Small molecule inhibitors of Bcl-2-associated death promoting factor (BAD) phosphorylation
阅读说明：本技术 Bcl-2相关死亡促进因子(BAD)磷酸化的小分子抑制剂 (Small molecule inhibitors of Bcl-2-associated death promoting factor (BAD) phosphorylation ) 是由 彼得·爱德华·罗别 维贾伊·库马·潘迪 兰加帕·坎楚加拉科帕尔苏贝戈达 巴萨帕·萨隆地 莫汉 于 2018-04-18 设计创作，主要内容包括：本发明涉及通式(I)化合物：其中R<Sup>1</Sup>、n、R<Sup>2a</Sup>、R<Sup>2b</Sup>和R<Sup>3</Sup>如本文中所限定。所述化合物是Bcl-2相关死亡促进因子(BAD)磷酸化的抑制剂并且具有抗凋亡活性,并且可用于治疗癌症,特别是乳腺癌、子宫内膜癌、卵巢癌、肝癌、结肠癌、前列腺癌或胰腺癌。<Image he="311" wi="700" file="DDA0002238818000000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to compounds of general formula (I): wherein R is 1 、n、R 2a 、R 2b And R 3 As defined herein. The compounds are inhibitors of Bcl-2-related death promoting factor (BAD) phosphorylation and have anti-apoptotic activity and are useful in the treatment of cancer, in particular breast cancer, endometrial cancer,Ovarian, liver, colon, prostate, or pancreatic cancer.)
1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof or a deuterated or tritiated variant thereof, including all stereoisomers:
wherein:
each R1Independently halogen, OH, cyano, nitro, NR10R11、C(O)R10、C(O)OR10、C(O)NR10R11、-S(O)qNR10R11、C1-6Alkyl radical, C1-6Haloalkyl, -O (C)1-6Alkyl), -O (C)1-6Haloalkyl), aryl, heteroaryl, -O-aryl or-O-heteroaryl,
wherein
R10And R11Each independently selected from H or C1-6Alkyl radical, said C1-6Alkyl is optionally substituted by one or more substituents selected from OH, halogen, cyano, NH2Aryl or heteroaryl, substituted with one or more substituents;
alkyl and haloalkyl radicals R1Optionally substituted with one or more substituents selected from: OH, cyano, -S (O)PNR4R5、-C(O)NR4R5Aryl, heteroaryl, -O-aryl or-O-heteroaryl, -O (C) optionally substituted with aryl1-6Alkyl), or-O (C)1-6Haloalkyl);
aryl or heteroaryl R1Optionally substituted with one or more substituents selected from: halogen, OH, cyano, nitro, -NR4R5、-S(O)PNR4R5、-C(O)NR4R5、-C(O)R4、-C(O)OR4or-C1-6Alkyl or-O (C)1-6Alkyl), any of which is optionally selected from OH, halogen, aryl, heteroaryl, -O (C)1-6Alkyl), O (C)1-6Haloalkyl), -O-aryl or-O-heteroaryl) with one or more substituents;
p is 1 or 2;
R4and R5Each independently selected from H or C1-4Alkyl, or R4And R5Together with the nitrogen atom to which they are attached may form a 3 or 8 membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, N and S;
n is 0, 1, 2, 3, 4 or 5;
R2aand R2bEach independently is C1-6Alkyl radical, said C1-6Alkyl is optionally substituted with one or more substituents selected from halogen, OH, aryl or heteroaryl; or
R2aAnd R2bTogether with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, N or S, and optionally substituted with one or more substituents R6Substitution;
each R6Independently selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl, carbocyclyl, heterocyclyl, -O-carbocyclyl, -O-heterocyclyl, R12、OR12、C(O)R12、C(O)OR11、C(O)NR11R12、CN、OH，
R11And R12Each independently is H or C1-4Alkyl, any of which may be substituted with one or more aryl or heteroaryl groups, wherein the aryl and heteroaryl groups are substituted with one or more substituents selected from the group consisting of: halogen, OH, cyano, nitro, -NR4R5、-S(O)PNR4R5、-C(O)NR4R5、-C(O)R4、-C(O)OR4or-C1-6Alkyl or-O (C)1-6Alkyl), any of which is optionally selected from OH, halogen, aryl, heteroaryl, -O (C)1-6Alkyl), O (C)1-6Haloalkyl), -O-aryl or-O-heteroaryl) with one or more substituents;
wherein R is4And R5As defined above; or R11And R12May be combined with the nitrogen atom to which they are attached to form a 3-to 8-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, N and S and optionally substituted with C1-4Alkyl radical, C1-4Haloalkyl or halogen substitution;
R3is aryl, heteroaryl, carbocyclyl or heterocyclyl, any of which is optionally substituted with one or more substituents R7Substituted, said R7Selected from halogen, optionally aryl-substituted-C1-4Alkyl, optionally aryl-substituted-O (C)1-4Alkyl), -C1-4Haloalkyl, -O (C)1-4Haloalkyl) or-C (O) NR8R9；
R8And R9Each independently selected from H, C1-4Alkyl or C3-6Cycloalkyl, or R8And R9Together with the nitrogen atom to which they are attached may form a 5 or 6 membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, N and S.
