CN112424174A - 可用于治疗疾病的杂环化合物 - Google Patents
可用于治疗疾病的杂环化合物 Download PDFInfo
- Publication number
- CN112424174A CN112424174A CN201980047732.7A CN201980047732A CN112424174A CN 112424174 A CN112424174 A CN 112424174A CN 201980047732 A CN201980047732 A CN 201980047732A CN 112424174 A CN112424174 A CN 112424174A
- Authority
- CN
- China
- Prior art keywords
- pyrazol
- biphenyl
- fluoro
- chloro
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 64
- 201000010099 disease Diseases 0.000 title claims description 48
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 5
- 230000001419 dependent effect Effects 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 250
- -1 Phenyl moiety Chemical group 0.000 claims description 247
- 239000000203 mixture Substances 0.000 claims description 204
- 238000000034 method Methods 0.000 claims description 123
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 229910052799 carbon Inorganic materials 0.000 claims description 68
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 54
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 claims description 53
- 125000004432 carbon atom Chemical group C* 0.000 claims description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000004122 cyclic group Chemical group 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 16
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 12
- NLVIETRETNMBPT-GOSISDBHSA-N 1-[4-[4-[4-chloro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound ClC=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=CC=C(C=C1)C1(CC1)C(=O)O NLVIETRETNMBPT-GOSISDBHSA-N 0.000 claims description 10
- JXKNHWYELIAHTI-LJQANCHMSA-N 1-[4-[4-[4-cyano-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound C(#N)C=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=CC=C(C=C1)C1(CC1)C(=O)O JXKNHWYELIAHTI-LJQANCHMSA-N 0.000 claims description 9
- XDMDPYZKKFPYAC-MRXNPFEDSA-N 1-[4-[5-[4-chloro-5-[[(1R)-1-(2-chlorophenyl)ethoxy]carbonylamino]pyrazol-1-yl]pyridin-2-yl]phenyl]cyclopropane-1-carboxylic acid Chemical compound ClC=1C=NN(C=1NC(=O)O[C@H](C)C1=C(C=CC=C1)Cl)C=1C=CC(=NC=1)C1=CC=C(C=C1)C1(CC1)C(=O)O XDMDPYZKKFPYAC-MRXNPFEDSA-N 0.000 claims description 9
- ZDIJGIHMESWCFF-MRXNPFEDSA-N 1-[4-[5-[5-[[(1R)-1-(2-chlorophenyl)ethoxy]carbonylamino]-4-fluoropyrazol-1-yl]pyridin-2-yl]phenyl]cyclopropane-1-carboxylic acid Chemical compound ClC1=C(C=CC=C1)[C@@H](C)OC(=O)NC1=C(C=NN1C=1C=CC(=NC=1)C1=CC=C(C=C1)C1(CC1)C(=O)O)F ZDIJGIHMESWCFF-MRXNPFEDSA-N 0.000 claims description 9
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical class CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 9
- GQABVSVOJJRXED-QGZVFWFLSA-N 1-[3-chloro-4-[4-[4-chloro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound ClC1=C(C=CC(=C1)C1(CC1)C(=O)O)C1=CC=C(C=C1)N1N=CC(=C1NC(=O)O[C@H](C)C1=CC=CC=C1)Cl GQABVSVOJJRXED-QGZVFWFLSA-N 0.000 claims description 8
- DLIQMGMHZXADTM-QGZVFWFLSA-N 1-[3-chloro-4-[4-[4-fluoro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound ClC1=C(C=CC(=C1)C1(CC1)C(=O)O)C1=CC=C(C=C1)N1N=CC(=C1NC(=O)O[C@H](C)C1=CC=CC=C1)F DLIQMGMHZXADTM-QGZVFWFLSA-N 0.000 claims description 8
- BYBREJDTMCSPBO-QGZVFWFLSA-N 1-[4-[4-[4-chloro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]-2-fluorophenyl]cyclopropane-1-carboxylic acid Chemical compound ClC=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=CC(=C(C=C1)C1(CC1)C(=O)O)F BYBREJDTMCSPBO-QGZVFWFLSA-N 0.000 claims description 8
- PSRAUDUUUYAQQW-QGZVFWFLSA-N 1-[4-[4-[4-chloro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]-3-fluorophenyl]cyclopropane-1-carboxylic acid Chemical compound ClC=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=C(C=C(C=C1)C1(CC1)C(=O)O)F PSRAUDUUUYAQQW-QGZVFWFLSA-N 0.000 claims description 8
- MFFBTZGSWIPPND-LJQANCHMSA-N 1-[4-[4-[4-fluoro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]-3-methylphenyl]cyclopropane-1-carboxylic acid Chemical compound FC=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=C(C=C(C=C1)C1(CC1)C(=O)O)C MFFBTZGSWIPPND-LJQANCHMSA-N 0.000 claims description 8
- FRRRMPQEWNBTPL-GOSISDBHSA-N 1-[4-[4-[4-fluoro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound FC=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=CC=C(C=C1)C1(CC1)C(=O)O FRRRMPQEWNBTPL-GOSISDBHSA-N 0.000 claims description 8
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 8
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 8
- 239000000651 prodrug Substances 0.000 claims description 8
- BZMSFKQBZWTPIF-QGZVFWFLSA-N 1-[2-fluoro-4-[4-[4-fluoro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound FC=1C=C(C=CC=1C1(CC1)C(=O)O)C1=CC=C(C=C1)N1N=CC(=C1NC(=O)O[C@H](C)C1=CC=CC=C1)F BZMSFKQBZWTPIF-QGZVFWFLSA-N 0.000 claims description 7
- KGMFHQGWBBOGMX-LJQANCHMSA-N 1-[4-[4-[4-chloro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]-3-methylphenyl]cyclopropane-1-carboxylic acid Chemical compound ClC=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=C(C=C(C=C1)C1(CC1)C(=O)O)C KGMFHQGWBBOGMX-LJQANCHMSA-N 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- FIEYNBQUIDBZII-QGZVFWFLSA-N 1-[3-fluoro-4-[4-[4-fluoro-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound FC1=C(C=CC(=C1)C1(CC1)C(=O)O)C1=CC=C(C=C1)N1N=CC(=C1NC(=O)O[C@H](C)C1=CC=CC=C1)F FIEYNBQUIDBZII-QGZVFWFLSA-N 0.000 claims description 6
- ZKHHWRLUSUNAFZ-LJQANCHMSA-N 2-[4-[4-[4-cyano-5-[[(1R)-1-phenylethoxy]carbonylamino]pyrazol-1-yl]phenyl]phenyl]-2-methylpropanoic acid Chemical compound C(#N)C=1C=NN(C=1NC(=O)O[C@H](C)C1=CC=CC=C1)C1=CC=C(C=C1)C1=CC=C(C=C1)C(C(=O)O)(C)C ZKHHWRLUSUNAFZ-LJQANCHMSA-N 0.000 claims description 6
- PAGVJHPXUMIFBP-GOSISDBHSA-N 2-[4-[4-[5-[[(1R)-1-(2-chlorophenyl)ethoxy]carbonylamino]-4-cyanopyrazol-1-yl]phenyl]phenyl]-2-methylpropanoic acid Chemical compound ClC1=C(C=CC=C1)[C@@H](C)OC(=O)NC1=C(C=NN1C1=CC=C(C=C1)C1=CC=C(C=C1)C(C(=O)O)(C)C)C#N PAGVJHPXUMIFBP-GOSISDBHSA-N 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910006069 SO3H Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- IQFLCIZRMFKVMW-UHFFFAOYSA-N NC(OC(N(C(C=C1)=CC=C1C1=CC=C(C2(CC2)C2=NN=NN2)C=C1)N=C1)=C1F)=O Chemical compound NC(OC(N(C(C=C1)=CC=C1C1=CC=C(C2(CC2)C2=NN=NN2)C=C1)N=C1)=C1F)=O IQFLCIZRMFKVMW-UHFFFAOYSA-N 0.000 claims description 2
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims 2
- IPCCFHHXDRGUOQ-QGZVFWFLSA-N (3R)-4-[2-[4-[1-(3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]-1,3-dimethylpiperazin-2-one Chemical compound ClC1=NN=C2N1N=C(C=C2)N1CCC(CC1)C1=CC=C(OCCN2[C@@H](C(N(CC2)C)=O)C)C=C1 IPCCFHHXDRGUOQ-QGZVFWFLSA-N 0.000 claims 1
- ZTGGMXOPIQGSBX-UHFFFAOYSA-N 1,1'-biphenyl;carbamic acid Chemical compound NC(O)=O.C1=CC=CC=C1C1=CC=CC=C1 ZTGGMXOPIQGSBX-UHFFFAOYSA-N 0.000 claims 1
- BCPFQYINSNBREZ-MRXNPFEDSA-N 1-[3-chloro-4-[4-[5-[[(1r)-1-(2-chlorophenyl)ethoxy]carbonylamino]-4-fluoropyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound O([C@H](C)C=1C(=CC=CC=1)Cl)C(=O)NC1=C(F)C=NN1C(C=C1)=CC=C1C(C(=C1)Cl)=CC=C1C1(C(O)=O)CC1 BCPFQYINSNBREZ-MRXNPFEDSA-N 0.000 claims 1
- KGBNHXHOPVUASI-QGZVFWFLSA-N 1-[4-[4-[5-[[(1r)-1-(2-chlorophenyl)ethoxy]carbonylamino]-4-fluoropyrazol-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound O([C@H](C)C=1C(=CC=CC=1)Cl)C(=O)NC1=C(F)C=NN1C(C=C1)=CC=C1C(C=C1)=CC=C1C1(C(O)=O)CC1 KGBNHXHOPVUASI-QGZVFWFLSA-N 0.000 claims 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
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Classifications
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Abstract
描述了为溶血磷脂酸受体配体的杂环化合物,这些杂环化合物可用于治疗溶血磷脂酸受体依赖型疾病和病症。
Description
相关申请的交叉引用
本申请要求2018年6月18日提交的美国专利申请号16/010,755的权益,将其全部内容通过引用而特此结合。
政府利益的声明
本发明是根据由美国国立卫生研究院(National Institutes of Health)授予的批准号DK092005在政府支持下进行。美国政府在本发明中具有一定权利。
技术领域
本发明涉及具有药理活性的化合物,涉及用于制备此类化合物的方法,涉及包括它们的药用组合物,以及涉及它们在有需要的受试者中治疗和预防疾病的用途,具体地而言用于人类和动物医生治疗疼痛、皮肤瘙痒、癌症、炎症和纤维化疾病。
背景技术
溶血磷脂影响基本的细胞功能,该基本的细胞功能包括增殖、分化、存活、迁移、粘附、侵染、和形态发生。功能异常影响许多导致疾病的生物过程,这些疾病包括但不限于纤维化疾病、炎症、癌症和外周神经损伤。溶血磷脂酸(LPA)是一种溶血磷脂,该溶血磷脂已经显示了以自分泌和旁分泌的方式通过特异的G蛋白偶联受体(GPCR)发挥作用。LPA受体拮抗剂可用于治疗其中LPA起到一定作用的疾病、障碍或病症。
与溶血磷脂酸受体[LPAR]相互作用通过那些受体以降低信号转导(即,通过竞争抑制或非竞争抑制,或作为反相激动剂)的药剂减少在此所述疾病的表现。疾病和病症的病因、进展或持久性完全受或部分受通过溶血磷脂酸受体亚型1(LPA1R)的信号传导的影响,这种疾病和病症被认为是LPA依赖型的。针对于治疗在此所述的LPA依赖型的那些以及其他病症和疾病,需要具有疗效的新型药剂。
发明内容
在此披露了抑制溶血磷脂酸(LPA)的生理学活性的化合物,并且因此其被用做药剂用于治疗或预防疾病,在这些疾病中LPA的生理学活性的抑制是有用的。
在一方面,这些化合物用于治疗器官纤维化(例如,肝脏、肾脏、肺、心脏等)、肝脏疾病(例如,急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生失败、非酒精性脂肪性肝炎(NASH)、肝机能减退、肝血流紊乱等)、细胞增殖疾病例如癌症(包括但不限于实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波氏肉瘤、白血病、慢性淋巴细胞白血病(CLL)、癌细胞的侵入性转移等)、炎症性疾病(包括但不限于银屑病、肾病、肺炎等)、胃肠道疾病(包括但不限于肠道易激综合症(IBS)、炎症性肠病(IBD)、胰腺分泌异常等)、肾脏疾病、尿路相关疾病(包括但不限于良性前列腺增生或与神经性膀胱疾病相关的症状、脊髓瘤、椎间盘疝气、椎管狭窄、糖尿病衍生的症状、下尿路疾病(包括但不限于下尿路梗阻等)、下尿路炎症性疾病(包括但不限于排尿困难、尿频等)、胰腺疾病、血管生成异常的相关疾病(包括但不限于动脉栓塞等)、硬皮病、大脑相关疾病(包括但不限于脑梗死、脑出血等)、神经系统疾病(包括但不限于神经痛、外周神经病变、皮肤瘙痒等)、眼病(包括但不限于年龄相关性黄斑病变(AMD)、糖尿病性视网膜病变、增生性玻璃体视网膜病变(PVR)、瘢痕性类天疱疮、青光眼滤过手术瘢痕等)。
本发明的化合物包括具有化学式I的化合物,该化学式I具有如下结构:
或其药学上可接受的盐或前药,
其中RA是-CO2H、-CO2RB、-CN、四唑基、-C(=O)NH2、-C(=O)NHRB、-C(=O)NHSO2RB或-C(=O)NHCH2CH2SO3H,或者具有如下结构;
L1是经取代的或未经取代的C1-C6亚烷基、经取代的或未经取代的C1-C6氟代亚烷基、经取代的或未经取代的C3-C8环亚烷基、经取代的或未经取代的C1-C6杂亚烷基;
其中A1是-N=或-CH;
其中环A具有以下之一的结构:
其中RC是-CN、-F、-Cl、-Br、-I、-OC1-C4烷基、C3-C6环烷基、或C1-C4氟代烷基;
以及RD是-N(RF)-C(=O)XCH(RG)-CY,其中X是O且CY是被一个RH所取代的苯基:
RE、RF和RG独立地是-H或C1-C4烷基或C3-C6环烷基,或者RE和RF独立地是-H或C1-C4烷基或C1-C6环烷基,并且一个RG是-C1-C4烷基并且和环A RD取代基的RH苯基部分以及RG与所述苯基部分所附接的碳原子一起定义一种经取代的或未经取代的碳环或经取代的或未经取代的杂环;
RH独立地是-H、卤素、-CN、-NO2、-OH、C1-C4烷基、C1-C4氟代烷基、C1-C4氟代烷氧基、或C1-C4烷氧基,
本发明的其他化合物具有由在此所编号的实施例和权利要求所表明的结构。
具体实施方式
定义
如在此使用的并且除非另行说明的或通过上下文所暗示的,在此使用的术语具有以下所定义的含义。除非另有禁忌或暗示,例如,通过包括互斥的元素或选项,在这些定义中并且贯穿本说明书,在上下文允许的情况下术语“一个/种(a/an)”意指一个或多个(一种或多种)并且术语“或”意指和/或。因此,除非上下文另外清楚地规定,否则如本说明书和所附权利要求中所使用的,单数形式“一个/种(a/an)”和“该(the)”包括复数个指示物。
在本披露中的不同位置处,例如,在任何披露的实施例中或在权利要求中,提到了化合物、组合物、或方法,它们“包含”一种或多种限定的组分、元素或步骤。发明实施例还具体包括那些化合物、组合物、组合或方法,它们是或它们由以下各项组成或它们基本上是由以下各项组成:那些指定的组分、元素或步骤。除非另外确切地说明,在美国专利法下,术语“包含”、“由……组成”和“基本上是由……组成”具有其正常可接受的含义。术语“包含(comprised of)”是与术语“包含(comprising)”可互换地使用并且是以等价术语进行阐述。例如,所披露的“包含”组分或步骤的组合物、装置、制品或方法是开放式的,并且它们包括或读为那些附加一种或多种另外组分或步骤的组合物或方法。类似地,所披露的由组分或步骤“组成”的组合物、装置、制品或方法是封闭式的,并且它们不包括或读为那些具有可观数量的一种或多种另外成分或一种或多种另外步骤的组合物或方法。此外,术语“包括(including)”、以及其他形式如“包括(include)”、“包括(includes)”和“包括(included)”的使用不是限制性的。本文使用的章节标题皆仅出于组织目的,而不应解释为限制所描述的主题内容。除非另外指明,使用质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学的常规方法。
如在此使用的“键”或“单键”意指两个原子之间、或两个部分(当通过键相连的原子被视为较大亚结构的部分时)之间的化学键。如通过上下文明确表示或暗示的,当在此所描述的基团是一种键时,被引用的基团是不存在的从而允许在剩余确定的基团的之间形成一种键。
如在此使用的“元环”意指任何环结构。术语“元”意在表示构成环的骨架原子的数量。因此,通过举例而不是限制,那些元环包括6元环的环己基、吡啶基、吡喃基和噻喃基,和5元环的环戊基、吡咯基、呋喃基、和噻吩基。
如在此使用的“部分”意指分子或化合物的一个具体的区段、片段或官能团。有时化学部分表示为嵌入或附加(即,取代基或可变的基团)至分子或化合物的化学实体。
如在此使用的“烷基”是一批共价连接在一起的碳原子,其以正常、二级、三级或环的安排,即,以直链的、支链的、环的安排或其一些组合。结构的烷基取代基是碳原子的链,该链通过取代基的sp3碳共价附接至该结构。如在此使用的烷基取代基包含一种或多种饱和部分或基团,并且可以另外地包含不饱和烷基部分或基团,即,如果这种不饱和烷基部分或基团存在,该取代基可以包括其组合的一个、两个、三个、或更多个独立选择的双键或三键,那典型的是一个双键或一个三键。
