CN111747924B - Lenalidomide/pomalidomide analogues and application thereof - Google Patents

Lenalidomide/pomalidomide analogues and application thereof Download PDF

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CN111747924B
CN111747924B CN201910251224.2A CN201910251224A CN111747924B CN 111747924 B CN111747924 B CN 111747924B CN 201910251224 A CN201910251224 A CN 201910251224A CN 111747924 B CN111747924 B CN 111747924B
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mmol
pomalidomide
lenalidomide
preparation
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CN111747924A (en
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姜雪峰
李一鸣
王玉红
张飞杭
李佳
周宇波
徐高亚
阚伟娟
汪玉洁
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Shanghai Institute of Materia Medica of CAS
East China Normal University
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Shanghai Institute of Materia Medica of CAS
East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention discloses lenalidomide/pomalidomide analogues shown in a formula (I), and belongs to the technical field of medicine synthesis. The lenalidomide/pomalidomide analogues disclosed by the invention can be used for treating and/or preventing multiple myeloma, leukemia and lymphoma, and have a wide application prospect in preventing and treating multiple myeloma, leukemia, lymphoma and the like.

Description

Lenalidomide/pomalidomide analogues and application thereof
Technical Field
The invention belongs to the field of biochemistry, and particularly relates to lenalidomide/pomalidomide analogues and application thereof.
Background
Hematological disorders, particularly hematological malignancy, are serious disorders in the current age that seriously compromise human health, clinically common are leukemia, aplastic anemia, myelodysplastic syndrome, thrombocytopenia, multiple myeloma, lymphoma, skeletal fibrosis, etc. With the continuous abundance of treatments for hematological disorders, a variety of new drugs such as proteasome inhibitors, targeted therapeutic drugs, immunomodulators, etc. have emerged.
As a second-generation immunomodulatory drug, lenalidomide has stronger immunomodulatory effect and antitumor activity compared with thalidomide, has smaller toxic and side effects, and is approved for treating blood system diseases such as myelodysplastic syndrome (MDS) subtype, multiple Myeloma (MM), lymphoma and the like. Pomalidomide is used as a third-generation immunomodulator, has the functions of directly killing tumor cells, regulating immunity, inhibiting angiogenesis and the like, and as other immunomodulators, the pomalidomide is combined with CRBN receptors in vivo to change the conformation of the binding site of CRBN, prevent the ligand of original endogenous substances from being combined with CRBN, and combine new endogenous substances, and the new endogenous substances pass through CRL4 in a subject body CRBN The E3 compound is ubiquitinated, and is further recognized and degraded by degradation proteins in the body, so that the immunoregulation and anticancer effects are exerted in the body.
Slight alterations in the structure of the immunomodulatory class may result in conformational changes in the binding site of CRBN, affecting its binding to CRBN, thereby preventing or aggregating the binding of certain endogenous substances to CRBN. The new compound with a brand new structure is continuously designed and discovered, new medicines with better curative effect and smaller toxic and side effects are developed, and the new medicine has reformable significance for treating malignant hematopathy.
Disclosure of Invention
The invention aims to provide lenalidomide/pomalidomide analogues and application thereof in preparing anti-tumor medicines.