2. A compound of formula (IA) or a pharmaceutically acceptable salt, solvate or hydrate thereof or a deuterated or tritiated variant thereof, including all stereoisomers:
wherein:
each R1Independently of one another, halogen, C1-6Alkyl radical, C1-6Haloalkyl, aryl or heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more substituents selected from: halogen, OH, cyano, nitro, -S (O)PNR4R5、-C(O)NR4R5Optionally aryl-substituted-C1-6Alkyl, -C1-6Haloalkyl, -O (C) optionally substituted by aryl1-6Alkyl), or-O (C)1-6Haloalkyl);
p is 0, 1 or 2;
R4and R5Each independently selected from H or C1-4Alkyl, or R4And R5Together with the nitrogen atom to which they are attached may form a 5 or 6 membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, N and S;
m is 0, 1, 2, 3 or 4;
R2aand R2bEach independently is C1-6Alkyl radical, said C1-6Alkyl is optionally substituted with one or more substituents selected from halogen, OH, aryl or heteroaryl; or
R2aAnd R2bTogether with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring, said heterocyclic ringThe ring optionally comprising one or more additional heteroatoms selected from O, N or S, and optionally substituted with one or more substituents R6Substitution;
each R6Independently selected from aryl, heteroaryl, -O-aryl, -O-heteroaryl or C substituted with one or more aryl or heteroaryl groups1-4Alkyl, wherein aryl and heteroaryl are selected from halogen, C1-4Alkyl radical, C1-4Haloalkyl, -O (C)1-4Alkyl) or-O (C)1-4Haloalkyl) with one or more substituents;
R3is aryl, heteroaryl, carbocyclyl or heterocyclyl, any of which is optionally substituted with one or more substituents R7Substituted, said R7Selected from halogen, optionally aryl-substituted-C1-4Alkyl, optionally aryl-substituted-O (C)1-4Alkyl), -C1-4Haloalkyl, -O (C)1-4Haloalkyl) or-C (O) NR8R9；
R8And R9Each independently selected from H, C1-4Alkyl or C3-6Cycloalkyl, or R8And R9Together with the nitrogen atom to which they are attached may form a 5 or 6 membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, N and S.
3. The compound of claim 1, wherein n is 1 or 2, and at least one R1The group is OH; or a compound according to claim 2, wherein m is 0 or 1.
4. A compound according to claim 2 or claim 3, wherein m is not 0 and R is1Is halogen or optionally substituted aryl or heteroaryl as defined in claim 2.
5. The compound of claim 4, wherein R1Is aryl or heteroaryl optionally substituted by: halogen, OH, cyano, nitro, -SO2NH2、-C(O)NR4R5Optionally aryl-substituted-C1-4Alkyl, -C1-4Haloalkyl, -O (C) optionally substituted by aryl1-4Alkyl), or-O (C)1-4Haloalkyl) wherein R4And R5Together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring.
6. The compound of claim 5, wherein R1Is aryl or heteroaryl optionally substituted by: chloro, fluoro, methyl, ethyl, trifluoromethyl, benzyl, methoxy, ethoxy, benzyloxy, trifluoromethoxy and piperidine-1-carbonyl.
7. A compound according to any one of claims 1 to 6, wherein R2aAnd R2bTogether with the nitrogen atom to which they are attached form an optionally substituted radical R6A substituted 6 membered heterocyclic ring.
8. The compound of claim 7, wherein R2aAnd R2bTogether with the nitrogen atom to which they are attached form a single R6(ii) a piperazine ring with the substituent substituted at the 4-position of piperazine such that the compound of formula (I) is a compound of formula (IB):
wherein R is1、n、R3And R6As defined in claim 2.
