6卤代烷基,其中R3 任选被 1、2、3或4 个R4取代基取代。
在本发明的另一实施方案中,R3 独立地选自:甲基,三氟甲基,叔丁基,和氨基;其中R3 任选被1、2或3个R4取代基取代。
在本发明的另一个实施方案中,R3 独立地选自:甲基,乙基,氟代,叔丁基,氧代,三氟甲基,叔丁基氧基羰基,异丙基,羟基,氨基,甲氧基,和叔丁基氧基羰基甲基,其中R3任选被1、2或3个R4取代基取代。
在本发明的一个实施方案中,R4 独立地选自羟基,(C1-6)烷基,(C1-6)烷氧基,(C1-10烷基)OH,卤素,-O(C=O)C1-C6烷基,三氟甲氧基,三氟乙氧基,三氟甲基,三氟乙基,氧代(O=),-O(0-1)(C1-10)卤代烷基,氨基(C1-6烷基)0-2和NH2。
在本发明的另一实施方案中,R4 独立地选自羟基,甲基,氧代,三氟甲基,甲氧基,1-羟基-1-甲基乙基,氨基,甲氧基乙基,二氟甲基,二甲基氨基,乙基,和NH2。
在本发明的特定的变形中,在式I的化合物中,取代基是:A 选自苯基,二氢苯并异噻唑基,和2,3-二氢苯并[d]异噻唑基;m和n都为0;p为4;X为CH2或O,其中仅一个X为O;R3 独立地选自:甲基,三氟甲基,叔丁基,和氨基;其中R3 任选被1、2或3个R4取代基取代;和R4 独立地选自羟基,甲基,氧代,三氟甲基,甲氧基,1-羟基-1-甲基乙基,氨基,甲氧基乙基,二氟甲基,二甲基氨基,乙基,和NH2。
在本发明的另一特定的变形中,在式I的化合物中,取代基是: A 选自苯基,吡啶基,2,3-二氢-1H-吲哚基,1,3-苯并噻唑基,2,3-二氢异吲哚基,二氢苯并异噻唑基,和2,3-二氢苯并[d]异噻唑基和; X为CH2或O,其中仅一个X为O; p为4或5; n 为0;m为0、1、2、3或4; R3 独立地选自:甲基,乙基,氟代,叔丁基,氧代,三氟甲基,叔丁基氧基羰基,异丙基,羟基,氨基,甲氧基,和叔丁基氧基羰基甲基;R1 选自:三氟乙基,亚氨基甲基,氧代,叔丁基氨磺酰基,异丁基,氰基,甲硫基,氟代,甲氧基,叔丁基氧基羰基甲基,氯代,甲基磺酰基,甲基亚磺酰基,羟基,叔丁基氨基甲基,异丁基氨基甲基,环戊基氨基甲基,二甲基丙基氨基甲基,环丁基氨基甲基,吡啶基甲基,二甲基氨基磺酰基,甲基,三氟甲基,甲基氨基甲基,哌嗪基甲基,叔丁基,2,2,2-三氟乙基,氧杂双环[2.2.2]辛基,三唑基甲基,叔丁基氨基磺酰基,(1,1-二甲基丙基)磺酰基,(1,1,2-三甲基丙基)磺酰基,二甲基氨基甲基,吡咯烷基甲基,环丙基氨基甲基,异丙基氨基甲基,乙基氨基甲基,氮杂环丁烷基磺酰基,吗啉基磺酰基,吡咯烷基磺酰基,甲氧基乙-2-基,叔丁基磺酰基,氨基甲基,异丙基羰基,异丙基磺酰基,异丙基,吡咯烷基,哌啶基,硫代吗啉基甲基,哌啶基羰基,氮杂环丁烷基甲基,1-羟基-1-甲基乙基,1-甲基乙基氨基,和羟基甲基,其中R1 任选被1、2、3或4 个R3取代基取代。
光学异构体- 非对映异构体 -几何异构体 - 互变异构体
式I的化合物含有一个或多个不对称中心,因此能够以外消旋物和外消旋混合物、单一的对映异构体,非对映体的混合物和单个的非对映异构体的形式出现。本发明意在包括所述式I的化合物的所有这些异构形式,无论是作为单一种类或它们的混合物。
本文中所述的一些化合物包含烯属双键,除非另有说明,意在包括E和Z这两种的几何异构体。
本文中所述的一些化合物可具有不同的氢的连接点而存在,称为互变异构体。这样的例子可以是酮和其作为酮 - 烯醇互变异构体已知的烯醇形式。式I的化合物包括单个的互变异构体以及它们的混合物。
本发明的具体实施方案包括选自本文中实施例的主题化合物的化合物或其药学上可接受的盐。
本发明的化合物可含有一个或多个不对称中心,因此能够以包括外消旋物和外消旋混合物,对映异构体混合物,单一的对映异构体,非对映异构体的混合物和单个的非对映异构体的“立体异构体”的形式出现。其它不对称中心可以依赖于分子上各种取代基的性质而存在。每个这样的不对称中心将独立地产生两种旋光异构体,意在将在混合物中以及作为纯的或部分纯化的化合物的所有可能的光学异构体和非对映异构体都包括在本发明的范围之内。本发明意在包括这些化合物的所有这些异构形式。当在手性碳上的键在本发明的式子中被描绘为直线时,理解为手性碳的(R)和(S)构型,因此,对映异构体及其混合物都包括在该式中。例如,式I显示了没有特定的立体化学的一类化合物的结构。当本发明的化合物含有一个手性中心时,术语“立体异构体”包括对映异构体及对映异构体的混合物,例如被称为外消旋混合物的特定的50:50混合物。
式(I)的化合物可以含有不对称或手性中心,因此以不同的立体异构形式存在。意在将式(I)的化合物的所有立体异构形式以及其混合物,包括外消旋混合物,形成本发明的一部分。此外,本发明包括所有的几何和位置异构体。例如,如果式(I)的化合物包含双键或稠环,则顺式和反式形式,以及混合物,包含在本发明的范围内。
非对映异构体混合物可通过本领域技术人员公知的方法、例如通过色谱法和/或分级结晶、基于其物理化学的差异而分离成它们的单个的非对映异构体。对映异构体可以通过下述这样分离,即,用与适当的光学活性化合物(例如,手性助剂如手性醇或Mosher的酰氯)的反应将对映异构体混合物转化成非对映异构体混合物,分离非对映异构体并将单个的非对映异构体转化(例如,水解)为相应的纯对映异构体。而且,一些式(I)的化合物可以是阻转异构体(例如,取代的联芳)并且被认为是本发明的一部分。对映异构体还可以通过使用手性HPLC柱分离。
也有可能是式(I)的化合物可以以不同的互变异构形式存在,并且所有这些形式都包括在本发明的范围之内。此外,例如,化合物的所有酮 - 烯醇和亚胺 - 烯胺形式也包括在本发明中。
本发明化合物的所有立体异构体(例如几何异构体、光学异构体等)(包括该化合物的盐、溶剂化物、酯和前药以及该前药的盐、溶剂化物和酯的那些立体异构体),例如由于各种取代基上的不对称碳而可存在的那些立体异构体,包括对映异构形式(甚至不存在不对称碳时也可存在)、旋转异构形式、阻转异构体和非对映异构体形式都被视为在本发明的范围内,正如位置异构体(例如,4-吡啶基和3-吡啶基)。(例如,如果式(I)的化合物包含双键或稠环,则顺式和反式形式,以及混合物,包含在本发明的范围内。此外,例如,化合物的所有酮-烯醇和亚胺-烯胺形式也包括在本发明中。)本发明的化合物的单个立体异构体可以例如基本上不含其它异构体,或可以例如作为外消旋体或与所有其它的混合,或其它选择的立体异构体。本发明的手性中心可具有如IUPAC 1974 推荐规范所定义的S或R构型。术语“盐”、“溶剂化物”、“酯”、“前药”等的使用意在同样适用于本发明化合物的对映异构体、立体异构体、旋转异构体、互变异构体、位置异构体、外消旋物或前药的盐、溶剂化物、酯和前药。
在本申请中,当一个特定的立体异构化合物在立体异构的名称中使用“和”来命名时,该“和”表示对映异构体的外消旋混合物。即,个体的对映异构体没有被单个地分离。
当立体异构命名包括“或”时,例如,该“或”表示外消旋物向个体的对映异构体的手性拆分被完成,但特定的对映异构体的实际的光学活性未必被确定。
如本领域已知的那样利用本文中记载的方法的适当的改变可实现这些非对映异构体的独立的合成或它们的色谱分离。它们的绝对立体化学可以通过结晶产物或如果必要,用含有已知绝对构型的不对称中心的试剂衍生化的结晶产物或结晶中间体的X射线结晶学来确定。如果需要的话,所述化合物的外消旋混合物可进行分离,以使单个的对映异构体被分离。所述分离可以通过本领域中公知的方法来实施,例如将化合物的外消旋混合物偶联至对映纯的化合物,以形成非对映异构体混合物,随后通过标准方法,如分级结晶或色谱法进行单个非对映异构体的分离。所述偶联反应通常是使用对映纯的酸或碱进行的盐的形成。非对映体衍生物然后可通过加入的手性残基的裂开而转化为纯对映异构体。化合物的外消旋混合物还可以通过利用手性固定相的色谱法直接分离,该方法是本领域是公知的。可选地,化合物的任何对映异构体可利用本领域中公知的方法、通过使用光学纯起始物料或已知构型的试剂的立体选择性合成来获得。
盐
术语“药学上可接受的盐”指由药学上可接受的无毒性碱、包括无机碱和有机碱制备的盐。源于无机碱的盐包括铝,铵,钙,铜,铁,亚铁,锂,镁,三价锰盐,二价锰,钾,钠,锌等。特别优选的是铵,钙,镁,钾和钠盐。源于药学上可接受的有机无毒碱的盐包括伯,仲和叔胺,取代的胺、包括天然存在的取代的胺,环胺,和碱性离子交换树脂、如精氨酸,甜菜碱,咖啡因,胆碱,N,N'- 二苄基亚乙基二胺,二乙胺,2-二乙基氨基乙醇,2-二甲基氨基乙醇,乙醇胺,亚乙基二胺,N-乙基吗啉,N-乙基哌啶,葡糖胺,氨基葡萄糖,组氨酸,哈胺,异丙胺,赖氨酸,甲基葡糖胺,吗啉,哌嗪,哌啶,聚胺树脂,普鲁卡因,嘌呤,可可碱,三乙胺,三甲胺,三丙胺,氨基丁三醇等的盐。
当本发明的化合物是碱时,盐可以由药学上可接受的无毒酸、包括无机酸和有机酸制备。这些酸包括乙酸,苯磺酸,苯甲酸,樟脑磺酸,柠檬酸,乙磺酸,富马酸,葡糖酸,谷氨酸,氢溴酸,盐酸,羟乙磺酸,乳酸,马来酸,苹果酸,扁桃酸,甲磺酸,粘酸,硝酸,扑酸,泛酸,磷酸,琥珀酸,硫酸,酒石酸,对甲苯磺酸,1-羟基-2-萘甲酸(xinafoate)等。特别优选的是柠檬酸,氢溴酸,盐酸,马来酸,磷酸,硫酸和酒石酸。
应该理解的是,除非另外指明,式I的化合物或其子集、其实施方案、以及特定的化合物的提及意思是还包括药学上可接受的盐和其立体异构体。
此外,本发明的化合物的一些晶形可以作为多晶型存在,同样地所有形式都旨在被包括在本发明中。此外,本发明的一些化合物可以与水(水合物)或常见的有机溶剂形成溶剂化物。这些溶剂化物包含在本发明的范围内。
示踪的化合物
在通式I的化合物中,原子可显示出它们的天然同位素丰度,或一个或多个原子可以被人为地富集在具有相同原子数、但原子质量或质量数不同于在自然界中主要被发现的原子质量或质量数的特定的同位素中。本发明意在包括通式I化合物的所有合适的同位素变体。例如,氢(H)的不同的同位素形式包括氕(1H)和氘(2H)。氕是自然界中发现的主要的氢同位素。富集氘可提供某些治疗优点,例如增加体内半衰期或减少剂量需求,或可以提供作为用于生物样品的表征标准有用的化合物。通式I中同位素富集的化合物可以无需过度的实验、通过本领域技术人员熟知的常规技术或通过与在本文的方案和实施例中记载的那些类似的方法、使用适当的同位素富集的试剂和/或中间体来制备。
效用
式I的化合物或其药学上可接受的盐和药物组合物可以用于治疗或预防多种由Janus激酶介导的病症或疾病,特别是可通过抑制Janus激酶、如JAK1、JAK2,JAK3或TYK2而得到改善的疾病或病症。这样的病症和疾病包括但不限于:(1)关节炎,包括类风湿关节炎,青少年性关节炎,和牛皮癣性关节炎;(2)哮喘和其他气道阻塞性疾病,包括慢性哮喘,晚期哮喘,气道高反应性,支气管炎,支气管哮喘,过敏性哮喘,内源性哮喘,外源性哮喘,粉尘性哮喘,经常性气道阻塞,慢性阻塞性肺疾病、包括肺气肿;(3)自身免疫性疾病或障碍,包括那些指定为单器官或单细胞型自身免疫疾病的疾病,例如桥本氏甲状腺炎,自身免疫性溶血性贫血,恶性贫血性萎缩性胃炎,自身免疫性脑脊髓炎,自身免疫性睾丸炎,古德帕斯彻病,自身免疫性血小板减少症,交感性眼炎,重症肌无力,格雷夫斯病,原发性胆汁性肝硬化,慢性活动性肝炎,溃疡性结肠炎和膜性肾小球肾炎,那些被指定为涉及全身性自身免疫障碍,例如全身性红斑狼疮,类风湿关节炎,干燥综合征,莱特尔氏综合征,多肌炎 - 皮肌炎,全身性硬化症,结节性多动脉炎,多发性硬化和大疱性类天疱疮,和另外的自身免疫性疾病,其可以是基于B细胞(体液)的或基于T细胞的、包括科根综合征,强直性脊柱炎,韦格纳肉芽肿病,自身免疫性秃头症,I型或青少年发病型糖尿病,和甲状腺炎;(4)癌症或肿瘤,包括消化道/胃肠道癌,结肠癌,肝癌,皮肤癌、包括肥大细胞瘤和鳞状细胞癌,乳房癌和乳腺癌,卵巢癌,前列腺癌,淋巴瘤,白血病,包括急性髓细胞性白血病和慢性骨髓性白血病,肾癌,肺癌,肌肉癌,骨癌,膀胱癌,脑癌,黑素瘤、包括口和转移性黑色素瘤,卡波西肉瘤,骨髓瘤、包括多发性骨髓瘤,骨髓增生性疾病,增殖性糖尿病性视网膜病变,和血管原-有关的病症、包括实体瘤;(5)糖尿病,包括I型糖尿病和来自糖尿病的并发症;(6)眼睛疾病、障碍或病状,包括眼的自身免疫性疾病,角膜结膜炎,春季结膜炎,葡萄膜炎、包括与白塞氏病有关的葡萄膜炎和透镜诱导的葡萄膜炎,角膜炎,疱疹性角膜炎,圆锥形角膜炎,角膜上皮营养不良,角膜白斑,眼天疱疮,角膜侵蚀性溃疡,巩膜炎,Grave眼病,小柳原田综合征,干燥性角结膜炎(干眼),小水疱,虹膜睫状体炎,结节病,内分泌性眼病,感性眼炎,过敏性结膜炎和眼部新生血管;(7)肠炎症、变态反应或病况,包括克罗恩病和/或溃疡性结肠炎,炎症性肠病,腹腔疾病,直肠炎,嗜酸性胃肠炎,肥大细胞增多症和; (8)神经变性疾病,包括运动神经元病,阿尔茨海默氏病,帕金森氏症,肌萎缩性侧索硬化症,亨廷顿氏病,脑缺血,或由创伤,击打,谷氨酸神经毒性或缺氧引起的神经变性疾病;中风中的缺血/再灌注损伤,心肌缺血,肾缺血,心脏病发作,心脏肥大,动脉粥样硬化和动脉硬化,器官缺氧,和血小板聚集;(9)皮肤疾病、病状或障碍,包括特应性皮炎,湿疹,银屑病,硬皮病,皮肤瘙痒和其他搔痒状况;(10)过敏性反应,包括过敏反应,过敏性鼻炎,过敏性皮炎,过敏性荨麻疹,血管性水肿,过敏性哮喘,或对于虫咬、食品、药物或花粉的过敏反应; 和(11)移植排斥,包括胰岛移植排斥,骨髓移植排斥,移植物抗宿主病,器官和细胞移植排斥、如骨髓,软骨,角膜,心脏,椎间盘,胰岛,肾,肢,肝,肺,肌肉,成肌细胞,神经,胰腺,皮肤,小肠,或气管,和异种移植。