The specific technical scheme for realizing the aim of the invention is as follows:
the invention provides lenalidomide/pomalidomide analogues or pharmaceutically acceptable salts or stereoisomers thereof, and the structures of the lenalidomide/pomalidomide analogues are shown as formula (I):
wherein,
a is sulfur atom or selenium atom;
x, Y is selected from O, N or absent;
b is CH 2 Or c=o;
r is selected from halogen, hydroxy, amino, C1-C20 saturated alkyl containing substituent, C3-C20 unsaturated alkyl containing substituent, C3-C20 cycloalkyl C3-C20 cycloalkyl having a substituent, aryl having a substituent, C1-C20 saturated alkoxy having a substituent, C3-C20 unsaturated alkoxy having a substituent, C3-C20 cycloalkoxy, C3-C20 cycloalkoxy containing substituents, aryloxy containing substituents, C1-C20 saturated alkylamine containing substituents, C3-C20 unsaturated alkylamine containing substituents, C3-C20 cycloalkylamine containing substituents, arylamine containing substituents;
wherein the substituents are selected from the group consisting of C1-C20 alkyl, formyl, carboxyl, ester, aminoacyl, haloacyl, cyano, polyhaloalkyl, C1-C20 alkoxy, aryloxy, arylalkoxy, hydroxy, amino, nitro, nitroso, isocyano, isothiocyano, amido, halogen, mercapto, sulfone, sulfoxide, sulfonimide, C1-C20 alkylthio, polythioC 1-C20 alkyl, polythioaryl, thiocyano, sulfonate, selenol, seleno-monooxo, seleno-dioxo, seleno-monooxo-imine, selenodioxo-imine, selenoether, polyselealkyl, polyselenoaryl, selenocyano, seleno-C1-C20 alkyl-boron, arylboron, boric acid, C1-C20 alkyl-silicon, aryl-silicon, C1-C20 alkyl-phosphino, aryl-phosphino, phosphoryl, heteroaryl containing substituents wherein the heteroatoms in the heteroaryl groups are selected from one or more of B, N, O, si, P, S, te, ge, te.
The aryl group, the aryl group containing substituent, the aryloxy group containing substituent, the aryl amino group containing substituent and the aryl in the aryl amino group containing substituent are selected from phenyl.
Preferably, the method comprises the steps of,
a is sulfur atom or selenium atom;
x, Y is selected from O, N or absent;
b is CH 2 Or c=o;
r is selected from the group consisting of C1-C10 saturated alkyl, C1-C10 saturated alkyl containing substituents, C3-C10 unsaturated alkyl containing substituents, C5-C6 cycloalkyl containing substituents, aryl containing substituents, C1-C10 saturated alkoxy containing substituents, C3-C10 unsaturated alkoxy a C3-C10 unsaturated alkoxy group having a substituent, a C3-C10 cycloalkoxy group having a substituent, a C1-C10 saturated alkylamine having a substituent, a C3-C10 unsaturated alkylamine having a substituent, a C3-C10 cycloalkylamine having a substituent;
wherein the substituents are as defined above.
Wherein the aryl group in the aryl group and the aryl group containing substituent is selected from phenyl.
It is further preferred that the composition comprises,
a is sulfur atom or selenium atom;
x, Y is selected from O, N or absent;
b is CH 2 Or c=o;
r is selected from one or more of methyl, ethyl, propyl, isopropyl, butyl isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl, nitro-substituted aryl, phenyl, fluoro-substituted aryl, chloro-substituted aryl, bromo-substituted aryl, cyano-substituted aryl, methyl-substituted aryl, ethyl-substituted aryl, methoxy-substituted aryl, trifluoromethyl-substituted aryl, cyclopentyl, cyclohexyl, quinoline, thiophene.
Wherein the aryl in the nitro-substituted aryl, fluorine-substituted aryl, chlorine-substituted aryl, bromine-substituted aryl, cyano-substituted aryl, methyl-substituted aryl, ethyl-substituted aryl, methoxy-substituted aryl and trifluoromethyl-substituted aryl is phenyl.
The novel compound provided by the invention has the following structure, but is not limited to the structure:
the invention also provides a pharmaceutical composition comprising lenalidomide/pomalidomide analogue shown in formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
Wherein the pharmaceutical composition is formulated as an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch or excipient, etc.
The invention also provides application of lenalidomide/pomalidomide analogues in preparing anti-tumor medicines.
Wherein the tumor is a hematological disease such as multiple myeloma, leukemia, lymphoma, myelofibrosis, myelodysplastic syndrome, etc.
Wherein the lenalidomide/pomalidomide analogue or a pharmaceutically acceptable salt or stereoisomer thereof is used for inhibiting the growth of multiple myeloma, leukemia and lymphoma.
