CN114605390A - 具有cdk激酶抑制活性的化合物、其药物组合物和用途 - Google Patents
具有cdk激酶抑制活性的化合物、其药物组合物和用途 Download PDFInfo
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- CN114605390A CN114605390A CN202011407322.XA CN202011407322A CN114605390A CN 114605390 A CN114605390 A CN 114605390A CN 202011407322 A CN202011407322 A CN 202011407322A CN 114605390 A CN114605390 A CN 114605390A
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- Prior art keywords
- compound
- substituted
- pharmaceutically acceptable
- alkyl
- unsubstituted
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
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- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 230000031168 regulation of transcription elongation, DNA-dependent Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
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- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229950000055 seliciclib Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000005029 transcription elongation Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000000169 tricyclic heterocycle group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003732 xanthenes Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本发明公开了一类具有CDK激酶抑制活性的化合物、其药物组合物和用途,具体为如通式I所示的化合物。本发明的化合物及包含这些化合物的药物组合物可用于预防或治疗相关疾病,所述疾病特别是由CDK激酶尤其CDK7/CDK9激酶的一种或多种异常活性介导的。
Description
技术领域
本发明涉及CDK激酶抑制剂、或其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药,以及其用途。本发明还涉及包含这些化合物的药物组合物以及这些化合物用于预防或治疗疾病的方法,所述疾病特别是由CDK激酶尤其CDK7/9激酶的一种或多种异常活性介导的。
背景技术
细胞周期异常是癌症的一个标志性特征,周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)是一类丝氨酸/苏氨酸激酶,在细胞周期中起中心作用,主导细胞周期的启动、进行和结束。CDK家族是细胞内重要的信号转导分子,其与周期素(cyclin)形成的CDK-cyclin复合物,参与细胞的生长、增殖、休眠和凋亡。
在过去的20年中,以CDK激酶为肿瘤治疗靶点的药物开发已经得到了广泛的关注,如Flavopiridol(Alvocidib),Seliciclib(CYC202),Dinaciclib(SCH727965)和Milciclib(PHA-848125)等都进入不同阶段临床研究。但是由于早期发现的CDK抑制剂对各CDK家族亚型抑制活性不高,或者缺乏一定的选择性,或者体内吸收不佳等情况而限制了临床应用。近几年,由于提高了CDK抑制剂对于各CDK家族亚型的选择性或者提高了CDK激酶的抑制活性,尤其是靶向CDK4/6的选择性抑制剂的发现,使得这一领域的药物研发再次成为热点。目前辉瑞公司的PD0332991(Palbociclib)、礼来公司的LY-2835219(abemaciclib)和诺华公司的LEE-011(Ribociclib)分别已经上市成为治疗ER阳性、HER2阴性乳腺癌的药物,同时还有大量临床前及早期临床研究阶段的类似化合物处于不同研发阶段。同时,研究发现CDK家族的CDK7激酶对于三阴性乳腺癌的调控具有非常重要的作用,抑制CDK7激酶对于三阴性乳腺癌细胞的生长具有显著的杀伤作用。另外,CDK9激酶主要在转录延伸的调控中发挥作用,而不影响细胞周期过程。CDK9抑制剂可通过降解、抑制CDK9来阻断正性转录延长因子P-TEFb(positive transcription elongation factor b)对RNA Poly-II C末端区域的磷酸化,抑制转录,迅速降低细胞内mRNA水平,从而引起肿瘤细胞凋亡。
CDK激酶抑制剂类药物研发尽管已经取得了非常重大的进展,但是同时还存在一些未能解决的问题,如已有CDK激酶抑制剂类药物的耐药性、对CDK激酶家族靶点的亚型选择性等,因此,本领域迫切需要研究和开发新的高效低毒、抗耐药性、具有临床应用价值的新型CDK激酶抑制剂,如CDK7或9激酶抑制剂。
发明内容
一方面,本发明提供了如通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,
其中:
M1选自:CR1和N;M2选自:CR2和N;
R1选自:H、氘、卤素、氰基、C1-6的烷基或卤代烷基、C3-C8环烷基或杂环烷基;R2选自:H、氘、卤素、氰基、C1-6的烷基或卤代烷基、C3-C8环烷基或杂环烷基;
Cy选自:取代或未取代的3-12元饱和碳环,所述的取代的C3-C12的环烷基为被一个或多个R3取代的C3-C12的环烷基,R3独立地选自:氢、氘、卤素、羟基、氰基、氨基、C1-6的烷基或卤代烷基、C1-C6烷氧基、C3-C8环烷基或杂环烷基;其中所述“取代”指具有一个或多个相同或不同的R3取代基;R3选自:氢、氘、卤素、羟基、氰基、氨基、C1-6的烷基或卤代烷基、C1-C6烷氧基、C3-C8环烷基或杂环烷基;
R4为氢或卤素;
R5为H或C1-C6烷基;
R6选自:氢、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、或取代或未取代的C3-C8环烷基;
R7和R8各自独立的选自:氢、卤素、取代或未取代的C1-C6烷基;或者R7和R8与所连接的碳一起形成3-7元碳环;
其中X1,X3各自独立的选自C或N;
X2为C(R9)nR10或NR10,n为0或1;其中,R9、R10各自独立的选自:氢、取代或未取代的C1-C6烷基和取代或未取代的C3-C8环烷基;或者,当X2为C(R9)nR10且n为1时,R9和R10与所连接的C一起形成取代或未取代4-7元碳环;或者,R10、R5和所连接的C和/或N一起形成取代或未取代4-7元碳环或杂环,且X1、X2和X3至多两个为N;
R独立地选自氢、氘、卤素、羟基、C1-10烷氧基、C1-10烷基、氨基、C1-10单烷基取代氨基、C1-10双烷基取代氨基、3-12元环烷基或杂环烷基、C1-10烷基酰基、C1-10烷基磺酰基、3-12元环烷基或杂环烷基酰基、3-12元环烷基或杂环烷基磺酰基、C1-10烷基OCONH-、C1-10烷基NHCONH-;