不饱和烷基部分或基团包括如以下针对烯基、炔基、环烷基、和芳基部分的所述的部分或基团。饱和烷基部分包含饱和碳原子(sp3)和非芳香烃的、sp2或sp碳原子。烷基部分或基团中的碳原子数可以改变并且典型的是1至约50个,例如,约1-30个或约1-20个,除非另外说明,例如,C1-8烷基或C1-C8烷基意指包含1个、2个、3个、4个、5个、6个、7个或8个碳原子的烷基部分并且C1-6烷基或C1-C6意指包含1个、2个、3个、4个、5个或6个碳原子的烷基部分。
当一种烷基取代基、部分或基团是指定的时,种类可以包括甲基、乙基、1-丙基(正丙基)、2-丙基(异丙基、-CH(CH3)2)、1-丁基(正丁基)、2-甲基-1-丙基(异丁基、-CH2CH(CH3)2)、2-丁基(仲丁基、-CH(CH3)CH2CH3)、2-甲基-2-丙基(叔丁基、-C(CH3)3)、戊基、异戊基、仲戊基和其他线性、环的和支链的烷基部分。除非另外说明,烷基基团可以包含针对以下所描述的种类和基团:环烷基、烯基、炔基基团、芳基基团、芳烷基基团、烷芳基基团以及类似物。
如在此使用的环烷基是一种仅由碳原子构成的单环的、二环的或三环的环系统。术语“环烷基”包括单环的或多环的脂肪族的、非芳香族基团,其中形成环(即骨架原子)的每个原子都是碳原子。环烷基取代基、部分或基团中的碳原子数可以改变并且典型的是3至约50,例如约1-30或约1-20,除非另外说明,例如,C3-8烷基或C3-C8烷基意指包含3个、4个、5个、6个、7个或8个碳原子的环烷基取代基、部分或基团,并且C3-6烷基或C3-C6意指包含3个、4个、5个或6个碳原子的环烷基取代基、部分或基团。环烷基取代基、部分或基团典型地将具有3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个或20个碳原子并且可以包含外环或内环双键或内环三键或两者的组合,其中内环双键或三键、或两者的组合不形成4n+2电子的环共轭系统;其中双环系统可以共享一个(即,螺环系统)或两个碳原子并且三环系统可以共享总共2个、3个或4个碳原子,典型的是2个或3个。
除非另外说明,环烷基取代基、部分或基团可以包含针对以下所描述的部分和基团:烯基、炔基、芳烷基、烷芳基以及类似物,并且可以包含一个或多个其他环烷基部分。因此,环烷基可以是饱和的、或部分不饱和的。环烷基可以与芳香族环相融合,并且该芳香族环的附着点处于环烷基取代基、部分或基团的一个或多个碳原子处,所述碳原子不是芳香族环碳原子。环烷基基团包括具有3至10环原子的基团。环烷基取代基、部分或基团包括环丙基、环戊基、环己基、金刚烷基或包含部分的其他环状的全碳。环烷基进一步包括环丁基、环戊烯基、环己烯基、环庚基和环辛基。环烷基基团可以是经取代的或未经取代的。取决于取代基结构,环烷基取代基可以是单价基团或二价基团(即环亚烷基,例如但不限于,环丙烷-1,1-二基、环丁烷-1,1-二基、环戊烷-1,1-二基、环己烷-1,1-二基、环己烷-1,4-二基、环庚烷-1,1-二基以及类似物)。当环烷基被用作马库什基团(即,一种取代基)时,将环烷基附接至马库什化学式,该环烷基通过碳与马库什化学式相关联,该碳是环烷基基团的环状的碳环系统碳中涉及的,该碳是非芳香族的碳。
如在此使用的“烷基胺”意指-N(烷基)xHy基团、部分或取代基,其中x和y独立地选自下组:x=1、y=1并且x=2、y=O。烷基胺包括那些-N(烷基)xHy基团,其中x=2并且y=0和烷基基团与它们所附接的氮原子一起形成了一种环状环系统。
如在此使用的“杂亚烷基”意指一种亚烷基(即,烷二基)基团、部分或取代基,其中烷基的一个或多个骨架原子选自非碳的原子,例如氧、氮、硫、磷或其组合。杂亚烷基包括C1-C6杂亚烷基和/或C1-C4杂亚烷基。示例性杂亚烷基包括但不限于,-OCH2-、-OCH(CH3)-、-OC(CH3)2-、-OCH2CH2-、-CH2O-、-CH(CH3)O-、C(CH3)2O-、-CH2CH2O-、-CH2OCH2-、-CH2OCH2CH2-、-CH2CH2OCH2-、-SCH2-、-SCH(CH3)-、-SC(CH3)2-、-SCH2CH2-、-CH2S-、-CH(CH3)S-、-C(CH3)2S-、-CH2CH2S-、-CH2SCH2-、-CH2SCH2CH2-、-CH2CH2SCH2-、-S(=O)2CH2-、-S(=O)2CH(CH3)-、-S(=O)2C(CH3)2-、-S(=O)2CH2CH2-、-CH2S(=O)2-、-CH(CH3)S(=O)2-、-C(CH3)2S(=O)2-、-CH2CH2S(=O)2-、-CH2S(=O)2CH2-、-CH2S(=O)2CH2CH2-、CH2CH2S(=O)2CH2-、-NHCH2-、-NHCH(CH3)-、-NHC(CH3)2-、-NHCH2CH2-、-CH2NH-、-CH(CH3)NH-、-C(CH3)2NH-、-CH2CH2NH-、-CH2NHCH2-、-CH2NHCH2CH2-、-CH2CH2NHCH2-、以及类似物。
如在此使用的“羧酸生物电子等排体”意指一种官能团、部分或取代基,其展现出了与羧酸部分相似的物理、生物和/或化学性质。通过举例而不是限制,羧酸生物电子等排体包括,
如在此使用的“烯基”意指一种取代基、部分或基团,除非烯基部分是乙烯基部分(例如,-CH=CH2),该取代基、部分或基团包括一个或多个双键部分(例如,-CH=CH-)或1个、2个、3个、4个、5个或6个或更典型地1个、2个或3个此类部分并且可以包括芳基部分或基团例如苯,并且还包括所连接的正常、二级、三级或环的碳原子,即,线性的,支链的、环状的或其任何组合。具有多个双键的烯基部分、基团或取代基可以具有连续(即,1,3-丁二烯基部分)或非连续安排的具有一个或多个插入的饱和碳原子或其组合的双键,其条件是环状的、连续的安排的双键不形成4n+2电子的环状的共轭系统(即,芳香族的)。烯基基团或部分中的碳原子数可以改变并且典型的是2至约50,例如约2-30或约2-20,除非另外说明,例如,C2-8烯基或C2-8烯基意指包含2个、3个、4个、5个、6个、7个或8个碳原子的烯基部分,并且C2-6烯基或C2-6烯基意指包含2个、3个、4个、5个或6个碳原子的烯基部分。烯基部分或基团将典型地具有2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个或20个碳原子。
当烯基部分、基团或取代基是指定的时候,种类包括在此所描述的具有一个或多个双键的任何烷基或环烷基、基团部分或取代基,通过举例并非限制,亚甲基(=CH2)、甲基亚甲基(=CH-CH3)、乙基亚甲基(=CH-CH2-CH3)、=CH-CH2-CH2-CH3、乙烯基(-CH=CH2)、芳基、1-甲基乙烯基、丁烯基、异丁烯基、3-甲基-2-丁烯基、1-戊烯基、环戊烯基、1-甲基-环戊烯基、1-己烯基、3-己烯基、环己烯基以及其他线性的、环状的和支链的全碳,其包含含有至少一个双键的部分。当烯基被用作马库什基团(即,一种取代基)时,将该烯基附接至马库什化学式,该烯基通过不饱和碳与马库什化学式相关联,除非另外说明,该不饱和碳是烯基部分或基团的双键的碳。
如在此使用的“炔基”意指取代基、部分或基团,除非该炔基部分是乙炔,该取代基、部分或基团包括一个或多个三键部分(即,-C≡C-),例如,1个、2个、3个、4个、5个、6个或更多个,典型的是1个或2个三键,可任选地包括1个、2个、3个、4个、5个、6个或更多个双键,剩余的键(如果存在)是单键并且包括所连接的正常、二级、三级或环的碳原子,即,线性的,支链的、环状的或其任何组合。炔基部分或基团中的碳原子数可以改变并且典型的是2至约50,例如约2-30或约2-20,除非另外说明,例如,C2-8炔基或C2-8炔基意指包含2个、3个、4个、5个、6个、7个或8个碳原子的炔基部分。炔基基团将典型地具有2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个或20个碳原子。
当炔基部分或基团是指定的时候,种类包括在此所描述的具有一个或多个三键的任何烷基部分、基团或取代基,通过举例并非限制,乙炔基、丙炔基、丁炔基、异丁炔基、3-甲基-2-丁炔基、1-戊炔基、环戊炔基、1-甲基-环戊炔基、1-己炔基、3-己炔基、环己炔基以及其他线性的、环状的和支链的全碳,其包含含有至少一个三键的部分。当炔基被用作马库什基团(即,一种取代基)时,将该炔基附接至马库什化学式,该炔基通过炔基官能团的不饱和碳原子之一与该马库什化学式相关联。
如在此使用的“芳香族的”是指具有离域π电子系统的平面环,该系统包含4n+2π电子,其中n是正整数。芳香族环可以由五个、六个、七个、八个、九个、十个、或多于十个原子形成。芳香族化合物是任选取代的。术语“芳香族的”包括羧基芳基(“芳基”,例如,苯基)和杂环芳基(或“杂芳基”或“杂芳香族的”)基团(例如吡啶)。该术语包括单环的或稠环多环的(即,共享相邻对碳原子的环)基团。
如在此使用的“芳基”意指不具有环杂原子的芳香族环系统或稠合环系统,该芳香族环系统或稠合环系统包括1个、2个、3个或4个至6个环,典型的是1个至3个环,其中这些环仅由碳原子构成;并且是指4n+2电子(休克尔规则)的环状共轭系统,典型的是6、10或14电子,这些电子中的一些可以另外参与外环共轭(交叉共轭,例如,醌)。芳基取代基、部分或基团典型地由五个、六个、七个、八个、九个、或多于九个碳原子形成。芳基取代基,部分或基团是任选取代的。示例性芳基包括C6-C10芳基,例如苯基和萘基和菲基。取决于结构,芳基基团可以是单价基团或二价基团(即,亚芳基基团)。示例性亚芳基包括但不限于苯基-1,2-烯、苯基-1,3-烯、和苯基-1,4-烯。当芳基被用作马库什基团(即,一种取代基)时,将该芳基附接至马库什化学式,该芳基通过芳基的芳香族的碳原子与该马库什化学式相关联。
在此使用的如“芳烷基”意指取代基、部分或基团,其中芳基部分结合至烷基部分,即,-烷基-芳基,其中烷基和芳基基团如以上所述,例如-CH2-C6H5或-CH2CH(CH3)-C6H5。当芳烷基被用作马库什基团(即,一种取代基)时,将该芳烷基的烷基部分附接至马库什化学式,该芳烷基通过烷基部分的sp3碳与该马库什化学式相关联。
在此使用的如“烷芳基”意指取代基、部分或基团,其中烷基部分结合至芳基部分,即,-芳基-烷基,其中芳基和烷基基团如以上所述,例如-C6H4-CH3或-C6H4-CH2CH(CH3)。当烷芳基被用作马库什基团(即,一种取代基)时,将该烷芳基的芳基部分附接至马库什化学式,该烷芳基通过芳基部分的sp2碳与该马库什化学式相关联。
如在此使用的“经取代的烷基”、“经取代的环烷基”、“经取代的烯基”、“经取代的炔基”、“经取代的烷芳基”、“经取代的芳烷基”、“经取代的杂环”、“经取代的芳基”以及类似物意指如在此所定义的或所披露的烷基、烯基、炔基、烷芳基、芳烷基、杂环、芳基或其他基团或部分,它们具有替代一个或多个氢原子的一个或多个取代基或中断碳原子链的一个或多个取代基。包括取代基的烯基和炔基基团在碳处是任选取代的,其为一个或多个从双键去除的亚甲基部分。
如在此使用的“任选取代的烷基”、“任选取代的烯基”、“任选取代的炔基”、“任选取代的烷芳基”“任选取代的芳烷基”、“任选取代的杂环”、“任选取代的芳基”、“任选取代的杂芳基”、“任选取代的烷基杂芳基”、“任选取代的杂芳烷基”以及类似物意指如在此所定义的或披露的烷基、烯基、炔基、烷芳基、芳烷基、杂环、芳基、杂芳基、烷基杂芳基、杂芳烷基、或其他取代基、部分或基团,它们具有可任选替代一个或多个氢原子的一个或多个取代基,或中断碳原子链的一个或多个取代基。此类取代基如在此描述的。针对于苯基部分,存在于芳香族环上的任何两个取代基的安排可以是邻(o)、间(m)、对(p)位的。任选取代的氟代烷基是烷基或环烷基部分,典型的是线性烷基,其中一个或多个氢原子被氟以及至少一个不是碳和氟的其他原子替代。
任选取代的或经取代的取代基、部分或基团包括具有一个或多个另外基团的那些,它们个别地替代其一个或多个氢原子并且独立地选自烷基、环烷基、芳基、杂芳基、杂脂环族的、羟基、烷氧基、芳氧基、烷硫基、芳硫基、烷基亚砜、芳基亚砜、烷基砜、芳基砜、氰基、卤素、硝基、卤代烷基、氟代烷基、氟代烷氧基、和氨基,该氨基包括单或双取代的氨基基团,及其所保护的衍生物。通过举例并非限制,一种或多种任选的取代基可以是卤化物、-CN、-NO2、或LsRs,其中每个Ls独立地选自键、-O-、-C(=O)-、-C(=O)O-、-S-、-S(=O)-、-S(=O)2-、-NH-、-NHC(=O)-、-C(=O)NH-、S(=O)2NH-、-NHS(=O)2、-OC(=O)NH-、-NHC(=O)O-、或-(C1-C6亚烷基)-;并且每个Rs选自-H、烷基、氟代烷基、杂烷基、环烷基、芳基、杂芳基、或杂环烷基。可以形成以上取代基的保护衍生物的保护基团可以发现于以上的来源例如Greene和Wuts中。可任选的取代基包括选自下组的那些,该组由以下各项组成:卤素、-CN、-NH2、-OH、-N(CH3)2、烷基、氟代烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、烷氧基、芳氧基、烷硫基、芳硫基、烷基亚砜、芳基亚砜、烷基砜、和芳基砜;包括自下组的那些,该组由以下各项组成:卤素、-CN、-NH2、-OH、NH(CH3)、-N(CH3)2、-CO2H、-CO2烷基、-C(=O)NH2、-C(=O)NH烷基、-C(=O)N(烷基)2、-S(=O)2NH2、-S(=O)2NH(烷基)、-S(=O)2N(烷基)2、烷基、环烷基、氟代烷基、杂烷基、烷氧基、氟代烷氧基、-S-烷基和-S(=0)2烷基;或包括自下组的那些,该组由以下各项组成:卤素、-CN、-NH2、-OH、-NH(CH3)、-N(CH3)2、-CH3、-CH2CH3、-CF3、-OCH3、和-OCF3。典型地,任选取代的取代基、部分或基团被前述的基团中的一个或两个所取代,或更典型的是被前述的基团中的一个所取代。在脂肪族碳原子(非环状或环状的、饱和的或不饱和的碳原子,不包括芳香族碳原子)上的可任选的取代基进一步包括氧代(=O)。
如在此使用的“杂环”或“杂环的”意指环烷基或芳香族环系统,其中一个或多个,典型的是1个、2个或3个,但是不是构成环系统的所有碳原子被杂原子所替代,该杂原子是非碳的原子,其包括N、O、S、Se、B、Si、P,典型的是N、O或S,其中两个或更多个杂原子可以是彼此相邻的或被一个或多个碳原子分开的,典型的是1-17碳原子、1-7原子或1-3原子。杂环包括在一个或多个环中包含一至四个杂原子的杂芳香族环(又称杂芳基)和杂环烷基环(又称杂脂环族基团),其中一个或多个环中的每个杂原子选自O、S和N,其中每个杂环基团在其环系统中具有4至10个原子,并且其条件是任何环不包含两个相邻的O或S原子。
非芳香族杂环、取代基、部分、或基团(又称杂环烷基)在它们的环系统中具有至少3个原子,并且芳香族杂环基团在它们的环系统中具有至少5个原子并且包括苯并稠合环系统。具有3个、4个、5个、6个和10个原子的杂环化合物分别包括吖丙啶基、氮杂环丁基、噻唑基、吡啶基和喹啉基。非芳香族杂环取代基、部分或基团是吡咯烷基、四氢呋喃基、二氢呋喃、四氢噻吩基、噁唑烷酮基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、硫代环氧乙基、哌嗪基、吖丙啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基,高哌啶基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫杂卓基、1,2,3,6-四氢吡啶基、吡咯啉-2-基、吡咯啉-3-基、吲嗪基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0)己基、3氮杂双环[4.1.0)庚基、3H-吲哚基和喹嗪基。通过举例并非限制,芳香族杂环包括吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并-硫苯基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、和呋喃并吡啶基。非芳香族杂环可以被一个或两个氧代(=O)部分取代,并且包括吡咯烷-2-酮。
当杂环被用作马库什基团(即,一种取代基),该杂环被附接至马库什化学式,该杂环通过杂环的碳或杂原子与该马库什化学式相关联,其中此类附接不产生碳或杂原子的不稳定的或禁止的形式氧化态。通过碳原子将C连接的杂环结合至分子,该杂环包括部分例如-(CH2)n-杂环,其中n是1、2或3或-C<杂环,其中C<代表在杂环中的碳原子。N连接的杂环是一种包含氮的杂环,将该杂环结合至杂环氮,该杂环氮有时被描述为-N<杂环,其中N<代表杂环中的氮原子。因此,含氮杂环可以是C连接的或N连接的,并且包括吡咯取代基,该吡咯取代基可以是吡咯-1-基(连接N的)或吡咯-3-基(C连接的),咪唑取代基,该咪唑取代基可以是咪唑-1-基或咪唑-3-基(二者都是N连接的)或咪唑-2-基、咪唑-4-基或咪唑-5-基(所有的都是C连接的)。
如在此使用的“杂芳基”意指芳基环系统,其中一个或多个,典型的是1个、2个或3个,但并不是构成芳基环系统的所有碳原子被杂原子替代,该杂原子是除碳以外的原子,其包括N、O、S、Se、B、Si、P,典型的是氧(-O-)、氮(-NX-)或硫(-S-),其中X是-H、保护基团或可C1-6任选取代的烷基,其中该杂原子通过在环系统中与相邻原子π结合或通过杂原子上的孤对电子参与共轭系统,并且该杂原子以保留环状的共轭系统的方式,在一个或多个碳或杂原子、或两者的组合上是任选取代的。
通过举例并非限制,杂环和杂芳基包括以下中所描述的杂环和杂芳基:Paquette,Leo A.;“Principles of Modern Heterocyclic Chemistry[现代杂环化学原理]”(W.A.Benjamin,纽约,1968),特别是第1章、第3章、第4章、第6章、第7章和第9章;“TheChemistry of Heterocyclic Compounds,A series of Monographs[杂环化合物化学,系列专著]”(约翰·威利父子出版社(John Wiley&Sons),纽约,1950至今),特别是第13、14、16、19和28卷;和J.Am.Chem.Soc.[美国化学学会会志]1960,82:5545-5473,特别是5566-5573。通过举例并非限制,杂芳基的实例包括吡啶基、噻唑基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、嘌呤基、咪唑基、苯并呋喃基、吲哚基、异吲哚基、喹啉基、异喹啉基、苯并咪唑基、哒嗪基、吡嗪基、苯并噻喃、苯并三嗪、异噁唑基、吡唑并嘧啶基、喹喔啉基、噻二唑基、三唑基以及类似物。通过举例并非限制,非杂芳基的杂环包括四氢硫苯基、四氢呋喃基、吲哚啉基、哌啶基、吡咯烷基、2-吡咯烷酮基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、八氢异喹啉基、2H-吡咯基、3H-吲哚基、4H-喹嗪基、咪唑烷基、咪唑啉基、吡唑烷基、哌嗪基、奎宁环基、吗啉基、噁唑烷基以及类似物。
通过举例并非限制,其他杂芳基包括以下部分:
通过举例并非限制,单环杂芳基包括吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、哒嗪基、三嗪基、噁二唑基、噻二唑基、和呋咱基。杂芳基包括那些包含0-3个N原子、1-3个N原子或0-3个N原子、0-1个O原子和0-1个S原子的取代基、部分或基团。杂芳基可以是单环的或双环的。杂芳环的环系统典型地包含1-9个碳(即,Cl-C9杂芳基)。单环杂芳基包括C1-C5杂芳基。单环杂芳基包括具有5元或6元环系统的那些。双环杂芳基包括C6-C9杂芳基。取决于结构,杂芳基基团可以是单价基团或二价基团(即,杂亚芳基基团)。
如在此使用的“杂环烷基”或“杂脂环族的”意指环烷基基团、部分或取代基,其中环烷基链的至少一个碳被杂原子替代,该杂原子选自下组,该组由氮、氧和硫组成。该杂环烷基可以与芳基或杂芳基融合。杂环烷基,还称作非芳香族杂环,通过举例并非限制,其包括:
通过举例并非限制,杂环烷基包括:噁唑烷酮基、吡咯烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、和二氢吲哚基。杂脂环族进一步包括所有环形式的碳水化物,包括但不限于单糖、二糖和低聚糖。典型地,杂环烷基是C2-C10杂环烷基并且包括C4-C10杂环烷基。杂环烷基可以包含0-2个N原子、0-2个O原子或0-1个S原子。
如在此使用的“杂芳烷基”意指取代基、部分或基团,其中将杂芳基部分结合至烷基部分,即,-烷基-杂芳基,其中烷基和杂芳基基团是如以上所描述的。当杂芳烷基被用作马库什基团(即,一种取代基)时,将该杂芳烷基的烷基部分附接至马库什化学式,该杂芳烷基通过烷基部分的sp3碳与该马库什化学式相关联。
如在此使用的“烷基杂芳基”意指取代基、部分或基团,其中将杂芳基部分结合至烷基部分,即,-杂芳基-烷基,其中杂芳基和烷基基团是如以上所描述的。当杂芳烷基被用作马库什基团(即,一种取代基)时,将该杂芳烷基的杂芳基部分附接至马库什化学式,该杂芳烷基通过烷基部分的sp2碳或杂原子与该马库什化学式相关联。
如在此使用的“卤素”(“halogen”或“halo”)意指氟、氯、溴或碘。
如在此使用的“卤代烷基”意指烷基取代基部分或基团,其中该取代基部分或基团的氢原子中的一个或多个被一个或多个独立选择的卤素原子替代。卤代烷基包括C1-C4卤代烷基。并非限制的实例C1-C4卤代烷基是-CH2Cl、CH2Br、-CH2I、-CHBrCl、-CHCl-CH2Cl和-CHCl-CH2I。
如在此使用的“卤代亚烷基”意指亚烷基取代基、部分或基团,其中一个或多个氢原子被一个或多个卤素原子替代。卤代亚烷基包括C1-C6卤代亚烷基或C1-C4卤代亚烷基。
如在此使用的“氟代烷基”意指烷基,其中一个或多个氢原子被氟原子替代。氟代烷基包括C1-C6和C1-C4氟代烷基。并非限制的实例氟代烷基包括-CH3F、-CH2F2和-CF3以及全氟代烷基。
如在此使用的“氟代亚烷基”意指亚烷基,其中一个或多个氢原子被氟原子替代。氟代亚烷基包括C1-C6氟代亚烷基和C1-C4氟代亚烷基。
术语“杂烷基”是指一种烷基基团,其中烷基的一个或多个骨架原子选自非碳的原子,例如氧、氮、硫、磷或其组合。在一方面,杂烷基是C1-C6杂烷基。
如在此使用的“保护基团”意指一种部分,该部分防止或减少它所连接的原子或官能团的能力,避免参与不需要的反应。非限制性实例是如对于-ORPR,其中RPR是针对发现于羟基中的氧原子的保护基团,同时对于-C(O)-ORPR,RPR可以是羧酸保护基团;对于-SRPR,RPR可以是硫醇类中硫的保护基团,并且对于-NHRPR或-N(RPR)2-,RPR中的至少一个是针对于伯或仲胺的氮原子保护基团。羟基、胺、酮、和其他反应基团可以需要保护来防止反应发生在分子中的别处。针对于氧、硫、氮原子的保护基通常被用来防止与亲电子化合物(例如酰化剂)的不需要的反应。针对原子或官能团的典型保护基团在以下中给出:Greene(1999),“Protective groups in organic synthesis,3rd ed.[有机合成中的保护基团,第3版]”,美国威力出版公司(Wiley Interscience)。
如在此使用的“酯”意为包含-C(O)-O-结构的取代基、部分或基团(即酯官能团),其中具有该结构的碳原子不直接与另一个杂原子相连,且与-H或另一个碳原子直接相连。典型地,酯包括或由有机部分组成,该有机部分包含1-50个碳原子、1-20个碳原子或1-8个碳原子和0至10个独立选择的杂原子(例如,O、S、N、P、Si),典型的是0-2个,其中将有机部分通过-C(O)-O-结构进行结合并且包括酯部分例如有机部分-C(O)-O-。有机部分通常包括一个或多个任何在此所描述的有机基团,例如,C1-20烷基部分、C2-20烯基部分、C2-20炔基部分、芳基部分、C3-8杂环或任何这些中的经取代的衍生物,例如,包括1个、2个、3个、4个或更多个取代基,其中每个取代基是独立选择的。在这些有机基团中,针对于氢或碳原子的、示例性、非限制性的取代基是如以上针对经取代的烷基和其他经取代的部分所描述的,并且是独立选择的。以上列出的取代基典型地是如下的取代基,该取代基可以用来替代一个或多个碳原子,例如,-O-或-C(O)-,或一个或多个氢原子,例如卤素,-NH2或-OH。通过举例并非限制,示例性的酯包括一个或多个独立选择的乙酸酯、丙酸酯、异丙酸酯、异丁酸酯、丁酸酯、戊酸酯、异戊酸酯、己酸酯(caproate)、异己酸酯(异caproate)、己酸酯(hexanoate)、庚酸酯、辛酸酯、苯乙酸酯或苯甲酸酯。当酯被用作马库什基团(即,一种取代基)时,将酯官能团的单键氧附接至与其关联的马库什化学式。