因此,本发明的另一个方面提供了一种用于JAK介导的疾病或障碍的治疗或预防的方法,该方法包括给予需要其的哺乳动物治疗有效量的式I的化合物。在一个实施方案中,这样的疾病包括哮喘和类风湿性关节炎。在另一实施方案中,这样的疾病包括经常性气道阻塞和慢性阻塞性肺病(COPD),或阻塞性气道疾病。在本实施方案的变形中,该疾病为COPD。
本发明的另一个方面提供了式I的化合物在制备用于JAK介导的疾病或障碍的治疗或预防的药物中的应用。
本发明的一个方面是式I的化合物或其药学上可接受的盐或立体异构体在制备用于治疗通过Janus激酶JAK1和JAK2的抑制而被改善的疾病或障碍的药物中的应用。
本发明的另一个方面是式I的化合物或其药学上可接受的盐或其立体异构体和第二活性剂在制造用于治疗通过抑制Janus激酶JAK1和JAK2而改善的疾病或障碍的药物中的使用。
剂量范围
式I的化合物的预防或治疗剂量的大小当然会随待治疗的病症的性质和严重程度以及随式I的特定化合物和其给药途径而变化。它也将根据各种因素,包括年龄、体重、一般健康状况、性别、饮食、给药时间、排泄率、药物联用和个体患者的反应而变化。一般而言,日剂量是每公斤哺乳动物的体重为约0.001毫克至约100毫克,优选每公斤为0.01毫克至约10毫克。另一方面,在一些情况下可能有必要使用这些限度之外的剂量。
可与载体物质组合以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的给药方式而变化。例如,意在用于人的口服给药的制剂可含有0.05毫克至5克的活性剂,与可在总组合物的约5%至约99.95%的范围变化的、合适和方便的量的载体材料配混。在一些情况下,剂量单位形式可以含有约0.05至约3克的活性成分。剂量单位形式通常会含有约0.1毫克至约0.4克之间的活性成分,典型地为0.1毫克,0.2毫克,0.3毫克,0.4毫克,0.5毫克,1毫克,2毫克,5毫克,10毫克,25毫克,50毫克,100毫克,200毫克或400毫克。
药物组合物
本发明的另一个方面提供了包含式I的化合物与药学上可接受的载体的药物组合物。对于任何的前列腺素类介导的疾病的治疗,式I化合物可以通过吸入喷雾口服地、局部地、肠胃外或直肠地以含有常见的无毒的药学上可接受的载体、佐剂和媒介物的剂量单位制剂给药。如本文所用的术语肠胃外包括皮下注射,静脉内,肌内,胸骨内注射或灌输技术。除了温血动物如小鼠、大鼠、马、牛、羊、狗、猫等的治疗,本发明的化合物可有效地治疗人。
含有活性成分的药物组合物可以是适于口服使用的形式,例如作为片剂,锭剂,菱形(lozenges),水性或油性悬浮液,可分散粉末或颗粒,乳剂,硬胶囊或软胶囊,或糖浆剂或酏剂。意在用于口服使用的组合物可以根据本领域已知的用于药物组合物的制造的任何方法来制备,且这样的组合物可以含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的物质,以便提供药学上美观和适口的制剂。片剂含有活性成分、混合有适于生产片剂的无毒的药学上可接受的赋形剂。这些赋形剂可以是例如惰性稀释剂、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,明胶或阿拉伯胶,和润滑剂、例如硬脂酸镁,硬脂酸或滑石。片剂可以是未包衣的或它们可以通过已知技术进行包衣以延迟在胃肠道中的崩解和吸收,从而提供较长时期的持续作用。例如,可采用延时材料、例如单硬脂酸甘油酯或二硬脂酸甘油酯。它们也可以通过在美国专利4256108;4166452和4265874中描述的技术包衣,以形成用于缓释的渗透性治疗片剂。
口服使用的制剂还可以呈现为硬胶囊,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,或者呈现为软胶囊,其中活性成分与可和水混溶的溶剂如丙二醇、PEGs和乙醇,或油介质、例如花生油、液体石蜡或橄榄油混合。
水性悬浮液含有活性物质、混合有适于制备水性混悬液的赋形剂。这样的赋形剂是悬浮剂,例如羧甲基纤维素钠,甲基纤维素,羟丙基甲基纤维素,海藻酸钠,聚乙烯吡咯烷酮,黄蓍胶和阿拉伯树胶;分散或润湿剂可以是天然存在的磷脂,例如卵磷脂,或氧化烯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的缩合产物、例如十七亚乙基氧基鲸蜡醇,或环氧乙烷与源于脂肪酸和己糖醇的偏酯的缩合产物、如聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与源于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。水性混悬液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,和一种或多种甜味剂,如蔗糖,糖精或阿司帕坦。
油性悬浮液可通过将活性成分悬浮在植物油、例如花生油、橄榄油、芝麻油或椰子油中,或悬浮在矿物油、如液体石蜡中来配制。油性悬浮液可包含增稠剂、例如蜂蜡,硬石蜡或鲸蜡醇。可加入甜味剂、如上面列出的那些和调味剂,以提供适口的口服制剂。这些组合物可以通过加入抗氧化剂、如抗坏血酸来保存。
适合于通过加入水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。合适的分散或润湿剂和悬浮剂可列举上述已提及的那些物质。另外的赋形剂,例如甜味剂、调味剂和着色剂,也可以存在。
本发明的药物组合物还可以是水包油乳液的形式。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、和源于脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨醇单油酸酯,以及所述偏酯与环氧乙烷的的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳剂也可含有甜味剂和调味剂。
糖浆剂和酏剂可以用甜味剂,例如甘油、丙二醇、山梨醇或蔗糖配制。这种制剂也可以含有缓和剂、防腐剂、调味剂和着色剂。药物组合物可以是无菌可注射水溶液或油性悬浮液的形式。这种悬浮液可以根据使用上述已经提到的那些合适的分散或润湿剂和悬浮剂的已知技术来配制。无菌注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。在可以使用的可接受的媒介物和溶剂中有水,林格氏溶液和等渗氯化钠溶液。助溶剂如乙醇、丙二醇或聚乙二醇也可以使用。此外,无菌、不挥发性油通常用作溶剂或悬浮介质。为此,任何温和的固定油都可以使用,包括合成的单或二甘油酯。此外,认为脂肪酸、如油酸可用于注射剂的制备中。
吸入给药的剂型可方便地配制为气雾剂或干粉剂。对于合适和/或适于吸入给药的组合物,优选活性物质是颗粒尺寸减小的形式,更优选获得尺寸减小的形式,或通过微粉化获得。
在一个实施方案中,药物制剂适于利用加压计量吸入器(pMDI)使用,所述加压计量吸入器(pMDI)在每次驱动时释放计量剂量的药物。用于pMDIs的该制剂可以是在卤化烃推进剂中的溶液或悬浮液的形式。在pMDIs中使用的推进剂的类型正转向氢氟烷烃(HFAs),也被称为氢氟烃(HFCs)。特别地,1,1,1,2-四氟乙烷(HFA134a)和1,1,1,2,3,3,3-七氟丙烷(HFA227)被用于几种目前市售的药物吸入产品。该组合物可以包括用于吸入使用的其它的药学上可接受的赋形剂,例如乙醇,油酸,聚乙烯吡咯烷酮等。
加压计量吸入器通常有两个组件。首先,有罐组件,在其中药物颗粒在压力下以悬浮液或溶液的形式储存。其次,有用于保持并驱动该罐的容器组件。典型地,罐将包含多剂量制剂,虽然也可能有单剂量罐。所述罐组件典型地包括该罐的内容物可以被排出的阀出口。气溶胶药物通过在罐组件上施加力以将其推入容器组件而由该加压计量吸入器分配,从而打开阀出口并使药物颗粒通过容器组件从阀出口被运送,并从该容器的出口排出。一旦从罐中排出,药物颗粒被“雾化”,形成气溶胶。意在患者用他或她的吸入调整雾化药物的排出,从而使药物颗粒被夹带在病人的呼吸流中并输送到肺部。典型地,加压计量吸入器使用推进剂以加压罐中的内容物,且推动药物颗粒离开容器组件的出口。在加压计量吸入器中,制剂以液体或悬浮液的形式提供,并与推进剂一起驻留在容器内。推进剂可以采取各种形式。例如,推进剂可包括压缩气体或液化气体。
在另一个实施方案中,药物制剂适于利用干粉吸入器(DPI)使用。适合用于干粉吸入器的吸入组合物通常包含活性成分和颗粒和药学上可接受的载体的颗粒。活性物质的粒径可从约0.1μm至约10μm而变化;然而,为了有效递送至末梢肺,至少95%的活性剂颗粒为5μm或更小。每种活性剂可以以0.01 - 99%的浓度存在。然而典型地,每种活性剂以组合物总重量的约0.05至50%,更典型地约0.2 - 20%的浓度存在。
如上所述,除了活性成分外,可吸入粉末优选包括药学上可接受的载体,其可以由任何吸入可接受的、药理学上惰性的材料或材料的组合组成。有利的是,载体颗粒由一种或多种结晶糖组成;载体颗粒可以由一种或多种糖醇或多元醇组成。优选地,载体颗粒是葡萄糖或乳糖的颗粒,特别是乳糖的颗粒。在使用常规的干粉吸入器、如Handihaler,Rotohaler,Diskhaler,Twisthaler和Turbohaler的本发明的实施方案中,载体颗粒的粒径可以为约10微米至约1000微米。在这些实施方案的某些方案中,载体颗粒的粒径可以为约20微米至约120微米。在某些其它的实施方案中,载体颗粒的至少90wt%的尺寸小于1000微米,优选在60微米至1000微米之间。这些载体颗粒的比较大的尺寸提供良好的流动和夹带特性。当存在时,基于粉末的总重量,载体颗粒的量通常为高达95wt%,例如,高达90wt%,有利地高达80wt%,优选高达50wt%。任何优质的赋形剂材料的量,如果存在的话,基于该粉末的总重量可以是高达50wt%,有利地高达30wt%,尤其高达20wt%。该粉末可以任选地包含性能改良剂,如L-亮氨酸或其它氨基酸,和/或硬脂酸的金属盐、如硬脂酸镁或硬脂酸钙。
式I的化合物还可以以药物的用于直肠给药的栓剂形式给予。这些组合物可以通过将药物与在环境温度下为固体、但在直肠温度下为液体、从而会在直肠中融化以释放药物的合适的无刺激性赋形剂混合来制备。这样的材料为可可脂和聚乙二醇。
对于局部使用,含有式I的化合物的霜剂,软膏剂,凝胶剂,溶液或悬浮液等被使用。(为了本申请的目的,局部施用应包括漱口水和含漱剂。)外用制剂一般可包含药用载体,助溶剂,乳化剂,渗透促进剂,防腐剂体系和润肤剂。
与其它药物的组合
对于JAK介导的疾病的治疗和预防,式I化合物可以与其它治疗剂共同给药。因此,在另一个方面,本发明提供用于治疗JAK介导的疾病的药物组合物,其包含治疗有效量的式I的化合物和一种或多种其它的治疗剂。特别地,对于炎性疾病类风湿性关节炎,银屑病,炎性肠病,COPD,哮喘和过敏性鼻炎的治疗,式I的化合物可与药剂(agent)联合,所述药剂例如为:(1)TNF-α抑制剂、如Remicade®和Enbrel®);(2)非选择性的COX-I / COX-2抑制剂(例如吡罗昔康,双氯芬酸,丙酸类、如萘普生,氟比洛芬,非诺洛芬,酮洛芬和布洛芬,芬那酸类、如甲灭酸,消炎痛,舒林酸,阿扎丙宗,吡唑啉酮类、如保泰松,水杨酸盐类、如阿司匹林);(3)COX-2抑制剂(例如美洛昔康,塞来昔布,罗非考昔,伐地考昔和艾托考昔);(4)其它用于治疗类风湿性关节炎的药剂,包括低剂量甲氨蝶呤,来氟米特,环索奈德,羟氯喹,d-青霉胺,金诺芬或者胃肠道外或口服金;(5)白三烯生物合成抑制剂,5-脂肪氧合酶(5-LO)抑制剂或5-脂肪氧合酶激活蛋白(FLAP)拮抗剂,例如齐留通;(6)LTD4受体拮抗剂诸如扎鲁司特,孟鲁司特和普仑司特;(7)PDE4抑制剂,例如罗氟司特;(8)抗组胺H 1受体拮抗剂,例如西替利嗪,氯雷他定,氯雷他定,非索非那定,阿司咪唑,氮卓斯汀,和扑尔敏;(9)α1-,α2肾上腺素受体激动剂血管收缩剂拟交感神经药,诸如六氢脱氧麻黄碱,苯肾上腺素,苯丙醇胺,伪麻黄碱,萘甲唑啉盐酸盐,盐酸羟甲唑啉,盐酸四氢唑啉,赛洛唑啉盐酸盐和乙基去甲肾上腺素盐酸盐;(10)抗胆碱能药、如溴化异丙托品,噻托溴铵,氧托溴铵,阿地溴铵,胃长宁,哌仑西平,和替仑西平;(11)β-受体激动剂,例如奥西那林,异丙肾上腺素,异丙肾上腺素,舒喘宁,沙丁胺醇,福莫特罗,沙美特罗,特布他林,奥西那林,甲磺酸比托特罗,和吡布特罗,或methylxanthanines包括茶碱和氨茶碱,色甘酸钠;(12)胰岛素样生长因子I型(IGF-1)模拟物;(13)具有降低的全身性副作用的吸入性糖皮质激素,如泼尼松,泼尼松龙,氟尼缩松,曲安奈德,二丙酸倍氯米松,布地奈德,丙酸氟替卡松,环索奈德和糠酸莫米松。
合成的方法
方案和实施例
本文中所用的缩写具有如下表列出的含义。没有在下表中列出的缩写具有其通常被使用的含义,除非另外特别说明。
ACN,MeCN | 乙腈 |
BAST | 双(2-甲氧基乙基)氨基三氟化硫 |
t-Bu XPhos | 2-二 叔丁基膦基-2′,4′,6′-三异丙基联苯 |
Chiral SFC | 手性超临界流体色谱 |
CO<sub>2</sub> | 二氧化碳 |
Cs2CO<sub>3</sub> | 碳酸铯 |
Dba | 二亚苄基丙酮 |
DBU | 1,8-二氮杂双环[5.4.0]十一-7-烯 |
DCE | 1,2-二氯乙烷 |
DCM | 二氯甲烷 |
DEA | 二乙胺 |