9. A compound according to any one of claims 1 to 8, wherein R6Is phenyl, heteroaryl, -O-phenyl, -O-heteroaryl, benzyl, -CH (phenyl)2、-CH2-heteroaryl and-CH (heteroaryl)2Wherein said heteroaryl is selected from the group consisting of pyridyl, indolyl, isoindolyl, benzo
10. A compound according to any one of claims 1 to 9, wherein R3Is optionally substituted by one or more substituents R7Substituted phenyl such that the compound of formula (I) is a compound of formula (IC):
wherein R is1、n、R2a、R2bAnd R7As defined for formula (I), and z is 0 to 5.
11. The compound of claim 10, wherein z is 0, 1 or 2, R7Is absent (i.e., z is 0), or R7Is halogen, -C1-4Alkyl, benzyl, -O (C)1-4Alkyl) benzyloxy, -C1-4Haloalkyl, -O (C)1-4Haloalkyl) or-C (O) NR8R9Wherein R is8And R9Together with the nitrogen atom to which they are attached form a piperidinyl ring or wherein R8Is H and R9Is C3-7A cycloalkyl group.
12. A compound according to any one of claims 1 to 10, which is a compound of general formula (ID):
wherein R is1、n、R6、R7And z is as defined above.
13. The compound according to claim 1, selected from:
2- ((2-chlorophenyl) (4- (4-methoxyphenyl) piperazin-1-yl) methyl) phenol (compound 1);
2- ((4-chlorophenyl) (4- (4-methoxyphenyl) piperazin-1-yl) methyl) phenol (compound 2);
2- ((4- (benzyloxy) -3-fluorophenyl) (4- (4-methoxyphenyl) piperazin-1-yl) methyl) phenol (compound 3);
(4- ((2-hydroxyphenyl) (4- (4-methoxyphenyl) piperazinyl) methyl) phenyl) (piperidin-1-yl) methanone (compound 4);
3- ((5-chloro-2-hydroxyphenyl) (4- (4-methoxyphenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 5);
2- ((4- (benzyloxy) -3-fluorophenyl) (4- (4-methoxyphenyl) piperazin-1-yl) methyl) -4-chlorophenol (compound 6);
2- ((4- (benzyloxy) -3-fluorophenyl) (4- (6-fluorobenzo [ d)]Different from each other
2- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (o-tolyl) methyl) phenol (compound 8);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) benzamide (compound 9, NPB);
2- ((4- (benzyloxy) -3-fluorophenyl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) phenol (compound 10);
2- ((4- ((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) (phenyl) methyl) phenol (compound 11);
2- ((4- ((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) (p-tolyl) methyl) phenol (compound 12);
2- ((4-chlorophenyl) (4- ((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) methyl) phenol (compound 13);
2- ((4- ((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) (4-ethylphenyl) methyl) phenol (compound 14);
(4- ((4- ((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) phenyl) (piperidin-1-yl) methanone (compound 15);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 16);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-2 '-methyl- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 17);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-3 '-methyl- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 18);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-4 '-methyl- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 19);
3- ((2 '-chloro-4-hydroxy- [1, 1' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 20);
3- ((3 '-chloro-4-hydroxy- [1, 1' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 21);
3- ((4 '-chloro-4-hydroxy- [1, 1' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 22);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4 '-ethyl-4-hydroxy- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 23);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-4 '- (piperidine-1-carbonyl) - [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 24);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-4 '-methoxy- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 25);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (2 '-ethyl-4-hydroxy- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 26);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (2 '-fluoro-4-hydroxy- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 27);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (3 '-fluoro-4-hydroxy- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 28);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4 '-fluoro-4-hydroxy- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 29);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-3 '-nitro- [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 30);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-3 '-sulfamoyl- [1, 1' -biphenyl-3-yl) methyl) benzamide (compound 31);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-2 '- (trifluoromethyl) - [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 32);