如在此使用的“乙缩醛”、“硫缩醛”、“缩酮”、“硫缩酮”以及类似物意指包括或由碳组成的部分、基团或取代基,该碳结合了两个相同或不同的杂原子,其中这些杂原子是独立选择的S和O。针对于乙缩醛,该碳具有两个结合的氧原子、一个氢原子以及一个有机部分。针对于缩酮,该碳具有两个结合的氧原子和两个独立选择的有机部分,其中该有机部分是如在此所描述的烷基或任选取代的烷基部分。针对于硫缩醛和硫缩酮,缩醛和缩酮中的氧原子中的一个或二者分别被硫替代。有时,将缩酮和硫缩酮中的氧或硫原子通过任选取代的烷基部分连接。典型地,烷基部分是任选取代的C1-8烷基或支链烷基结构例如-C(CH3)2-、-CH(CH3)-、-CH2-、-CH2-CH2-、-C[(C2-C4烷基)2]1,2,3-或-[CH(C2-C4烷基)]1,2,3-。这些部分中的一些可以作为针对醛或酮的保护基团,通过举例并非限制,包括针对醛的乙缩醛和针对酮的缩酮以及包含-O-CH2-CH2-CH2-O-或-O-CH2-CH2-O-部分,它们与羰基碳形成螺环,并且可以通过化学合成方法或通过细胞或生物学流体中的代谢去除。
如在此使用的“酯”意指一种有机部分、基团或取代基,该有机部分、基团或取代基包括或由1个、2个、3个、4个或更多个-O-部分组成的,通常是1个或2个,其中没有两个-O-部分是彼此紧密相邻的(即,所直接附接的)。典型地,醚包括有机部分,该有机部分包含1-50个碳原子、1-20个碳原子或1-8个碳原子和0至10个独立选择的杂原子(例如,O、S、N、P、Si),典型的是0-2个。醚部分、基团或取代基包括有机部分-O-,其中有机部分是如在此针对烷基或任选取代的烷基基团所描述的。当醚被用作马库什基团(即,一种取代基)时,将醚官能团的氧附接至与其相关联的马库什化学式。当醚被用作马库什基团中的取代基时,有时该醚命名为“烷氧基”基团。烷氧基包括C1-C4醚取代基,通过举例并非限制,例如甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基。醚进一步包括那些取代基、部分或基团,这些取代基、部分或基团顺序包含一个(不包括缩酮)或多个-OCH2CH2O-部分(即,聚乙烯或PEG部分)。
如在此使用的“碳酸酯”意指取代基、部分或基团,该取代基、部分或基团包含-O-C(=O)-O-结构(即,碳酸酯官能团)。典型地,如在此使用的碳酸酯基团包括或由有机部分组成,该有机部分包含通过-O-C(=O)-O-结构(例如,有机部分-O-C(=O)-O-)结合的1-50个碳原子、1-20个碳原子或1-8个碳原子和0至10个独立选择的杂原子(例如,O、S、N、P、Si),典型的是0-2个。当碳酸酯被用作马库什基团(即,一种取代基)时,将碳酸酯官能团的单键氧原子之一附接至与其相关联的马库什化学式。
如在此使用的“氨基甲酸酯”或“尿烷”意指取代基、部分或基团,该取代基、部分或基团包含-O-C(=O)N(RPR)-、-O-C(=O)N(RPR)2、-O-C(=O)NH(任选取代的烷基)或-O-C(=O)N(任选取代的烷基)2-结构(即,氨基甲酸酯官能团),其中RPR和任选取代的烷基是独立选择的,并且RPR独立地是如针对酯、烷基或任选取代的烷基所描述的-H、保护基团或有机部分。典型地,如在此使用的氨基甲酸酯基团包括或由有机部分组成,该有机部分包含通过-O-C(=O)-NRPR结构(例如,有机部分-O-C(=O)-NRPR-或-O-C(=O)-NRPR-有机部分)结合的约1-50个碳原子、1-20个碳原子或1-8个碳原子和0至10个独立选择的杂原子(例如,O、S、N、P、Si),典型的是0-2个。当氨基甲酸酯被用作马库什基团(即,一种取代基)时,将氨基甲酸酯官能团的单键氧(O连接的)或氮(N连接的)附接至与其相关联的马库什化学式。氨基甲酸酯取代基的键是在这种取代基涉及到的上下文中明确表示(连接N或O的)或暗示的。
针对于任何通过已给出的碳原子范围所描述的取代基基团或部分,指定范围意指碳原子的任何个体数是所描述的。因此,例如,参考“C1-C4任选取代的烷基”“C2-6烯基的任选取代的烯基”、“C3-C8任选取代的杂环”具体意指如在此所定义的1个、2个、3个或4个碳的任选取代的烷基部分是存在的,或2个、3个、4个、5个或6个碳烯基,或包括如在此所定义的杂环或任选取代的烯基部分的3个、4个、5个、6个、7个或8个碳部分是存在的。所有此类命名明确旨在披露所有的个体碳原子基团,并且此类“C1-C4任选取代的烷基”包括,例如,3碳烷基、经4碳取代的烷基和4碳烷基,所有此类命名包括披露所有的位置异构物以及类似物并且可以明确指代或命名。针对于通过已给出碳原子范围所定义的酯、碳酸酯和氨基甲酸酯,指定范围包括各自官能团的羰基碳。因此,C1酯是指甲酸酯并且C2酯是指乙酸酯。在此所描述的、并且针对其他任何其他部分在此所描述的有机取代基、部分和基团通常将不包括不稳定部分,除了其中此类不稳定部分是瞬态粒子之外,该瞬态粒子可以用来制作具有足够化学稳定性的化合物,用于在此所描述的一种或多种用途。明确排除通过在此定义的操作产生的具有五价碳的那些的取代基、部分或基团。
如在此使用的“LPA依赖型的”、“LPA介导的”或此类术语意指疾病或病症,其病因、进展或持久性通过一个或多个溶血磷脂酸受体亚型,受信号全部或部分地影响,通过举例并非限制其包括溶血磷脂酸受体亚型1-6(LPARs)。LPA依赖型或LPA介导的疾病和病症包括但不限于器官纤维化(例如,肝脏、肾脏、肺、心脏等)、肝脏疾病(例如,急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生失败、非酒精性脂肪性肝炎(NASH)、肝机能减退、肝血流紊乱等)、细胞增殖疾病(例如,癌症,包括但不限于实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波氏肉瘤、白血病、慢性淋巴细胞白血病(CLL)、癌细胞的侵入性转移等)、炎症性疾病(例如,银屑病、肾病、肺炎等)、胃肠道疾病(例如,肠道易激综合症(IBS)、炎症性肠病(IBD)、胰腺分泌异常等)、肾脏疾病、尿路相关疾病(例如,良性前列腺增生或与神经性膀胱疾病相关的症状)、脊髓瘤、椎间盘疝气、椎管狭窄、糖尿病衍生的症状、下尿路疾病(例如,下尿路梗阻等)、下尿路炎症性疾病(例如,排尿困难、尿频等)、胰腺疾病、血管生成异常的相关疾病(例如,动脉栓塞等)、硬皮病、大脑相关疾病(例如,脑梗死、脑出血等)、神经系统疾病(例如,神经痛、外周神经病变、皮肤瘙痒等)、眼病(例如,年龄相关性黄斑病变(AMD)、糖尿病性视网膜病变、增生性玻璃体视网膜病变(PVR)、瘢痕性类天疱疮、青光眼滤过手术瘢痕等)。
如在此使用的“LPA1R选择剂”“LPA1R选择化合物”以及类似术语意指试剂或化合物,该试剂或化合物与溶血磷脂酸亚型1受体相互作用优先于溶血磷脂酸受体2-6。典型地,相比于其他已知的LPARs,如通过实验确定的KD值所测量的,通过强过10倍的试剂至LPA1R的结合亲和力显示出了优先选择。
如在此使用的“药学上可接受的配制品”意指包含活性药物成分的组合物,例如具有化学式I-VI的化合物还有一种或多种药学上可接受的赋形剂;或是指由活性药物成分和一种或多种药学上可接受的赋形剂所制备的组合物,其中该组合物适用于施用至有需要的受试者,例如人类或动物。针对于适用于施用至人类的药学上可接受的配制品,该配制品必须具有生物学活性,用于治疗或预防在此所披露的疾病或病症,或一定存在一种希望,配制品将具有“有意向治疗”的疾病或病症的所希望的活性。典型地,“有意向治疗”的疾病或病症是溶血磷脂酸受体介导的病症或疾病。更典型地,需要治疗或预防的疾病或病症是溶血磷脂酸1型受体介导的疾病或病症。适用于施用至动物的药学上可接受的配制品不一定需要用于治疗或预防疾病或病症的生物学活性,并且可以为了评估化学式I-XII的化合物的潜在药理学或生物学活性将其施用至动物。因此,在有需要的动物中,那些配制品可以适用于治疗或预防在此所披露的疾病或病症,或适用于评估化学式I-XII的化合物的药理学或生物学活性。从药学上可接受的配制品的定义中,明确排除只适用于体外测定的组合物,或包含药物产品中所不允许的量的载体、组分或赋形剂的组合物。
药学上可接受的配制品可以包含,或由以下各项制备:一个、两个或多个化学式I-XII的化合物,典型的是一个或两个,以及一种或多种药学上可接受的赋形剂。更典型地,配制品将基本上由以下各项组成或由以下各项组成:单一化学式I-XII的化合物以及一种或多种药学上可接受的赋形剂。其他配制品可以包含以下各项、基本上由以下各项组成、或由以下各项组成:一种、两种或更多种化学式I-XII的化合物和一种、两种或更多种化合物以及一种或多种药学上可接受的赋形剂,该一种、两种或更多种化合物当前用于治疗溶血磷脂酸1型受体介导的疾病或病症。典型地,那些配制品将基本上由以下各项组成或由以下各项组成:单一化学式I-XII的化合物、单一化合物以及一种或多种药学上可接受的赋形剂,该单一化合物当前用于治疗溶血磷脂酸1型受体介导的疾病或病症。
如在此使用的“固体配制品”是指一种药学上可接受的配制品,其包括以固体形式的至少一种化学式I-XII的化合物和一种或多种药学上可接受的赋形剂,其中该配制品是以单位剂型,适用于固体的施用。剂量单位包括片剂、胶囊剂、囊片、软胶囊、混悬剂和其他剂量单位,它们典型地与肠外和肠内(口服)施用固体相关。
如在此使用的“液体配制品”是指药学上可接受的配制品,其中至少一种化学式I-XII的化合物与一种或多种药学上可接受的赋形剂相混合或相接触,其中赋形剂中的至少一种是以液体配制品所需的比例的液体形式,即,这样一种或多种化学式I-XII的化合物的质量的大部分溶解于非固体赋形剂。包含液体配制品的剂量单位包括糖浆剂、凝胶、软膏剂和其他剂量单位,它们典型地与向对其以液体形式有需要的受试者肠外和肠内施用药物配制品相关。
如在此使用的“预防(“prevent”、“preventing”)”以及类似术语在医学领域内采取其正常并且惯用的手段,并且因此不需要术语涉及的每种情况肯定地被避免。
编号的实施例
以下实施例举例说明本发明并非意指以任何方式限制本发明。在某些实施例中,在此提供的化合物具有一种或多种立构中心并且每个中心独立地以R或S构型存在。在此提供的化合物包括所有的非对映异构体的、对映异构体的、和差向异构体的形式以及其适当的混合物。如果希望的话,通过方法来获得立体异构体,例如立体选择合成和/或立体异构体通过手性层析柱的分离。在此所描述的方法和配制品包括具有化学式(I-VI)的结构的化合物的药学上可接受的盐以及这些具有相同类型活性的化合物的活性代谢物的用途。在一些情况下,化合物可以作为互变异构体存在。所有的互变异构体包括于在此提供的化合物的范围内。在具体的实施例中,在此所描述的化合物将作为盐存在,包括药学上可接受的盐。盐形式包括无机加成盐例如F-、Cl-、Br-、I-和硫酸盐,以及有机加成盐例如甲磺酸盐、苯磺酸盐、托西酸盐、柠檬酸盐、丁二酸盐、延胡索酸盐和丙二酸盐。在其他实施例中,在此所描述的化合物作为季铵盐存在。
实施例1.一种具有化学式I的化合物,该化学式I具有如下结构
或其药学上可接受的盐或前药,
其中RA是-CO2H、-CO2RB、-CN、四唑基、-C(=O)NH2、-C(=O)NHRB、C(=O)NHSO2RB或-C(=O)NHCH2CH2SO3H,或者具有如下结构;
其中RB是经取代的或未经取代的C1-C4烷基;
L1是经取代的或未经取代的C1-C6亚烷基、经取代的或未经取代的C1-C6氟代亚烷基、经取代的或未经取代的C3-C8环亚烷基、经取代的或未经取代的C1-C6杂亚烷基;
其中A1是-N=或-CH;
其中环A具有以下之一的结构:
其中RC是-CN、-F、-Cl、-Br、-I、-OC1-C4烷基、C3-C6环烷基、或C1-C4氟代烷基;
并且RD是-N(RF)-C(=O)XCH(RG)-CY,其中X是O且CY是被一个RH所取代的苯基:
RE、RF和RG独立地是-H或C1-C4烷基或C3-C6环烷基,或者RE和RF独立地是-H或C1-C4烷基或C1-C6环烷基,并且一个RG是-C1-C4烷基并且和环A RD取代基的RH苯基部分以及RG与所述苯基部分所附接的碳原子一起定义一种经取代的或未经取代的碳环或经取代的或未经取代的杂环;
RH独立地是-H、卤素、-CN、-NO2、-OH、C1-C4烷基、C1-C4氟代烷基、C1-C4氟代烷氧基、或C1-C4烷氧基,
在一些实施例中,RC是-CN、-F、-Cl、-Br、-I、-OC1-C4烷基、C1-C4烷基、C3-C6环烷基、或C1-C4氟代烷基,并且RD是-N(RF)-C(=O)OCH(RG)-CY,
其中RF和每个RG独立地是-H或C1-C4烷基。
在优选的实施例中,RA是-CO2H、-CONHCN、四唑基、或-C(=O)NHSO2RB,其中RB是经取代的或未经取代的C1-C4烷基。
在具体优选实施例中,RA是-CO2H、-CONHCN、四唑基、或-C(=O)NHSO2RB,其中RB是-CH3。
在一些实施例中,L1是经取代的或未经取代的C1-C6亚烷基、C1-C6氟代亚烷基、或经取代的或未经取代的C1-C6杂亚烷基。
在一些实施例中,化学式I的化合物具有RC,该RC被定义为-CN、-F、-Cl或C1-C4氟代烷基。
在更优选实施例中,化学式I的化合物具有RC,该RC被定义为-F、或-Cl。
在一些实施例中,化学式I的化合物具有RD,该RD被定义为-N(RF)C(=O)-OCH(RG)-CY,其中RF是-H或C1-C4烷基,并且X、CY和RG是如前所定义的。
在更优选实施例中,化学式I的化合物具有RD,该RD被定义为-N(RF)C(=O)OCH(RG)-CY,其中RF是-H,且CY和RG是如前所定义的。
在一些实施例中,化学式I的化合物具有RF,该RF被定义为H、C1-C4烷基或C3-C6环烷基。
在更优选实施例中,化学式I的化合物具有RF,该RF被定义为-H。
在化学式I的化合物的一些实施例中,RG独立地是-H或C1-C4烷基。
在更优选实施例中,化学式I的化合物具有RG,该RG被定义为-CH3。
在化学式I的化合物的一些实施例中,CY是经取代的或未经取代的芳基,或经取代的或未经取代的杂芳基,其中如果CY是经取代的,则CY被1、2或3个独立地选择的RH取代。
在优选的化学式I的化合物中,RA是-CO2H,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF、RG和CY是如前所定义的。
在其他优选的化学式I的化合物中,RA是四唑基,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF、RG和CY是如前所定义的。
在其他优选的化学式I的化合物中,RA是-C(=O)NHSO2RB,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RB、RF、RG和CY是如前所定义的。
在其他优选的化学式I的化合物中,RA是-CONHCN,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF、RG和CY是如前所定义的。
实施例2.如实施例1所述的化合物,其中RA是-CO2H或CONHCN。
实施例3.如实施例1所述的化合物,其中RA是四唑基。
实施例4.如实施例1所述的化合物,其中RA是-C(=O)NHSO2RB,其中RB是-CH3。
实施例5.如实施例1-4所述的化合物,其中RC是-CN、-F或-Cl。
实施例6.如实施例1-5所述的化合物,其中RC是-F或-Cl。
实施例7.如实施例1-6所述的化合物,其中L1(当存在时)是成对地取代的烷基、环烷基或杂环烷基基团。
实施例9.如实施例1-8中任一项所述的化合物,其中RF为-H。
实施例10.如实施例1-9中任一项所述的化合物,其中RG为-CH3。
实施例11.如实施例1-10中任一项所述的化合物,其中CY是经取代的或未经取代的苯基。
实施例12.如实施例1-11中任一项所述的化合物,其中RH是-H、卤素、-CN、-NO2、-OH、C1-C4烷基、C1-C4氟代烷基、C1-C4氟代烷氧基、和C1-C4烷氧基。
实施例13.如实施例1-12中任一项所述的化合物,其中RH独立地选自-H、卤素或经取代的或未经取代的C1-C4烷基或经取代的C1-C4烷氧基。
实施例14.如实施例1-13中任一项所述的化合物,其中RH独立地是-H、-Cl、-F、-CH3、-CF3、-OCH3或-OCF3。
实施例15.一种具有化学式II的化合物,该化学式II具有如下结构:
或其药学上可接受的盐或前药,
其中RA是-CO2H、-CO2RB、四唑基、-C(=O)NH2、-CONHCN或C(=O)NHSO2RB;
RB是任选取代的C1-C4烷基
A1是=N-或=CH-;
环A具有以下结构:
RC是-CN、-F、-Cl或C1-C4氟代烷基;
RD是-N(RF)-C(=O)XCH(RG)-CY,其中X是O且CY是被一个RH取代的苯基:
RE、RF和RG独立地是-H或C1-C4烷基或C3-C6环烷基,或者RE和RF独立地是-H或C1-C4烷基或C1-C6环烷基,并且一个RG是-C1-C4烷基并且和环A RD取代基的RH苯基部分以及RG与所述苯基部分所附接的碳原子一起定义一种经取代的或未经取代的碳环或经取代的或未经取代的杂环;
RH是-H、卤素、-CN、-NO2、-OH、C1-C4烷基、C1-C4氟代烷基、C1-C4氟代烷氧基、或C1-C4烷氧基;
在具体优选的化学式II的化合物中,RA是-CO2H、-CONHCN、-C(=O)NHSO2RB或四唑基,RB是CH3,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF、RG和CY是如前所定义的。
实施例16.一种具有化学式III的化合物,该化学式II具有如下结构:
或其药学上可接受的盐或前药,
其中RA是-CO2H、-CONHCN、四唑基、或-C(=O)NHSO2RB;
RB是任选取代的C1-C4烷基
A1是=N-或=CH-;
环A具有以下之一的结构:
RC是-CN、-F或-Cl;
其中CY是被一个RH取代的苯基;
RF和RG独立地是-H或C1-C4烷基或C3-C6环烷基,或者RF独立地是-H或C1-C4烷基或C1-C6环烷基,并且一个RG是-C1-C4烷基并且和环A RD取代基的RH苯基部分和RG与所述苯基部分所附接的碳原子一起定义一种经取代的或未经取代的碳环或经取代的或未经取代的杂环;
RH是-H、卤素、-CN、-NO2、-OH、C1-C4烷基、C1-C4氟代烷基、C1-C4氟代烷氧基、或C1-C4烷氧基;
在优选的化学式III的化合物中,RA是-CO2H、-CONHCN、-C(=O)NHSO2RB或四唑基,RB是CH3,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF是-H,RG是-CH3,且CY是如前所定义的。
实施例17.一种组合物,其包含以下各项、基本上由以下各项组成或由以下各项组成:一种或多种具有化学式I-III的化合物和一种或多种赋形剂。
在优选实施例中,该组合物包含以下各项、基本上由以下各项组成或由以下各项组成:一种具有化学式I-III的化合物和一种或多种赋形剂。
在其他优选实施例中,该组合物是一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:一种具有化学式I-III的化合物和一种或多种药学上可接受的赋形剂。
实施例18.一种具有化学式I-III的化合物或其药学上可接受的盐或前药,其中该化合物对溶血磷脂酸受体-1(LPA1R)的结合亲和力在约10μM和1pM之间或更少。
实施例19.如实施例1-18所述的化合物,其中该化合物是一种选择性溶血磷脂酸受体-1(LPA1R)化合物。
实施例20.一种具有化学式I-III的化合物或其药学上可接受的盐、或前药,其中该化合物是一种选择性溶血磷脂酸受体-1(LPA1R)化合物。
实施例21.如实施例1-20所述的化合物,其中该化合物是一种选择性溶血磷脂酸受体-1(LPA1R)化合物,其中该LPA1R化合物的结合亲和力(即,KD)在约1μM和1pM之间或更少。在优选实施例中,该KD是100nM或更少,更优选的是10nM或更少。
实施例22.表1的化合物。
实施例23.如实施例22所述的化合物,其中该化合物是(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(3-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、或(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯;
实施例24.如实施例22所述的化合物,其中该化合物是(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、或(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸;
实施例25.如实施例22所述的化合物,其中该化合物是(R)-1-{4'-[5-(1-苯基-乙氧基羰基氨基)-4-三氟甲基-吡唑-1-基]-联苯基-4-基}-环丙烷甲酸、或(R)-1-{2-氟-4'-[5-(1-苯基-乙氧基羰基氨基)-4-三氟甲基-吡唑-1-基]-联苯基-4-基}-环丙烷甲酸;
实施例26.如实施例22所述的化合物,其中该化合物是(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸、或(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸;
实施例27.如实施例22所述的化合物,其中该化合物是(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、或(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯;
实施例28.如实施例22所述的化合物,其中该化合物是(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯;
实施例29.如实施例22所述的化合物,其中该化合物是(R)-1-苯乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯;
实施例30.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:表1的化合物和一种或多种药学上可接受的赋形剂。
实施例31.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:实施例23的化合物和一种或多种药学上可接受的赋形剂。
实施例32.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:实施例24的化合物和一种或多种药学上可接受的赋形剂。
实施例33.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:实施例25的化合物和一种或多种药学上可接受的赋形剂。
实施例34.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:实施例26的化合物和一种或多种药学上可接受的赋形剂。
实施例35.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:实施例27的化合物和一种或多种药学上可接受的赋形剂。
实施例36.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:实施例28的化合物和一种或多种药学上可接受的赋形剂。
实施例37.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:实施例29的化合物和一种或多种药学上可接受的赋形剂。
实施例38.一种方法,该方法包括向患有LPA依赖型或LPA介导的疾病或病症的受试者施用有效量的化学式I-III的化合物。
实施例39.如实施例38所述的方法,其中该LPA依赖型或LPA介导的疾病或病症是具有器官纤维化的疾病。
实施例40.如实施例39所述的方法,其中该纤维化是肝脏、肾脏、肺、心脏、眼以及类似物的纤维化。
实施例41.如实施例38所述的方法,其中该LPA依赖型或LPA介导的疾病或病症是慢性疼痛
实施例42.如实施例38所述的方法,其中该LPA依赖型或LPA介导的疾病或病症是皮肤瘙痒
实施例43.如实施例38所述的方法,其中该LPA介导的疾病是一种增生性疾病,其包括癌症(实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波氏肉瘤、白血病、慢性淋巴细胞白血病(CLL)等)和癌细胞的侵入性转移,其包括卵巢、乳房和三阴性乳癌等,