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,
R5为H或CH3;
各R7和R8各自独立的选自氢和C1-C6烷基;
各R9、R10各自独立的选自:氢、取代或未取代的C1-C6烷基和取代或未取代的C3-C8环烷基;或者,R9、R10与所连接的C一起形成取代或未取代4-7元碳环;或者,R11、R5与所连接的C和/或N一起形成取代或未取代4-7元碳环或杂环;
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,
各R7和R8各自独立地选自氢和C1-C6烷基;
各R9独立地选自:氢、C1-C4烷基;
p为Re取代基的个数,且为0、1、2、3和4;
各Re独立地选自:H、卤素、-OH、CN、NR11R12、未取代或取代的C1-C6烷基、未取代或取代的C1-C6烷氧基和或取代或未取代的C3-C8环烷基;
所述取代指被选自下组的一个或多个取代基取代:卤素、OH、C1-C4烷基、-NR11R12;R11和R12各自独立地为H、C1-C4烷基或C1-C4卤代烷基;
r为C原子的个数,且为1、2或3;优选r为1。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,
R4为氢或卤素;
R7和R8各自独立的选自H或C1-C4烷基;
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,
Cy选自:环己烷环;L选自-CO-;
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,
R选自:-NH2、-NHR13、-NHCOR14、-NHCOOR14,其中R13选自3-8元的环烷基或杂环烷基,R14选自C1-10的直链或支链的烷基或卤代烷基;
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R1选自:H、卤素、C1-C6烷基;优选的,R1为H、F、Cl。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R2选自:H、卤素、C1-C6烷基;优选的,R2为H。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R和L处于环Cy的1-3位或者1-4位。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R7和R8各自独立的选自:取代或未取代的C1-C6烷基;优选的,R7和R8各自独立的选自:C1-C4烷基。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为N,M2为CH。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为C-H、C-F,M2为N。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为CH、-C-F,M2为CH。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为N,M2为N。
在一个实施方案中,本发明提供了通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中所述化合物选自:
在另一方面,本发明提供了一种药物组合物,其特征在于,包括治疗有效量的式I所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,以及药学上可接受的赋形剂。
在另一方面,本发明提供了式I所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药在制备用于预防、治疗、或减轻患者由异常细胞增殖,自身免疫,炎症或感染引起的障碍或疾病的药物中的用途。
在一个实施方案中,本发明提供了如上所述的式I的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药的用途,其特征在于,所述异常细胞增殖,自身免疫,炎症或感染是由细胞周期蛋白依赖性激酶改变引起的。
另一方面,本发明提供了药物组合物,其包含治疗有效量的式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药,以及药学上可接受的载体。在所述药物组合物的某些实施方案中,药物组合物被配制用于静脉内施用、肌内施用、口服施用、直肠施用、吸入施用、鼻施用、局部施用、眼睛施用或耳施用。在所述药物组合物的其它实施方案中,药物组合物是片剂、丸剂、胶囊、液体剂、吸入剂、鼻喷雾溶液剂、栓剂、溶液剂、乳剂、软膏剂、滴眼剂或滴耳剂。在所述药物组合物的其它实施方案中,其还包含一种或多种另外的治疗剂。
另一方面,本发明提供了式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药在制备用于预防、治疗、或减轻患者由异常细胞增殖、自身免疫、炎症或感染引起的障碍或疾病的药物中的用途。
在一些实施方案中,所述异常细胞增殖、自身免疫、炎症或感染是由细胞周期蛋白依赖性激酶改变引起的。
另一方面,本发明提供了式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药在制备用于预防、治疗、或减轻由CDK激酶尤其CDK7/9激酶的一种或多种异常活性介导的障碍或疾病的药物中的用途。
另一方面,本发明提供了预防、治疗、或减轻由CDK激酶尤其CDK7/9激酶的一种或多种异常活性介导的障碍或疾病的方法,该方法包括向有此类治疗需要的个体施用有效量的式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药或者包含它们的药物组合物。
在本发明的一些实施方案中,所述障碍或疾病包括但不限于细胞增殖疾病、自身免疫疾病、炎症疾病或感染疾病。
在本发明的一些实施方案中,所述细胞增殖疾病包括但不限于包括但不限于恶性肿瘤,例如黑素瘤、成胶质细胞瘤、卵巢癌、胰腺癌、前列腺癌、肺癌、乳癌、肾癌、宫颈癌、甲状腺癌、原发性实体肿瘤的继发性部位的转移、慢性髓细胞性白血病、急性淋巴细胞性白血病、其他骨髓增殖性病症、乳头状甲状腺癌、非小细胞肺癌和/或间皮瘤。
在本发明的一些实施方案中,所述自身免疫疾病包括但不限于类风湿性关节炎、系统性红斑狼疮、特发性血小板减少性紫癜、溶血性贫血或银屑病。
在本发明的一些实施方案中,所述炎症疾病包括但不限于骨关节炎、痛风性关节炎、溃疡性结肠炎和/或炎性肠病等。
在本发明的一些实施方案中,所述感染疾病包括但不限于败血症、脓毒性休克、内毒素性休克、革兰氏阴性败血症和/或中毒性休克综合征。
术语说明
在本发明中,除非另外明确地说明,本发明所使用的术语具有下面所定义的含义。本发明未明确定义的术语具有本领域技术人员所普遍理解的一般含义。
如本文所用,术语“烷基”指完全饱和的直链或支链的烃基团。烷基优选包含1-20个碳原子,更优选1-16个碳原子、1-10个碳原子、1-6个碳原子或1-4个碳原子。烷基的代表性示例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。
如本文所用,术语“烯基”指包含至少一个双键的直链或支链的烃基团。烯基优选包含2-20个碳原子,更优选2-10个碳原子、2-6个碳原子或2-4个碳原子。烯基的代表性示例包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、戊烯基、异戊烯基、己烯基、庚烯基、辛烯基等。