n-cyclopentyl-3- (((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-3 '- (trifluoromethyl) - [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 33);
n-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4-hydroxy-4 '- (trifluoromethyl) - [1, 1' -biphenyl ] -3-yl) methyl) benzamide (compound 34);
3- ((2 '-cyano-4-hydroxy- [1, 1' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 35);
3- ((3 '-cyano-4-hydroxy- [1, 1' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 36)
3- ((4 '-cyano-4-hydroxy- [1, 1' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 37);
3- ((2 ' -chloro-4-hydroxy-4 ' - (trifluoromethyl) - [1, 1 ' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 38);
n-cyclopentyl-3- ((2 ', 4 ' -dichloro-4-hydroxy- [1, 1 ' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) benzamide (compound 39);
3- (((4 ' -chloro-2 ', 4-dihydroxy- [1, 1 ' -biphenyl ] -3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) -N-cyclopentylbenzamide (compound 40);
3- ((4- (4-chlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) -N-cyclopentylbenzamide (Compound 41, NCK1)
2- ((4-chlorophenyl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) phenol (Compound 42, NCK2)
2- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (3-methoxyphenyl) methyl) phenol (Compound 43, NCK3)
1- (5- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) thiophen-2-yl) ethanone (Compound 44, NCK4)
2- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (naphthalen-1-yl) methyl) phenol (Compound 45, NCK5)
5- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) furan-2-carbaldehyde (Compound 46, NCK6)
2- ((4- (5, 6-Dichlorocyclohexa-1, 5-dien-1-yl) piperazin-1-yl) (2-fluoro-3-methylpyridin-4-yl) methyl) phenol (Compound 47, NCK7)
2- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4- (trifluoromethyl) phenyl) methyl) phenol (Compound 48, NCK8)
2- ((6-chloro-5-methylpyridin-3-yl) (4- (2, 3-dichlorophenyl) piperazin-1-yl) methyl) phenol (Compound 49, NCK9)
2- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (pyridin-3-yl) methyl) phenol (Compound 50, NCK10)
1- (5- ((4- (4-chlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) thiophen-2-yl) ethanone (Compound 51, NCK14)
3- ((4- (4-chlorophenyl) piperazin-1-yl) (4- (diethylamino) -2-hydroxyphenyl) methyl) -N-cyclopentylbenzamide (Compound 52, NCK16)
N-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (4- (diethylamino) -2-hydroxyphenyl) methyl) benzamide (compound 53, NCK18)
N-cyclopentyl-3- ((4- (2, 3-dichlorophenyl) piperazin-1-yl) (2-hydroxy-4, 6-dimethoxyphenyl) methyl) benzamide (compound 54, NCK19)
2- ((4-chlorophenyl) (4- (4-chlorophenyl) piperazin-1-yl) methyl) phenol (Compound 55, NCK20)
2- ((4- (4-chlorophenyl) piperazin-1-yl) (6-methylpyridin-3-yl) methyl) phenol (Compound 56, NCK21)
2- (o-tolyl (4- (p-tolyl) piperazin-1-yl) methyl) phenol (compound 57, SG1)
2- ((4- (p-tolyl) piperazin-1-yl) (4- (trifluoromethyl) phenyl) methyl) phenol (Compound 58, SG2)
N-cyclopentyl-4- ((2-hydroxyphenyl) (4- (p-tolyl) piperazin-1-yl) methyl) benzamide (compound 59, SG3)
2- ((4-chlorophenyl) (4- (p-tolyl) piperazin-1-yl) methyl) phenol (Compound 60, SG4)
2- ((3-methoxyphenyl) (4- (p-tolyl) piperazin-1-yl) methyl) phenol (compound 61, SG5)
5- ((2-hydroxyphenyl) (4- (p-tolyl) piperazin-1-yl) methyl) furan-2-carbaldehyde (Compound 62, SG6)
2- ((6-methylpyridin-3-yl) (4- (p-tolyl) piperazin-1-yl) methyl) phenol (compound 63, SG 7);
or a pharmaceutically acceptable salt, solvate or hydrate thereof or a deuterated or tritiated variant thereof, including all stereoisomers.
14. A process for the preparation of a compound according to any one of claims 1 to 13, which process comprises:
by suzuki coupling reaction in the presence of a palladium catalyst:
i. reacting an aldehyde of formula (II) with a compound of formula (III) and a boronic acid of formula (IV):
wherein R is1And n is as defined in claim 1;
wherein R is2aAnd R2bAs defined in claim 1;
wherein R is3As defined in claim 1; or
ii. reacting in which R1Reacting a compound of formula (I) which is halogen with a compound of formula (V):
wherein R is1aIs aryl or heteroaryl, optionally substituted as defined for R1 in claim 1;
to obtain wherein R1Is R1aA compound of the general formula (I).
15. A compound according to any one of claims 1 to 13 for use in medicine.
16. A compound according to any one of claims 1 to 13 for use in the treatment of cancer.
17. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of cancer.