实施例44.如实施例38所述的方法,其中该LPA介导的疾病是一种炎症性疾病,其包括银屑病、肾病、肺炎等,
实施例45.如实施例38所述的方法,其中该LPA介导的疾病是一种胃肠疾病,例如炎症性肠病,
实施例46.如实施例38所述的方法,其中该LPA介导的疾病是一种眼病,其包括与年龄相关的黄斑变性(AMD)、糖尿病性视网膜病、增生性玻璃体视网膜病变(PVR)、瘢痕性类天疱疮、青光眼滤过手术瘢痕、葡萄膜炎等,
实施例47.如实施例38所述的方法,其中该LPA介导的疾病是一种肝病,其包括急性肝炎、慢性肝炎、肝纤维化、肝硬变、胆汁郁积型瘙痒、门静脉高压、再生失败、非酒精性脂肪性肝炎(NASH)、肝机能减退、肝血流紊乱等,
实施例48.如实施例38所述的方法,其中该LPA介导的疾病是一种肾脏疾病,其包括慢性肾脏疾病、末期肾脏疾病、尿毒症瘙痒、包括糖尿病性肾病的肾病变等,
实施例49.如实施例38所述的方法,其中该LPA介导的疾病是一种皮肤病,其包括硬皮病、皮肤瘢痕、特异性皮炎、银屑病等,
实施例50.如实施例38-49中任一项所述的方法,其中受试者是人类。
实施例51.如实施例38-50中任一项所述的方法,其中化合物选自表1。
实施例52.如实施例78-90中任一项所述的方法,其中化合物是(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(3-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸、(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸;
实施例53.如实施例38-50中任一项所述的方法,其中化合物选自实施例23。
实施例54.如实施例38-50中任一项所述的方法,其中化合物选自实施例24。
实施例55.如实施例38-50中任一项所述的方法,其中化合物选自实施例25。
实施例56.如实施例38-50中任一项所述的方法,其中化合物选自实施例26。
实施例57.如实施例38-50中任一项所述的方法,其中化合物选自实施例27。
实施例58.如实施例38-50中任一项所述的方法,其中化合物选自实施例28。
实施例59.如实施例38-50中任一项所述的方法,其中化合物选自实施例29。
实施例60.一种化合物,其包含以下各项、基本上由以下各项组成或由以下各项组成:一种或多种具有化学式(I-III)的化合物和一种或多种药剂,该一种或多种药剂当前被用于治疗LPA依赖型或LPA介导的疾病或在此所描述的疾病或病症。
实施例61.一种药学上可接受的配制品,其包含以下各项、基本上由以下各项组成或由以下各项组成:一种或多种具有化学式(I-III)的化合物、一种或多种药剂和一种或多种药学上可接受的赋形剂,该一种或多种药剂当前被用于治疗LPA依赖型或LPA介导的疾病。
实施例62.一种方法,该方法包括向患有LPA依赖型或LPA介导的疾病或病症组合施用或共同施用一种具有化学式(I-III)的化合物以及当前使用的药剂来治疗LPA依赖型或LPA介导的疾病。
一种或多种不是具有化学式(I-III)的化合物的另外的治疗活性剂选自:皮质激素、免疫抑制剂、镇痛药、抗癌剂、抗炎药、趋化因子受体拮抗剂、支气管扩张药、白细胞三烯受体拮抗剂、白细胞三烯形成抑制剂、血小板活化因子受体拮抗剂、单酰甘油激酶抑制剂、磷脂酶A1抑制剂、磷脂酶A2抑制剂、和溶血磷脂酶D(lysoPLD)抑制剂、自毒素抑制剂、减充血剂、肥大细胞稳定剂、抗组胺药、黏痰溶解药、抗胆碱能的、镇咳药、祛痰药、和β-2激动剂。
在优选实施例中,当前使用的一种或多种药剂选自描述于默克索引(MerckIndex)的已知来影响溶血磷脂酸受体信号转导的那些。在其他优选实施例中,该化学式(I-III)的化合物选自表1。
在其他实施例中,针对于治疗LPA依赖型或LPA介导的疾病或病症,在此包括如下疗法,这些疗法将具有化学式(I-III)的化合物与当前使用的药剂相结合,该当前使用的药剂作用于不同的LPA合成的信号传导途径或信号传导途径以便提供互补的临床结果。
额外治疗剂的实例包括但不限于,任何以下各项:棉子酚、根纳三思、多酚E、氯融蛋白、全反式维甲酸(all trans-retinoic acid)(ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-a-2'-脱氧胞苷、全反式维甲酸(all trans retinoic acid)、阿霉素、长春新碱、依托泊苷、吉西他滨、伊马替尼、格尔德霉素、17-N-烯丙氨基-17-去甲氧基格尔德霉素(17-AAG)、黄酮吡多、LY294002、硼替佐米、群司珠单抗、BAY 11-7082、PKC412、或PD 184352、TaxolTM(紫杉醇)、和TaxolTM的类似物(例如TaxotereTM、U0126、PD 98059、PD184352、PD 0325901、ARRY-142886、SB239063、SP600 125、BAY 43-9006、渥曼青霉素、或LY294002)、阿霉素、更生霉素、博来霉素、长春碱、顺铂、阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;醋酸阿美蒽醌;氨基格鲁米特;安吖啶;阿那曲唑;安曲霉素;门冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸比生群;甲磺酸双奈法德;比折来新;硫酸博莱霉素;布喹那钠;溴匹立明;白消安;放线菌素;卡普睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗霉素;克拉屈滨;甲磺酸克立那托;环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸柔红霉素;地西他滨;右奥马铂;脱氮鸟嘌呤;脱氮鸟嘌呤甲磺酸;地吖醌;阿霉素;盐酸阿霉素;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索比星;雌氮芥;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;氯苯乙嘧胺;盐酸法倔唑;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;依弗酰胺;iimofosine;白细胞介素II(包括重组白细胞介素II、或rIL2)、干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-l a;干扰素γ-l b;异丙铂;盐酸依立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;美坦辛;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔;巯基嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托克星;丝裂红素;米托洁林;米托马星;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑(nocodazoie);诺拉霉素;奥马铂;奥昔舒仑;培门冬酶;培利霉素;戊氮芥;硫酸培洛霉素;过磷酰胺;哌泊溴烷;泊舒凡;盐酸吡罗蒽醌;光辉霉素;普洛美坦;卟吩姆钠;泊非霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌罗霉素;盐酸嘌呤霉素;吡唑呋喃菌素;利波腺苷;罗谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠;司帕霉素;斯皮罗锗盐酸;螺莫司汀;螺铂;链黑霉素;链脲菌素;磺氯苯脲;他利霉素;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫泊芬(temoporfm);替尼泊苷;替罗昔隆;睾内酪;硫咪嘌呤;硫鸟嘌呤;噻替派;噻唑呋林;替拉扎明;枸橼酸托瑞米芬;醋酸曲托龙;磷酸曲西立滨;三甲曲沙;葡萄糖醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸长春罗辛;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星、氮芥、环磷酰胺、苯丁酸氮芥、美法仑、等等)、乙烯亚胺、六甲蜜胺、噻替派、白消安)、卡莫司汀、洛莫司汀(lomusitne)、司莫司汀、链佐星、ortriazenes、达卡巴嗪、甲氨蝶呤、氟尿嘧啶、氟尿苷(floxouridine)、阿糖胞苷、巯基嘌呤、硫鸟嘌呤、喷司他丁、己酸羟孕酮、醋酸甲地孕酮、醋酸甲羟孕酮、雌激素、二乙基己烯雌酚、乙炔雌二醇、它莫西芬)、丙酸睾酮、氟甲睾酮、氟他胺、亮丙立德、顺铂、卡铂、米托蒽醌)、丙卡巴肼、米托坦、氨基格鲁米特、厄布洛唑、多拉司他汀10、羟乙磺米伏布林、长春新碱、NSC-639829、盘皮海绵内酯、ABT-751、阿托海汀A和阿托海汀C)、海绵素1-9、盐酸西马多丁、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、埃坡霉素E、埃坡霉素F、埃坡霉素B N氧化物、埃坡霉素AN氧化物、16-氮杂-埃坡霉素B、21氨基埃坡霉素B、21-羟基埃坡霉素D、26-氟代埃坡霉素、澳瑞他汀(Auristatin)PE、索利多汀(Soblidotin)、念珠藻环肽52、Vitilevuamide、微管蛋白抑制剂(Tubulysin)A、加纳单索(Canadensol)、矢车菊黄素、Oncocidin Al Fijianolide B、Laulimalide、那可丁、Nascapine、哈米特林、二茂基乙酰丙酮化钒、茚满诺星艾榴塞洛素(例如,脱甲基艾榴塞洛素、脱乙酰基艾榴塞洛素、异艾榴塞洛素A、和Z-艾榴塞洛素)、卡利贝苷(Caribaeoside)、卡利贝林(Caribaeolin)、软海绵素B、Diazonamide A、箭根酮内酯A、Diozostatin、(-)-苯丙氨酸、肌基质蛋白B、力司弗拉司达汀(Resverastatin)磷酸钠、阿瑞吡坦、大麻、屈大麻酚(marinol)、屈大麻酚(dronabinol)、促血红细胞生长素-α、非格司亭、利妥昔单抗、那他珠单抗、环磷酰胺、青霉胺、环孢霉素、亚硝基脲、顺铂、卡铂、奥沙利铂、甲氨蝶呤、硫唑嘌呤、巯基嘌呤、嘧啶类似物、蛋白质合成抑制剂、更生霉素、蒽环类、丝裂霉素C、博来霉素、光辉霉素、巴利昔单抗、达利珠单抗、环胞素、他克莫司、西罗莫司、干扰素类、类罂粟碱、英利昔单抗、依那西普、阿达木单抗、戈利木单抗、来氟米特、柳氮磺吡啶、羟基氯代奎宁、米诺环素、雷帕霉素、麦考酚酸、吗替麦考酚酯、FTY720、环胞素A(CsA)或他克莫司(FK506)、阿司匹林、水杨酸、龙胆酸、水杨酸胆碱镁、水杨酸胆碱、水杨酸胆碱镁、水杨酸胆碱、水杨酸镁、水杨酸钠、二氟尼柳、卡洛芬、非诺洛芬、非诺洛芬钙、氟比洛芬、布洛芬、酮洛芬、萘丁酮(nabutone)、酮咯酸、酮咯酸氨丁三醇、萘普生、奥沙普秦、双氯芬酸、依托度酸、吲哚美辛、舒林酸、托美丁、甲氯芬那酸钠、甲氯芬那酸钠、甲芬那酸、吡罗昔康、美洛昔康、伐地考昔、帕瑞考昔、艾托考昔、芦米考昔、倍他米松、泼尼松、阿氯米松、醛甾酮、安西奈德、倍氯米松、倍他米松、布地奈德、环索奈德、氯倍他索、氯倍他松、氯可托龙、氯泼尼醇、可的松、可的伐唑、地夫可特、脱氧皮质酮、地奈德、去羟米松、去氧皮质酮、地塞米松、二氟拉松、二氟可龙、二氟泼尼酯、氟氯奈德、氟氢可的松、氟氢缩松、氟米松、氟尼缩松、氟轻松、醋酸氟轻松、氟可丁、氟可龙、氟米龙、氟培龙、氟泼尼定、氟替卡松、福莫可他、哈西奈德、卤米松、氢化可的松/氢化可的松、醋丙氢可的松、氢化可的松丁丙酸酯、氢化可的松丁酸酯、氯替泼诺、甲羟松、甲泼尼松、甲泼尼龙、醋丙甲泼尼龙、莫米松糠酸酯、帕拉米松、泼尼卡酯、泼尼松/泼尼松龙、利美索龙、替可的松、曲安西龙、乌倍他索、吡格列酮、氯贝特、非诺贝特二甲苯氧庚酸、叶酸、伊波格雷、奥扎格雷、利多格雷、达唑氧苯、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、尼伐他汀、和罗苏伐他汀、依达拉奉、维生素C、TROLOXTM、胞磷胆碱和minicycline、(2R)-2-丙基辛酸、普萘洛尔、纳多洛尔、噻吗洛尔、吲哚洛尔、拉贝洛尔、美托洛尔、阿替洛尔、艾司洛尔和醋丁洛尔、美金刚、曲索罗地、替罗非班拉米非班、阿加曲班、恩纳普利、环扁桃酯、氯沙坦、缬沙坦、坎地沙坦、厄贝沙坦、替米沙坦、奥美沙坦、卡那格列弗津、达帕利弗津、恩格列净、埃格列净、格列净、鲁格列净、依碳酸瑞格列净、索格列净、托格列净、艾塞那肽、利拉鲁肽、利西那肽、阿必鲁泰、索马鲁肽、美吡拉敏(新安替根)、安他唑啉、苯海拉明、卡比沙明、多西拉敏、氯马斯汀、茶苯海明、非尼拉敏、氯苯那敏(chlorphenamine)(氯苯那敏(chlorpheniramine))、右氯苯那敏、溴苯那敏、曲普立啶、西替利嗪、赛克力嗪、氯环力嗪、羟嗪、氯苯甲嗪、氯雷他定、氯雷他定、异丙嗪、阿利马嗪(三甲泼拉嗪)、赛庚啶、阿扎他定、酮替芬、阿伐斯汀、阿司咪唑、西替利嗪、咪唑斯汀、特非那定、氮卓斯汀、依匹斯汀、左卡巴斯汀、奥洛他定、左西替利嗪、非索非那定、卢帕他定、贝他斯汀)、黏痰溶解药、抗胆碱能类、止咳药、镇痛药、祛痰药、沙丁胺醇、麻黄碱、肾上腺素、福莫特罗、奥西那林、特布他林、布地奈德、环索奈德、地塞米松、氟尼缩松、丙酸氟替卡松、曲安奈德、异丙托溴铵、假麻黄碱、茶碱、孟鲁司特、普仑司特、托鲁司特、扎鲁司特、安立生坦、波生坦、恩拉生坦、西他生坦、替唑生坦、伊洛前列素、曲前列尼、吡非尼酮、肾上腺素、异丙肾上腺素、奥西那林、黄嘌呤、齐留通。
实施例63.如实施例60-62所述的方法,其中受试者是人类。
实施例64.如实施例60-62所述的方法,其中一种或多种化学式I-III的化合物选自表1。
实施例65.如实施例60-62所述的化合物,其中该化学式I-III的化合物选自由以下组成的组:(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(3-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸、(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸;
实施例66.如实施例60-63所述的方法,其中一种或多种化学式I-III的化合物选自实施例23。
实施例67.如实施例60-63所述的方法,其中一种或多种化学式I-III的化合物选自实施例24。
实施例68.如实施例60-63所述的方法,其中一种或多种化学式I-III的化合物选自实施例25。
实施例69.如实施例60-63所述的方法,其中一种或多种化学式I-III的化合物选自实施例26。
实施例70.如实施例60-63所述的方法,其中一种或多种化学式I-III的化合物选自实施例27。
实施例71.如实施例60-63所述的方法,其中一种或多种化学式I-III的化合物选自实施例28。
实施例72.如实施例60-63所述的方法,其中一种或多种化学式I-III的化合物选自实施例29。
实施例73.如实施例60所述的组合物,其中当前使用的药剂是肥大细胞稳定剂。
实施例74.如实施例60所述的组合物,其中当前使用的药剂是血小板活化因子受体拮抗剂,
实施例75.如实施例73所述的组合物,其中该肥大细胞稳定剂是色甘酸盐、奈多罗米、氮卓斯汀、贝他斯汀、依匹斯汀、酮替芬、奥洛他定和卢帕他定。
实施例76.如实施例74所述的组合物,其中血小板活化因子受体拮抗剂是卢帕他定、SM-12502、CV-3988和WEB 2170。
实施例1A.一种化合物,其中该化合物具有化学式I的结构
或其药学上可接受的盐或前药,
其中RA是-CO2H、-CONHCN、四唑基、或C(=O)NHSO2RB;
其中RB是经取代的或未经取代的C1-C4烷基;
L1是经取代的或未经取代的C1-C6亚烷基、经取代的或未经取代的C1-C6氟代亚烷基、经取代的或未经取代的C3-C8环亚烷基、经取代的或未经取代的C1-C6杂亚烷基;
其中A1是-N=或-CH;
其中环A具有以下之一的结构:
其中RC是-CN、-F、-Cl、-Br、-I、-OC1-C4烷基、C3-C6环烷基、或C1-C4氟代烷基;
并且RD是-N(RF)-C(=O)XCH(RG)-CY,其中X是O且CY是被一个RH所取代的苯基:
RE、RF和RG独立地是-H或C1-C4烷基或C3-C6环烷基,或者RE和RF独立地是-H或C1-C4烷基或C1-C6环烷基,并且一个RG是-C1-C4烷基并且和环A RD取代基的RH苯基部分以及RG与所述苯基部分所附接的碳原子一起定义一种经取代的或未经取代的碳环或经取代的或未经取代的杂环;
RH独立地是-H、卤素、-CN、-NO2、-OH、C1-C4烷基、C1-C4氟代烷基、C1-C4氟代烷氧基、或C1-C4烷氧基,
在一些实施例中,RC是-CN、-F、-Cl、-Br、-I、-OC1-C4烷基、C1-C4烷基、C3-C6环烷基、或C1-C4氟代烷基,并且RD是-N(RF)-C(=O)OCH(RG)-CY,
其中RF和每个RG独立地是-H或C1-C4烷基。
在优选的实施例中,RA是-CO2H、-CONHCN、四唑基、或-C(=O)NHSO2RB,其中RB是经取代的或未经取代的C1-C4烷基。
在具体优选实施例中,RA是-CO2H、-CONHCN、四唑基、或-C(=O)NHSO2RB,其中RB是-CH3。
在一些实施例中,L1是经取代的或未经取代的C1-C6亚烷基、C1-C6氟代亚烷基、或经取代的或未经取代的C1-C6杂亚烷基。
在一些实施例中,化学式I的化合物具有RC,该RC被定义为-CN、-F、-Cl或C1-C4氟代烷基。
在更优选实施例中,化学式I的化合物具有RC,该RC被定义为-F、或-Cl。
在一些实施例中,化学式I的化合物具有RD,该RD被定义为-N(RF)C(=O)-OCH(RG)-CY,其中RF是-H或C1-C4烷基,且X、CY和RG是如前所定义的。
在更优选实施例中,化学式I的化合物具有RD,该RD被定义为-N(RF)C(=O)OCH(RG)-CY,其中RF是-H,且CY和RG是如前所定义的。
在一些实施例中,化学式I的化合物具有RF,该RF被定义为H、C1-C4烷基或C3-C6环烷基。
在更优选实施例中,化学式I的化合物具有RF,该RF被定义为-H。
在化学式I的化合物的一些实施例中,RG独立地是-H或C1-C4烷基。
在更优选实施例中,化学式I的化合物具有RG,该RG被定义为-CH3。
在化学式I的化合物的一些实施例中,CY是经取代的或未经取代的芳基,或经取代的或未经取代的杂芳基,其中如果CY是经取代的,则CY被1、2或3个独立地选择的RH取代。
在优选的化学式I的化合物中,RA是-CO2H,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF、RG和CY是如前所定义的。
在其他优选的化学式I的化合物中,RA是四唑基,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF、RG和CY是如前所定义的。
在其他优选的化学式I的化合物中,RA是-C(=O)NHSO2RB,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RB、RF、RG和CY是如前所定义的。
在其他优选的化学式I的化合物中,RA是-CONHCN,RC是-F或-Cl,RD是-NRFC(=O)OCH(RG)-CY,且RF、RG和CY是如前所定义的。
实施例2A.如实施例1A所述的化合物,其中:
RC是-F、-Cl、-CN或-CF3;
RF是-H;
RG是处于R构型的-CH3;并且
实施例3A.如实施例2A所述的化合物,其中:
RA是-CO2H;
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物1,(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸。
实施例4A.如实施例2A所述的化合物,其中:
RA是-CO2H;
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物2,(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸。
实施例5A.如实施例2A所述的化合物,其中
实施例6A.如实施例5A所述的化合物,其中:
RA是-CO2H;并且
实施例7A.如实施例6A所述的化合物,其中:
实施例8A.如实施例7A所述的化合物,其中
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物3,(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例9A.如实施例7A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物4,(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例10A.如实施例7A所述的化合物,其中:
RC是-CN;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物5,(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例11A.如实施例7A所述的化合物,其中:
RC是-CN;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物6,(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例12A.如实施例6A所述的化合物,其中:
实施例13A.如实施例12A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物7,(R)-1-(3-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸,以及化合物8,(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例14A.如实施例12A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物9,(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸,以及化合物10,(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例15A.如实施例6A所述的化合物,其中:
实施例16A.如实施例15A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物11,(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例17A.如实施例15A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物12,(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例18A.如实施例6A所述的化合物,其中:
实施例19A.如实施例18A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物13,(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例20A.如实施例18A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物14,(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。
实施例21A.如实施例5A所述的化合物,其中:
RA是-C(=O)NH2;
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物15,(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯。
实施例22A.如实施例5A所述的化合物,其中:
RA是-C(=O)NHSO2RB,其中RB是-CH3;并且
实施例23A.如实施例22A所述的化合物,其中:
实施例24A.如实施例23A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物16,(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