如本文所用,术语“烷氧基”指烷基-O-基团,其中烷基是上文所定义的。烷氧基的代表性示例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基、环丙基氧基、环己基氧基等。优选地,烷氧基含有约1-6个或者约1-4个碳。
如本文所用,术语"碳环"指饱和或不饱和的单环、二环或三环的3-12个碳原子的烃基团。碳环优选具有3-8个环碳原子,例如含有3-7、或4-7环碳原子。示例性的单环碳环包括但不限于环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环庚烷、环庚烯等。示例性的二环烷包括四氢萘、十氢萘、二环[2.1.1]己烷、二环[2.2.1]庚烷等。示例性的三环烃基团包括金刚烷基等。
如本文所用,术语"环烷基"指饱和或不饱和的单环、二环或三环的3-12个碳原子的烃基团。环烷基优选含有3-8个环碳原子,例如含有3-7、或4-7环碳原子。示例性的单环烃基团包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基等。示例性的二环烃基团包括冰片基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基等。示例性的三环烃基团包括金刚烷基等。
如本文所用,术语"杂芳基"指含有选自N、O或S的1-8个杂原子的5-14元的单环或二环或稠合多环的芳族环。优选地,杂芳基含有选自N、O或S的1-3个杂原子。杂芳基优选为5-10元杂芳基,更优选为5-6元杂芳基。优选地,杂芳基包括但不限于:吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、唑基、异唑基、噻唑基、异噻唑基、三唑基、二唑基、噻二唑基、四唑基、三唑基、噻三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、嗪基、二英基、噻嗪基、三嗪基、5,6-二氢-4H-吡咯并[1,2-b]吡唑基、7H-吡咯并[2,3-d]嘧啶基、咪唑并[1,2-b]哒嗪基、2,3-二氢-1H-咪唑并[1,2-b]吡唑基、咪唑并[2,1-b][1,3]噻唑基、噻吩并[3,2-b]呋喃基、噻吩并[3,2-b]噻吩基、噻吩并[2,3-d][1,3]噻唑基、噻吩并[2,3-d]咪唑基、四唑并[1,5-a]吡啶基、吲哚基、吲嗪基、异吲哚基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、异苯并噻吩基、吲唑基、苯并咪唑基、1,3-苯并唑基、1,2-苯并异唑基、2,1-苯并异唑基、1,3-苯并噻唑基、1,2-苯并异噻唑基、2,1-苯并异噻唑基、苯并三唑基、1,2,3-苯并二唑基、2,1,3-苯并二唑基、1,2,3-苯并噻二唑基、2,1,3-苯并噻二唑基、噻吩并吡啶基、嘌呤基、咪唑并[1,2-a]吡啶基、6-氧代-哒嗪-1(6H)-基、2-氧代吡啶-1(2H)-基、6-氧代-哒嗪-1(6H)-基、2-氧代吡啶-1(2H)-基、1,3-苯并二氧杂环戊烯基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、7-氮杂吲哚基、6-氮杂吲哚基、5-氮杂吲哚基、4-氮杂吲哚基。
如本文所用,术语“杂环”指完全饱和的或不饱和的、芳香的或非芳香的环状基团,例如其是4-至7-元单环、7-至12-元二环或10-至15-元三环的环系,该环系在包含至少一个碳原子的环上含有至少一个杂原子。包含杂原子的杂环的每一个环可以含有1-6个,优选1、2或3个杂原子,所述杂原子选自氮原子、氧原子或硫原子,其中氮和硫杂原子还可以任选被氧化。优选地,杂环是4-至7-元单环杂环。
示例性的单环杂环包括吡咯烷、吡咯、吡唑、氧杂环丁、吡唑啉、咪唑、咪唑啉、咪唑烷、三唑、唑、唑烷、异唑啉、异唑、噻唑、噻二唑、噻唑烷、异噻唑、异噻唑烷、呋喃、四氢呋喃、噻吩、二唑、哌啶、哌嗪、2-氧代哌嗪、2-氧代哌啶、2-氧代吡咯烷、2-氧代氮杂氮杂4-哌啶酮、吡啶、吡嗪、嘧啶、哒嗪、四氢吡喃、吗啉、硫吗啉、硫吗啉亚砜、硫吗啉砜、1,3-二氧戊环和四氢-1,1-二氧代噻吩、1,1,4-三氧代-1,2,5-噻二唑烷-2-等。
示例性的二环杂环包括吲哚、二氢吲哚、苯并噻唑、苯并嗪、苯并唑、苯并噻吩、苯并噻嗪、奎宁环、喹啉、四氢喹啉、十氢喹啉、异喹啉、四氢异喹啉、十氢异喹啉、苯并咪唑、苯并吡喃、吲嗪、苯并呋喃、色原酮、香豆素、苯并吡喃、噌啉、喹喔啉、吲唑、吡咯并吡啶、呋喃并吡啶(例如呋喃并[2,3-c]吡啶、呋喃并[3,2-b]-吡啶]或呋喃并[2,3-b]吡啶)、二氢异吲哚、1,3-二氧代-1,3-二氢异吲哚-2-、二氢喹唑啉(例如3,4-二氢-4-氧代-喹唑啉)、酞嗪等。
“杂环基”是指由上述定义的杂环失去一或多个氢原子而形成的基团。杂环基团可以在杂原子或碳原子处进行连接。
术语“Boc”意指叔丁氧羰基。
如本文所用,术语“卤素”或“卤代”指氟、氯、溴和碘。
在本文中,烷基、烯基、烷氧基、碳环、环烷基、杂芳基、杂环、杂环基等基团可被取代基取代,所述取代基包括但不限于:OH、Boc、卤素、氰基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的环烷基、取代或未取代的杂环基;NRR’、C(O)R、C(O)NRR’或C(O)OR,且各R和b’各自独立的选自:H和取代或未取代的烷基。
如本文所用,术语“药学上可接受的盐”指保持本发明化合物的生物学效应和性能的盐,并且该盐在生物学上或其它方面不是不被期望的。所述盐的非限制性示例包括本发明化合物的无毒的、无机或有机的碱或酸的加成盐。在许多情况下,由于氨基和/或羧基或与之相似的基团的存在,本发明化合物能够形成酸盐和/或碱盐。可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。可以用无机和有机碱形成药学上可接受的碱加成盐。可以由其衍生得到盐的无机碱包括例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等;特别优选的是铵、钾、钠、钙和镁盐。可以由其衍生得到盐的有机碱包括例如伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代的胺)、环状的胺、碱性离子交换树脂等,尤其例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。通过常规化学方法,可以从母体化合物(碱性或酸性部分)合成本发明药学上可接受的盐。一般来讲,可以如下制备所述的盐:使所述化合物的游离酸形式与化学计算量的适当的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或使所述化合物的游离碱形式与化学计算量的适当的酸反应。这类反应通常在水或有机溶剂或两者的混合溶剂中进行。一般来讲,在可行时,非水介质例如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。其它合适的盐可以见于Remington氏药物科学(Remington's PharmaceuticalSciences),第20版,Mack出版公司(Mack Publishing Company),Easton,Pa.,(1985),将其引入文中作为参考。
如本文所用,术语“药学上可接受的赋形剂”包括任何和所有的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料、所述类似的物质和其组合,其是本领域普通技术人员所公知的(见,例如,Remington氏药物科学(Remington's Pharmaceutical Sciences),第18版,Mack出版公司(Mack PrintingCompany),1990,pp.1289-1329,引入文中作为参考)。除非任何常规载体是与活性成分不能共存的,可以考虑在治疗或药物组合物中使用它。