DIPEA | N,N-二异丙基乙胺 |
DMEA | 二甲基乙胺 |
DMF | N,N-二甲基甲酰胺 |
DMSO | 二甲基亚砜 |
DSC | N,N-二琥珀酰亚胺基碳酸酯 |
EDC | 3-(乙基亚氨基亚甲基氨基)-N,N-二甲基-丙-1-胺 |
EtOAc | 乙酸乙酯 |
GCMS | 气相色谱/ 质谱法 |
HATU | O-(7-氮杂-1H-苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐 |
HCl | 氯化氢 |
HOBt | 1-羟基苯并三唑 |
HPLC | 高效液相色谱 |
IPA | 2-丙醇 |
LDA | 二异丙基氨基锂 |
m-CPBA | 间氯过氧化苯甲酸 |
LR | 低分辨率 |
LRMS | 低分辨率 质谱法 |
MeI | 碘代甲烷 |
Me-THF | 2-甲基四氢呋喃 |
Me<sub>4</sub>-t-Bu-X-Phos | 二(叔丁基)[3,4,5,6-四甲基-2',4',6'-三(丙烷-2-基)联苯-2-基]磷烷 |
MgSO<sub>4</sub> | 硫酸镁 |
MP-(OAc)<sub>3</sub>BH | 负载于固体的(多孔)三乙酰氧基硼氢化物 |
MPLC | 中压液相色谱 |
NaH | 氢化钠 |
Na<sub>2</sub>SO<sub>4</sub> | 硫酸钠 |
NaBH<sub>4</sub> | 硼氢化钠 |
NaHCO<sub>3</sub> | 碳酸氢钠 |
NaOMe | 甲醇钠 |
NMO | 4-甲基吗啉 N-氧化物 |
Pd<sub>2</sub>(dba)<sub>3</sub> | 三(二亚苄基丙酮)合二钯(0) |
POCl<sub>3</sub> | 氯氧化磷(V) |
PyBOP | (7-氮杂苯并三唑-1-基氧基)三吡咯烷基磷鎓六氟磷酸盐 |
SEM-Cl | 2-(三甲基甲硅烷基)乙氧基甲基氯化物 |
SFC | 超临界流体色谱 |
SiliaCat® DPP-Pd | 硅胶结合的二苯基膦钯(II) |
TBAF | 四-正丁基氟化铵 |
TBS-Cl | 叔丁基二甲基甲硅烷基氯化物 |
t-BuOH | 叔丁醇 |
t-Bu Xphos | 2-二-(叔丁基)膦基-2’,4’,6’-三异丙基联苯 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
THF | 四氢呋喃 |
TPAP | 四-正丙基高钌酸(VII)铵 |
X-Phos | 2-二环己基膦基-2′,4′,6′-三异丙基联苯 |
HCOOH | 甲酸 |
Kt-OBu | 叔丁醇钾 |
Na<sub>2</sub>S<sub>2</sub>O<sub>5</sub> | 焦亚硫酸钠 |
NMR | 核磁共振 |
TLC | 薄层色谱 |
(EtO)<sub>2</sub>P(O)CH<sub>2</sub>CN | (氰基甲基)膦酸二乙酯 |
MsCl | 甲磺酰氯 |
TsOH | 对甲苯磺酸 |
KCN | 氰化钾 |
Si-DMT | 负载于硅胶上的二巯基三嗪 |
TMS | 三甲基硅烷 |
CF<sub>3</sub>TMS | (三氟甲基)三甲基硅烷 |
烷基缩写
Me | 甲基 |
Et | 乙基 |
n-Pr | 正丙基 |
<i>i</i>-Pr | 异丙基 |
<i>n</i>-Bu | 正丁基 |
<i>i-</i>Bu | 异丁基 |
<i>s</i>-Bu | 仲丁基 |
<i>t-</i>Bu | 叔丁基 |
<i>c</i>-Pr | 环丙基 |
<i>c</i>-Bu | 环丁基 |
<i>c-</i>Pen | 环戊基 |
<i>c-</i>Hex | 环己基 |
合成的方法
本发明的化合物可根据使用适当的材料的以下的一般方案进行制备,并且进一步被随后的具体实施例举例说明。在实施例中举例说明的化合物不应被解释为形成被认作为本发明的唯一种类。以下的说明性实施例因此不被列出的化合物或用于说明的目的的任何特定取代基所限制。方案中所示的取代基编号不一定与权利要求中使用的相关,通常为了清楚起见,单个取代基被显示连接到上文本发明的定义下多个取代基被允许的化合物上。
本领域技术人员将容易理解,以下制备步骤的条件和过程的已知变化可用于制备这些化合物。本发明现在将在下面的非限制性实施例中被说明,其中,除非另有说明:
所有用于制备本文中记载的中间体和最终化合物的起始原料从商业供应商获得,且一收到就被使用。
除非特别指出,否则所有反应在氮或氩的惰性气氛下被搅拌(机械,搅拌棒/搅拌板,或摇动)和进行。
所有用于制备本文中记载的中间体和最终化合物的起始原料从商业供应商获得,且一收到就被使用。
除非另有说明,所有温度是摄氏度(℃)。
环境温度为15–25℃。
大多数化合物通过反相制备HPLC、MPLC/硅胶、SFC、重结晶和/或swish(悬浮在溶剂中,随后进行固体的过滤)纯化。
在反应过程之后进行薄层色谱(TLC)和/或LCMS和/或NMR,且反应时间的给出仅是为了说明。
所有最终产物通过NMR和LCMS分析。
中间体通过NMR和/或TLC和/或LCMS进行分析。
方法1
制备本发明的中间体的一般步骤在方案1中描述。使用适当的碱、例如DBU,在合适的溶剂、如MeCN,EtOH,n-BuOH或tert-BuOH中,在25-110℃之间的温度下,被保护的吡唑并吡啶酮 I可以与任选取代的丙烯腈进行共轭加成,得到烷基化的被保护的吡唑并吡啶酮II,一种在本发明的实施例的合成中的中间体。然后II向游离的烷基化吡啶酮III的脱保护可在合适的溶剂、如EtOAc、 EtOH、MeOH中,或使用这些溶剂的组合,使用合适的酸、例如TFA,或在使用了钯-碳、在约1个大气压的氢的氢解条件下实现。
方案 1
方法2
本发明的制备例的一般步骤在方案2中描述。使用适当的催化的钯-配体体系,例如Pd2(dba)3或Pd2(dba)3∙CHCl3,和2-二-(叔丁基)膦基-2′,4′,6′-三异丙基联苯(t-BuXPhos)或二(叔丁基)[3,4,5,6-四甲基-2',4',6'-三(丙烷-2-基)联苯-2-基]磷烷(Me4 t-Bu-XPhos),或2-二环己基膦基-2′,4′,6′-三异丙基联苯(XPhos),将烷基化的3-氨基吡唑并嘧啶III(A=H)交叉偶联到芳基和杂芳基卤化物IV上。可选地,合适的预催化剂络合物 、例如 [t-Bu XPhos Pd G3](Aldrich 目录 # 762229) 也可以代替独立的钯源和配体来使用。典型的条件是相对于用10-25% Pd 预催化剂加载的吡唑并嘧啶使用1–2 当量的芳基/杂芳基卤化物。典型地,该交叉偶联使用2-丙醇、t-BuOH或叔戊醇溶剂,使用KOAc或K3PO4作为碱来实施。反应典型地在65-90℃之间实施,以得到本发明的中间体V。
方案 2
方法3
本发明的制备例的一般步骤在方案3中描述。被保护的吡唑并嘧啶V在酸、例如TFA或HCl的存在下脱保护,得到脱保护的吡唑并吡啶酮 VI。可选地,在水解不稳定的吡啶酮的保护基团(例如PG=Bn)的情况下,脱保护可以在适当的溶剂如EtOAc、EtOH、MeOH中或这些溶剂的组合中、在氢的存在下,在使用钯-碳的氢解作用的条件下实现。
方案 3
中间体
下列实验步骤详细说明了在本发明的实施例的合成中所用的化学材料的制备。所例示的步骤是仅用于说明的目的,并不意在以任何方式限制本发明的范围。
中间体1
4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-3-胺
步骤1: 2-(苄基氧基)-4-甲氧基烟腈
在室温下向2-羟基-4-甲氧基烟腈(60克,0.40 mol)的甲苯(0.60 L)溶液中加入Ag2CO3(0.14 kg,0.51 mol)和BnBr(87克,0.51 mol)。将该混合物在50℃搅拌3小时。将该混合物过滤并该滤饼用DCM洗涤。将滤液在真空下浓缩并将石油醚(100 毫升)加入到残余物中,将固体过滤,产生作为固体的化合物 I-la。 C14H13N2O2 [M+H]+ 的LRMS (ESI)计算值:241,实测值 241。1H NMR(600 MHz CDCl3):δ 8.21(d,J=6.6 Hz,1H),7.48(d,J=7.8 Hz,2H),7.38(m,2H),7.32(m,1H),6.58(d,J=6.0 Hz,1H),5.51(s,2H),3.99(s,3H)。
步骤2: 4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-3-胺
将2-(苄基氧基)-4-甲氧基烟腈(100克,410 毫摩尔)在水合肼(0.20 kg,4.1mol)和n-BuOH(600 毫升)中的悬浮液加热回流一夜。将该混合物在真空中浓缩并利用硅胶层析法纯化,用25% 乙酸乙酯/己烷洗脱。将需要的级分在真空中浓缩,得到作为固体的化合物 I-1。1H NMR(400 MHz CDCl3):δ9.97(s,1H),7.75(d,J=6.4 Hz,1H),7.40(d,J=7.2Hz,2H),7.24–7.33(m,3H),6.69(d,J=6.4 Hz,1H),5.46(s,2H),4.50(s,2H)。
中间体2
3,6-二氢-2H-吡喃-4-甲腈
在氮气氛下向三甲基硅烷甲腈(713克,7.19 mol)的二氯甲烷(2.50 L)溶液中加入噁烷-4-酮(600克,5.99 mol),随后在0℃滴加三甲基甲硅烷基三氟甲磺酸酯(40.0克,180 毫摩尔)。向其中加入吡啶(5 L),随后滴加磷酰氯(2.74 kg,17.8 mol),并将所得的溶液在70℃搅拌一夜,然后通过倒入20 L的水/冰中进行淬灭。将pH用HCl水溶液(2 M)调节至7 ,将固体滤出。将滤液用二氯甲烷(× 3)萃取,并将合并的有机层用盐水(× 2)洗涤,用无水硫酸钠干燥,进行过滤并在真空中浓缩。将该粗品在减压(10 mm Hg)下利用蒸馏纯化,在35℃收集作为液体的级分。1H NMR(600 MHz,CDCl3):δ 6.64(m,1H),4.25(q,J=2.9 Hz,2H),3.81(t,J=5.8 Hz,2H),2.35(m,2H)。
中间体 I-3A和I-3B
(3S,4R)和(3R,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈
在氮气氛下向4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-3-胺 I-1(300克,1.25mol)的ACN(6.00 L)溶液中加入 3,6-二氢-2H-吡喃-4-甲腈(398克,3.65 mol),和DBU(469克,3.08 mol)。将所得的溶液在80℃搅拌一夜,然后冷却并在真空中浓缩。将残余物用硅胶层析法纯化,用50% 乙酸乙酯/己烷洗脱,得到固体。使用Phenomenex Lux-4柱 、用25% 甲醇改性剂 /CO 2进行SFC分离。保留时间为3.8分钟(中间体3A)和5.0分钟(中间体3B)。C19H20N5O2 [M+H]+ 的LRMS (ESI)计算值:350,实测值 350。1H NMR(600 MHz,CDCl3):δ 7.89(d,J=6.4 Hz,1H),7.48(d,J=7.1 Hz,2H),7.41(t,J=7.1 Hz,2H),7.34(m,1H),6.82(d,J=6.4 Hz,1H),5.53(s,2H),4.97(br s,2H),4.40(dt,J=10.6,4.7 Hz,1H),4.04(dd,J=11.7,4.0 Hz,1H),4.00(dd,J=11.7,4.5 Hz,1H),3.74(t,J=11.4 Hz,1H),3.52(dt,J=11.9,4.5Hz,1H),3.45(dt,J=12.1,1.8 Hz,1H),2.23(dm,J=13.8 Hz,1H),2.14(app. dq,J=13.1,4.4 Hz,1H)。
中间体4
(3R,4S)-3-(3-氨基-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈
在室温下将10% 钯/碳(1.06克,10 wt.%)加入到(3R,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈(3.49克,10.0 毫摩尔)(I-3B)在EtOAc(75 毫升)和MeOH(25 毫升)的混合物中的溶液中。将该烧瓶密封并利用抽空和用氢(× 3)回填脱气,在氢气球、在室温下搅拌18小时。将该混合物用 MeOH稀释,通过CELITE®(Celite Corporation,Lompo,CA USA)过滤,并将滤液在真空下浓缩,产生作为固体的标题化合物。 C12H14N5O2 [M+H] +的LRMS (ESI)计算值:260,实测值 260。
中间体 5,6,7和8
(3R,4S或3S,4R)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈(I-5A)和
(3S,4R或3R,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈(I-5B)
(3R,4R或3S,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈(I-6A)和
(3S,4S或3R,4R)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈(I-6B)