Wherein the multiple myeloma cells are MM-1S cells, the leukemia cells are MV-4-11 cells, and the lymphoma cells are human mantle cell lymphoma cells.
The compounds of the present invention may be prepared by the following method:
(1) The synthesis method comprises the following steps:
wherein A is a sulfur atom or a selenium atom;
[X.Wang,G.D.Cuny,T.Angew.Chem.Int.Ed.2013,52,7860-7864]；
(2) The synthesis method II comprises the following steps:
[Y.Li,J.Pu,X.Jiang,Org.Lett.2014,16,2692-2695]；
(3) And a synthesis method III:
[Y.Li,W.Xie,X.Jiang,Chem.Eur.J.2015,21,16059-16065]。
the invention has the beneficial effects that: the lenalidomide/pomalidomide analogues provided by the invention can be applied to preparing medicines for treating and/or preventing multiple myeloma, leukemia and lymphoma, and have wide application prospects for preventing and treating multiple myeloma, leukemia, lymphoma and the like.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1 preparation of Compound 1
The specific synthesis method comprises the following steps: n (N) 2 Future nadimide (336.9 mg,1.3 mmol), [ Ru (bpy) under protection 3 Cl 2 ]·6H 2 O(7.5mg,0.01mmol)，TsOH·H 2 O (2.8 mg,0.015 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) were added to a 25mL Schlenk reaction tube, acetonitrile (5 mL) was added, and the mixture was stirred at room temperature for 5min and then transferred to under a 23w incandescent lamp, and tert-butyl nitrite (250. Mu.L, 2.6 mmol) was slowly added dropwise. TLC monitored reaction was complete. Water (0.1-0.2 mL) was added to the reaction solution, silica gel (0.5-1.0 g) was added, the solvent was removed by suction filtration under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/petroleum ether/ethyl acetate=1:1:8) to give compound 1. For safety reasons, the silica gel is treated after wetting with water.
1 H NMR(400MHz,DMSO)δ10.90(s,1H),7.58-7.28(m,3H),5.04(dd,J＝13.3,5.1Hz,1H),4.19(dd,J＝57.3,17.3Hz,2H),2.89-2.73(m,1H),2.51(d,J＝12.1Hz,2H),2.46-2.30(m,3H),1.99-1.85(m,1H)。
Example 2 preparation of Compound 2
Specific preparation referring to example 1, compound 2 was prepared by substituting dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with dimethyl diselenide 2a (188.0 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.76-7.42(m,3H),5.14(dd,J＝13.3,5.1Hz,1H),4.28(dd,J＝53.9,17.2Hz,2H),3.00-2.80(m,1H),2.64-2.53(m,2H),2.43(s,3H),2.02-1.98(m,J＝12.0,6.1Hz,1H)。
EXAMPLE 3 preparation of Compound 3
Specific preparation referring to example 1, compound 3 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with ethanethiol 3a (62.1 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.63-7.51(m,3H),5.13(dd,J＝13.2,5.0Hz,1H),4.28(dd,J＝57.2,17.4Hz,2H),3.09(q,J＝7.3Hz,2H),2.98-2.82(m,1H),2.59(d,J＝17.1Hz,1H),2.49-2.38(m,1H),2.06-1.93(m,1H),1.25(t,J＝7.3Hz,3H)。
EXAMPLE 4 preparation of Compound 4