如本所用,术语“溶剂化物”意指包含化学计量的或非化学计量的溶剂的溶剂加成形式。如果溶剂是水,则形成的溶剂化物是水合物,当溶剂是乙醇时,则形成的溶剂化物是乙醇合物。水合物是通过一个或多个分子的水与一分子所述物质形成的,其中水保留其H2O的分子状态,这样的组合能形成一种或多种水合物,例如半水合物、一水合物和二水合物。
如本所用,“前药”是指被化学修饰的活性或非活性的化合物,给药至个体后,其经过体内的生理作用(例如水解、新成代谢等)变为本发明化合物。有关制造和使用前药的适应性和技术是本领域技术人员众所周知的。
术语本发明化合物的"治疗有效量"指可以引起个体生物学或医学反应或改善症状、减慢或延缓疾病恶化或预防疾病等的本发明化合物的量
如本文所用,术语“个体”指动物。优选地,动物是哺乳动物。个体还指例如灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在一优选实施方案中,个体是人。
如本文所用,术语"抑制"指特定的病患、症状或病症或疾病的减轻或抑制,或者生物学活性或过程基线活性的显著降低。
如本文所用,在一实施方案中术语"治疗"任何疾病或病症指改善疾病或病症(即阻止或减缓疾病或其至少一种临床症状的发展)。在另一个实施方案中,“治疗"指改善至少一种身体参数,其可能不为患者所察觉。在另一个实施方案中,“治疗"指身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。
在本发明化合物中的任何不对称碳原子可以以(R)-、(S)-或(R,S)-构型存在,优选以(R)-或(S)-构型存在。不饱和键原子的取代基(如果可能的话)可以以顺-(Z)-或反-(E)-形式存在。因此,本发明化合物可以以可能的异构体之一或其混合物的形式存在,例如,作为基本纯的几何(顺式或反式)异构体、非对映异构体、光学异构体(对映体)、外消旋物或其混合物存在。
可以根据组分的物理化学差异将任何得到的异构体混合物分离成为纯的几何或光学异构体、非对映异构体、外消旋物,例如通过色谱法和/或分步结晶分离。
在本发明中,如果没有另外说明并且根据上下文不矛盾的情况下,根据本领域的一般理解,化合物结构中的C、N、S、O等原子上未指明具体基团的开放价键表示连接有氢原子。例如化合物结构与化合物结构表示相同的化合物。
施用和药物组合物
对于本文提供的化合物(包括式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药)的治疗用途和/或方法,单独或作为药物组合物以治疗有效量施用此类化合物。因此,本文提供了药物组合物,其包含至少一种式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,和一种或多种药学上可接受的赋形剂。此外,此类化合物和组合物可单独地施用或与一种或多种其它治疗剂联合施用。此类化合物和组合物的施用方法包括但不限于,口服施用、直肠施用、肠胃外、静脉施用、玻璃体内施用、皮下施用、肌肉施用、吸入、皮肤施用、局部施用、眼施用或颊施用、气管施用、支气管施用、舌下施用或耳施用。
治疗有效量将尤其取决于表明的疾病、疾病严重程度、受试者年龄和相对健康、所施用的化合物的效能、施用模式和所期望的治疗。
在某些实施方案中,单独地施用式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。在其它实施方案中,作为药物组合物施用本发明的化合物、及其盐和溶剂化物。因此,本文提供了药物组合物,其包含包含至少一种式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,和一种或多种药学上可接受的赋形剂。此外,本文另一方面提供了制备此类药物组合物的方法,包括使本文描述的式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药与一种或多种药学上可接受的赋形剂混合。合适的药学上可接受的赋形剂对于本领域技术人员而言是众所周知的,包括但不限于结合剂、填充剂、崩解剂、润滑剂、吸收剂、着色剂、调味剂、防腐剂、稳定剂、湿润剂、乳化剂、促溶剂、用于调节渗透压的盐和/或缓冲剂等。
联合治疗
在某些实施方案中,与本发明化合物(即式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药)与其它治疗剂联合使用,用于治疗、预防或减轻异常细胞增殖、自身免疫、炎症或感染引起的障碍或疾病。
在某些实施方案中,与本发明化合物与其它治疗剂联合使用,用于治疗、预防或减轻由CDK激酶尤其CDK7/9激酶的一种或多种异常活性介导的障碍或疾病。
在一些实施方案中,所述其它治疗剂包括但不限于本发明化合物之外的抗细胞增殖剂、自身免疫调节剂、抗炎剂和抗感染剂。
此外,本发明还提供了药物组合,例如药盒,其包含:a)第一种化合物,其为游离形式或药学上可接受的盐形式的如本文所述的本发明化合物;以及b)至少另一种其它治疗剂。该试剂盒可包含用于其施用的说明书。
合成方案
方案A:
通式化合物(I)的制备,可以由中间体化合物A与相应的醛或酮原料在酸性催化条件下发生还原氨化反应获得。所选用的酸性催化剂包括冰醋酸、三氟乙酸、四异丙氧基钛等;所述的还原剂包括硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钾等。
方案B:
通式化合物(I)的制备,可以由中间体化合物B与相应的酰基化合物原料(如羧酸、酰氯、氯甲酸酯、异氰酸酯等)在碱性条件下发生取代反应获得。所述的碱包括常用的有机碱或无机碱,如三乙胺、DIPEA、吡啶、碳酸氢钠、碳酸钾、氢氧化钠、碳酸钠等。
本发明的主要优点在于本发明的化合物对CDK7和或9激酶具有较高的活性和选择性,副作用更少,具有高的抗耐药性(即对于已对当前的激酶抑制剂耐药的疾病具有高活性),具有高的生物利用度并且具有高的临床应用价值。
具体实施方式
在本申请中,当化学名称和结构式不一致时,应当以结构式所示为准,除非根据上下文可以推断化学名称而非结构式是正确的。
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,否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
各实施例中,实验仪器说明(例如1H NMR由Varian Mercury-300或VarianMercury-400型核磁共振仪记录,13C NMR由Varian Mercury-400或Varian Mercury-500型或Varian Mercury-600型核磁共振仪记录,化学位移以δ(ppm)表示;质谱由Finnigan/MAT-95(EI)与Finnigan LCQ/DECA and Micromass Ultra Q-TOF(ESI)型质谱仪记录;反相制备HPLC分离用硅胶为200-300目)。
其中,化学式或英文字母缩写代表的试剂中文名称表如下:
iPrOH:异丙醇;EtOH:乙醇;DCM:二氯甲烷;TFA:三氟乙酸;MeOH:甲醇;NaOH:氢氧化钠;HCl:氯化氢;TEA:三乙胺;Raney Ni:雷尼镍;1,4-dioxane:1,4-二氧六环;NaH:氢化钠;H2O:水;Pd/C:钯/炭;H2:氢气;HATU:2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯;DMF:N,N-二甲基甲酰胺;THF:四氢呋喃;Boc2O:二碳酸二叔丁酯;NBS:N-溴代丁二酰亚胺;NCS:N-氯代丁二酰亚胺;NIS:N-碘代丁二酰亚胺;MeCN:乙腈;DIPEA:N,N-二异丙基乙胺;NaBH4:硼氢化钠;AcOH:醋酸;ethyl acetate:乙酸乙酯;NaBH3CN:氰基硼氢化钠;K2CO3:碳酸钾;Cs2CO3:碳酸铯;nBuLi:正丁基锂;LiAlH4:氢化铝锂;Pd(dppf)Cl2:[1,1’-双(二苯基膦基)二茂铁]二氯化钯;KOAc:醋酸钾。Fumaronitrile:富马酸腈;P(nBu)3:三正丁基膦;LDA:二异丙基氨基锂;LiOH:氢氧化锂;MeI:碘甲烷;EtI:碘乙烷;(CH2O)n:多聚甲醛;HCO2H:甲酸;CH3COCl:乙酰氯;LCMS:液相色谱质谱联用;Xantphos:4,5-双二苯基膦-9,9-二甲基氧杂蒽;TLC:薄层色谱法;eq.:当量;DCE:1,2-二氯乙烷;HEPES:4-羟乙基哌嗪乙磺酸;EGTA:乙二醇双(2-氨基乙基醚)四乙酸;DTT:二硫苏糖醇