实施例25A.如实施例23A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物17,(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
实施例26A.如实施例23A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物18,(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
实施例27A.如实施例22A所述的化合物,其中:
实施例28A.如实施例27A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物27,(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
实施例29A.如实施例27A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物20,(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
实施例30A.如实施例5A所述的化合物,其中:
实施例31A.如实施例30A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物21,(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯。
实施例32A.如实施例30A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物22,(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯。
实施例33A.如实施例30A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物23,(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯。
实施例34A.如实施例5A所述的化合物,其中:
RA是CONHCN
实施例35A.如实施例34A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物24,(R)-1-苯乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
实施例36A.如实施例33A所述的化合物,其中:
RC是-Cl;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物25,(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
实施例37A.如实施例5A所述的化合物,其中:
RA是CONHCN
实施例38A.如实施例37A所述的化合物,其中:
RC是-F;并且
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物26,(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯。
实施例39A.如实施例2A所述的化合物,其中:
RA是-CO2H;
且RC是-CN。
实施例40A.如实施例39A所述的化合物,其中:
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物27,(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸。
实施例41A.如实施例39A所述的化合物,其中:
在该实施例中,可以理解RH可以单独地位于环环和CY环中任何可用的碳原子处。具有该结构的一个示例性分子是化合物28,(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸。
实施例42A.如实施例1A所述的化合物,其中RG处于R或S构型。
实施例43A.如实施例2A所述的化合物,其中该化合物选自表1。
实施例44A.如实施例43A所述的化合物,其中该化合物是(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(3-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸、(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸。
实施例45A.如实施例1A-44A中任一项所述的化合物,用于药物的制备,该药物用于治疗LPA依赖型疾病或病症。
表1的化合物是本发明的示例并非限制,其中根据用于制备化合物1-28的实例的适当修改的程序来制备另外的化合物。
表1
实例
HPLC方法
使用由安捷伦(Agilent)HPLC泵、脱气装置和UV检测器组成的、配备有安捷伦1100系列自动进样器的HPLC,记录针对所合成的实例的HPLC示踪。出于记录质谱数据的目的,结合使用MS检测器(APCI)PE Sciex API 150EX。使用如下三种层析法之一来获得HPLC/质谱示踪:
方法1:柱Zorbax C18,尺寸4.6mm X 7.5cm;溶剂A:在水中的0.05%TFA,溶剂B:在乙腈中的0.05%TFA;流速-0.7mL/min;梯度:在9min内,5%B至100%B,保持100%B持续4min并且在0.5min内,100%B至5%B;UV检测器-通道1=220nm,通道2=254nm。
方法2:柱Zorbax C18,尺寸4.6mm X 7.5cm;溶剂A:在水中的0.05%TFA,溶剂B:在乙腈中的0.05%TFA;流速-0.7mL/min;梯度:在5min内,5%B至100%B,保持100%B持续2min并且在0.5min内,100%B至5%B;UV检测器-通道1=220nm,通道2=254nm。
方法3:SunFireTM(沃特斯)C18,尺寸2.1mm X 50mm;溶剂A:在水中的0.05%TFA,溶剂B:在乙腈中的0.05%TFA;流速-0.8mL/min;梯度:在2.4min内,10%B至90%B,保持90%B持续1.25min并且在0.25min内,90%B至10%B,保持10%B持续1.5min;UV检测器-通道1=220nm,通道2=254nm。
方法4:柱Zorbax C18,尺寸4.6mm X 50mm,5μ粒度;溶剂A:乙腈;溶剂B:在水中的0.1%HCOOH;流速-1.5mL/min;在2.5分钟内梯度10%-95%A。
实例1:(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸[化合物1]。
步骤1:乙基2-(6-氯-3-吡啶基)-2H-吡唑-3-甲酸酯
将丙酮酸乙酯(3.89mL,35.0mmol)、二甲基甲酰胺二甲基乙酸醛(9.30mL,70.0mmol)和对甲苯磺酸(10mg)的混合物在室温下搅拌过夜,然后加热至80℃持续2小时。将混合物冷却至室温并在真空中浓缩至干燥。将粗乙基4-(二甲基氨基)-2-氧代-3-丁烯酸酯溶解于乙醇(90mL)中,并用(6-氯-3-吡啶基)肼盐酸盐(7.5g,35.0mmol)和浓缩的盐酸(250μL)处理。将所得混合物加热至88℃过夜,然后冷却至室温,并在真空中浓缩。将粗残余物通过硅胶柱色谱法纯化,用己烷/乙酸乙酯梯度洗脱。分离两个区域异构体,即首先从柱洗脱所希望的异构体A[乙基2-(6-氯-3-吡啶基)-2H-吡唑-3-甲酸酯],并将不希望的区域异构体B[乙基1-(6-氯-3-吡啶基)-1H-吡唑-3-甲酸酯]作为更极性的化合物进行分离。获得呈黄色油状物的所需产物,静置时固化。
异构体A,产率=216mg(2%)。方法3,Rt 2.68min。MS(ESI)m/z 251.9[M+H+]。1HNMR(CDCl3)δ8.50(d,J=2.0Hz,1H);7.78(dd,J1=6.8Hz,J2=2.0Hz,1H);7.75(d,J=1.6Hz,1H);7.43(d,J=6.8Hz,1H);7.08(d,J=1.6Hz,1H);4.28(q,J=5.6Hz,2H);1.31,(t,J=5.6Hz,3H)。
异构体B,产率=150mg(1.7%)。方法3,Rt 2.70min。MS(ESI)m/z 251.9[M+H+]。1HNMR(CDCl3)δ8.77(d,J=2.4Hz,1H);8.15(dd,J1=7.2Hz,J2=2.4Hz,1H);7.96(d,J=2.0Hz,1H);7.46(d,J=6.8Hz,1H);7.04(d,J=2.0Hz,1H);4.45(q,J=5.6Hz,2H);1.43,(t,J=5.6Hz,3H)。
步骤2:2-(6-氯-3-吡啶基)-2H-吡唑-3-甲酸
将乙基2-(6-氯-3-吡啶基)-2H-吡唑-3-甲酸酯[实例1,步骤1](205mg,0.814mmol)在THF(4mL)中的溶液用2M LiOH水溶液(4mL)处理,并且将所得混合物在室温下剧烈搅拌16小时。LCMS显示完全转化为产物。将反应混合物转移至分液漏斗,并用0.1N HCl水溶液处理,使其pH大约为1。将产物用乙酸乙酯萃取。将有机层用无水MgSO4干燥,过滤并蒸发以产生呈白色固体的产物。产率=190mg(定量)。方法3,Rt 1.71min(宽峰)。MS(ESI)m/z 224.5[M+H+]。
步骤3:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(6-氯-3-吡啶基)-2H-吡唑
将2-(6-氯-3-吡啶基)-2H-吡唑-3-甲酸[实例1,步骤2](190mg,0.82mmol)悬浮于二氯甲烷(4mL)中,并在室温下用催化量的N,N-二甲基甲酰胺(2滴)处理。将反应混合物在冰/水浴中冷却至0℃。逐滴添加草酰氯(143μL,1.64mmol),并将所得的混合物在0℃搅拌15分钟并在室温下搅拌2小时。将等分试样在甲醇中溶解,并进行LCMS分析,该分析表明完全转化为相应的酸性氯化物。将挥发物在减压下去除,以产生呈白色固体的粗酸性氯化物。将该材料悬浮于乙酸乙酯(4mL)中,并在室温下在剧烈的磁力搅拌下,用NaN3(107mg,1.64mmol)在水(4mL)中的溶液处理。1小时后,将等分试样在甲醇中溶解,并进行LCMS分析,该分析表明完全转化为相应的酰基叠氮。分离有机层,用无水MgSO4干燥,在室温下过滤并真空蒸发以产生呈白色固体的粗酰基叠氮。将该材料悬浮于甲苯(4mL)中并伴随搅拌加热至95℃持续30分钟,直到观察到气体逸出。添加(R)-1-(o-氯苯基)-1-乙醇(157mg,1.0mmol),并且将所得混合物加热至65℃过夜。将反应混合物冷却至室温,真空浓缩至干燥,并将粗残余物通过硅胶色谱法直接纯化,该硅胶色谱法用己烷/乙酸乙酯梯度进行洗脱。获得呈无色油状物的纯产物。产率=308mg(定量)。方法3,Rt 2.97min。MS(ESI)m/z377.2[M+H+]。
步骤4:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(6-氯-3-吡啶基)-4-氟-2H-吡唑
室温下,向包含3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(6-氯-3-吡啶基)-2H-吡唑[实例1,步骤3](100mg,0.27mmol)在乙腈(2.7mL)和冰乙酸(270μL)中的搅拌溶液中添加(236mg,0.67mmol)。将所得混合物搅拌过夜,然后真空除去挥发物。将该残余物溶解于乙酸乙酯中,并用饱和NaHCO3水溶液和盐水洗涤。分离有机层,用无水MgSO4干燥,过滤并蒸发。通过制备型薄层色谱法(TLC)(用己烷/乙酸乙酯的4:1v/v混合物洗脱)纯化,以提供呈无色薄膜形式的纯产物。产率=42mg(40%)。方法3,Rt 3.04min。MS(ESI)m/z395.3[M+H+]。
步骤5:(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(6-氯-3-吡啶基)-4-氟-2H-吡唑[实例1,步骤4](42mg,0.107mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(360μL)和4-[(1-甲氧羰基)环丙基]苯基硼酸频哪醇酯(48mg,0.161mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.005mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,用乙酸乙酯萃取产物。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将该粗产物直接溶解于THF(1mL)中,并用1M LiOH水溶液(1mL)处理。将所得的混合物在室温下搅拌16小时。用1M HCl水溶液处理反应混合物,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将残余物通过硅胶制备型薄层色谱法(用50:50v/v己烷/乙酸乙酯混合物进行洗脱)纯化。产率=19mg(34%)。方法3,Rt 2.98min。MS(ESI)m/z 521.5[M+H+]。
实例2:(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸[化合物2]
步骤1:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氯-2-(6-氯-3-吡啶基)-2H-吡唑
在室温下在搅拌下用N-氯代丁二酰亚胺(64mg,0.48mmol)处理3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(6-氯-3-吡啶基)-2H-吡唑[实例1,步骤3](158mg,0.42mmol)在乙腈(2.1mL)中的溶液。将所得混合物加热至80℃持续1小时。将所得混合物冷却至室温,并直接通过制备型薄层色谱法(用分别为己烷/乙酸乙酯的4:1v/v混合物洗脱)纯化。以Rf=0.2分离呈白色固体的所希望的产物。产率=13mg(8%)。方法3,Rt 3.09min。MS(ESI)m/z411.4[M+H+]。
步骤2:(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氯-2-(6-氯-3-吡啶基)-2H-吡唑[实例2,步骤1](13mg,0.032mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(300μL)和甲基1-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酸酯(15mg,0.048mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(4mg,0.0032mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续8小时。将反应混合物冷却至室温,用乙酸乙酯萃取产物。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将该粗产物直接溶解于THF(1mL)中,并用1M LiOH水溶液(1mL)处理。将所得的混合物在室温下搅拌16小时。用1M HCl水溶液处理反应混合物,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将残余物通过硅胶制备型薄层色谱法(用50:50v/v己烷/乙酸乙酯混合物进行洗脱)纯化。产率=1.7mg(10%)。方法3,Rt 3.07min。MS(ESI)m/z 537.1[M+H+]。
实例3:(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸。[化合物3]。
步骤1:乙基-2-乙酰基-3-(二甲基氨基)丙烯酸脂
在室温下搅拌乙酸乙酯(200.0g,1.54mol)和二甲基甲酰胺二甲基乙缩醛(219.7g,1.84mol)的混合物持续16小时。通过薄层色谱法(在己烷中的30%乙酸乙酯)监测反应。将反应混合物减压浓缩以产生290.0g的粗产物,将其不经进一步纯化用于下一步。方法4,Rt 1.584min。MS(ESI)m/z 186.00-187.00[M+H+]。
1H NMR(DMSO-d6)δ7.60(s,1H);4.13(q,2H);3.34-2.90(br,6H);2.14(s,3H);1.24(t,3H)。
步骤2:乙基1-(p-溴苯基)-5-甲基-1H-吡唑-4-甲酸酯
室温下向乙基-2-乙酰基-3-(二甲基氨基)丙烯酸脂[实例3,步骤1](290.0g,1.57mol)在乙醇(4.35L)中的溶液中添加4-溴苯基肼盐酸盐(315.0g,1.41mol)。将所得混合物回流3小时。通过薄层色谱法(在己烷中的40%乙酸乙酯)监测反应进程。在减压下将反应混合物浓缩至干燥以产生粗产物,将粗产物用在己烷中的10%乙醚重结晶以产生174.0g的呈淡黄色固体的标题化合物。将母液浓缩至干燥,并用在己烷中的10%乙醚重结晶以产生另外116.0g的产物。总产率=290.0g(60%)。方法4,Rt 2.954min。MS(ESI)m/z 309.00-310.00[M+H+]。
1H NMR(DMSO-d6)δ8.03(s,1H);7.78(d,2H);7.53(d,2H);4.26(m,2H);3.34(s,3H);1.30(m,3H)。
步骤3:1-(p-溴苯基)-5-甲基-1H-吡唑-4-甲酸
室温下向乙基1-(p-溴苯基)-5-甲基-1H-吡唑-4-甲酸酯[实例3,步骤2](200.0g,0.65mol)在乙醇(1.4L)中的溶液中添加KOH(72.45g,1.29mol)溶解在水(1L)中的水溶液。将所得混合物回流3小时。通过薄层色谱法(在氯仿中的10%甲醇)监测反应。将反应混合物减压浓缩以产生相应的钾盐,将钾盐溶解于水并用乙醚洗涤。用6N HCl水溶液中和水层并用乙酸乙酯萃取。用水、盐水洗涤有机层,然后用无水硫酸钠干燥,过滤,减压浓缩,以产生172.0g呈灰白色固体的产物(产率=95%)。方法4,Rt 2.341min。MS(ESI)m/z 280.8-280.9[M+H+]。
1H NMR(DMSO-d6)δ12.48(s,1H);7.99(s,1H);7.77(d,2H);7.53(d,2H);3.36(s,3H)。
步骤4:1-(p-溴苯基)-5-甲基-1H-吡唑
将1-(p-溴苯基)-5-甲基-1H-吡唑-4-甲酸[实例3,步骤3](300.0g,1.07mol)放置在3升圆底烧瓶中,并在260℃下搅拌(浴温280至300℃)10h。通过薄层色谱法(在氯仿中的10%甲醇)监测反应。将反应混合物用乙醚稀释,并用10%碳酸钠、水和盐水洗涤,然后用硫酸钠干燥并过滤。减压浓缩有机层以产生200.0g呈浅棕色液体的产物(产率-79%)。方法4,Rt 2.739min。MS(ESI)m/z 237.0-239.9[M+H+]。
步骤5:2-(p-溴苯基)-2H-吡唑-3-甲酸
用KOH(141.7g,2.53mol)在RT下溶解在水(1L)中的水溶液,然后用KMnO4(266.6g,1.69mol)处理1-(p-溴苯基)-5-甲基-1H-吡唑[实例3,步骤4](200.0g,0.84mol)在叔丁醇(2L)中的溶液。将所得的混合物回流3小时,然后在1小时的间隔内两次添加等量的KMnO4,继续加热10小时。通过薄层色谱法(在氯仿中的10%甲醇)监测反应。将反应混合物通过硅藻土垫过滤并用热水洗涤。用乙醚洗涤水溶液,然后用6N HCl溶液中和并用乙酸乙酯萃取。用水、盐水洗涤有机层,然后用硫酸钠干燥,过滤并减压浓缩,以产生120.0g呈浅黄色固体的产物(产率=53%)。方法4,Rt 2.210min。MS(ESI)m/z 269.00[M+H+]。
1H NMR(DMSO-d6)δ13.40(s,1H);7.79(s,1H);7.66(d,2H);7.43(d,2H);7.03(s,1H)。
步骤6:3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑
按顺序用三乙胺(1.07mL,7.63mmol)、(R)-1-苯基-1-乙醇(1.16g,9.54mmol)和二苯基磷酰基叠氮化物(1.94g,7.04mmol)处理2-(p-溴苯基)-2H-吡唑-3-甲酸[实例3,步骤5](1.69g,6.36mmol)在甲苯(64mL)中的悬浮液。将所得溶液加热至90℃并保持6小时,用LCMS监测反应。将反应物冷却至室温,真空去除挥发物。将粗残余物通过硅胶色谱法(用己烷/乙酸乙酯梯度洗脱)纯化。获得呈黄色油状物的产物,静置时固化。产率=839mg(34%)。方法3,Rt 3.05min。MS(ESI)m/z 388.0[M+H+]。
步骤7:3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑
将3-[(R)-1-乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑[实例3,步骤6](385mg,1.0mmol)在乙腈(3.3mL)和乙酸(1.3mL)中的搅拌溶液用(354mg,1.0mmol)处理,并将所得的混合物在室温下搅拌过夜。LCMS显示90%转化为产物。添加另一部分(70mg),让反应在室温下再搅拌10小时。LCMS表明反应完成。反应混合物在真空中浓缩,粗残余物在乙酸乙酯和水之间分配。用水、饱和NaHCO3水溶液和盐水洗涤有机层。用无水MgSO4干燥有机物,过滤并蒸发。将浓稠的琥珀色膜通过硅胶色谱法(用己烷/乙酸乙酯梯度洗脱)纯化。产率=278mg(69%)。方法3,Rt 3.36min。MS(ESI)m/z 404-.1-406.0[M+H+]。
步骤8:(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例3,步骤7](55mg,0.136mmol)、甲苯和乙醇的2:1v/v混合物(1.4mL)、2M Na2CO3水溶液(450μL)和4-[(1-甲氧羰基)环丙基]苯基硼酸频哪醇酯(54mg,0.180mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(8mg,0.0068mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,用乙酸乙酯萃取产物。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将该粗产物直接溶解于THF(1mL)中,并用1MLiOH水溶液(1mL)处理。将所得的混合物在室温下搅拌16小时。用1M HCl水溶液处理反应混合物,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将残余物在硅-胶上通过制备薄层色谱法纯化,用95:5v/v二氯甲烷/甲醇混合物进行洗脱。产率=28mg(43%)。方法3,Rt 3.25min。MS(ESI)m/z 486.2[M+H+]。
实例4:(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物4]
步骤1:3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑
室温下,向包含3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑[实例3,步骤6](281mg,0.73mmol)在乙腈(3.7mL)中的搅拌溶液中添加N-氯代丁二酰亚胺(97mg,0.73mmol)。将所得的混合物加热至80℃持续5小时,在此后通过LCMS,确信该反应完全。将反应混合物冷却至室温,真空浓缩,并直接通过硅胶色谱法(用己烷/乙酸乙酯梯度进行洗脱)纯化。获得呈黄色油状物的产物,静置后固化。产率=277mg(91%)。方法3,Rt 3.24min。MS(ESI)m/z 422.1[M+H+]。
步骤2:甲基1-(4'-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氯-1H-吡唑-1-基}-4-联苯基基)环丙烷甲酸酯