Specific preparation referring to example 1, compound 4 was prepared by substituting dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with diethyl diselenide 4a (216.1 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.75(d,J＝7.2Hz,1H),7.65(d,J＝7.3Hz,1H),7.50(t,J＝7.6Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.29(dd,J＝56.9,17.4Hz,2H),3.05(q,J＝7.3Hz,2H),2.98-2.82(m,1H),2.68-2.52(m,2H),2.02-1.98(m,1H),1.36(t,J＝7.4Hz,3H)。
EXAMPLE 5 preparation of Compound 5
Specific preparation referring to example 1, compound 5 was prepared by substituting only dimethyl disulfide 1a (94 mg,1.0 mmol) in example 1 with propanethiol 5a (76.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.13(s,1H),7.87-7.69(m,2H),7.63(d,J＝6.6Hz,1H),5.12(dd,J＝12.7,5.4Hz,1H),3.11(t,J＝7.2Hz,2H),2.95-2.81(m,1H),2.57(dd,J＝23.9,11.6Hz,2H),2.06(dd,J＝9.1,3.6Hz,1H),1.74-1.67(m,2H),1.03(t,J＝7.3Hz,3H)。
EXAMPLE 6 preparation of Compound 6
Specific preparation referring to example 1, compound 6 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with butanethiol 6a (90.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl3)δ10.90(s,1H),7.70(dd,J＝6.4,2.1Hz,1H),7.50-7.45(m,2H),5.24(dd,J＝17.6,7.8Hz,1H),4.34(dd,J＝43.8,16.5Hz,2H),2.98(t,J＝9.6Hz,2H),2.91-2.77(m,2H),2.46-2.31(m,1H),2.26-2.18(m,1H),1.67-1.61(m,2H),1.52-1.39(m,2H),0.93(t,J＝7.3Hz,3H)。
EXAMPLE 7 preparation of Compound 7
Specific preparation referring to example 1, compound 7 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 7a (104.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.81(s,1H),7.67(dd,J＝6.8,1.8Hz,1H),7.45-7.40(m,2H),5.23(dd,J＝13.4,5.2Hz,1H),4.31(dd,J＝54.6,16.6Hz,2H),2.95(t,J＝7.2Hz,2H),2.88-2.77(m,2H),2.40-2.29(m,1H),2.19-2.14(m,1H),1.68-1.61(m,2H),1.43-1.26(m,4H),0.87(t,J＝7.2Hz,3H)。
EXAMPLE 8 preparation of Compound 8
Specific preparation referring to example 1, compound 8 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 8a (118.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.52(s,1H),7.69(dd,J＝6.4,2.0Hz,1H),7.487.42(m,2H),5.23(dd,J＝13.2,5.2Hz,1H),4.32(dd,J＝56.0,16.5Hz,2H),2.97(t,J＝7.6Hz,2H),2.91-2.78(m,2H),2.42-2.31(m,1H),2.23-2.17(m,1H),1.69-1.61(m,2H),1.46-1.38(m,2H),1.32-1.23(m,4H),0.87(t,J＝7.0Hz,3H)。
EXAMPLE 9 preparation of Compound 9
Specific preparation referring to example 1, compound 9 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 9a (132.3 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.55(s,1H),7.69(dd,J＝6.4,2.0Hz,1H),7.47-7.44(m,2H),5.24(dd,J＝13.3,4.8Hz,1H),4.32(dd,J＝56.3,16.5Hz,2H),2.97(t,J＝7.4Hz,2H),2.88-2.78(m,2H),2.42-2.31(m,1H),2.21-2.16(m,1H),1.68-1.61(m,2H),1.43-1.37(m,2H),1.31-1.26(m,6H),0.87(t,J＝6.8Hz,3H)。
Example 10 preparation of Compound 10
Specific preparation referring to example 1, compound 10 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 10a (146.3 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.63(s,1H),7.69(dd,J＝6.4,2.0Hz,1H),7.59-7.37(m,2H),5.24(dd,J＝13.3,5.0Hz,1H),4.32(dd,J＝55.8,16.5Hz,2H),2.96(t,J＝7.2Hz,2H),2.85(dd,J＝12.1,4.9Hz,2H),2.40-2.31(m,1H),2.25-2.10(m,1H),1.68-1.61(m,2H),1.44-1.35(m,2H),1.35-1.18(m,8H),0.86(t,J＝6.9Hz,3H)。