关键中间体的合成
中间体1:N-(5-氟-4-(3-异丙基-2-甲基咪唑并[1,2-a]吡啶-6-基)嘧啶-2-基)-5,6,7,8-四氢-1,6-二氮杂萘-2-胺
第一步:在干燥的单口瓶里依次加入2-氨基-5-溴吡啶(24.5g,14.2mmol),溴丙酮(19.6g,14.3mmol),室温搅拌15min后,加入乙醇(300mL),回流16h。反应完毕后,减压浓缩,加乙酸乙酯(500mL)稀释,用碳酸氢钠饱和水溶液洗涤(500mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩。减压浓缩得粗产品,用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯=2/1)纯化,得到6-溴-2-甲基咪唑并[1,2-a]吡啶(12.6g,黄色固体)。LCMS:211.1(M+H)+;1H-NMR(400MHz,CDCl3)δ8.18(s,1H),8.40(d,1H,J=9.6Hz),7.31(s,1H),7.17(d,1H,J=9.6Hz),2.45(s,3H)。
第二步:在干燥的单口瓶里依次加入6-溴-2-甲基咪唑并[1,2-a]吡啶(12.6g,60mmol),乙腈(200mL),NIS(14.2g,63mmol),室温搅拌4h。反应完毕后过滤,滤饼用水洗涤(30mL×1),干燥得到6-溴-3-碘-2-甲基咪唑并[1,2-a]吡啶(19.2g,黄色固体)。LCMS:337.0(M+H)+;1H-NMR(400MHz,CDCl3)δ8.19(s,1H),8.40(d,1H,J=9.2Hz),7.26(d,1H,J=9.2Hz),2.49(s,3H)。
第三步:在干燥的三口瓶里依次加入6-溴-3-碘-2-甲基咪唑并[1,2-a]吡啶(19.2g,57.0mmol),异丙烯基硼酸频哪醇酯(10.5g,62.7mmol),碳酸钾(23.6g,171mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.1g,2.8mmol),二氧六环(300mL)和水(60mL),氮气置换。升温至100℃,搅拌5h。反应完毕后,冷却至室温,用乙酸乙酯(500mL)稀释,加水洗涤(500mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(石油醚/乙酸乙酯=3/1)纯化所得残余物,得到6-溴-2-甲基-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶(9.9g,红色液体)。LCMS:551.2(M+H)+。
第四步:在干燥的三口瓶里依次加入6-溴-2-甲基-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶(9.9g,39.6mmol),联硼酸频哪醇酯(15g,59.4mmol),乙酸钾(11.6g,119mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.44g,1.98mmol)和二氧六环(300mL),氮气置换。升温至100℃,搅拌4h。反应完毕后,冷却至室温,加水(500mL),用二氯甲烷/甲醇=10/1(500mL*2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(二氯甲烷/甲醇=10/1)纯化所得残余物(2-甲基-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶-6-基)硼酸酯(3.9g,黑色液体),后加大极性以洗脱剂体系(甲醇加1%氨水)纯化所得残余物(2-甲基-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶-6-基)硼酸(5.8g,黑色固体)。两者合并,直接用于下一步反应。
第五步:在干燥的三口瓶里依次加入上述硼酸酯和硼酸混合物(5.5g),4-氯-5-氟嘧啶-2-胺(2.16g,14.7mmol),碳酸钾(4.1g,29.4mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(530mg,0.74mmol),乙二醇二甲醚(160mL)和水(40mL),氮气置换。升温至90℃,搅拌3h。反应完毕后,冷却至室温,加水(200mL),用二氯甲烷/甲醇=10/1(200mL×2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(乙酸乙酯含5%二氯甲烷)纯化所得残余物,得到5-氟-4-(2-甲基-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶-6-基)嘧啶-2-胺(2.73g,黄色固体)。LCMS:284.3(M+H)+;1H-NMR(400MHz,CD3OD)δ8.93(s,1H),8.25(d,1H,J=4.0Hz),7.99(d,1H,J=9.6Hz),7.53(d,1H,J=9.6Hz),5.69(s,1H),5.31(s,1H),2.43(s,3H),2.19(s,3H)。
第六步:在干燥的单口瓶里依次加入5-氟-4-(2-甲基-3-(丙-1-烯-2-基)咪唑并[1,2-a]吡啶-6-基)嘧啶-2-胺(2.73g,9.6mmol),甲醇(80mL),乙酸乙酯(40mL),10%Pd/C(500mg),氢气置换,室温搅拌16h。反应完毕后,过滤,滤液减压浓缩,用乙酸乙酯打浆。过滤得固体5-氟-4-(3-异丙基-2-甲基咪唑并[1,2-a]吡啶-6-基)嘧啶-2-胺(2.6g,白色固体)。LCMS:286.3(M+H)+;1H-NMR(400MHz,CDCl3)δ8.83(s,1H),8.24(d,1H,J=4.0Hz),7.85(d,1H,J=9.6Hz),7.56(d,1H,J=9.2Hz),5.03(s,2H),3.40-3.44(m,1H),2.51(s,3H),1.46(d,6H,J=6.8Hz)。
中间体2:5-氟-4-(4-氟-1-异丁基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-胺
在干燥的微波管里下依次加入4-氟-2-甲基-1-异丁基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H苯并[d]咪唑(100mg,0.30mmol),碳酸钠(74mg,0.60mmol),PdCl2(dppf)(22mg,0.03mmol),4-氯-5-氟嘧啶-2-胺(44mg,0.30mmol)和乙二醇二甲醚DME(4mL),水(1mL),氩气置换3次。微波升温至100摄氏度,搅拌1个小时。反应完毕后,减压浓缩。减压浓缩得粗产品,用用硅胶板色谱法以洗脱剂体系(乙酸乙酯:石油醚=1:1)纯化得5-氟-4-(4-氟-1-异丁基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-胺(80mg,白色固体)。LC-MS:318.2(M+H)。