18. A method for treating cancer, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 13.
19. A compound for use, use or method according to any one of claims 16 to 18 wherein the cancer is a cancer in which BAD phosphorylation is present, for example breast, endometrial, ovarian, liver, colon, prostate or pancreatic cancer in which BAD is phosphorylated, or any other cancer of epithelial origin.
20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable excipient.
21. The pharmaceutical composition of claim 20, formulated for intraperitoneal administration, transhepatic portal vein administration, intravenous administration, intra-articular administration, transpancreatic-duodenal artery administration, or intramuscular administration, or any combination thereof.
Example 1
Synthesis and characterization of Compounds of formula T
General Synthesis of Compounds of formula I
Piperazine (0.8mmol) and salicylaldehyde (0.8mmol) were placed in RBF and stirred for about 10 minutes using dioxane as solvent. After about 10 minutes, arylboronic acid (0.8mmol) was added to the mixture and refluxed for about 8 hours with continuous stirring on a hot plate maintained at about 90 ℃ using dioxane as solvent. After about 8 hours, ethyl acetate and water were added to the reaction mixture, and the ethyl acetate layer was separated using a separatory funnel and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated to obtain the product. The desired phenolic compound product is obtained by separation using column chromatography.
Specific reagents for obtaining
TABLE 1
NPB bromide (see
TABLE 2
Characterization of
1H NMR(CDCl3，400MHz)δ：3.691(s，3H)，5.303(s，1H，C-H)，1.184-3.691(m，8H-piperazine protons)，7.597-7.615(d，1H，J＝7.2Hz)，7.341-7.323(d，1H，J＝7.2Hz)，7.060-7.189(m，4H-ArH)，6.555-6.815(m，5H-ArH)，6.956-6.974，(d，1H，J＝7.2Hz)11.85(s，1H-OHbrd peak)；13C NMR(400MHz，CDCl3)δ：50.854，55.521，69.50，114.45，117.17，118.44，119.547，122.05，127.78，128.83，129.01，129.19，129.84，129.93，133.89，145.11，156.60；
Melting point 120-. (FIG. 1)
Characterization of
1H NMR(CDCl3，400MHz)δ：2.539-3.065(m，8H)，3.674(s，3H)，4.359(s，1H)，6.651(m，1H)，6.740-6.804(m，5H)，6.855-6.872(d，1H，J＝6.8Hz)，7.086(m，1H)，7.165(m，2H)，7.280(m，1H)，7.361(m，1H)；13C NMR(400MHz，CDCl3)δ：50.74，51.76，55.52，75.86，114.49，117.24，118.43，119.62，124.41，126.58，128.28，128.54，128.92，129.20，130.28，134.66，141.63，145.07，154，156.18；
The melting point is 85-89 ℃. (FIG. 2)
Characterization of
1H NMR(CDCl3，400MHz)δ：1.194-3.079(m，8H)，3.689(s，3H)，4.336(s，1H)，5.041(s，2H)，6.672-6.702(m，1H)，6.781-6.819(m，5H)，6.863-6.867(m，2H)，7.026-7.082(m，2H)，7.196(m，1H)，7.279-7.348(m，5H)；13C NMR(400MHz，CDCl3)δ：50.770，55.52，71.26，75.36，114.46，115.46，117.16，118.42，119.54，124.82，127.34，128.14，128.62，128.76，129.14，145.04，156.14；
Melting point 72-76 ℃. (FIG. 3)
Characterization of compound 4:
1H NMR(CDCl3，400MHz)δ：1.183-2.469(m，10H)，2.557-3.684(m，8H)，3.684(s，3H)，4.412(s，1H)，6.631(m，2H)，6.745-6.813(m，4H)，7.059-7.095(m，1H)，7.191-7.216(m，1H)，7.261-7.269(m，2H)，7.351-7.409(m，2H)；13C NMR(400MHz，CDCl3)δ：24.51，26.525，29.68，43.60，48.73，50.71，51.80，55.51，76.04，114.45，117.134，118.366，119.198，119.52，124.75，126.74，127.50，128.04，128.50，128.79，129.29，136.18，141.02，145，154，156.2，169.79(C＝O)；
melting point 78-82 ℃. (FIG. 4)
Characterization of compound 5:
1H NMR(CDCl3，400MHz)δ：1.186-1.650(m，8H)，1.978-3.633(m，8H)，3.689(s，3H)，4.298-4.345(m，1H)，4.421(s，1H)，5.979-5.992(s，1H)6.736-6.803(m，5H)，6.860(m，1H)，7.192(s，1H)，7.737(s，1H)，7.304-7.339(m，1H)，7.540-7.557(m，2H)；13C NMR(400MHz，CDCl3)δ：23.79，33.18，50.67，51.83，55.51，67.06，75.06，114.46，118.45，118.58，124.02，126.11，126.42，128.72，128.87，129.39，139.39，144.89，154.19，154.95，166.68；
melting point 102-. (FIG. 5)
Characterization of compound 6:
1H NMR(CDCl3，400MHz)δ：1.179-3.620(m，8H)，3.676(s，3H)，4.261(s，1H)，5.029(s，2H)，6.716-6.791(m，5H)，6.823(m，1H)，6.862-6.882(m，1H)，6.973-7.015(m，2H)，7.110-7.139(m，1H)，7.243-7.258(m，2H)，7.280-7.317(m，1H)，7.331-7.350(m，2H)；13CNMR(400MHz，CDCl3)δ：50.70，51.59，55.52，71.27，74.93，114.48，115.52，118.58，123.97，124.39，126.3，127.3，128.2，128.8，132.1，136.27，144.96，146.74，154.19，154.93；
the melting point is 60-64 ℃. (FIG. 6)
Characterization of compound 7:
1H NMR(CDCl3，400MHz)δ：2.648-3.820(m，8H)4.245(s，1H)，5.009(s，1H)，5.651(s，2H)，7.276(s，1H)，7.436-7.485(m，3H)，7.606-7.682(m，3H)，7.797(m，2H)，7.876-7.954(m，5H)，8.185(s，1H)；13C NMR(400MHz，CDCl3)δ：30.972，50.76，67.60，71.79，75.85，98.16，100.9，104.9，113.16，115.97，117.65，119.96，122.84，125.4，127.8，128.6，129.1，129.6，133.2，136.8，157.06，160.87，164.51，165.86；
melting point 58-62 ℃. (FIG. 7)
Characterization of compound 8:
1H NMR(CDCl3，400MHz)δ：2.479(s，3H)，4.927(s，1H)，2.260-3.063(m，8H)，6.533-6.551(d，1H，J＝7.2Hz)，6.631-6.692(m，2H)，6.739-6.758(d，1H，J＝7.6Hz)，6.789-6.809(d，1H，J＝8Hz)，6.864(m，3H)，7.092-7.183(m，1H)，7.281-7.297(m，1H)，7.537-7.552(d，1H，J＝6Hz)；13C NMR(400MHz，CDCl3)δ：20.92，51.16，51.42，73.44，116.07，116.96，117.14，118.716，119.27，119.83，124.965，125.24，126.445，127.12，127.545，128.266，128.729，129.260，130.869，134.072，138.171，150.600，156.443
melting point 108-. (FIG. 8)
Characterization of compound 9 (NPB):
1H NMR(CDCl3，400MHz)δ：1.183-1.647(m，8H)，2.019-3.067(m，8H)，4.509(s，1H)，4.312-4.327(m，1H，NH)，5.965(s，1H)，6.668(m，1H)，6.801-6.896(m，3H)，7.073-7.190(m，3H)，7.305(m，1H)，7.527-7.542(m，2H)，7.770(s，1H)；13C NMR(400MHz，CDCl3)δ：23.78，33.18，51.22，51.78，76.10，117.14，118.59，119.67，124.69，124.98，126.22，127.53，128.85，129.29，131.08，134.08，135.53，140.28，150.5，156.1，166.73；m/z(M+2，526.2，527.2)
melting point 174-. (FIG. 9)
Characterization of compound 10:
1H NMR(CDCl3，400MHz)δ：1.183-3.074(m，8H)，4.361(s，1H)，5.034(s，2H)，6.658-6.694(t，1H，J＝7，2Hz)，6.768(m，1H)，6.856-6.873(m，3H)，7.023(m，1H)，7.055-7.094(m，3H)，7.164(m，1H)，7.231(m，1H)，7.266(m，1H)，7.304(m，1H)，7.322-7.355(m，2H)；13C NMR(400MHz，CDCl3)δ：51.264，71.260，75.434，117.15，118.6，119.6，124.8，124.9，127.3，127.5，128.1，128.6，128.8，129.18，150.5，156.09；
the melting point is 75-80 ℃. (FIG. 10)
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