(4R,5S或4S,5R)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈 (I-7A)
和
(4S,5R或4R,5S)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈 (I-7B);
(4S,5S或4R,5R)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈(I-8A);
(4R,5R或4S,5S)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈(I-8B)
步骤1:氧杂环庚烷-4-酮
在-25℃向搅拌的二氢-2H-吡喃-4(3H)-酮(16.8 毫升,0.100 mol)和三氟化硼二乙醚(25 毫升,0.11 mol)的二氯甲烷(400 毫升)溶液中通过注射器缓慢加入(三甲基甲硅烷基)重氮甲烷(100 毫升,110 毫摩尔,在己烷中2.0 M)。将该反应混合物在-25℃搅拌2.5小时。将该反应混合物用水(500 毫升)稀释,并用二氯甲烷(× 3)萃取。将有机层用氯化铵饱和水溶液/氢氧化铵(10/1)和盐水的混合物洗涤,用无水硫酸钠干燥并过滤。将滤液在真空下浓缩并将所得的残余物利用硅胶层析法纯化,用1:10 EtOAc:石油醚洗脱,得到氧杂环庚烷-4-酮:1H NMR(300 MHz,CDCl3)δ 3.88–3.84(m,4H),2.71–2.65(m,4H),1.89–1.81(m,2H)。
步骤2: 4-((三甲基甲硅烷基)氧基)氧杂环庚烷-4-甲腈
在250 毫升圆底烧瓶中放入氧杂环庚烷-4-酮(5.8克,0.051 mol)的二氯甲烷(100 毫升)溶液。在0℃加入碘化锌(0.81克,2.5 毫摩尔)和三甲基甲硅烷基氰化物(6.04克,60.9 mol)。在环境温度下将所得的混合物搅拌90分钟,然后通过加入水(100 毫升)淬灭。将所得的溶液用二氯甲烷(× 3)萃取,并将合并的有机层用盐水洗涤,用无水硫酸钠干燥并过滤。将滤液在真空下浓缩并利用硅胶层析法纯化,用3:1 石油醚:EtOAc洗脱,得到4-((三甲基甲硅烷基)氧基)氧杂环庚烷-4-甲腈:1H NMR(300 MHz,CDCl3)δ 3.78–3.72(m,2H),3.70–3.64(m,2H),2.19–1.83(m,6H),0.26(s,9H)。
步骤3: 2,3,6,7-四氢氧杂䓬-4-甲腈和2,5,6,7-四氢氧杂䓬-4-甲腈
向4-((三甲基甲硅烷基)氧基)氧杂环庚烷-4-甲腈(2.0克,9.4 毫摩尔)的吡啶(10 毫升)溶液中加入三氯氧磷(6.9 毫升,75 毫摩尔)。将所得的混合物回流16小时,冷却至环境温度,然后加入水(50 毫升)以淬灭反应。将该混合物用乙酸乙酯(× 3)萃取并将合并的有机层用盐水洗涤,用无水硫酸钠干燥并过滤。将滤液在真空下浓缩并将残余物用硅胶层析法纯化,用1:1 乙酸乙酯:石油醚洗脱,得到2,3,6,7-四氢氧杂䓬-4-甲腈和2,5,6,7-四氢氧杂䓬-4-甲腈的混合物(在 1H NMR上1/2比例)。2,3,6,7-四氢氧杂䓬-4-甲腈:1HNMR(300 MHz,CDCl3)δ 6.82–6.78(m,1H),3.80–3.69(m,4H),2.64–2.62(m,4H),2.56–2.50(m,2H);和2,5,6,7-四氢氧杂䓬-4-甲腈:1H NMR(300 MHz,CDCl3)δ 6.56–6.54(m,1H),4.27–4.25(m,2H),3.86–3.81(m,2H),2.60–2.50(m,2H),1.99–1.97(m,2H)。
步骤4 :(3R,4S或3S,4R)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1- 基)氧杂环庚烷-4-甲腈(I-5A);
(3S,4R或3R,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈(I-5B);
(3R,4R或3S,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈(I-6A);
(3S,4S或3R,4R)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈(I-6B);
(4R,5S或4S,5R)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈 (I-7A);
(4S,5R或4R,5S)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈 (I-7B);
(4S,5S或4R,5R)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈(I-8A);
(4R,5R或4S,5S)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂
环庚烷-4-甲腈(I-8B)
向氮净化的烧瓶中加入4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-3-胺(6.34克,26.5 毫摩尔)(I-1),2,3,6,7-四氢氧杂-4-甲腈和2,5,6,7-四氢氧杂䓬-4-甲腈(6.5克,0.053 mol)的混合物和乙腈(24 毫升)。将该溶液搅拌 15分钟,然后加入 1,5-二氮杂双环[4.3.0]壬-5-烯(9.6克,0.053 mol)。在80℃将该反应搅拌16小时,然后加入水(30 毫升),并将该混合物用乙酸乙酯(× 3)萃取。将合并的有机层用盐水洗涤,用无水硫酸钠干燥并过滤。将滤液在真空下浓缩,将所得的残余物利用硅胶层析法纯化,用1:1 乙酸乙酯:石油醚洗脱,得到3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈和5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c] 吡啶-1-基)氧杂环庚烷-4-甲腈的异构体的混合物。
将3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈的4种异构体利用具有CHIRALCEL® IC-H ,4.6 × 100 mm,3 μm柱子的手性Prep-HPLC、使用30% 的乙醇(具有0.1% DEA)/己烷(具有0.1% DEA)纯化,得到作为固体的所需的化合物。
(3R,4S或3S,4R)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在3.9分钟洗脱(I-5A),和(3S,4R或3R,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在4.5分钟洗脱(I-5B):1H NMR(400 MHz,CDCl3)δ 7.91(d,J=6.0 Hz,1H),7.52–7.41(m,2H),7.39–7.29(m,3H),6.87(d,J=6.0 Hz,1H),5.58(s,2H),4.54(s,1H),4.62–4.58(m,1H),4.05–4.00(m,1H),3.92–3.78(m,2H),3.53–3.46(m,1H),2.30–2.29(m,1H),2.14–2.01(m,3H)。
(3R,4R或3S,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在5.4分钟洗脱(I-6A)和(3S,4S或3R,4R)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在 6.1分钟洗脱(I-6B):1H NMR(400 MHz,CDCl3)δ 7.90(d,J=6.4 Hz,1H),7.52–7.43(m,2H),7.41–7.37(m,3H),6.82(d,J=6.4 Hz,1H),5.59(s,2H),4.81–4.75(m,1H),4.54(s,2H),4.33–4.21(m,2H),4.04–3.89(m,1H),3.88–3.85(m,1H),3.44–3.41(m,1H),2.59–2.54(m,1H),2.08–2.04(m,2H),1.96–1.93(m,1H)。
将5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈的4种异构体通过使用了CHIRACEL® OJ-3,2.0 × 250 mm,3m 的手性Prep-HPLC,用25%丙烷-2-醇(具有0.1% DEA)/己烷(具有0.1% DEA)洗脱,得到作为固体的所需的异构体。
(4R,5S或4S,5R)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在 5.5分钟洗脱(I-7A)和(4S,5R或4R,5S)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在 6.7分钟洗脱(I-7B):1H NMR(400 MHz,CDCl3)δ 7.91(d,J=6.4 Hz,1H),7.52(d,J=7.2 Hz,2H),7.45–7.38(m,3H),6.84(d,J=6.4Hz,1H),5.58(s,2H),4.69–4.63(m,1H),4.53(s,2H),4.01–3.92(m,2H),3.81(m,2H),3.63(m,1H),2.49(m,1H),2.32(m,1H),2.24(m,1H),2.16(m,1H)。
(4S,5S或4R,5R)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在 8.0分钟洗脱(I-8A)和(4R,5R或4S,5S)-5-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)氧杂环庚烷-4-甲腈在 10.3分钟洗脱(I-8B):1H NMR(400 MHz,CDCl3)δ 7.88(d,J=6.0 Hz,1H),7.51(d,J=7.2 Hz,2H),7.45–7.37(m,3H),6.81(d,J=6.4Hz,1H),5.57(s,2H),4.73–4.69(m,1H),4.55(s,2H),4.09–3.98(m,1H),3.91(m,2H),3.86(m,1H),3.37(s,1H),2.91–2.84(m,1H),2.40(m,1H),2.24(m,1H),2.16(m,1H)。
中间体9
5-溴-2-(2,2,2-三氟乙基)-2,3-二氢-1H-异吲哚-1-酮
将5-溴-2,3-二氢-1H-异吲哚-1-酮(100 毫克,0.47 毫摩尔)溶解在DMF(4.7 毫升)中,并在0℃搅拌。小心地以两部分加入NaH(38 毫克,0.94 毫摩尔,60 wt.% 悬浮在油中),使所得的混合物在0℃ 搅拌15分钟,之后加入三氟甲磺酸2,2,2-三氟乙基酯(110 毫克,0.47 毫摩尔)。使该混合物在0℃搅拌30分钟,之后小心加入饱和碳酸氢钠水溶液(10毫升),并将该混合物用EtOAc萃取。将有机层用水、盐水洗涤,用无水硫酸镁干燥,过滤,并在真空下浓缩。将残余物用硅胶层析法纯化,用0–20% EtOAc/己烷梯度洗脱。 C10H8BrF3NO[M+H] +的LRMS (ESI)计算值:294,实测值:294。
中间体10-1
5-溴-2-(叔丁基)-2,3-二氢苯并[d]异噻唑 1,1-二氧化物
步骤1: 4-溴-2-甲基苯-1-磺酰氯
将氯磺酸(63克,0.54 mol)缓慢加入到1-溴-3-甲基苯(10.0克,58 毫摩尔)的CHCl3(100 毫升)冷溶液(0℃)中。使该反应在0℃搅拌2小时下进行,然后将反应混合物倒入冰水中,用EtOAc萃取,并将有机层用盐水洗涤,用NaSO4干燥,过滤并在真空中浓缩,得到作为固体的化合物 I-10a。1H NMR(400 MHz,CDCl3):δ 7.90(d,J=8.4 Hz,1H),7.59–7.53(m,2H),2.75(s,3H)。
步骤2: 4-溴-N-(叔丁基)-2-甲基苯磺酰胺
在 0℃向 I-10a(2.0克,7.4 毫摩尔)的CH2Cl2(15 毫升)溶液中加入2-甲基丙-2-胺(0.65克,8.9 毫摩尔)和三乙胺(0.90克,8.9 毫摩尔)的CH2Cl2(30 毫升)溶液。将该反应混合物在0℃ 搅拌2小时,然后在室温下搅拌16小时。将该混合物用0.1 M HCl,饱和碳酸氢钠水溶液洗涤,用硫酸钠干燥,过滤并将滤液在真空下浓缩。在减压下除去溶剂后,得到作为固体的I-10b。1H NMR(400 MHz,DMSO-d6):δ 7.78(d,J=8.4 Hz,1H),7.63(d,J=1.6 Hz,1H),7.59–7.56(m,2H),2.57(s,3H),1.09(s,9H)。
步骤3: 5-溴-2-(叔丁基)苯并[d]异噻唑-3(2H)-酮 1,1-二氧化物