中间体3:6-(6-氯嘧啶-4-基)-4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑
在干燥的10mL微波管中室温下依次加入4-氟-1-异丙基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H苯并[d]咪唑(150mg,0.471mmol),乙二醇二甲醚(2mL)和水(1mL),4,6-二氯嘧啶(80mg,0.519mmol),Pd(PPh3)4(27mg,0.024mmol),碳酸钾(132mg,0.942mmol),氮气置换3次。升温至100摄氏度,微波搅拌反应1个小时。反应完毕后,加入20mL水,用乙酸乙酯萃取(20mL×3),合并有机相。饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩,用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚=1:1)纯化所得残余物,得到产物6-(6-氯嘧啶-4-yl)-4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑(131mg,淡黄色固体)。LCMS:305.1(M+H)。
按照中间体1第四、第五步和中间体2,3的合成方法,采用不同的溴代物或硼酸或硼酸酯与4-氯-5-氟嘧啶-2-胺或6-氯-4-氨基嘧啶或2,4-二氯-5氟嘧啶或4,6-二氯嘧啶反应,制备得到以下中间体。
中间体14:5-氟-4-(3-异丙基-2,7,7-三甲基-2,4,6,7-四氢-5H-吡唑[4,3-c]吡啶-5-基)嘧啶-2-胺
在100mL烧瓶中加入3-异丙基2,7,7三甲基-4,5,6,7-四氢-2H-吡唑并[4,3-c]吡啶(1.5g,7.25mmol)至30mL的四氢呋喃中,然后加入三乙胺(2196mg,21.75mmol)和4-氯-5-氟嘧啶-2-胺(1278mg,8.69mmol)。40℃下搅拌反应过夜,待反应完毕后,加入50mL的水,用二氯甲烷萃取3次(3×50mL)。过滤干燥溶液,滤液旋转蒸干,利用柱层析(石油醚/乙酸乙酯=2/1)纯化,得到产品5-氟-4-(3-异丙基-2,7,7三甲基-6,7-二氢-2H-吡唑并[4,3-c]吡啶-5(4H)-基)嘧啶-2-胺(1600mg,黄色固体)。LCMS:319.4(M+H)+;1H-NMR(400MHz,CDCl3)δ7.73(d,1H,J=7.2Hz),4.70(s,2H),4.59-4.61(m,2H),3.78(s,3H),3.65(s,2H),3.00-3.08(m,1H),1.25-1.34(m,12H)。
中间体13:6-(3-异丙基-2,7,7三甲基-6,7-二氢-2H-吡唑并[4,3-c]吡啶-5(4H)-基)嘧啶-4-胺
在100mL烧瓶中加入3-异丙基-2,7,7三甲基-4,5,6,7-四氢-2H-吡唑并[4,3-c]吡啶(1.5g,7.25mmol)至30mL的DMF中,然后加入三乙胺(2196mg,21.75mmol)和6-氯嘧啶-4-胺(1121mg,8.69mmol)。100℃下搅拌反应2天,待反应完毕后,加入50mL的水,用二氯甲烷萃取3次(3×50mL)。过滤干燥溶液,滤液旋转蒸干,利用柱层析(二氯甲烷/甲醇=30/1)纯化得到产品6-(3-异丙基-2,7,7三甲基-6,7-二氢-2H-吡唑并[4,3-c]吡啶-5(4H)-基)嘧啶-4-胺(400mg,棕色固体)。LCMS:301.3(M+H)+;1H-NMR(400MHz,CDCl3)δ8.20(s,1H),5.64(s,1H),4.54(s,2H),3.78(s,3H),3.58(s,2H),3.02-3.09(m,1H),1.22-1.38(m,12H)。
实施例制备
实施例1:tert-butyl(cis-3-((6-(3-异丙基-2-甲基-2H-吲唑-5-yl)嘧啶-4-yl)carbamoyl)环己基)原甲酸酯
将cis-3-((tert-丁氧羰基)氨基)环己烷-1-carboxylic acid(100mg,0.41mmol),6-(3-异丙基-2-甲基-2H-吲唑-5-yl)嘧啶-4-胺(110mg,0.41mmol)溶于吡啶(20mL),冰浴冷却下滴加三氯氧磷()。完毕,室温反应18小时。EA稀释,Na2CO3水溶液洗2遍,干燥,浓缩,柱层析分离纯化得到目标化合物(白色固体,104mg)。LC-MS(ESI+)493.5;1H-NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.90(d,J=0.8Hz,1H),8.60(d,J=10.0Hz,2H),7.86(dd,J=1.6,9.2Hz,1H),7.64(d,J=8.8Hz,1H),6.83(d,J=8.4Hz,1H),4.14(s,3H),3.59-3.63(m,1H),2.61-2.69(m,2H),1.93-1.99(m,1H),1.77-1.80(m,3H),1.50(d,J=6.8Hz,6H),1.38(s,9H),1.12-1.34(m,4H)。
实施例2:cis-3-氨基-N-(6-(3-异丙基-2-甲基-2H-吲唑-5-yl)嘧啶-4-yl)环己烷-1-甲酰胺
将实施例1化合物(140mg,0.28mmol)溶于二氯甲烷(3mL)中,冰浴冷却下滴加三氟乙酸(1mL),完毕,室温下搅拌2小时。反应结束,减压浓缩得到目标化合物(白色固体,104mg)。LC-MS(ESI+)393.2;1H-NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.92(s,1H),8.61(d,J=16.0Hz,2H),7.84-7.87(m,4H),7.65(d,J=9.2Hz,1H),4.14(s,3H),3.60-3.63(m,1H),3.07-3.16(m,1H),2.67-2.69(m,1H),1.84-2.08(m,4H),1.50(d,J=7.2Hz,6H),1.23-1.37(m,4H)。
实施例3:cis-3-乙酰胺-N-(6-(3-异丙基-2-甲基-2H-吲唑-5-yl)嘧啶-4-yl)环己烷-1-甲酰胺
将实施例2化合物(80mg,0.21mmol)溶于DCM(20mL),加入三乙胺(42.42mg,0.42mmol)和醋酸酐(25.7mg,0.25mmol),室温下搅拌5分钟。倒入碳酸氢钠水溶液中,用二氯甲烷萃取,饱和食盐水洗涤,Na2SO4干燥,过滤,浓缩,柱层析分离得到实施例3化合物(白色固体,72mg)。LC-MS(ESI+)435.3;1H-NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.90(s,1H),8.60(d,J=11.2Hz,2H),7.80-7.86(m,2H),7.64(d,J=9.2Hz,1H),4.14(s,3H),3.58-3.64(m,1H),2.68(br s,2H),1.78-1.96(m,7H),1.50(d,J=6.8Hz,6H),1.09-1.35(m,4H)。
实施例4:tert-butyl(cis-3-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-yl)嘧啶-2-yl)carbamoyl)环己基)原甲酸酯
采用实施例1相同的方法制备得到实施例4化合物(淡黄色固体,120mg)。LC-MS(ESI+)529.4;1H-NMR(400MHz,CD3OD)δ8.59(d,J=9.2Hz,1H),8.34(s,1H),7.83(d,J=12.0Hz,1H),4.89-4.94(m,1H),3.39-3.45(m,1H),2.63(br s,4H),2.08-2.12(m,1H),1.79-1.90(m,3H),1.80(d,J=6.4Hz,6H),1.15-1.44(m,13H)。