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例4,步骤1](43mg,0.103mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(343μL)和甲基1-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酸酯(40mg,0.134mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.052mmol)处理。将所得混合物加热至85℃,并在那个室温下搅拌过夜。将反应混合物冷却至室温,用乙酸乙酯萃取产物。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,残余物通过硅胶层析纯化,用己烷/乙酸乙酯梯度洗脱。产率=45mg(85%)。方法3,Rt 3.34min。MS(ESI)m/z 516.1[M+H+]。
步骤3:(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸
将甲基1-(4'-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氯-1H-吡唑-1-基}-4-联苯基基)环丙烷甲酸酯[实例4,步骤2](45mg,0.087mmol)溶解于THF(1mL)并且用1M LiOH水溶液(1mL)处理。将所得的混合物在室温下搅拌24小时。用1M HCl水溶液处理反应混合物,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将残余物在硅-胶上通过制备薄层色谱法纯化,用95:5v/v二氯甲烷/甲醇混合物进行洗脱。产率=23mg(53%)。方法3,Rt 3.11min。MS(ESI)m/z 502.3[M+H+]。
实例5:(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物5]。
步骤1:3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑-4-甲腈
用三乙胺(730μL,5.26mmol)在甲苯(40mL)中的溶液逐滴处理包含5-氨基-1-(4-溴苯基)-1H-吡唑-4-甲腈(262mg,1.0mmol)和三光气(436mg,1.5mmol)在THF(4.8mL)中的搅拌悬浮液。将所得混合物加热至90℃持续30分钟,然后用(R)-1-苯基乙醇(160μL,1.3mmol)处理。将反应加热至105℃持续3小时,在此之后用TLC(在甲苯中的5%丙酮)监测,表明有一个主要产物形成。将反应冷却至室温并在真空中浓缩。将残余物直接通过制备型薄层色谱法(用分别为甲苯和丙酮的95:5v/v混合物洗脱)纯化。获得呈固体的产物。产率=153mg(37%)。方法3,Rt 3.53min。MS(ESI)m/z 411.5-413.6[M+H+]。
步骤2:甲基1-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酸酯
在甲醇(20mL)中溶解1-(p-溴苯基)环丙烷甲酸(1.22g,5.0mmol),用冰水(2份)和盐(1份)将其冷却至-20℃。向这个溶液中逐滴添加亚硫酰氯(1.45mL,20.0mmol)。添加完成后,将反应物在-20℃搅拌15分钟,然后在2小时内升温至室温。LCMS表明产物形成。将反应物在真空中浓缩,并且将残余物在二氯甲烷和饱和的Na2CO3水溶液之间分配。将有机层用无水MgSO4干燥,过滤蒸发以产生甲基1-(p-溴苯基)环丙烷甲酸酯(1.08g,4.2mmol,84%)。将该材料溶解于1,4-二噁烷(20mL)中,用双(频哪醇合)二硼(3.19g,12.1mmol)、KOAc(1.24g,12.6mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)处理,与二氯甲烷(328mg,0.54mmol)络合。将所得混合物加热至100℃过夜,然后冷却至室温,通过硅藻土垫过滤,并用甲醇冲洗。将滤液在真空中浓缩。部分粗材料在硅胶上通过制备薄层色谱法纯化,用己烷洗脱。产物为白色固体。产率=270mg。方法3,Rt 3.08min。MS(ESI)m/z 303.4[M+H+]。
步骤3:甲基1-(4'-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氰基-1H-吡唑-1-基}-4-联苯基基)环丙烷甲酸酯
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑-4-甲腈[实例5,步骤1](58mg,0.14mmol)、1,4-二噁烷(2mL)、2M Na2CO3水溶液(315μL)和甲基1-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酸酯[实例5,步骤2](51mg,0.17mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(23mg,0.02mmol)处理。将所得混合物加热至95℃过夜。将反应混合物冷却至室温,用硅藻土垫过滤,并用甲醇冲洗。将滤液在真空中浓缩,将粗残余物直接通过制备型薄层色谱法(用分别为己烷和乙酸乙酯的70:30v/v混合物洗脱)纯化。产率=18mg(26%)。方法3,Rt 3.13min。MS(ESI)m/z 507.6[M+H+]。
步骤4:(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸
将甲基1-(4'-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氰基-1H-吡唑-1-基}-4-联苯基基)环丙烷甲酸酯[实例5,步骤3](18mg,0.03mmol)溶解于THF(1mL)中并且用1M LiOH水溶液(1mL)处理,所得混合物在室温下搅拌过夜。通过薄层色谱法(在己烷中的30%乙酸乙酯)监测反应进程。用1M HCl的水溶液(3mL)处理反应,并用乙酸乙酯萃取产物。用无水MgSO4干燥有机层,过滤并蒸发。将粗残余物通过制备型薄层色谱法(用分别为甲苯和丙酮的70:30v/v混合物洗脱)纯化。获得呈白色固体的产物。产率=10mg(71%)。方法3,Rt2.77min。MS(ESI)m/z 493.6[M+H+]。
实例6:(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物6]。
步骤1:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑-4-甲腈
用三乙胺(730μL,5.26mmol)在甲苯(40mL)中的溶液逐滴处理包含5-氨基-1-(4-溴苯基)-1H-吡唑-4-甲腈(262mg,1.0mmol)和三光气(436mg,1.5mmol)在THF(4.8mL)中的搅拌悬浮液。将所得混合物加热至90℃持续30分钟,然后用(R)-1-(2-氯苯基)乙醇(172μL,1.3mmol)处理。将反应加热至105℃持续3小时,在此之后用TLC(在甲苯中的5%丙酮)监测,表明有一个主要产物形成。将反应冷却至室温并在真空中浓缩。将残余物直接通过制备型薄层色谱法(用分别为甲苯和丙酮的95:5v/v混合物洗脱)纯化。获得呈固体的产物。产率=153mg(37%)。方法3,Rt 2.94min。MS(ESI)m/z 445.5-447.5[M+H+]。
步骤2:甲基1-(4'-{5-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氰基-1H-吡唑-1-基}-4-联苯基基)环丙烷甲酸酯
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑-4-甲腈[实例6,步骤1](51mg,0.14mmol)、1,4-二噁烷(2mL)、2M Na2CO3水溶液(315μL)和甲基1-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酸酯[实例5,步骤2](51mg,0.17mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(23mg,0.02mmol)处理。将所得混合物加热至95℃过夜。将反应混合物冷却至室温,用硅藻土垫过滤,并用甲醇冲洗。将滤液在真空中浓缩,将粗残余物直接通过制备型薄层色谱法(用分别为己烷和乙酸乙酯的70:30v/v混合物洗脱)纯化。产率=25mg(33%)。方法3,Rt 3.20min。MS(ESI)m/z 541.3[M+H+]。
步骤3:(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸
将甲基1-(4'-{5-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氰基-1H-吡唑-1-基}-4-联苯基基)环丙烷甲酸酯[实例6,步骤2](25mg,0.03mmol)溶解于THF(1mL)并且用1MLiOH水溶液(1mL)处理,并将所得混合物在室温下搅拌过夜。通过薄层色谱法(在己烷中的30%乙酸乙酯)监测反应进程。用1M HCl水溶液(3mL)处理反应,并用乙酸乙酯萃取产物。用无水MgSO4干燥有机层,过滤并蒸发。将粗残余物通过制备型薄层色谱法(用分别为甲苯和丙酮的70:30v/v混合物洗脱)纯化。获得呈白色固体的产物。产率=12mg(76%)。方法3,Rt2.88min。MS(ESI)m/z 527.5[M+H+]。
实例7:(R)-1-(3-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物7]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例3,步骤7](55mg,0.136mmol)、甲苯和乙醇的2:1v/v混合物(1.4mL)、2M Na2CO3水溶液(450μL)和4-(1-羧基环丙基)-3-苯基硼酸频哪醇酯(55mg,0.180mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(8mg,0.0068mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,并用1M HCl水溶液处理,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将粗产物通过硅胶制备型薄层色谱法(用95:5v/v二氯甲烷/甲醇混合物进行洗脱)纯化。产率=7mg(10%)。方法3,Rt 3.26min。MS(ESI)m/z 504.2[M+H+]。
实例8-(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物8]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例3,步骤7](55mg,0.136mmol)、甲苯和乙醇的2:1v/v混合物(1.4mL)、2M Na2CO3水溶液(450μL)和4-(1-羧基环丙基)-2-苯基硼酸频哪醇酯(55mg,0.180mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(8mg,0.0068mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,并用1M HCl水溶液处理,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将粗产物通过硅胶制备型薄层色谱法(用95:5v/v二氯甲烷/甲醇混合物进行洗脱)纯化。产率=19mg(28%)。方法3,Rt 3.27min。MS(ESI)m/z 504.2[M+H+]。
实例9:(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物9]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例4,步骤1](43mg,0.103mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(343μL)和1-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酸(41mg,0.134mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.052mmol)处理。将所得混合物加热至85℃,并在该温度下搅拌过夜。将反应混合物冷却至室温,并小心地用1M HCl水溶液处理,以使pH值约为1。添加乙酸乙酯(1mL)并将所得混合物剧烈搅拌5分钟。将有机层分离,并直接通过制备型薄层色谱法(用分别为二氯甲烷和甲醇的95:5v/v混合物洗脱)纯化。产率=17mg(32%)。方法3,Rt 3.33min。MS(ESI)m/z 520.2[M+H+]。
实例10:(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物10]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例4,步骤1](43mg,0.103mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(343μL)和1-[3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酸(41mg,0.134mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.052mmol)处理。将所得混合物加热至85℃,并在该温度下搅拌过夜。将反应混合物冷却至室温,并小心地用1M HCl水溶液处理,以使pH值约为1。添加乙酸乙酯(1mL)并将所得混合物剧烈搅拌5分钟。将有机层分离,并直接通过制备型薄层色谱法(用分别为二氯甲烷和甲醇的95:5v/v混合物洗脱)纯化。产率=9mg(17%)。方法3,Rt 3.14min。MS(ESI)m/z 520.3[M+H+]。
实例11:(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物11]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例3,步骤7](55mg,0.136mmol)、甲苯和乙醇的2:1v/v混合物(1.4mL)、2M Na2CO3水溶液(450μL)和1-[3-氯-4-(二羟基硼烷基)苯基]环丙烷-1-甲酸(43mg,0.180mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(8mg,0.0068mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,并用1M HCl水溶液处理,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将粗产物通过硅胶制备型薄层色谱法(用95:5v/v二氯甲烷/甲醇混合物进行洗脱)纯化。产率=13mg(19%)。方法3,Rt 3.31min。MS(ESI)m/z 520.3[M+H+]。
实例12:(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物12]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例4,步骤1](43mg,0.103mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(343μL)和1-[3-氯-4-(二羟基硼烷基)苯基]环丙烷-1-甲酸(32mg,0.134mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.052mmol)处理。将所得混合物加热至85℃,并在该温度下搅拌过夜。将反应混合物冷却至室温,并小心地用1M HCl水溶液处理,以使pH值约为1。添加乙酸乙酯(1mL)并将所得混合物剧烈搅拌5分钟。将有机层分离,并直接通过制备型薄层色谱法(用分别为二氯甲烷和甲醇的95:5v/v混合物洗脱)纯化。产率=21mg(38%)。方法3,Rt3.20min。MS(ESI)m/z 536.1[M+H+]。
实例13:(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物13]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例3,步骤7](55mg,0.136mmol)、2:1v/v甲苯和乙醇的混合物(1.4mL)、2M Na2CO3水溶液(450μL)和1-[4-(二羟基硼烷基)-3-甲基苯基]环丙烷-1-甲酸(30mg,0.180mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(8mg,0.0068mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,并用1M HCl水溶液处理,以使pH值达到1。将产物用乙酸乙酯萃取。将有机层用水和盐水洗涤,用无水MgSO4干燥并过滤。真空浓缩后,将粗产物通过硅胶制备型薄层色谱法(用95:5v/v二氯甲烷/甲醇混合物进行洗脱)纯化。产率=12mg(18%)。方法3,Rt 3.13min。MS(ESI)m/z 500.4[M+H+]。
实例14:(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[化合物14]。
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例4,步骤1](43mg,0.103mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(343μL)和1-[4-(二羟基硼烷基)-3-甲基苯基]环丙烷-1-甲酸(29mg,0.134mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.052mmol)处理。将所得混合物加热至85℃,并在该温度下搅拌过夜。将反应混合物冷却至室温,并小心地用1M HCl水溶液处理,以使pH值约为1。添加乙酸乙酯(1mL)并将所得混合物剧烈搅拌5分钟。将有机层分离,并直接通过制备型薄层色谱法(用分别为二氯甲烷和甲醇的95:5v/v混合物洗脱)纯化。产率=23mg(43%)。方法3,Rt3.18min。MS(ESI)m/z 516.3[M+H+]。
实例15:(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯[化合物15]
步骤1:1-(p-溴苯基)环丙烷甲酰胺
用1M KOH水溶液(0.3mL)和30%H2O2(3mL)处理1-(p-溴苯基)环丙烷甲腈(500mg,2.25mmol)在乙醇(5mL)中的搅拌溶液。将所得混合物加热至85℃持续2小时。将反应物冷却至室温,用水淬灭,并将产物用乙酸乙酯萃取。将有机层用盐水洗涤,经无水MgSO4干燥、过滤并蒸发。获得呈白色固体的粗产物,无需进一步纯化直接用于下一步骤。产量=0.44g(81%)。
步骤2:1-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酰胺
将1-(p-溴苯基)环丙烷甲酰胺[实例15,步骤1](430mg,1.8mmol)溶解于1,4-二噁烷(5mL)中,用KOAc(210mg,2.1mmol)和双(频哪醇合)二硼(545mg,2.1mmol)处理。将所得混合物在N2下脱气5分钟,用[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷加合物(73mg,0.08mmol)处理,并加热至95℃持续4小时。将反应物冷却,通过硅藻土垫过滤并用乙酸乙酯冲洗。用水和盐水洗涤滤液。将有机层用盐水洗涤、经无水Na2SO4干燥、过滤并蒸发。获得呈深色油状物的粗品(0.99g)。该材料不需进行进一步纯化即可用于下一步骤。
步骤3:乙基(E)-4-(二甲基氨基)-2-氧代-丁-3-烯酸酯
将丙酮酸乙酯(5g,43.1mmol)溶解于CH2Cl2(86mL)中,并且用二甲基甲酰胺二甲基乙酸醛(5.73mL,43.1mmol)处理。将反应在室温下搅拌2小时,并在真空中浓缩。将粗品照原样用于下一步骤。产率=7.4g。
步骤4:乙基2-(4-溴苯基)吡唑-3-甲酸酯
将4-溴苯基肼盐酸盐(2.0g,8.95mmol)溶解于MeOH(18mL),并且用粗乙基(E)-4-(二甲基氨基)-2-氧代-丁-3-烯酸酯[实例15,步骤3](1.54g,9.0mmol)处理。将所得的混合物在室温下搅拌6小时。在真空中去除挥发物,并且将残余物在硅胶上通过色谱法纯化,该硅胶用己烷/乙酸乙酯的95:5v/v混合物进行洗脱,随着时间增加极性至9:1。分离两种异构体产物:呈橘黄色固体的乙基2-(4-溴苯基)吡唑-3-甲酸酯(0.82g,2.78mmol,31%)和呈红色固体的乙基1-(4-溴苯基)吡唑-3-甲酸酯(0.44g,1.49mmol,17%)。
乙基2-(4-溴苯基)吡唑-3-甲酸酯:HPLC(254nm):方法2Rt 5.22min。MS(ESI)m/z297[M+H+];294.8[M+H+];252[(M-EtO)+H+];250[(M-EtO)+H+]。
1H NMR(500MHz,CDCl3)δ7.69(d,J=1.9Hz,1H);7.58(d,J=8.7Hz,2H);7.32(d,J=8.7Hz,2H);7.03(d,J=1.9Hz,1H);4.26(q,J=7.1Hz,2H);1.28(t,J=7.1Hz,3H)。
乙基1-(4-溴苯基)吡唑-3-甲酸酯:1H NMR(500MHz,CDCl3)δ7.91(d,J=2.4Hz,1H);7.65(d,J=7.2Hz,2H);7.60(d,J=7.2Hz,2H);7.00(d,J=2.4Hz,1H);4.44(q,J=7.0Hz,2H);1.43(t,J=7.0Hz,3H)。
步骤5:2-(4-溴-苯基)-4-氟-2H-吡唑-3-甲酸乙酯
将乙基2-(4-溴苯基)吡唑-3-甲酸酯[实例15,步骤4](1.08g,3.68mmol)溶解于乙腈(12mL)中,并且将所得混合物用冰乙酸(4.6mL)处理。向此溶液中,一次性添加1-氯甲基-4-氟-1,4-重氮化二环[2.2.2]辛烷双(四氟硼酸酯)(3.91g,11.04mmol),并且将所得混合物加热至105℃持续18小时。将混合物冷却至室温,并且在真空中去除挥发物。将粗残余物直接装载到硅胶柱上,并且通过用己烷/乙酸乙酯v/v的95:5混合物洗脱来纯化,该洗脱随着时间增加极性至9:1。将产物分离为白色固体(410mg,1.31mmol,36%),并且回收起始材料(272mg,0.93mmol,25%)。针对于2-(4-溴-苯基)-4-氟-2H-吡唑-3-甲酸乙酯:HPLC(254nm):方法3Rt 2.97min。MS(ESI)m/z 313.1[M+H+]。
1H NMR(500MHz,CDCl3)δ7.60(s,1H);7.58(d,J=9Hz,2H);7.29(d,J=9Hz,2H);4.30(q,J=7.1Hz,2H);1.28(t,J=7.1Hz,3H)。
步骤6:2-(4-溴-苯基)-4-氟-2H-吡唑-3-甲酸
将在THF(13mL)中的2-(4-溴-苯基)-4-氟-2H-吡唑-3-甲酸乙酯[实例15,步骤5](410mg,1.31mmol)的搅拌溶液用LiOH 1N水溶液(13mL)处理,并且将产生的混合物在室温下搅拌过夜。通过薄层色谱法和HPLC/MS,确信反应完全。将反应混合物分配在乙酸乙酯和1N HCl溶液(100mL v/v)之间,并且转移至分液漏斗。分离有机层,并且将水层用乙酸乙酯(30mL)进行反萃取。将合并的有机层用无水MgSO4干燥,过滤并且在真空中浓缩,以提供呈白色固体的纯产物(347mg,1.22mmol,93%)。HPLC(254nm):方法3Rt 2.82min。MS(ESI)m/z285.1[M+H+]。
步骤7:(R)-[2-(4-溴-苯基)-4-氟-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯
将2-(4-溴-苯基)-4-氟-2H-吡唑-3-甲酸[实例15,步骤6](347mg,1.22mmol)悬浮于甲苯(12mL)中,并且用三乙胺(205μL,1.46mmol)处理。将产生的溶液用二苯基磷酰基叠氮化物(316μL,1.46mmol)处理,并且加热至65℃。将(R)-1-(2-氯-苯基)-乙醇(230mg,1.46mmol)添加至反应混合物中,并且将温度升高至105℃持续30分钟,在此期间观察到剧烈的气体放出。使反应到达65℃,并且在室温下搅拌4小时。通过HPLC/MS,确信反应完全。在冷却后,将挥发物在真空中去除,并且将粗残余物通过硅胶色谱法纯化,该硅胶色谱法用己烷/乙酸乙酯的梯度进行洗脱。将产物分离为白色固体(452mg,1.03mmol,85%)。HPLC(254nm):方法3Rt 3.16min。MS(ESI)m/z 440.1[M+H+]。
步骤8:(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯
将(R)-[2-(4-溴-苯基)-4-氟-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯[实例15,步骤7](200mg,0.45mmol)和1-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]环丙烷甲酰胺[实例15,步骤2](196mg,0.68mmol)溶解于乙腈(3mL)中,并用2M Na2CO3水溶液(1.5mL)处理。所得混合物在N2下脱气10分钟,用Pd[Ph3P]4(8mg,0.006mmol)处理,并加热至80℃持续6小时,在此后通过LCMS,确信该反应完全。冷却至室温后,将反应混合物通过硅藻土垫过滤并用乙酸乙酯冲洗。用水和盐水洗涤滤液。将有机层用盐水洗涤、经无水Na2SO4干燥、过滤并蒸发。将残余物通过硅胶色谱法(用己烷/乙酸乙酯梯度洗脱)纯化。获得呈黄褐色固体的纯产物。产率=28mg(12%)。方法3,Rt 3.07min。MS(ESI)m/z 518.4[M+H+]。
实例16:(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯[化合物16]。
步骤1:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑
将2-(p-溴苯基)-2H-吡唑-3-甲酸[实例3,步骤5](100g,376mmol)在二氯甲烷(1880mL)和N,N-二甲基甲酰胺(1mL)中的悬浮液机械搅拌,并在N2氛围下冷却至0℃。大约30分钟后通过加料漏斗逐滴添加草酰氯(65.6mL,752mmol)。将所得悬浮液加热至室温,然后加热至回流。回流2小时后,LCMS显示完全转化为酸性氯化物。将反应混合物冷却至rt,并且在真空中去除挥发物至干燥。获得呈米色固体的酸性氯化物。将该材料溶解于乙酸乙酯(940mL)中,用NaN3(48.88g,752mmol)溶解在H2O(940mL)中的溶液处理。在rt下搅拌1小时后,LCMS显示完全转化为酰基叠氮。分离有机层,用无水MgSO4干燥,在室温下真空过滤并蒸发。获得呈米色固体的酰基叠氮。伴随机械搅拌使该材料溶解于甲苯(1880mL)中。将反应加热至100℃持续1小时,并观察到N2逸出。MeOH淬灭后,用LCMS监测向异氰酸酯中间体的转化。逐滴添加(1R)-1-(o-氯苯基)-1-乙醇(64.77g,413.6mmol),并且将所得混合物加热至65℃过夜。冷却反应物,并在真空中浓缩至干燥。粗品是一种浓稠的琥珀色油。将该油在iPr2O(500mL)中溶解,并在rt下搅拌1小时。过滤浓稠的米色沉淀物,用iPr2O冲洗并风干。获得97g(61%)的纯产物。将母液浓缩至干燥,并将所得油状残余物在iPr2O(200mL)中重新溶解,并在rt下搅拌过夜。过滤固体,用iPr2O冲洗并风干。获得10g(6%)。总产率=107g(67%)。方法3,Rt 3.18min。MS(ESI)m/z 422.1[M+H+]。
步骤2:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑
将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑[实例16,步骤1](50g,119mmol)在乙腈(1190mL)和乙酸(119mL)中的搅拌溶液用(105.4g,297.5mmol)处理,并将所得的混合物加热至50℃。1.5小时后,LCMS表明完全转化为产物。将反应混合物冷却并在真空中浓缩。将粗残余物在乙酸乙酯和水之间分配。将有机层用水和盐水洗涤。用无水MgSO4干燥有机物,过滤并蒸发。在iPr2O(300mL)中溶解浓稠的琥珀色油,并在室温下搅拌。将沉淀物在真空下过滤并风干,以产生40g(77%)纯产物。方法3,Rt3.38min。MS(ESI)m/z 439.8[M+H+]。
步骤3:1-(4-溴-3-氟苯基)-N-(甲磺酰基)环丙烷-1-甲酰胺
将1-(4-溴-3-氟苯基)环丙烷甲酸(5.18g,20.0mmol)悬浮于二氯甲烷(100mL)中,并在室温下用催化量的N,N-二甲基甲酰胺(3滴)处理。将反应混合物在冰/水浴中冷却至0℃。逐滴添加草酰氯(3.49mL,40.0mmol),并将所得的混合物在0℃搅拌15分钟,并在室温下搅拌30分钟,然后加热至回流持续1.5小时。将等分试样在甲醇中溶解,并进行LCMS分析,该分析表明完全转化为相应的酸性氯化物。将挥发物在减压下去除,以产生呈白色固体的粗酸性氯化物,该粗酸性氯化物立即被使用。将一部分酸性氯化物(833mg,3.0mmol)溶解于甲苯中,并用三乙胺(2.1mL,15.0mmol)和甲基磺酰胺(1.43g,15.0mmol)处理。将所得混合物加热至回流持续2小时。将该反应物冷却至室温,并将该溶剂在真空下去除。将该残余物溶解于乙酸乙酯中,用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。用乙醚研磨粗固体并过滤。获得呈米色固体的产物。产率=439mg(44%)。方法3,Rt 2.60min。MS(ESI)m/z 338.4[M+H+]。
步骤4:1-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-N-(甲磺酰基)环丙烷-1-甲酰胺
将1-(4-溴-3-氟苯基)-N-(甲磺酰基)环丙烷-1-甲酰胺[实例16,步骤3](437mg,1.30mmol)溶解于1,4-二噁烷(13mL)中,并用乙酸钾(287mg,2.93mmol)和频哪醇乙硼烷(826mg,3.25mmol)处理。将所得混合物在N2下脱气10分钟。添加与二氯甲烷(53mg,0.065mmol)络合的[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II),并将该所得混合物加热至95℃持续16小时。冷却后,将反应混合物通过硅藻土垫过滤并用乙酸乙酯冲洗并浓缩。将粗残余物通过硅胶色谱法(用己烷和乙酸乙酯的1:1v/v混合物洗脱)纯化。从乙醚中研磨后,获得呈白色固体的产物。产率=273mg(55%)。方法3,Rt 2.80min。MS(ESI)m/z 384.5[M+H+]。
步骤5:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氟-2-{2'-氟-4'-[1-(甲磺酰基氨基)羧基环丙基]-4-联苯基基}-2H-吡唑
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例16,步骤2](44mg,0.10mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(333μL)和1-[3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]-N-(甲磺酰基)环丙烷-1-甲酰胺[实例16,步骤4](57mg,0.15mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.005mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续6小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过制备型薄层色谱法(用分别为丙酮和二氯甲烷的90:10v/v混合物洗脱)纯化。产率=8mg(13%)。方法3,Rt 3.24min。MS(ESI)m/z 615.2[M+H+]。
实例17:(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯[化合物17]
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例3,步骤7](37mg,0.092mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(333μL)和1-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-N-(甲磺酰基)环丙烷-1-甲酰胺[实例16,步骤4](57mg,0.15mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.005mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续6小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过制备型薄层色谱法(用分别为丙酮和二氯甲烷的90:10v/v混合物洗脱)纯化。产率=6mg(11%)。方法3,Rt 3.34min。MS(ESI)m/z 581.4[M+H+]。
实例18:(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯[化合物18]
步骤1:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑
室温下,向包含3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑[实例16,步骤1](486mg,1.16mmol)在乙腈(6mL)中的搅拌溶液中添加N-氯代丁二酰亚胺(155mg,1.16mmol)。将所得的混合物加热至80℃持续4小时,在此后通过LCMS,确信该反应完全。将反应混合物冷却至室温,真空浓缩,并直接通过硅胶柱色谱法纯化,该硅胶色谱法用己烷/乙酸乙酯梯度进行洗脱。获得呈黄色油状物的产物,静置时固化。产率=328mg(62%)。方法3,Rt 3.27min。MS(ESI)m/z 455.8[M+H+]。
步骤2:(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例18,步骤1](45mg,0.10mmol)、甲苯和乙醇的2:1v/v混合物(1mL)、2M Na2CO3水溶液(333μL)和1-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-N-(甲磺酰基)环丙烷-1-甲酰胺[实例16,步骤4](57mg,0.15mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(6mg,0.005mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续6小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过制备型薄层色谱法(用分别为丙酮和二氯甲烷的90:10v/v混合物洗脱)纯化。产率=4.8mg(8%)。方法3,Rt 3.11min。MS(ESI)m/z631.7[M+H+]。
实例19:(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯[化合物19]
步骤1:1-(4-溴苯基)-N-(甲磺酰基)环丙烷-1-甲酰胺
将1-(p-溴苯基)环丙烷甲酸(2.41g,10.0mmol)悬浮于二氯甲烷(50mL)中,并在室温下用催化量的N,N-二甲基甲酰胺(3滴)处理。将反应混合物在冰/水浴中冷却至0℃。逐滴添加草酰氯(1.75mL,20.0mmol),并将所得的混合物在0℃搅拌15分钟,并在室温下搅拌30分钟,然后加热至回流持续1.5小时。将等分试样在甲醇中溶解,并进行LCMS分析,该分析表明完全转化为相应的酸性氯化物。将挥发物在减压下去除,以产生呈白色固体的粗酸性氯化物,该粗酸性氯化物立即被使用。将酸性氯化物(2.60g,10.0mmol)溶解于甲苯(25mL)中,并用三乙胺(7.01mL,50.0mmol)和甲基磺酰胺(4.75g,50.0mmol)处理。将所得混合物加热至回流持续2小时。将该反应物冷却至室温,并将该溶剂在真空下去除。将该残余物溶解于乙酸乙酯中,用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。用二异丙醚研磨粗固体并过滤。获得呈黄褐色固体的产物。产率=997mg(31%)。方法3,Rt 2.74min。MS(ESI)m/z 318.3-319.8[M+H+]。
步骤2:N-(甲磺酰基)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)环丙烷-1-甲酰胺
将1-(4-溴苯基)-N-(甲磺酰基)环丙烷-1-甲酰胺[实例19,步骤1](997mg,3.13mmol)溶解于1,4-二噁烷(30mL)中,并用乙酸钾(690mg,7.04mmol)和频哪醇乙硼烷(1.99g,7.83mmol)处理。将所得混合物在N2下脱气10分钟。添加与二氯甲烷(128mg,0.157mmol)络合的[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II),并将该所得混合物加热至95℃持续16小时。冷却后,将反应混合物通过硅藻土垫过滤并用乙酸乙酯冲洗并浓缩。将粗残余物通过硅胶色谱法(用己烷和乙酸乙酯梯度洗脱)纯化。从乙醚中研磨后,获得呈白色固体的产物。产量=1.00g(88%)。方法3,Rt 2.95min。MS(ESI)m/z 366.0[M+H+]。
步骤3:(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例4,步骤1](210mg,0.5mmol)、甲苯和乙醇的2:1v/v混合物(5mL)、2M Na2CO3水溶液(1.67mL)和N-(甲磺酰基)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)环丙烷-1-甲酰胺[实例19,步骤2](219mg,0.6mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(29mg,0.025mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过硅胶色谱法(用己烷和乙酸乙酯梯度洗脱)纯化。获得呈白色固体的产物。产率=140mg(48%)。方法3,Rt 3.36min。MS(ESI)m/z 579.4[M+H+]。
实例20:(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯[化合物20]
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例15,步骤5](219mg,0.5mmol)、甲苯和乙醇的2:1v/v混合物(5mL)、2M Na2CO3水溶液(1.67mL)和N-(甲磺酰基)-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)环丙烷-1-甲酰胺[实例19,步骤2](219mg,0.6mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(29mg,0.025mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续16小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过硅胶色谱法(用己烷和乙酸乙酯梯度洗脱)纯化。获得呈白色固体的产物。产率=110mg(37%)。方法3,Rt 3.21min。MS(ESI)m/z 597.4[M+H+]。
实例21:(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯[化合物21]
步骤1:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-[4'-(1-氰基环丙基)-4-联苯基基]-4-氟-2H-吡唑
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氟-2H-吡唑[实例15,步骤5](438mg,1.0mmol)、甲苯和乙醇的2:1v/v混合物(10mL)、2M Na2CO3水溶液(3.3mL)和4-(1-氰基环丙基)苯基硼酸(243mg,1.3mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(58mg,0.05mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续3小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过硅胶色谱法(用己烷和乙酸乙酯梯度洗脱)纯化。产率=403mg(81%)。方法3,Rt 3.20min。MS(ESI)m/z 501.7[M+H+]。
步骤2:(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯
用二丁基锡(IV)氧化物(dibutyltin(IV)oxide)(27mg,0.10mmol)和三甲基硅烷基叠氮化物(36μL,0.27mmol)处理包含在甲苯(10mL)中的3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-{6-[p-(1-氰基环丙基)苯基]-3-吡啶基}-4-氟-2H-吡唑[实例21,步骤1](50mg,0.10mmol)的搅拌溶液。将所得混合物加热至100℃持续16小时,然后冷却至室温,并在真空中浓缩。将粗产物通过制备薄层色谱法(用分别为二氯甲烷和甲醇的95:5v/v混合物洗脱)纯化。产率=17mg(31%)。方法3,Rt 3.29min。MS(ESI)m/z 544.5[M+H+]。
实例22:(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯[化合物22]
步骤1:3-[(R)-1-苯基乙氧基羰基氨基]-4-氯-2-[4'-(1-氰基环丙基)-4-联苯基基]-2H-吡唑
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例4,步骤1](210mg,0.5mmol)、甲苯和乙醇的2:1v/v混合物(5mL)、2M Na2CO3水溶液(1.7mL)和4-(1-氰基环丙基)苯基硼酸(112mg,0.6mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(29mg,0.025mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续3小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过硅胶色谱法(用己烷和乙酸乙酯梯度洗脱)纯化。获得呈白色固体的产物。产率=173mg(72%)。方法3,Rt 3.36min。MS(ESI)m/z 483.5[M+H+]。
步骤2:(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯
用二丁基锡(IV)氧化物(58mg,0.23mmol)和三甲硅基叠氮化物(75μL,0.57mmol)处理在甲苯(1mL)中的包含3-[(R)-1-苯基乙氧基羰基氨基]-4-氯-2-[4'-(1-氰基环丙基)-4-联苯基基]-2H-吡唑[实例22,步骤1](101mg,0.21mmol)的搅拌溶液。将所得混合物加热至100℃持续16小时,然后冷却至室温,并在真空中浓缩。将该残余物溶解于乙酸乙酯中,并用1N HCl水溶液处理,并用盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。通过C-18反相色谱法(用水和乙腈+0.1%TFA梯度洗脱)纯化粗产物。产率=39mg(35%)。方法3,Rt3.07min。MS(ESI)m/z 526.1[M+H+]。
实例23:(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯[化合物23]
步骤1:3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氯-2-[4'-(1-氰基环丙基)-4-联苯基基]-2H-吡唑
在N2下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例18,步骤1](227mg,0.5mmol)、甲苯和乙醇的2:1v/v混合物(5mL)、2M Na2CO3水溶液(1.7mL)和4-(1-氰基环丙基)苯基硼酸(112mg,0.6mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(29mg,0.025mmol)处理。将产生的混合物加热至85℃,并在该温度下搅拌持续3小时。将反应混合物冷却至室温,用乙酸乙酯(50mL)萃取,并用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗产物通过硅胶色谱法(用己烷和乙酸乙酯梯度洗脱)纯化。获得呈白色固体的产物。产率=189mg(73%)。方法3,Rt 3.48min。MS(ESI)m/z517.3[M+H+]。
步骤2:(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯
用二丁基锡(IV)氧化物(58mg,0.23mmol)和三甲硅基叠氮化物(75μL,0.57mmol)处理在甲苯(1mL)中的包含3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氯-2-[4'-(1-氰基环丙基)-4-联苯基基]-2H-吡唑[实例23,步骤1](108mg,0.21mmol)的搅拌溶液。将所得混合物加热至100℃持续16小时,然后冷却至室温,并在真空中浓缩。将该残余物溶解于乙酸乙酯中,并用1N HCl水溶液处理,并用盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。通过C-18反相色谱法(用水和乙腈+0.1%TFA梯度洗脱)纯化粗产物。产率=36mg(31%)。方法3,Rt 3.18min。MS(ESI)m/z 560.1[M+H+]。
实例24:(R)-1-苯乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯[化合物24]
将(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[实例4](200mg,0.40mmol)与吡啶(10mL)一起共蒸发两次,并在DMF(4.5mL)中溶解。将所得溶液用吡啶(300μL,3.75mmol)处理,然后逐滴添加五氟苯基三氟乙酸酯(125μL,0.71mmol)。室温下2小时后,LCMS分析表明完全转化为相应的五氟苯基酯。将反应混合物用乙酸乙酯(30mL)稀释,并用饱和NaHCO3水溶液处理。分离有机层,用盐水洗涤,经无水MgSO4干燥、过滤并蒸发。残余物被吸收到DMF(4mL)中,并在室温下用氰胺一钠(77mg,1.2mmol)处理过夜。第二天早晨,将反应物用乙酸乙酯(30mL)稀释,并用饱和NaHCO3水溶液处理。分离有机层,用盐水洗涤,经无水MgSO4干燥、过滤并蒸发。将产物通过制备薄层色谱法(用分别为二氯甲烷和甲醇的90:10v/v混合物洗脱)纯化。产率=36mg(32%)。方法3,Rt 2.84min。MS(ESI)m/z 526.5[M+H+]。
实例25:(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯[化合物25]
步骤1:1-(4-溴苯基)-N-氰基环丙烷-1-甲酰胺