将H5IO6(5.9克,26 毫摩尔)在乙腈(50 毫升)中的混合物在室温下搅拌1小时,然后加入CrO3(33 毫克,0.33 毫摩尔),随后加入醋酸酐(2.67克,26.2 毫摩尔)。将所得的橙色溶液冷却至0℃,并加入I-10b(1.0克,3.3 毫摩尔)。在 0℃ 搅拌15分钟后,使该反应加热至室温并搅拌16小时。将溶剂在真空中除去并将残余物用EtOAc(× 3)萃取,将合并的有机层用饱和NaHCO3水溶液、盐水洗涤,用硫酸钠干燥,过滤并将滤液在真空下浓缩。将残余物用硅胶层析法纯化,用5% EtOAc/己烷洗脱,将所需的级分在真空中浓缩,得到作为固体的I-10c。1H NMR(400 MHz,DMSO-d6):δ 8.82–8.14(m,3H),1.66(s,9H)。
步骤4: 5-溴-2-(叔丁基)-2,3-二氢苯并[d]异噻唑-1,1-二氧化物
向 I-10c (0.20克,0.63 毫摩尔)的THF(4 毫升)溶液中加入BH3∙Me2S(240 毫克,3.16 毫摩尔)。将该反应混合物回流16小时。在冷却至室温后,将该反应用2 M HCl淬灭,并用EtOAc(× 2)萃取,将合并的萃取物用盐水洗涤,用Na2SO4干燥,过滤,和将滤液在真空下浓缩。将残余物用制备TLC纯化,得到化合物 I-10-1。1H NMR(400 MHz,DMSO-d6):δ 7.83–7.56(m,3H),4.55(s,2H),1.46(s,9H)。
遵循与上述中间体10-1概述的方法类似的方法,制备表1中的下述中间体:
中间体11
1-(4-溴苯基)-2,2,2-三氟乙胺
在室温下向 1-(4-溴苯基)-2,2,2-三氟乙酮(1.00克,3.95 毫摩尔)的甲苯(14毫升)溶液中加入(滴加)双(三甲基硅基)氨基锂(4.35 毫升,4.35 毫摩尔,在THF中1M)的溶液。将该反应在室温下搅拌15分钟,然后加入BH3∙THF(7.90 毫升,7.90 毫摩尔,在THF中1M)。将该反应在室温下搅拌20分钟,然后在 0℃通过缓慢加入NaOH水溶液(5.93 毫升,11.9 毫摩尔,2M)淬灭。将该混合物在室温下搅拌90分钟,然后分离有机层并用1N NaOH水溶液洗涤,用硫酸钠干燥,进行过滤并在真空中浓缩。关于反应混合物粗品的对映异构体的SFC分离使用CHIRALPAK® AZ-H、用7% 甲醇改性剂 /CO2实现:保留时间= 2.4(I-11A)&2.9(I-11B)分钟。 C8H8NBrF3 [M+H]+ 的LRMS (ESI)计算值:254,实测值 254。1H NMR(600MHz,CDCl3):δ 7.53(d,J=8.5 Hz,2H),7.32(d,J=8.5 Hz,2H),4.38(q,J=7.5 Hz,1H),1.78(br s,2H)。
中间体12-1
4-溴-N-(叔丁基)-N-甲基苯磺酰胺
在室温下向 4-溴-N-(叔丁基)苯磺酰胺(1.00克,3.42 毫摩尔)和碳酸钾(0.946克,6.84 毫摩尔)的DMF(20 毫升)溶液中加入碘甲烷(0.43 毫升,6.8 毫摩尔)。将该反应搅拌6小时,然后通过加入水淬灭,并用EtOAc(× 3)萃取。将有机层用硫酸钠干燥,过滤,和在真空中浓缩并用硅胶层析纯化,用 0–10% EtOAc/己烷洗脱,产生I-12-1。 C11H17NBrO2SNa[M+Na]+ 的LRMS (ESI)计算值:328,实测值 328。1H NMR(600 MHz,CDCl3):δ 7.69(d,J=8.7Hz,2H),7.62(d,J=8.7 Hz,2H),2.97(s,3H),1.35(s,9H)。
表2中的下述中间体通过类似于上述I-12-1、在50℃使用Cs2CO3或在0–25℃使用NaH和使用中间体 I-10-4来制造。
中间体13
1-溴-4-(叔丁基磺酰基)苯
在室温下向(4-溴苯基)(叔丁基)硫烷(1.00克,4.08 毫摩尔)的DCM(10.0 毫升)溶液中加入 m-CPBA(2.01克,8.97 毫摩尔,77 wt.%)。将所得的溶液在室温下搅拌1小时,然后用饱和Na2S2O3水溶液和饱和Na2CO3水溶液淬灭。将该反应用DCM(× 3)萃取,用硫酸钠干燥,过滤并在真空中浓缩,得到作为固体的I-13。1H NMR(600 MHz,DMSO-d6):δ 7.89(d,J=8.7 Hz,2H),7.75(d,J=8.7 Hz,2H),1.24(s,9H)。
中间体14
1-溴-4-((2,3-二甲基丁烷-2-基)磺酰基)苯
在-78℃向1-溴-4-(异丙基磺酰基)苯(100 毫克,0.38 毫摩尔)的干THF(2 毫升)溶液中缓慢加入LDA(0.19 毫升,0.38 毫摩尔,2.9 M /THF/庚烷/乙基苯)。1.5小时后加入碘乙烷(91 μL,1.1 毫摩尔)并使该混合物加热一夜至室温。将该混合物用氯化铵饱和水溶液稀释,用乙酸乙酯(× 3)萃取,并将合并的有机层用Na2SO4干燥,进行过滤并在真空中浓缩。将残余物用硅胶层析法纯化,用0–40% 乙酸乙酯/己烷洗脱,得到作为固体的中间体 I-14-1。1H NMR(600 MHz,CDCl3):δ 7.71(d,J=8.8 Hz,2H),7.67(d,J=8.2 Hz,2H),1.71(q,J =7.6 Hz,2H),1.25(s,6H),0.93(t,J=7.6 Hz,3H)。
表3中的下述中间体通过类似地使用I-14-1的以上概述的步骤来制备。
中间体15
5-溴-2-异丙基-2,3-二氢-1H-异吲哚
向 5-溴-2,3-二氢-1H-异吲哚盐酸盐(2.00克,8.53 毫摩尔)的N,N-二甲基甲酰胺(50 毫升)溶液中加入氢化钠(0.850克,60% /矿物油,21.3 毫摩尔)。将该混合物在20℃搅拌45分钟,然后滴加 2-碘代丙烷(2.17克,12.8 毫摩尔)。将所得的溶液在50℃、在油浴中搅拌16小时,冷却至环境温度,并通过加入水(80 毫升)淬灭。将该反应用乙酸乙酯(×3)萃取,将合并的有机层用水、盐水洗涤,并用无水硫酸钠干燥,过滤。将滤液在真空下浓缩,得到作为固体的I-15: C11H14BrN [M + H]+ 的LRMS (ESI)计算值:240,242(1:1),实测值 240,242(1:1); 1H NMR(300 MHz,CDCl3):δ 7.46–7.32(m,2H),7.07(d,J=7.8 Hz,1H),4.92(d,J=7.8 Hz,4H),2.79–2.71(m,1H),1.19(d,J=6.3 Hz,6H)。
中间体16
5-溴-2-异丁基异吲哚啉
在0℃向5-溴异吲哚啉盐酸盐(1.50克,6.40 毫摩尔)在MeOH(50 毫升)和异丁醛(2.31克,32.0 毫摩尔)中的混合物中加入(分多次)NaBH4(1.45克,38.4 毫摩尔)。将上述混合物在 15℃ 搅拌 1小时,然后冷却,并通过加入水淬灭。将该混合物用乙酸乙酯(× 3)萃取,并将合并的有机级分用盐水洗涤,用Na2SO4干燥,过滤并将溶剂在真空中蒸发。将残余物用硅胶层析法纯化,用1:5 EtOAc/石油醚洗脱,产生作为油的 I-16。1H NMR(400 MHz,CDCl3):δ 7.41(d,J=8.1 Hz,1H),7.35(s,1H),7.07(d,J=8.1 Hz,1H),4.50(q,J=9.3 Hz,2H),4.14(q,J=10.2 Hz,2H),2.87(q,J=5.4 Hz,2H),2.40–2.35(m,1H),1.03(d,J=6.9 Hz,6H)。
中间体17
5-溴-3-甲氧基苯并[d]异噁唑
在20 毫升Biotage 微波瓶(Biotage,Charlotte,NC USA)中,向5-溴-3-氯苯并[d]异噁唑(1.74克,7.50 毫摩尔)的MeOH(20.0 毫升)溶液中加入甲醇钠(2.03克,37.5 毫摩尔)。将该瓶密封,在微波中在120℃加热1.5小时。将该反应用乙酸乙酯稀释并用水、盐水洗涤,和将有机层用硫酸钠干燥,过滤,加入硅胶,将该浆液在真空中浓缩。将残余物通过用10–60% CH2Cl2/己烷洗脱的硅胶层析法纯化,产生作为固体的I-17。1H NMR(500 MHz,DMSO-d6): δ 8.02(d,1H,J=2.0 Hz),8.24(dd,1H,J=8.7,2.0 Hz),7.69(d,1H,J=8.7 Hz),4.15(s,3H)。
中间体18
1-(4-溴苯基)-5,5-二甲基-2-氧杂双环[2.2.2]辛-3-酮
在-78℃向 1-溴-4-碘代苯(600 毫克,2.12 毫摩尔)/THF 中(7.1 毫升)加入(滴加)n-BuLi(1.46 毫升,2.33 毫摩尔,在己烷中1.60 M),并将该反应在-78℃搅拌 2小时。然后滴加2,2-二甲基-4-氧代环己烷甲酸甲酯(430 毫克,2.33 毫摩尔)的 THF(1.5 毫升)溶液,并将该反应搅拌一夜至室温。将该反应通过倒入含有水的分液漏斗中淬灭,用乙酸乙酯(× 3)萃取。将有机层合并,用Na2SO4干燥,过滤,并在真空下浓缩。将粗品然后用硅胶层析法纯化,用 0–50% EtOAc/己烷洗脱。收集产物并浓缩,得到作为油的I-18。 C15H18BrO2 [M+H]+ 的LRMS (ESI)计算值:309,实测值 309。
中间体 19-1和19-2
(R或S)1-溴-4-(1,1,1-三氟-2-甲氧基丙烷-2-基)苯
步骤1:(R或S)2-(4-溴苯基)-1,1,1-三氟丙烷-2-醇
在N2气氛下,在烘干的圆底烧瓶中装入1-(4-溴苯基)-2,2,2-三氟乙酮(2.0克,7.9 毫摩尔)和THF(13 毫升)。将该溶液冷却至 0℃,加入甲基溴化镁(17 毫升,23.7 毫摩尔,在乙醚中1.4 M)。将该反应混合物用1–2小时加热至室温,通过加入饱和NH4Cl水溶液(10 毫升)淬灭。将所得的混合物用Et2O(× 3)萃取,并将合并的有机层在真空中浓缩 ,得到残余物,其用硅胶层析法纯化,用己烷/EtOAc梯度洗脱,产生外消旋 2-(4-溴苯基)-1,1,1-三氟丙烷-2-醇。1H NMR(CDCl3,500MHz):δ 7.54(d,J=8.3 Hz,2H),7.47(d,J=8.3 Hz,2H),2.44(s,1H),1.78(s,3H)。对映异构体的拆分通过使用了手性Technology AZ-H(5%MeOH /CO2)的SFC纯化来实现。Tr=2.6分钟(中间体 I-19-1A)& 3.2分钟(中间体 I-19-1B)。
I-19-1A(S或R)-2-(4-溴苯基)-1,1,1-三氟丙烷-2-醇。 C9H9BrF3O [M+H]+ 的LRMS (ESI)计算值:269,实测值 269。I-19-1B(S或R)-2-(4-溴苯基)-1,1,1-三氟丙烷-2-醇。 C9H9BrF3O [M+H]+ 的LRMS (ESI)计算值:269,实测值 269。
步骤2:(R或S)1-溴-4-(1,1,1-三氟-2-甲氧基丙烷-2-基)苯(I-19-2A & I-19- 2B)
在N2的气氛下向具有磁性搅拌棒的烘干圆底烧瓶中装入2-(4-溴苯基)-1,1,1-三氟丙烷-2-醇 I-19-1A(300 毫克,1.10 毫摩尔)和DMF(3.5 毫升)。将该溶液冷却至 0℃,加入氢化钠(67 毫克,1.7 毫摩尔,60% wt. /矿物油),并将该反应搅拌30分钟。然后加入碘代甲烷(0.21 毫升,3.3 毫摩尔),并将该反应混合物用1–2小时加热至室温,通过加入饱和NH4Cl水溶液(10 毫升)淬灭,并用Et2O(× 3)萃取。将合并的有机层在真空中浓缩,得到残余物,其用硅胶层析法纯化,用己烷/EtOAc梯度洗脱,产生I-19-2A。使用I-19-1B,以类似于上述I-19-2A的方式制备 I-19-2B。1H NMR(CDCl3,500 MHz):δ 7.54(d,J=8.2 Hz,2H),7.38(d,J=8.1 Hz,2H),3.23(s,3H),1.76(s,3H)。
中间体 I-20
(4-溴-2-甲基苯基)(4,4-二氟哌啶-1-基)甲酮
向 4-溴-2-甲基苯甲酸(0.75克,3.5 毫摩尔)的 DMF(9 毫升)溶液中加入 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓 3-氧化物六氟磷酸盐;(HATU)(2.6克,7.0 毫摩尔),Hunig碱(2.4 毫升,14 毫摩尔),和4,4-二氟哌啶(0.84克,7.0 毫摩尔)。将所得的反应混合物搅拌12–16小时,在真空中浓缩,将所得的油粗品利用硅胶层析法纯化,用己烷/EtOAc梯度洗脱,产生I-20。1H NMR(500 MHz,CDCl3):δ 7.42–7.37(m,2H),7.05(d,J=8.1 Hz,1H),4.02(m,1H),3.82(m,1H),3.36(m,2H),2.30(s,3H),2.09(m,2H),1.88(m,2H)。
中间体 I-21
N-(1-(4-溴苯基)-2,2,2-三氟乙基)-2-甲基丙-2-胺
步骤1: 1-(4-溴苯基)-2,2,2-三氟乙醇
将1-(4-溴苯基)-2,2,2-三氟乙酮(1.73克,6.84 毫摩尔)溶解在 THF(3.4 毫升)中,并在0℃用硼氢化钠(0.285克,7.52 毫摩尔)处理。然后将该反应加热至室温,搅拌一夜。将该反应混合物用DCM稀释,并用水和盐水洗涤。将合并的有机层用Na2SO4干燥,过滤,和将滤液在真空下浓缩。将残余物用硅胶层析法纯化,用5–30% EtOAc/己烷洗脱,将所需的级分在真空中浓缩,得到I-21-1a。1H NMR(500 MHz,CDCl3)δ 7.56(d,J=8.5 Hz,2H),7.36(d,J =8.5 Hz,2H),5.06–4.96(m,1H),2.63(d,J=4.5 Hz,1H)。
步骤2: 三氟甲磺酸1-(4-溴苯基)-2,2,2-三氟乙酯