实施例5:cis-3-氨基-N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-yl)嘧啶-2-yl)环己烷-1-甲酰胺
采用实施例2相同的方法制备得到实施例5化合物(白色固体,80mg)。LC-MS(ESI+)429.3;1H-NMR(400MHz,CD3OD)δ8.73(br s,1H),8.61(s,1H),8.19(d,J=11.6Hz,1H),5.11-5.16(m,1H),3.23-3.30(m,1H),2.98(s,3H),2.80-2.81(m,1H),2.23-2.26(m,1H),1.99-2.11(m,3H),1.81(d,J=6.8Hz,6H),1.39-1.75(m,4H)
实施例6:cis-3-乙酰胺-N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-yl)嘧啶-2-yl)环己烷-1-甲酰胺
采用实施例3相同的方法制备得到实施例6化合物(白色固体,50mg)。LC-MS(ESI+)471.4;1H-NMR(400MHz,CD3OD)δ8.59(br s,1H),8.33(s,1H),7.83(d,J=11.6Hz,1H),4.86-4.94(m,1H),3.72-3.78(m,1H),2.69(br s,4H),2.08-2.11(m,1H),1.82-2.01(m,6H),1.71(d,J=6.8Hz,6H),1.21-1.52(m,4H)。
实施例7:tert-butyl(trans-4-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-yl)嘧啶-2-yl)氨基)环己基)原甲酸酯
将6-(2-chloro-5-氟嘧啶-4-yl)-4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑e(60mg,0.22mmol)溶于N-甲基吡咯烷酮(20mL),加入tert-butyl(trans-4-氨基环己基)原甲酸酯(57mg,0.27mmol)和NaHCO3(37mg,0.44mmol),氮气保护下,110度反应过夜。旋干,柱层析分离得到实施例7化合物(白色固体,41mg)。LC-MS(ESI+)501.5;1H-NMR(400MHz,DMSO-d6)δ8.41(d,J=4.0Hz,1H),8.17(br s,1H),7.59(d,J=12.0Hz,1H),7.16(d,J=7.6Hz,1H),6.76(br s,1H),4.81-4.84(m,1H),3.59-3.62(m,1H),3.20-3.30(m,1H),2.63(s,3H),1.78-2.02(m,4H),1.59(d,J=6.8Hz,6H),1.23-1.38(m,13H)。
实施例8:trans-N1-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-yl)嘧啶-2-yl)环己烷-1,4-二胺
采用实施例2相同的方法制备得到实施例8(白色固体,25mg)。LC-MS(ESI+)401.3;1H-NMR(400MHz,DMSO-d6)δ8.43(d,J=4.0Hz,1H),8.14(br s,1H),7.61(d,J=12.0Hz,1H),7.25(d,J=7.6Hz,1H),4.80-4.87(m,1H),4.11(br s,1H),3.56-3.67(m,2H),2.98-3.03(m,1H),2.63(s,3H),1.98-2.07(m,4H),1.60(d,J=7.2Hz,6H),1.23-1.48(m,4H)。
实施例9:trans-N1-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-yl)嘧啶-2-yl)-N4-(四氢-2H-吡喃-4-yl)环己烷-1,4-二胺
将实施例8化合物(25mg,0.06mmol)溶于DCM(20mL),加入四氢-4H-吡喃-4-酮(12mg,0.12mmol)和醋酸硼氢化钠(38mg,0.18mmol),室温下搅拌过夜。浓缩,柱层析分离得到实施例9(白色固体,9.5mg)。LC-MS(ESI+)485.3;1H-NMR(400MHz,DMSO-d6)δ8.42(d,J=3.6Hz,1H),8.19(br s,1H),7.61(d,J=11.6Hz,1H),7.24(d,J=7.6Hz,1H),4.81-4.85(m,1H),3.85-3.89(m,2H),3.60-3.64(m,1H),2.75-3.20(m,4H),2.60(s,3H),1.83-2.08(m,6H),1.60(d,J=6.8Hz,6H),1.16-1.43(m,6H)。
实施例10:叔丁基(trans-4-((6-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-4-基)氨基)环己基)原甲酸酯
参照实施例1相同的方法合成得到实施例10(白色固体,78mg)。LC-MS:m/z 465.3[M+H]+。
实施例11:trans-N1-(6-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-4-基)环己烷-1,4-二胺
参照实施例2相同的方法合成得到实施例11(白色固体,80mg)。LC-MS(ESI+)365.4;1H-NMR(400MHz,CD3OD)δ8.48(s,1H),8.45(s,1H),7.75(d,J=8.8Hz,1H),7.59(d,J=9.2Hz,1H),6.86(d,J=0.8Hz,1H),4.15(s,3H),3.88(brs,1H),3.57-3.64(m,1H),2.91(brs,1H),2.02-2.15(m,4H),1.58(d,J=7.2Hz,6H),1.34-1.51(m,4H)。
实施例12:trans-N1-(6-(3-异丙基-2-甲基-2H-吲唑-5-yl)嘧啶-4-yl)-N4-(四氢-2H-吡喃-4-yl)环己烷-1,4-二胺
参照实施例9相同的方法制备得到实施例12(白色固体,11mg)。LC-MS(ESI+)449.5;1H-NMR(400MHz,CD3OD)δ8.48(s,1H),8.44(s,1H),7.74(d,J=8.8Hz,1H),7.59(d,J=9.2Hz,1H),6.85(s,1H),4.15(s,3H),3.87-3.97(m,3H),3.56-3.63(m,1H),3.42(td,J=1.6,12.0Hz,2H),2.90-2.95(m,1H),2.74-2.78(m,1H),2.03-2.15(m,4H),1.83-1.87(m,2H),1.57(d,J=6.8Hz,6H),1.27-1.46(m,6H)。
参照实施例1,2和实施例7,8相同的方法制备得到以下实施例化合物:
生物活性测定:检测实施例化合物在CDK7/CycH/MAT1(Carna)和CDK9/CycT1(Carna)激酶上的抑制率,以PHA-793887和Dinaciclib作为阳性对照化合物。利用Mobilityshift assay的方法,在2种激酶上进行实施例化合物的活性测试。