将1-(p-溴苯基)环丙烷甲酸(2.41g,10.0mmol)悬浮于二氯甲烷(34mL)中,并在室温下用催化量的N,N-二甲基甲酰胺(2滴)处理。将反应混合物在冰/水浴中冷却至0℃。逐滴添加草酰氯(1.75mL,20.0mmol),并将所得的混合物在0℃搅拌15分钟,并在室温下搅拌30分钟,然后加热至回流持续2小时。将等分试样在甲醇中溶解,并进行LCMS分析,该分析表明完全转化为相应的酸性氯化物。将挥发物在减压下去除,以产生呈白色固体的粗酸性氯化物,该粗酸性氯化物立即被使用。将酸性氯化物(2.60g,10.0mmol)溶解于DMF(30mL)中,取10mL该溶液的等分试样(3.3mmol),并用氰胺一钠(640mg,10.0mmol)处理。将所得混合物在室温下搅拌过夜。用乙酸乙酯稀释反应物,用1N HCl水溶液和盐水洗涤。用无水MgSO4干燥有机层,过滤并蒸发。将粗固体产物不经任何进一步纯化而用于下一步骤。获得呈固体的产物。产率=650mg(74%)。方法3,Rt 2.68min。MS(ESI)m/z 267.3[M+H+]。
步骤2:N-氰基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)环丙烷-1-甲酰胺
将1-(4-溴苯基)-N-氰基环丙烷-1-甲酰胺[实例25,步骤1](650mg,2.44mmol)溶解于1,4-二噁烷(12mL)中,用双(频哪醇合)二硼(1.94g,7.33mmol)、KOAc(720mg,7.33mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)处理,与二氯甲烷(193mg,0.32mmol)络合。将所得混合物加热至100℃过夜,然后冷却至室温,通过硅藻土垫过滤,并用甲醇冲洗。将滤液在真空中浓缩。将粗材料通过硅胶制备型薄层色谱法(用己烷和乙酸乙酯的1:1v/v混合物洗脱)纯化。产物为白色固体。产率=400mg(53%)。方法3,Rt 2.86min。MS(ESI)m/z 313.6[M+H+]。
步骤3:(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-((氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯
在氮气下,将3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-4-氯-2H-吡唑[实例18,步骤1](127mg,0.28mmol)、1,4-二噁烷(3mL)、2M Na2CO3水溶液(630μL)和N-氰基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)环丙烷-1-甲酰胺[实例25,步骤2](106mg,0.34mmol)的搅拌悬浮液脱气10分钟,并用Pd[Ph3P]4(46mg,0.04mmol)处理。在95℃下,伴随着搅拌,将所得混合物浸入油浴持续12小时。将反应冷却,转移至分液漏斗并且用乙酸乙酯(50mL)稀释。将混合物小心的用1N HCl水溶液(20mL)处理。分离有机层,用盐水洗涤,用无水MgSO4干燥,过滤并且在真空中浓缩。将粗残余物通过制备型TLC板(1000μm)纯化,该板用二氯甲烷/甲醇的9:1v/v混合物进行洗脱。获得呈白色固体的产物。产率=18mg(12%)。HPLC(254nm):方法3,Rt 3.15min。MS(ESI)m/z 560.5[M+H+]。
实例26:(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯[化合物26]
步骤1:(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸
在氮气下,将(R)-[2-(4-溴-苯基)-4-氟-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯[实例15,步骤5](88mg,0.2mmol)、2:1v/v甲苯/乙醇(2mL)、2M Na2CO3的水溶液(670μL)和1-[4-(二羟基硼烷基)-3-氟苯基]环丙烷-1-甲酸(45mg,0.20mmol)的搅拌悬浮液脱气10分钟,并用Pd[Ph3P]4(12mg,0.01mmol)处理。在90℃下,伴随着搅拌,将所得混合物浸入油浴持续12小时。将反应冷却,转移至分液漏斗并且用乙酸乙酯(50mL)稀释。将混合物小心的用1N HCl水溶液(20mL)处理。分离有机层,用盐水洗涤,用无水MgSO4干燥,过滤并且在真空中浓缩。将粗残余物通过制备型TLC板(1000μm)纯化,用1:1v/v己烷/乙酸乙酯混合物进行洗脱。获得呈白色固体的产物。产率=40mg(37%)。HPLC(254nm):方法3,Rt3.14min。MS(ESI)m/z 538.3[M+H+]。
步骤2:(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯
室温下,用N,N'-二环己基碳二亚胺(41mg,0.2mmol)处理包含(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸[实例26,步骤1](107mg,0.2mmol)、THF(1mL)和N-羟基丁二酰亚胺(23mg,0.2mmol)的搅拌混合物。将所得混合物搅拌3小时,然后过滤分离的固体,并将滤液添加到氰胺一钠(38mg,0.6mmol)在水(1mL)中的搅拌溶液中。将所得混合物在室温下搅拌2天。将反应混合物用乙酸乙酯(30mL)稀释,用0.1NHCl水溶液处理至pH约为3。分离有机层,用盐水洗涤,经无水MgSO4干燥、过滤并蒸发。将粗产物通过制备薄层色谱法(用分别为二氯甲烷和甲醇的90:10v/v混合物洗脱)纯化。产率=36mg(32%)。方法3,Rt 3.13min。MS(ESI)m/z561.9[M+H+]。
实例27:(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸[化合物27]
在N2下,将包含2-(p-溴苯基)-2-甲基丙酸(66mg,0.27mmol)、四羟基二硼(109mg,1.22mmol)、KOAc(26mg,1.22mmol)在乙醇(3mL)中的混合物脱气,然后用XPhosPdG3(6mg,0.007mmol)处理。在磁力搅拌下将该混合物加热至80℃持续2小时,然后冷却至室温。然后依次用3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑-4-甲腈[实例6,步骤1](54mg,0.12mmol)、2M K2CO3水溶液(270μL)和XPhosPdG3(2mg,0.0023)处理该反应物。所得混合物用N2脱气5分钟,然后加热至80℃持续16小时。将反应物冷却至室温,用硅藻土垫过滤,并用乙醇冲洗。将滤液在真空中浓缩,并将残余物直接通过制备型薄层色谱法(用分别为甲苯和丙酮的70:30v/v混合物洗脱)纯化。获得呈白色固体的产物(12mg,19%)。方法3,Rt 3.23min。MS(ESI)m/z 529.5[M+H+]。
实例28-(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸[化合物28]
步骤1:甲基2-甲基-2-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]丙酸酯
在甲醇(20mL)中溶解2-(p-溴苯基)-2-甲基丙酸(1.22g,5.0mmol),用冰水(2份)和盐(1份)将其冷却至-20℃。向这个溶液中逐滴添加亚硫酰氯(1.45mL,20.0mmol)。添加完成后,将反应物在-20℃搅拌15分钟,然后在2小时内升温至室温。LCMS表明产物形成。将反应物在真空中浓缩,并且将残余物在二氯甲烷和饱和的Na2CO3水溶液之间分配。将有机层经无水MgSO4干燥,过滤并蒸发以产生甲基2-(p-溴苯基)-2-甲基丙酸酯(0.9g,3.5mmol,70%)。将该材料溶解于1,4-二噁烷(20mL)中,用双(频哪醇合)二硼(2.69g,10.1mmol)、KOAc(1.03g,10.5mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)处理,与二氯甲烷(328mg,0.44mmol)络合。将所得混合物加热至100℃过夜,然后冷却至室温,通过硅藻土垫过滤,并用甲醇冲洗。将滤液在真空中浓缩。部分粗材料通过硅胶制备型薄层色谱法(用己烷洗脱)纯化。产物为白色固体。产率=153mg。方法3,Rt 3.37min。MS(ESI)m/z 305.8[M+H+]。
步骤2:甲基2-(4'-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氰基-1H-吡唑-1-基}-4-联苯基基)-2-甲基丙酸酯
在N2下,将3-[(R)-1-苯基乙氧基羰基氨基]-2-(p-溴苯基)-2H-吡唑-4-甲腈[实例5,步骤1](58mg,0.14mmol)、1,4-二噁烷(2mL)、2M Na2CO3水溶液(315μL)和甲基2-甲基-2-[p-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]丙酸酯[实例24,步骤1](51mg,0.17mmol)的搅拌混合物脱气10分钟,并用Pd[Ph3P]4(23mg,0.02mmol)处理。将所得混合物加热至95℃过夜。将反应混合物冷却至室温,用硅藻土垫过滤,并用甲醇冲洗。将滤液在真空中浓缩,将粗残余物直接通过制备型薄层色谱法(用分别为己烷和乙酸乙酯的70:30v/v混合物洗脱)纯化。产率=20mg(28%)。方法3,Rt 3.17min。MS(ESI)m/z 509.3[M+H+]。
步骤3:(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸
将甲基2-(4'-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氰基-1H-吡唑-1-基}-4-联苯基基)-2-甲基丙酸酯[实例28,步骤1](18mg,0.03mmol)溶解于THF(1mL)中,并用1M LiOH水溶液(1mL)处理,并将所得混合物在室温下搅拌过夜。通过薄层色谱法(在己烷中的30%乙酸乙酯)监测反应进程。用1M HCl水溶液(5mL)处理反应,并用乙酸乙酯萃取产物。用无水MgSO4干燥有机层,过滤并蒸发。将粗残余物通过制备型薄层色谱法(用分别为甲苯和丙酮的70:30v/v混合物洗脱)纯化。获得呈白色固体的产物。产率=15mg(定量)。方法3,Rt2.93min。MS(ESI)m/z 495.8[M+H+]。
根据针对化合物1-28所概述的程序,制备表1的化合物及其衍生物。基于在引文1-19中所描述的方法,制备集合相应的氨基甲酸酯所需要的杂环胺或杂环酯。
遵循适当的芳基吡唑的构造制备某些吡唑取代(8,方案1)。直接氟化、氯化或三氟甲基化提供了芳基溴化物(9),根据实例1-28所述的步骤,该中间体适于进一步修饰本发明的化合物。
方案1
可替代地,核心吡唑(8)可以根据方案2中描述的方法制备:
方案2
当考虑到作为氰基的RC的要求时,相应的核心氰基吡唑(9)根据方案3中描述的步骤制备:
方案3
实例29.受体结合测定
基于其从CHO细胞中替换氚标记的溶血磷脂酸([3H]-LPA)的能力确定具有化学式I-III的化合物的结合亲和力,该CHO细胞以在参考文献17中所描述的相似的方案表达LPA1R。在96孔格中,将CHO细胞表达的人类LPA1R[Cerep]用[3H]-LPA(2nM)进行处理。以递增浓度将测试化合物添加至各孔中,并且在室温下孵育90分钟。此时,洗涤板并且针对放射活性将孔进行计数。将结果与对照进行比较,其中在存在10μM未标记的LPA情况下,将细胞用[3H]-LPA处理。将受体的特异性配体结合定义为在非标记配体过量存在下,所确定的所有的结合和非特异性结合之间的差。将结果表示为在测试化合物存在下所获得的对照特异性结合的百分率((所测量的特异性结合/对照特异性结合)x 100)和对照照特异性结合的抑制百分率(100-(所测量的特异性结合/对照特异性结合)x 100))。通过非线性回归分析的竞争曲线,确定IC50值(引起半数最大抑制对照特异性结合的浓度)和希尔系数(nH),该竞争曲线使用希尔方程曲线拟合用平均重复值生成的(Y=D+[(A-D)/(1+(C/C50)nH)],其中Y=特异性结合,D=最小特异性结合,A=最大特异性结合,C=化合物浓度,C50=IC50,并且nH=坡度因子)。使用Cerep研发的软件(希尔软件)进行该分析,并且通过与由以下软件产生的数据进行比较来确认:商业软件4.0适用于(1997by SPSS公司)。使用Cheng Prusoff方程(Ki=IC50/(1+(L/KD)),其中L=测定中的放射性配体的浓度,并且KD=放射性配体对于受体的亲和力)计算抑制常数(Ki)。将斯卡查德图用来确定Kd。
实例30.钙流动测定
在96孔板格中,使用FLIPR技术,可以将抑制LPA-刺激的Ca2+流动用来评估化合物效力。所使用的测定缓冲液是一种修饰的Hanks平衡盐溶液(HBSS),其中在pH7.4下,将HBSS补充以包含20mM HEPES和2.5mM丙磺舒(密理博(Millipore),GPCR)。将LPA1R表达细胞(密理博(Millipore))铺板,并且在测定测试品之前的24小时进行制备。从基于荧蒽的免洗Ca2+染料的荧光,评估Ca2+离子流。从板中产生了拮抗剂数据,该板具有足以产生80%功效[EC80]的LPA浓度。根据具有化学式I-VI的化合物的浓度,从功效的减少计算抑制百分率。针对于剂量反应,将该抑制数据用来计算化合物IC50。
在FLIPRTETRA仪器上进行激动剂测定,其中在建立荧光基线之后,将一种或多种测试化合物、载体对照、和参考激动剂添加至测定板。激动剂测定总共是180秒,并且被用来评估每个化合物活化每个所测定的GPCR能力。当完成激动剂测定时,从FLIPRTETRA上去除测定板,并且在25℃下孵育七(7)分钟。在孵育期后,将测定板放回FLIPRTETRA中,并且开始拮抗剂测定。
拮抗剂测定:在建立荧光基线后,使用在拮抗剂测定期间所确定的EC80势值,将预孵育的样品化合物孔用参考激动剂的EC80浓度进行激发。使用同样的测定板进行拮抗剂测定,该测定板被用于激动剂测定。在FLIPRTETRA仪器上进行拮抗剂测定,其中将9个载体对照和EC80浓度的参考激动剂添加至适当的孔。拮抗剂测定总共是180秒,并且被用来评估每个化合物抑制每个所测定的GPCR能力。
数据处理:所有的测定板数据都将受到适当的基线校正。在应用基线校正后,将最大荧光值输出并且数据处理以计算激活百分率(相对于Emax参考激动剂和载体对照的值)、抑制百分率(相对于EC80和载体对照的值)、和额外的统计值(即,Z’,在复制数据值之间的百分率变动),以评估每个板的质量。当驳回测定板数据的情况下,进行额外的试验。使用绘制医学图表生成所有的剂量反应曲线。当底部参数拟合为“0”的情况下,通过利用“形剂量效应(可变斜率)”拟合曲线。当通过所测定的浓度没能生成一条完整曲线,适当的时候,将顶部参数拟合为“100”以更好预测势值。
针对代表性化合物的拮抗活性数据呈现于表2中,该代表性化合物是根据在此披露的合成方法所制备的。
表2.针对具有化学式I-III的代表性化合物的体外生物数据,除非另外指出,在LPA1R Ca2+通量功能测定中所测试的化合物具有小于50μM的IC50。
化合物 | LPA1 R拮抗活性 | 实例编号 | LPA1 R拮抗活性 |
1 | A | 15 | A |
2 | A | 16 | A |
3 | A | 17 | A |
4 | A | 18 | A |
5 | A | 19 | A |
6 | A | 20 | A |
7 | A | 21 | C |
8 | A | 22 | A |
9 | A | 23 | C |
10 | A | 24 | C |
11 | A | 25 | C |
12 | A | 26 | A |
13 | A | 27 | A |
14 | A | 28 | A |
除非另外指出,在LPA1R Ca2+通量功能测定中所测试的化合物具有小于50μM的IC50。A=小于0.3μM;B=大于0.3μM且小于1μM;C=大于1μM且小于50μM;D=大于50μM
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Claims (22)
1.一种具有化学式I的结构的化合物
或其药学上可接受的盐或前药,
其中RA是-CO2H、四唑基、-C(=O)NH2、-C(=O)NHRB、-CONHCN、-C(=O)NHSO2RB或-C(=O)NHCH2CH2SO3H或羧酸电子等排体;
A1是N或C;
环A具有以下之一的结构:
RC是-CN、-F、-Cl、-Br、-I、-OC1-C4烷基、C3-C6环烷基、或C1-C4氟代烷基;
RD是-N(RF)-C(=O)XCH(RG)-CY,其中X是O且CY是被一个RH取代的苯基:
RE、RF和RG独立地是-H或C1-C4烷基或C3-C6环烷基,或者RE和RF独立地是-H或C1-C4烷基或C1-C6环烷基,并且一个RG是-C1-C4烷基并且和环ARD取代基的RH苯基部分和RG与所述苯基部分所附接的碳原子一起定义一种经取代的或未经取代的碳环或经取代的或未经取代的杂环,并且另一个RG,如果存在,是如对RE所定义的;
每个RH独立地是-H、卤素、C1-C4烷基。
4.根据权利要求3所述的化合物,其中该化合物是(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸或(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸。
6.根据权利要求5所述的化合物,其中该化合物是
(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸或(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸。
8.根据权利要求7所述的化合物,其中该化合物是(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、1-(4'-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氯-1H-吡唑-1-基}-2-氟-4-联苯基基)环丙烷甲酸、(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、或1-[4-(p-{5-[(R)-1-苯基乙氧基羰基氨基]-4-氯-1H-吡唑-1-基}苯基)甲苯基]环丙烷甲酸。
10.根据权利要求9所述的化合物,其中该化合物是(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯。
12.根据权利要求11所述的化合物,其中该化合物是(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、或(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
14.根据权利要求13所述的化合物,其中该化合物是(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯或(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯。
16.根据权利要求15所述的化合物,其中该化合物是(R)-1-苯乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(4'-(1-(氰基氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯或(R)-1-(2-氯苯基)乙基(1-(4'-(1-(氰基氨基甲酰基)环丙基)-2'-氟-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯。
17.根据权利要求2和12所述的化合物,其中该化合物是(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯。
18.根据权利要求1所述的化合物,其中RG处于R或S构型。
19.一种药物组合物,该药物组合物包含:
根据权利要求1所述的化合物;以及
药学上可接受的赋形剂。
20.一种用于在有需要的受试者中治疗溶血磷脂酸依赖型疾病或病症的方法,该方法包括:
向该受试者施用治疗有效量的根据权利要求1所述的化合物。
21.根据权利要求79所述的方法,其中该溶血磷脂酸依赖型疾病或病症是糖尿病性肾病或非酒精性脂肪性肝炎(NASH)。
22.一种化合物,该化合物选自由以下组成的组:(R)-1-(4-(5-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氟-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4-(5-(4-氯-5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-1H-吡唑-1-基)吡啶-2-基)苯基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(3-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氟-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-3-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-氟-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯-4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氟-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(4'-(4-氯-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-2-甲基-[1,1'-联苯基]-4-基)环丙烷-1-甲酸、(R)-1-(2-氯苯基)乙基(1-(4'-(1-氨基甲酰基环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氟-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氯-1-(2'-氟-4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(4-氯-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(4-氟-1-(4'-(1-((甲磺酰基)氨基甲酰基)环丙基)-[1,1'-联苯基]-4-基)-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氟-1H-吡唑-5-基)氨基甲酸酯、(R)-1-苯乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、(R)-1-(2-氯苯基)乙基(1-(4'-(1-(1H-四唑-5-基)环丙基)-[1,1'-联苯基]-4-基)-4-氯-1H-吡唑-5-基)氨基甲酸酯、3-[(R)-1-苯基乙氧基羰基氨基]-4-氯-2-{4'-[1-(氨基氰)羧基环丙基]-4-联苯基基}-2H-吡唑、3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-4-氯-2-{4'-[1-(氨基氰)羧基环丙基]-4-联苯基基}-2H-吡唑、3-[(R)-1-(o-氯苯基)乙氧基羰基氨基]-2-{4'-[1-(氨基氰)羧基环丙基]-2'-氟-4-联苯基基}-4-氟-2H-吡唑、(R)-2-(4'-(5-(((1-(2-氯苯基)乙氧基)羰基)氨基)-4-氰基-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸、(R)-2-(4'-(4-氰基-5-(((1-苯乙氧基)羰基)氨基)-1H-吡唑-1-基)-[1,1'-联苯基]-4-基)-2-甲基丙酸。
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