将 1-(4-溴苯基)-2,2,2-三氟乙醇(1.5克,5.9 毫摩尔)和2,6-二甲基吡啶(1.10毫升,9.41 毫摩尔)的DCE(12 毫升)溶液冷却至-15℃并滴加三氟甲磺酸酐(8.82 毫升,8.82 毫摩尔,在DCM中1.0 M)。将该反应在 -15℃与室温之间搅拌1小时,然后用DCM稀释,并用水,1N HCl水溶液,和盐水洗涤。将合并的有机层用Na2SO4干燥,过滤,和将滤液在真空下浓缩,产生作为液体的 I-21-1b。1H NMR(500 MHz,CDCl3)δ 7.64(d,J=8.3 Hz,2H),7.37(d,J=8.3 Hz,2H),5.85–5.74(m,1H)。
步骤3: N-(1-(4-溴苯基)-2,2,2-三氟乙基)-2-甲基丙-2-胺
将三氟甲磺酸1-(4-溴苯基)-2,2,2-三氟乙酯(7.59克,19.6 毫摩尔)溶解在环己烷(70 毫升)和 2-甲基丙-2-胺(6.23 毫升,58.8 毫摩尔)中,加入 DMAP(0.240克,1.96毫摩尔),和磨碎、干燥的碳酸钾(5.42克,39.2 毫摩尔)(用真空在60℃干燥1小时)。将该反应混合物加热至75℃并搅拌48小时。将该反应混合物用DCM稀释,用水洗涤,和将合并的有机层用Na2SO4干燥,过滤,和将滤液在真空下浓缩。将残余物用硅胶层析法纯化,用 2–20%EtOAc/己烷洗脱,并将所需的级分在真空中浓缩,得到作为液体的I-21-1。 C12H16BrF3N [M+H]+ 的LRMS (ESI)计算值:310,实测值 310。
遵循与对于以上的中间体I-21-1概述的方法类似的方法,合成表14中的下述中间体。在选择的情况下,将一般步骤通过下述这样进行修改:不使用DMAP和/或原样使用粗品。在某些情况下,也可以使用2.0–3.0当量的胺和/或1.5–3.0 当量的磨碎、干燥的碳酸钾。
中间体 I-22
2-(4-溴苯基)-N-异丙基丙-2-胺
将2-(4-溴苯基)丙-2-胺(0.5克,2.3 毫摩尔)溶解在DCM(20 毫升)和丙酮(2.5毫升)中,然后分多次加入三乙酰氧基硼氢化钠(1.5克,7.0 毫摩尔)。将浑浊的反应混合物在室温搅拌48小时。然后将该反应混合物用乙酸乙酯稀释,并用饱和碳酸氢钠和盐水洗涤。将合并的有机层用Na2SO4干燥,过滤,和将滤液在真空下浓缩。将残余物用硅胶层析法纯化,用5–40% EtOAc/己烷洗脱,得到作为液体的 I-22。 C12H19BrN [M+H]+ 的LRMS (ESI)计算值:256,实测值 256。
中间体23
(5-溴-2-氯苯基)(甲基)硫烷
将5-溴-2-氯苯硫醇(0.40克,1.8 毫摩尔)在无水THF(9.0 毫升)中搅拌,并加入一部分的氢化钠(0.11克,2.7 毫摩尔,60 wt.% /矿物油)。将所得的混合物在环境温度下搅拌10分钟,之后加入碘代甲烷(0.25克,1.8 毫摩尔)。将该混合物搅拌16小时,用水稀释,并用EtOAc萃取。将有机层用饱和碳酸氢钠水溶液、盐水洗涤,用无水硫酸镁干燥,过滤,然后在真空中浓缩,得到I-23-1。1H NMR(500 MHz,CDCl3):δ 7.22(s,1H),7.19(m,2H),2.48(s,3H)。
遵循与对于以上的I-23-1概述的方法类似的方法,制备表5中的下述中间体:
`中间体24
1-((4-溴苯基)磺酰基)氮杂环丁烷
向4-溴苯-1-磺酰氯(507 毫克,1.98 毫摩尔)的DCM(6.0 毫升)溶液中加入氮杂环丁烷(280 毫克,4.90 毫摩尔),将该反应混合物在室温下、在氮气氛下搅拌一夜。然后将该反应通过加入饱和NH4Cl水溶液淬灭,并将该反应混合物用DCM(× 3)萃取。将有机层用水洗涤,用硫酸钠干燥,进行过滤并在真空中浓缩。将残余物用硅胶层析法纯化,用0–60%EtOAc/己烷洗脱,得到作为固体的 I-24-1。 C9H11BrNO2S [M+H]+ 的LRMS (ESI)计算值:278,实测值 278。 1H NMR(600 MHz,CDCl3):δ 7.73(d,2H,J=8.6 Hz),7.70(d,2H,J=8.6Hz),3.79(t,4H,J=7.4 Hz),2.11(pentet,2H,J=7.9 Hz)。
遵循对于以上的I-24-1概述的方法类似的方法,制备表6中的下述中间体。在某些的情况下,通过将DIPEA或TEA添加到反应中来将一般步骤进行修改。
中间体 I-25
2-(1-(4-溴苯基)乙基)-2H-1,2,3-三唑
步骤1: 1-溴-4-(1-溴乙基)苯(I-25a)
向1-溴-4-乙基苯(5.10克,27.6 毫摩尔)的氯仿(100 毫升)溶液中加入N-溴琥珀酰亚胺(5.77克,32.4 毫摩尔)和偶氮-二-异丁腈(0.89克,5.4 毫摩尔)。将该混合物回流3小时,冷却至环境温度,并加入水(100 毫升)。将有机层用盐水洗涤,用无水硫酸钠干燥,过滤,并在真空下浓缩。将残余物用硅胶层析法纯化,用1:20 乙酸乙酯:己烷洗脱,得到 I-25a。1H NMR(300 MHz,CDCl3)δ 7.44(d,J=8.4 Hz,2H),7.31(d,J=8.4 Hz,2H),5.15(q,J=6.9 Hz,1H),2.01(d,J=6.9 Hz,3H)。
步骤2: 2-(1-(4-溴苯基)乙基)-2H-1,2,3-三唑(I-25)
向1-溴-4-(1-溴乙基)苯(4.60克,17.5 毫摩尔)的N,N-二甲基甲酰胺(60 毫升)溶液中加入 1H-1,2,3-三唑(1.5克,21 毫摩尔)和碳酸钾(6.04克,43.8 毫摩尔)。将该溶液在80℃搅拌5小时,然后通过倒入到水(100 毫升)中淬灭。将所得的混合物用乙酸乙酯(× 3)萃取,并将合并的有机层用无水硫酸钠干燥,过滤,并在真空下浓缩。将所得的固体用乙酸乙酯/石油醚(1/3,10 毫升)磨碎并过滤,得到 I-25且作为N1和N2异构体的混合物,其可在交叉偶联步骤后被分离。所需的N2 异构体C10H10BrN3 [M + H]+ 的LCMS(ESI) 计算值:252,254(1:1),实测值 252,254(1:1); 1H NMR(300 MHz,CDCl3)δ 7.62(s,2H),7.44(d,J=8.4 Hz,2H),7.16(d,J=8.4 Hz,2H),5.82(q,J=7.2 Hz,1H),1.96(d,J=7.2 Hz,3H)。
中间体 I-26和I-27
(R或S)-2-(4-溴苯基)-2-(三氟甲基)哌啶和(R或S)-2-(4-溴苯基)-2-(三氟甲基)哌啶
步骤1: 4-溴苯甲酰氯
将 4-溴苯甲酸(10.0克,49.7 毫摩尔)的二氯化硫(59.2克,0.50 mol)溶液在80℃加热 16小时。然后将该混合物在真空中浓缩,得到标题化合物,其没有进一步纯化而用于下一步骤。
步骤2:3-(4-溴苯甲酰基)-2-氧代哌啶-1-甲酸叔丁酯
在 -78℃将双(三甲基硅基)氨基锂(2.11 毫升,2.11 毫摩尔,在THF中1.0 M)加入到2-氧代哌啶-1-甲酸叔丁酯(0.20克,1.0 毫摩尔)的THF(2 毫升)溶液中。将所得的混合物搅拌10分钟,然后加入4-溴苯甲酰氯(0.22克,1.0 毫摩尔)。将该反应加热至环境温度并搅拌1小时,然后加入氯化铵饱和水溶液(20 毫升)。将该淬灭的反应用EtOAc(× 3)萃取,将合并的有机层用无水 Na2SO4干燥,进行过滤并在真空中浓缩。将该残余物在硅胶上纯化,用0–1% EtOAc/己烷洗脱,得到标题化合物。:C17H21BrNO4 [M + H]+ 的LRMS (ESI)计算值:382,384(1:1),实测值 382,384(1:1)。
步骤3: 6-(4-溴苯基)-2,3,4,5-四氢吡啶
在环境温度下将3-(4-溴苯甲酰基)-2-氧代哌啶-1-甲酸叔丁酯(2.00克,5.23 毫摩尔)与HCl(8.0 M,43.6 毫升,0.52 mol)合并。将所得的溶液在 80℃加热16小时。然后将该反应倒入饱和Na2CO3水溶液 (50 毫升)中,并用EtOAc(× 3)萃取。将合并的有机层用Na2SO4干燥,进行过滤并在真空中浓缩。将该残余物在硅胶上纯化,用 0–1% EtOAc/己烷洗脱,得到标题化合物。C11H13BrN [M + H]+ 的LRMS (ESI)计算值:238,240(1:1),实测值238,240(1:1); 1H NMR(300 MHz,CDCl3)δ 7.66–7.63(m,2H),7.52–7.47(m,2H),3.90(m,2H),2.59(m,2H),1.88–1.79(m,2H),1.78–1.66(m,2H)。
步骤4:( R或S)-2-(4-溴苯基)-2-(三氟甲基)哌啶和(R或S)-2-(4-溴苯基)-2-(三 氟甲基)哌啶
在 0–4℃向6-(4-溴苯基)-2,3,4,5-四氢吡啶(1.0克,4.2 毫摩尔)的乙腈(10 毫升)溶液中依次加入三氟甲磺酸(3.30克,22.0 毫摩尔),氟氢化钾(3.94克,50.4 毫摩尔)和三甲基(三氟甲基)硅烷(5.97克,42.0 毫摩尔)。将所得的混合物在环境温度下搅拌 48小时。然后将该反应用饱和碳酸氢钠水溶液(50 毫升)淬灭,随后用EtOAc(× 3)萃取。将合并的有机层用无水Na2SO4干燥,进行过滤并在真空中浓缩。将该残余物在硅胶上纯化,用0–1% DCM/石油醚洗脱,得到外消旋标题化合物。然后将标题化合物通过使用了Chiralpak IA柱的SFC来分离,用15% i-PrOH /CO2 洗脱,得到峰 A(I-26)(Tr=4.7分钟)和峰 B(I-27)(Tr=5.5分钟)。 C12H14BrF3N [M + H]+ 的LRMS (ESI)计算值:308,310(1:1),实测值 308,310(1:1); 1H NMR(300 MHz,CDCl3)δ 7.66(m,2H),7.59(m,2H),3.16–3.03(m,1H),2.73–2.63(m,1H),2.50–2.42(m,1H),2.25–1.93(m,1H),1.75(m,1H),1.67–1.53(m,3H),1.33(m,1H)。
中间体 I-28
(R或S)-1-苄基-3-(4-溴苯基)-3-(三氟甲基)吡咯烷
步骤1:1-溴-4-(3,3,3-三氟丙-1-烯-2-基)苯
在氮气氛下向烘干的圆底烧瓶中加入甲基三苯基溴化鏻(6.35克,17.8 毫摩尔)和THF(13.2 毫升)。将该混合物冷却至0℃,然后加入双(三甲基硅基)氨基锂(17.8 毫升,17.8 毫摩尔,在THF中1M)。将该反应混合物在0℃搅拌 30分钟,冷却至-78℃,加入1-(4-溴苯基)-2,2,2-三氟乙酮(3.00克,11.9 毫摩尔)。用 1小时使该反应混合物加热至室温,然后通过倒入 1:1 冰水/饱和NH4Cl水溶液中进行淬灭,将水层用EtOAc(× 3)萃取。将合并的有机层用盐水洗涤,用硫酸钠干燥,过滤并在真空中浓缩,得到所需的化合物。1H NMR(600 MHz,CDCl3):δ 1H NMR δ 7.50(d,J=8.3 Hz,2H),7.30(d,J=8.2 Hz,2H),5.96(s,1H),5.75(s,1H)。
步骤2:1-苄基-3-(4-溴苯基)-3-(三氟甲基)吡咯烷
在氮气氛下向烘干的圆底烧瓶中加入 1-溴-4-(3,3,3-三氟丙-1-烯-2-基)苯(0.25克,1.0 毫摩尔),N-苄基-1-甲氧基-N-((三甲基甲硅烷基)甲基)甲胺(0.51 毫升,2.0 毫摩尔),和DCM(5 毫升)。将该混合物冷却至0℃,然后加入三氟乙酸(7.7 μL,0.10 毫摩尔)。将该反应混合物搅拌并用3小时加热至室温,用饱和碳酸氢钠水溶液(20 毫升)淬灭。将水层用EtOAc(× 3)萃取并将合并的有机层用盐水洗涤,用硫酸钠干燥,过滤并在真空中浓缩,得到所需的化合物。1H NMR(600 MHz,CDCl3):δ 7.45(d,J=8.2 Hz,2H),7.29–7.35,(m,4H),7.21(m,3H),3.66(m,2H),3.18(m,1H),2.77(m,1H),2.58(m,1H),2.37(m,1H),1.25(m,1H),0.85(m,1H)。
中间体 I-29-1
1-(4-溴苯基)-2,2,2-三氟-1-(吡啶-2-基)乙醇
在氮气氛下向烘干的圆底烧瓶中装入(4-溴苯基)(吡啶-2-基)甲酮(1.00克,3.82毫摩尔)和THF(5.2 毫升)。将该溶液冷却至 0℃,并加入(三氟甲基)三甲基硅烷(2.82 毫升,19.1 毫摩尔),随后缓慢滴加(温升)四丁基氟化铵(4.8 毫升,4.8 毫摩尔,在THF中1M)。将该反应混合物搅拌并加热一夜至室温。将该反应用饱和碳酸氢钠水溶液淬灭,用EtOAc稀释,并将层分离,将水层用EtOAc(× 3)萃取。将合并的有机层用盐水洗涤,用Na2SO4干燥,并在真空下浓缩。将所得的油利用硅胶层析法纯化,用5–50% EtOAc/己烷洗脱,形成标题化合物。1H NMR(CDCl3,500MHz):δ 8.59(d,J=4.9 Hz,1H),7.75(td,J=7.8,1.7 Hz,1H),7.52–7.44(m,5H),7.36(m,1H),7.00(br s,1H)。
遵循与对于以上的中间体I-29-1概述的方法类似的方法,合成表7中的下述中间体。
中间体 I-30
6-溴-3-(异丙基氨基)-3-甲基吲哚啉-2-酮