具体操作流程如下:(1)配制1×Kinase buffer;(2)化合物浓度梯度的配制:受试化合物测试浓度为10000nM起始,在384source板中稀释成100倍终浓度的100%DMSO溶液,3倍稀释化合物,10个浓度。使用分液器Echo 550向目的板384-well-plate转移250nL 100倍终浓度的化合物。用1×Kinase buffer配制2.5倍终浓度的激酶溶液。(3)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μL的1×Kinasebuffer。(4)1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟。(5)用1×Kinasebuffer配制5/3倍终浓度的ATP和Kinase substrate的混合溶液。(6)加入15μl的5/3倍终浓度的ATP和底物的混合溶液,起始反应。(7)将384孔板1000rpm离心30秒,振荡混匀后室温孵育相应的时间。(8)加入30μl终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀。(9)用Caliper EZ Reader读取转化率。(10)计算公式%Inhibition=Conversion%_max-Conversion%_sampleConversion%_max-Conversion%_min×100,其中:Conversion%_sample是样品的转化率读数;Conversion%_min:阴性对照孔均值,代表没有酶活孔的转化率读数;Conversion%_max:阳性对照孔均值,代表没有化合物抑制孔的转化率读数。拟合量效曲线以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response–Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。计算公式是Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))。
结果表明:本发明的大部分实施例化合物在1uM/0.1uM浓度下具有良好的CDK7和/或9抑制活性,IC50小于100nM;部分实施例化合物具有良好的CDK9抑制活性,与CDK7激酶体现了较高的选择性,如实施例4,5,6,7,10,11等。具体抑制活性数据如下表所示。
其中抑制率表示++++≥80%;80%<+++≤60%;60%<++≤30%;+<30%;IC50表示A≤20nM;20nM<B≤100nM;100nM<C≤1000nM;D>1000nM。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (17)
1.一种如通式I所示的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,
其中:
M1选自:CR1或N;M2选自:CR2或N;
R1选自:H、氘、卤素、氰基、C1-6烷基或卤代烷基、C3-C8环烷基或杂环烷基;
R2选自:H、氘、卤素、氰基、C1-6的烷基或卤代烷基、C3-C8环烷基或杂环烷基;
Cy选自:取代或未取代的3-12元饱和碳环,所述取代的3-12元饱和碳环指具有一个或多个相同或不同R3取代基的3-12元饱和碳环;其中,R3独立地选自:氢、氘、卤素、羟基、氰基、氨基、C1-6的烷基或卤代烷基、C1-C6烷氧基、C3-C8环烷基或杂环烷基;
L选自无或者-CO-;
R4为氢或卤素;
R5为H或C1-C6烷基;
R6选自:氢、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、和取代或未取代的C3-C8环烷基;
R7和R8各自独立地选自:氢、卤素、取代或未取代的C1-C6烷基;或者R7和R8与所连接的碳一起形成3-7元碳环;
其中X1,X3各自独立地选自C或N;
X2为C(R9)nR10或NR10,n为0或1,且R9、R10各自独立地选自:氢、取代或未取代的C1-C6烷基和取代或未取代的C3-C8环烷基;或者,当X2为C(R9)nR10且n为1时,R9和R10与所连接的C一起形成取代或未取代4-7元碳环;或者,R10、R5和所连接的C和/或N一起形成取代或未取代4-7元碳环或杂环,且X1、X2和X3至多两个为N;
R独立地选自氢、氘、卤素、羟基、C1-10烷氧基、C1-10烷基、氨基、C1-10单烷基取代氨基、C1-10双烷基取代氨基、3-12元环烷基或杂环烷基、C1-10烷基酰基、C1-10烷基磺酰基、3-12元环烷基或杂环烷基酰基、3-12元环烷基或杂环烷基磺酰基、C1-10烷基OCONH-、C1-10烷基NHCONH-。
3.一种如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,
各R7和R8各自独立地选自氢或C1-C6烷基;
各R9独立地选自:氢、C1-C4烷基;
p为Re取代基的个数,且为0、1、2、3或4;
各Re独立地选自:H、卤素、-OH、CN、NR11R12、未取代或取代的C1-C6烷基、未取代或取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基;
所述取代指被选自下组的一个或多个取代基取代:卤素、OH、C1-C4烷基、-NR11R12;R11和R12各自独立的为H、C1-C4烷基和C1-C4卤代烷基;
r为C原子的个数,且为1、2或3;优选r为1。
5.一种如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,Cy选自:环己烷环;L选自-CO-。
6.一种如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R选自:-NH2、-NHR13、-NHCOR14、-NHCOOR14,其中R13选自3-8元的环烷基或杂环烷基,R14选自C1-10的直链或支链的烷基或卤代烷基。
7.一种如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R1选自:H、卤素、C1-C6烷基;优选的,R1为H、F、Cl。
8.一种如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R2选自:H、卤素、C1-C6烷基;优选的,R2为H。
9.一种如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R和L处于环Cy的1-3位或者1-4位。
10.一种如权利要求1所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,R7和R8各自独立的选自:取代或未取代的C1-C6烷基;优选的,R7和R8各自独立地为C1-C4烷基。
11.一种如权利要求1-10中任意一项所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为N,M2为CH。
12.一种如权利要求1-10中任意一项所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为C-H、C-F,M2为N。
13.一种如权利要求1-10中任意一项所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为CH-C-F,,M2为CH。
14.一种如权利要求1-10中任意一项所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其特征在于,M1为N,M2为N。
16.一种药物组合物,其特征在于,包括治疗有效量的如权利要求1-15任意一项所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,以及药学上可接受的赋形剂。
17.一类如权利要求1-15任意一项所述的化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、溶剂化物或前药或如权利要求16所述的药物组合物在制备用于预防、治疗、或减轻患者由异常细胞增殖,自身免疫,炎症或感染引起的障碍或疾病的药物中的应用,所述异常细胞增殖,自身免疫,炎症或感染是由细胞周期蛋白依赖性激酶改变引起的。
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