将6-溴吲哚-2,3-二酮(1.00克,4.42 毫摩尔)和丙-2-胺(0.392克,6.64 毫摩尔)的EtOH(5 毫升)溶液在微波中、在130℃加热 1小时。将该反应在真空中浓缩,并将过量的EtOH与甲苯共沸,随后将该亚胺中间体由乙醚磨碎,得到固体。在0℃将该亚胺中间体吸纳在乙醚(15 毫升)中,加入BF3∙OEt2(0.68 毫升,5.4 毫摩尔)并将该反应搅拌15分钟。然后加入MeMgBr(1.8 毫升,5.4 毫摩尔,在THF中3M)并将该反应逐渐加热至环境温度。将该反应用饱和NH4Cl水溶液淬灭,用EtOAc和饱和NaHCO3水溶液稀释,分离有机层,用盐水洗涤,用硫酸钠干燥,进行过滤并在真空中浓缩。利用硅胶层析法纯化,用0–50% EtOAc/己烷洗脱,随后用0–20% MeOH/DCM洗脱,得到作为固体的标题化合物。 C12H16BrN2O [M + H]+ 的LRMS(ESI)计算值:283,285(1:1),实测值 283,285(1:1); 1H NMR(500 MHz DMSO-d6): δ10.42 (s,1H),7.20(m,(2H),6.91(s,1H),2.39(m,1H),1.20(s,3H),1.0(d,1H),0.65(d,6H)。
实施例1-1
(3S,4R)-3-(3-((4-(甲基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈
步骤1:(3S,4R)-3-(4-(苄基氧基)-3-((4-(甲基磺酰基)苯基)氨基)-1H-吡唑并 [4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈
在脱气、密封的微波瓶中,向(3S,4R)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈(中间体3A)(40.0 毫克,0.114 毫摩尔),1-溴-4-(甲基磺酰基)苯(53.8 毫克,0.229 毫摩尔),Pd2dba3(26 毫克,0.029 毫摩尔),磷酸三钾(48.6 毫克,0.229 毫摩尔),2-二-(叔丁基)膦基-3,4,5,6-四甲基-2',4',6'-三异丙基-1,1'-联苯(41 毫克,0.086 毫摩尔)中加入叔戊醇(1.53 毫升),并将该反应加热至75℃,保持18小时。然后将该反应在真空中浓缩并利用硅胶层析法纯化,用5–60% EtOAc/己烷洗脱,得到作为固体的所需产物,1-1a。 C26H26N5O4S[M+H]+ 的LRMS (ESI)计算值:504,实测值504。
步骤2: (3S,4R)-3-(3-((4-(甲基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡 唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈
向 1-1a(71 毫克,0.14 毫摩尔)和Pd/C(15 毫克,10 wt.% Pd)中加入乙酸乙酯(0.71 毫升),并将该反应排气并用氢气(1大气压)回填。然后将该反应在25℃搅拌一夜,通过CELITE®过滤,并在真空中浓缩并利用硅胶层析法纯化,用1–6% 甲醇/DCM洗脱,得到固体,1-1。 C19H20N5O4S[M+H]+ 的LRMS (ESI)计算值:414,实测值 414。1H NMR(600 MHz,DMSO-d6):δ 11.23(s,1H),8.71(s,1H),7.89(d,J=8.8 Hz,2H),7.79(d,J=8.8 Hz,2H),7.29(m,1H),6.78(d,J=7.4 Hz,1H),4.92(dt,J=10.7,4.6 Hz,1H),4.00(dd,J=11.4,4.7 Hz,1H),3.96(dd,J=7.7,4.0 Hz,1H),3.75(dt,J=11.4,3.7 Hz,1H),3.70(t,J=10.8 Hz,1H),3.50(t,J=11.8 Hz,1H),3.14(s,3H),2.20(d,J=12.1 Hz,1H),2.05(app. dq,J=12.6,4.5 Hz,1H)。
表8中概述的以下实施例通过类似地使用实施例1-1的以上概述的一般步骤来制备。在选择的情况下,一般步骤可以进行修改,以可选地利用KOAc碱,代替2-二 - 叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯配体、利用 [(2-二叔丁基膦基-2′,4′,6′-三异丙基-1,1′-联苯)-2-(2′-氨基-1,1′-联苯)]钯(II) 甲磺酸盐 (t-BuXPhos Pd G3) 预催化剂代替个体的膦和钯源 ,和/或叔戊醇或DMF代替2-丙醇。另外,在某些情况下,交叉偶联可以在70-90℃之间进行。在选择的情况下,氢解反应可选地在MeOH或THF中或使用具有促进起始物质溶解的任何上述溶剂的合适的共溶剂来进行。
实施例2-1
(3S,4S)-3-{3-[(2-甲基-1,3-苯并噻唑-6-基)氨基]-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基}四氢-2H-吡喃-4-甲腈
将(3R,4S)-3-(3-氨基-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈(52 毫克,0.20 毫摩尔),6-溴-2-甲基苯并[d]噻唑(50.2 毫克,0.220 毫摩尔),Pd2(dba)3(22 毫克,0.024 毫摩尔),t-Bu-XPhos(20 毫克,0.048 毫摩尔)和乙酸钾(39.3 毫克,0.400 毫摩尔)加入到微波瓶中,随后加入2-丙醇(2.50 毫升)。将该瓶密封并利用连续的排气/氩回填(× 3)脱气。将所得的混合物在85℃搅拌18小时,然后冷却至环境温度和在真空中浓缩。将该残余物吸纳在DMSO(2.50 毫升)中,过滤,并将所得的溶液直接利用反相HPLC(5–50% 乙腈/具有0.1% TFA改性剂的水)纯化。将含有纯产物的级分冷冻,并冻干,得到作为固体的TFA盐的、标题化合物。 C20H19N6O2S [M+H]+ 的LRMS (ESI)计算值:407,实测值 407。 1H NMR(500 MHz,DMSO-d6):δ 11.24(d,J=6.3 Hz,1H),8.40(d,J=1.9Hz,1H),8.35(s,1H),7.83(d,J=8.8 Hz,1H),7.72(dd,J=2.3,8.8 Hz,1H),7.31(dd,J=5.9,7.3 Hz,1H),6.80(d,J=7.3 Hz,1H),4.93(dt,J=4.5,10.7 Hz,1H),4.01(m,2H),3.83(dt,3.8,J=11.8 Hz,1H),3.78(t,J=10.7 Hz,1H),2.79(s,3H),2.25(d,J=12.6 Hz,1H),2.09(dq,J=4.7,12.6 Hz,1H)。
表9中概述的以下实施例通过类似地使用实施例2-1的以上概述的一般步骤来制备。在选择的情况下,一般步骤可以进行修改,以可选地利用KOAc碱,代替2-二 - 叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯配体、利用 [(2-二叔丁基膦基-2′,4′,6′-三异丙基-1,1′-联苯)-2-(2′-氨基-1,1′-联苯)]钯(II) 甲磺酸盐 (t-BuXPhos Pd G3) 预催化剂代替个体的膦和钯源 ,和叔戊醇代替2-丙醇。另外,在某些情况下,交叉偶联可以在70–85℃之间进行。
实施例 3-1
(3R,4S)-3-(3-((4-氯-3-(甲基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈
步骤1: (3R,4S)-3-(4-(苄基氧基)-3-((4-氯-3-(甲硫基)苯基)氨基)-1H-吡唑 并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈(3-1a)
在脱气、密封的微波瓶中,向(3R,4S)-3-(3-氨基-4-(苄基氧基)-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈(I-3B)(0.12克,0.34 毫摩尔),(5-溴-2-氯苯基)(甲基)硫烷(90 毫克,0.38 毫摩尔),Pd2dba3(38 毫克,0.041 毫摩尔),乙酸钾(51 毫克,0.52毫摩尔),2-二-(叔丁基)膦基-3,4,5,6-四甲基-2',4',6'-三异丙基-1,1'-联苯(35 毫克,0.082 毫摩尔)中加入丙烷-2-醇(3.5 毫升),并将该反应加热至85℃ ,保持18小时。然后将该反应在真空中浓缩并利用硅胶层析法纯化,用50–100% EtOAc/己烷洗脱,得到所需的产物3-1a。 C26H25ClN5O2S [M+H]+ 的LRMS (ESI)计算值:507,实测值 507。
步骤2: (3R,4S)-3-(3-((4-氯-3-(甲硫基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡 唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈(3-1b)
将(3R,4S)-3-(4-(苄基氧基)-3-((4-氯-3-(甲硫基)苯基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈(3-1a)(0.10克,0.20 毫摩尔)在 1:1 DCM:TFA(2毫升)中在环境温度下搅拌16小时。然后将该混合物小心地用饱和碳酸氢钠水溶液稀释并用EtOAc萃取。将有机层用盐水洗涤,用无水硫酸镁干燥,过滤,并在真空中浓缩,得到标题化合物,3-1b。残余物不进行进一步的纯化而用于下面的步骤。 C19H19ClN5O2S [M+H]+ 的LRMS (ESI)计算值:416,实测值 416。
步骤3: (3R,4S)-3-(3-((4-氯-3-(甲基磺酰基)苯基)氨基)-4-氧代-4,5-二氢- 1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈
在环境温度下向 3-1b(0.10克,0.24 毫摩尔)/1:1 DCM:EtOAc(9.6 毫升)中加入m-CPBA(54 毫克,0.24 毫摩尔)。将该反应混合物搅拌 1小时,然后用饱和硫代硫酸钠水溶液稀释并用EtOAc(× 2)萃取。将合并的有机萃取物用饱和硫代硫酸钠水溶液洗涤,用无水硫酸镁干燥,进行过滤并在真空中浓缩。将该残余物用反相色谱纯化,得到化合物 3-1。C19H19ClN5O4S [M+H] +的LRMS (ESI)计算值:448,实测值 448。1H NMR(500 MHz,DMSO-d6):δ11.18(s,1H);8.82(s,1H);8.72(d,J=2.8 Hz,1H);7.94(m,1H);7.56(d,J=8.7 Hz,1H);7.26(t,J=6.1 Hz,1H);6.75(d,J=7.3 Hz,1H);4.88–4.96(m,1H);3.92–4.04(m,2H);3.72(t,J=10.8 Hz,1H);3.55–3.63(m,1H);3.33–3.43(m,4H);2.15–2.25(m,1H);1.97–2.07(m,1H)。
表 10中概述的以下实施例通过类似地使用实施例3-1的以上概述的一般步骤来制备,所述实施例3-1使用合适量的m-CPBA以实现硫化物的单氧化。
生物学检测
Jak生化HTRF检测方案
化合物抑制JAK1、JAK2、JAK3和TYK2的活性的能力,在HTRF方式的生化检测中使用每种酶的重组纯化的GST标记的催化结构域(Invitrogen JAK1 #M4290, JAK2 #M4290,JAK3 #M4290, TYK2 #M4290)进行测定。该反应使用一个共同的肽底物,LCB-EQEDEPEGDYFEWLW-NH2(in-house)。基本试验方案如下:首先,将250nL在DMSO中稀释的化合物使用Labcyte Echo 555 声学分配器(acoustic dispenser)分配到干燥的384孔的黑色板(Greiner #781076)的孔中。随后试剂的添加采用安捷伦Bravo。接着,将18微升的1.11X酶和1.11X底物/1X检测缓冲液(Invitrogen激酶缓冲液#PV3189,2mM DTT,0.05%BSA)加入到孔中,并振摇,然后在室温下预孵育30分钟,以使化合物结合达到平衡。平衡之后,加入2微升的10X ATP/1X检测缓冲液,以引发激酶反应并将板振摇,然后在室温下孵育120分钟。在孵育结束时,加入20微升的2X终止缓冲液(链霉亲和素-Dylight 650(Thermo #84547B/100mL),铕标记的pY20抗体((Perkin Elmer #AD0067),EDTA,HEPES,和Triton),以淬灭反应。将板进行振摇和离心,然后在室温下孵育60分钟,然后在Perkin Elmer Envision(λex=337 nm, λem=665 和 615 nm, TRF 延迟时间= 20 µs)上读取。 HTRF信号= 10,000 * 665纳米的读数/ 615 nm的读数。标准化至未处理对照后,计算在各化合物浓度的HTRF信号的抑制百分比。抑制百分比对化合物浓度的对数的曲线图用4-参数剂量响应方程(4-parameter dose response equation)来拟合,计算IC50值。
最终的反应条件是:
试验的化合物浓度为1496,499,175,49.9,18.7,6.2,2.1,0.75,0.24,0.075,和0.0125 nM,具有1.25%剩余的DMSO。
生物学数据
本发明的实施例在如上所述的JAK1和JAK2体外结合检测中进行评价。下表列出了本发明公开的JAK1 IC50 值和JAK2 IC50值。
实施例 | JAK1 IC<sub>50</sub> | JAK2 IC<sub>50</sub> |
1-1 | 7.06 | 11.47 |
1-2 | 0.05 | 0.35 |
1-3 | 0.11 | 1.39 |
1-4 | 0.04 | 0.34 |
1-5 | 0.05 | 0.15 |
1-6 | 0.07 | 0.21 |
1-7 | 0.05 | 0.29 |
1-8 | 0.06 | 0.22 |
1-9 | 0.09 | 0.29 |
1-10 | 0.08 | 0.21 |
1-11 | 0.09 | 0.34 |
1-12 | 0.10 | 0.30 |
1-13 | 0.08 | 0.21 |
1-14 | 0.22 | 0.41 |
1-15 | 0.12 | 0.27 |
1-16 | 0.36 | 5.04 |
1-17 | 0.09 | 2.52 |
1-18 | 0.07 | 0.13 |
1-19 | 0.05 | 0.08 |
1-20 | 0.07 | 0.30 |
1-21 | 0.08 | 0.28 |
1-22 | 17.3 | 21.2 |
1-23 | 0.25 | 0.69 |
1-24 | 12.4 | 14.7 |
1-25 | 2.27 | 3.43 |
1-26 | 0.71 | 2.13 |
1-27 | 22.37 | 60.73 |
1-28 | 5.34 | 12.65 |
1-29 | 4.38 | 5.91 |
1-30 | 0.25 | 4.65 |
1-31 | 0.12 | 0.96 |
1-32 | 0.24 | 2.11 |
1-33 | 0.04 | 0.09 |
1-34 | 0.03 | 1.18 |
1-35 | 0.12 | 0.16 |
1-36 | 0.24 | 0.27 |
1-37 | 0.22 | 0.33 |
1-38 | 0.09 | 0.13 |
1-39 | 0.13 | 0.17 |
1-40 | 0.16 | 0.78 |
1-41 | 0.14 | 0.60 |
1-42 | 0.05 | 0.13 |
1-43 | 0.04 | 0.08 |
1-44 | 0.12 | 0.18 |
1-45 | 0.14 | 0.21 |
1-46 | 0.14 | 0.21 |
1-47 | 0.27 | 0.43 |
1-48 | 0.65 | 1.73 |
1-49 | 0.18 | 0.30 |
1-50 | 0.08 | 0.09 |
1-51 | 0.08 | 0.14 |
1-52 | 0.08 | 0.11 |
1-53 | 0.08 | 0.09 |
1-54 | 0.07 | 0.14 |
1-55 | 0.08 | 0.12 |
1-56 | 0.06 | 0.14 |
1-57 | 0.09 | 0.22 |
1-58 | 0.07 | 0.13 |
1-59 | 0.05 | 0.08 |
1-60 | 0.21 | 0.59 |
1-61 | 0.30 | 0.30 |
1-62 | 0.05 | 0.29 |
1-63 | 0.10 | 0.30 |
1-64 | 0.04 | 0.30 |
1-65 | 0.09 | 0.26 |
1-66 | 0.07 | 0.16 |
1-67 | 0.70 | 1.92 |
1-68 | 0.28 | 1.83 |
1-69 | 0.08 | 0.30 |
1-70 | 0.15 | 0.65 |
1-71 | 0.22 | 0.70 |
1-72 | 0.10 | 0.20 |
1-73 | 0.35 | 0.70 |
1-74 | 0.18 | 0.52 |
1-75 | 0.14 | 0.54 |
1-76 | 0.24 | 0.82 |
1-77 | 0.05 | 0.17 |
1-78 | 0.12 | 0.24 |
1-79 | 0.04 | 0.08 |
1-80 | 0.07 | 0.15 |
1-81 | 0.08 | 0.15 |
1-82 | 0.87 | 2.56 |
1-83 | 0.50 | 1.06 |
1-84 | 0.13 | 0.15 |
1-85 | 0.12 | 0.14 |
1-86 | 0.15 | 0.23 |
1-87 | 0.15 | 0.30 |
1-88 | 0.11 | 0.09 |
1-89 | 0.15 | 0.14 |
1-90 | 0.21 | 0.40 |
1-91 | 0.17 | 0.21 |
1-92 | 0.13 | 0.19 |
1-93 | 0.09 | 0.11 |
1-94 | 0.08 | 0.15 |
1-95 | 0.06 | 0.09 |
1-96 | 0.07 | 0.15 |
1-97 | 0.14 | 0.18 |
1-98 | 0.06 | 0.17 |
1-99 | 0.07 | 0.16 |
1-100 | 0.06 | 0.05 |
1-101 | 0.07 | 0.05 |
2-1 | 0.03 | 0.89 |
2-2 | 0.05 | 0.16 |
2-3 | 0.06 | 0.39 |
2-4 | 0.05 | 0.27 |
2-5 | 0.14 | 0.15 |
2-6 | 0.21 | 0.24 |
2-7 | 0.05 | 0.06 |
2-8 | 0.05 | 0.05 |
3-1 | 1.64 | 7.44 |
3-2 | 0.89 | 13.73 |
3-3 | 1.64 | 7.44 |
3-4 | 1.75 | 14.63 |
Claims (14)
1.化合物或其药学上可接受的盐、或立体异构体,其中该化合物选自:
3-(3-((4-(甲基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(4-氧代-3-(苯基氨基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-((2-甲基-1,1-二氧代-2,3-二氢苯并[d]异噻唑-5-基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-((2-(叔丁基)-1,1-二氧代-2,3-二氢苯并[d]异噻唑-5-基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
4-((1-(4-氰基四氢-2H-吡喃-3-基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基)氨基)-N,N-二甲基苯磺酰胺;
3-(3-((1,1-二氧代-2-(2,2,2-三氟乙基)-2,3-二氢苯并[d]异噻唑-5-基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
3-(3-((4-(1-氨基-2,2,2-三氟乙基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3- c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
N-(叔丁基)-4-((1-(4-氰基四氢-2H-吡喃-3-基)-4-氧代-4,5-二氢-1H-吡唑并[4,3- c]吡啶-3-基)氨基)苯磺酰胺;
3-(3-((4-(异丙基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈;
N-(叔丁基)-4-((1-(4-氰基四氢-2H-吡喃-3-基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-3-基)氨基)-N-甲基苯磺酰胺;
3-(3-((4-(叔丁基磺酰基)苯基)氨基)-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)四氢-2H-吡喃-4-甲腈。
2.药物组合物,其包含权利要求1的化合物或其药学上可接受的盐和药学上可接受的载体。
3.治疗有效量的权利要求1的化合物或其药学上可接受的盐在制备用于治疗JAK介导的疾病的药物中的应用。
4.治疗有效量的权利要求1所述的化合物或其药学上可接受的盐或立体异构体在制备治疗可通过抑制Janus激酶JAK1和JAK2而得到改善的哺乳动物的病症的药物中的应用,其中,所述病症选自关节炎、哮喘和阻塞性气道疾病、自身免疫性疾病或障碍、和癌症。
5.根据权利要求4所述的应用,其中所述病症是关节炎。
6.根据权利要求5所述的应用,其中所述病症选自类风湿性关节炎、青少年性关节炎,和牛皮癣性关节炎。
7.根据权利要求4所述的应用,其中所述病症是哮喘或阻塞性气道疾病。
8.根据权利要求4所述的应用,其中所述病症选自:慢性哮喘、晚期哮喘、气道高反应、支气管炎、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、经常性气道阻塞、和慢性阻塞性肺病(COPD)和肺气肿。
9.根据权利要求8所述的应用,其中所述过敏性哮喘是粉尘性哮喘。
10.根据权利要求4所述的应用,其中所述病症是自身免疫性疾病或障碍。
11.治疗有效量的权利要求1所述的化合物或其药学上可接受的盐在制备治疗需要治疗的哺乳动物的哮喘的药物中的应用。
12.治疗有效量的权利要求1所述的化合物或其药学上可接受的盐在制备治疗需要治疗的哺乳动物的关节炎的药物中的应用。
13.权利要求1所述的化合物或其药学上可接受的盐或立体异构体在制备用于治疗通过Janus激酶JAK1和JAK2的抑制而被改善的疾病或障碍的药物中的应用。
14.权利要求1所述的化合物或其药学上可接受的盐或立体异构体、和第二活性剂在制备用于治疗通过Janus激酶JAK1和JAK2的抑制而被改善的疾病或障碍的药物中的应用。
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PCT/CN2014/000298 WO2014146492A1 (en) | 2013-03-19 | 2014-03-19 | N-(2-cyano heterocyclyl)pyrazolo pyridones as janus kinase inhibitors |
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WO2016061751A1 (en) | 2014-10-22 | 2016-04-28 | Merck Sharp & Dohme Corp. | Ethyl n-boc piperidinyl pyrazolo pyridones as janus kinase inhibitors |
WO2018111663A1 (en) * | 2016-12-14 | 2018-06-21 | Merck Sharp & Dohme Corp. | Aminopyrazoles as janus kinase inhibitors |
EA202192575A1 (ru) | 2019-03-21 | 2022-01-14 | Онксео | Соединения dbait в сочетании с ингибиторами киназ для лечения рака |
US20220401436A1 (en) | 2019-11-08 | 2022-12-22 | INSERM (Institute National de la Santé et de la Recherche Médicale) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
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US9115133B2 (en) | 2011-03-22 | 2015-08-25 | Advinus Therapeutics Limited | Substituted fused tricyclic compounds, compositions and medicinal applications thereof |
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CA2901766A1 (en) | 2014-09-25 |
WO2014146492A1 (en) | 2014-09-25 |
US9957265B2 (en) | 2018-05-01 |
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EP2976338A1 (en) | 2016-01-27 |
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MX2015013414A (es) | 2016-02-26 |
KR20150130311A (ko) | 2015-11-23 |
RU2669922C2 (ru) | 2018-10-17 |
EP2976338B1 (en) | 2018-01-03 |
BR112015023878A2 (pt) | 2017-07-18 |
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