EXAMPLE 11 preparation of Compound 11
Specific preparation referring to example 1, compound 11 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 11a (174.3 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.44(s,1H),7.69(dd,J＝6.3,1.9Hz,1H),7.52-7.37(m,2H),5.24(dd,J＝13.0,4.0Hz,1H),4.33(dd,J＝56.5,16.5Hz,2H),2.97(t,J＝7.2Hz,2H),2.92-2.77(m,2H),2.48-2.29(m,1H),2.20(d,J＝11.0Hz,1H),1.74-1.57(m,2H),1.52-1.36(m,2H),1.34-1.17(m,12H),0.87(t,J＝7.8Hz,3H)。
EXAMPLE 12 preparation of Compound 12
Specific preparation referring to example 1, compound 12 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 12a (76.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 ):δ8.43(s,1H),7.75(d,J＝6.8Hz,1H),7.57-7.55(m,1H),7.46(t,J＝7.6Hz,1H),5.24(dd,J＝12,5.2Hz,1H),4.36(dd,J＝52.6,16.6Hz,2H),3.52-3.42(m,1H),2.93-2.79(m,2H),2.44-2.33(m,1H),2.24-2.17(m,1H),1.31(dd,J＝6.7,1.9Hz,6H)。
EXAMPLE 13 preparation of Compound 13
Specific preparation referring to example 1, compound 13 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 13a (90.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.74(s,1H),7.73(d,J＝7.3Hz,1H),7.53(d,J＝7.6Hz,1H),7.44(t,J＝7.5Hz,1H),5.24(d,J＝10.4Hz,1H),4.48-4.16(m,2H),3.26(dd,J＝12.9,6.4Hz,1H),2.86(s,2H),2.36(s,1H),2.21(s,1H),1.79-1.45(m,2H),1.27(d,J＝6.6Hz,3H),1.00(t,J＝7.3Hz,3H)。
EXAMPLE 14 preparation of Compound 14
Specific preparation referring to example 1, compound 14 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 14a (90.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.45(s,1H),7.88(d,J＝7.6Hz,1H),7.69(d,J＝7.2Hz,1H),7.49(t,J＝7.6Hz,1H),5.24(d,J＝9.2Hz,1H),4.45(dd,J＝51.6,16.8Hz,2H),2.92-2.80(m,2H),2.39(d,8.4Hz,1H),2.21(d,J＝10.2,7.8Hz,1H),1.33(s,6H)。
EXAMPLE 15 preparation of Compound 15
Specific preparation referring to example 1, compound 15 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 15a (102.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.27(s,1H),7.71(d,J＝7.2Hz,1H),7.57-7.50(m,1H),7.45(t,J＝7.6Hz,1H),5.23(dd,J＝13.2,4.8Hz,1H),4.33(dd,J＝55.3,16.5Hz,2H),3.71-3.64(m,1H),2.93-2.78(m,2H),2.42-2.32(m,1H),2.23-2.19(m,1H),2.09-2.07(m,2H),1.80-1.75(m,2H),1.63(s,4H)。
EXAMPLE 16 preparation of Compound 16
Specific preparation referring to example 1, compound 16 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 16a (116.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.68(s,1H),7.73(d,J＝7.6Hz,1H),7.54(d,J＝7.6Hz,1H),7.44(t,J＝7.6Hz,1H),5.24(dd,J＝13.2,4.8Hz,1H),4.34(dd,J＝52.2,16.6Hz,2H),3.22-3.17(m,1H),2.90-2.78(m,2H),2.41-2.31(m,1H),2.21-2.18(m,1H),1.96(d,J＝12.0Hz,2H),1.76(dd,J＝8.6,2.6Hz,2H),1.60(dd,J＝10.0,4.0Hz,1H),1.40-1.24(m,5H)。
EXAMPLE 17 preparation of Compound 17
Specific preparation referring to example 1, compound 17 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 17a (74.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.41(s,1H),7.73(d,J＝7.3Hz,1H),7.55-7.42(m,2H),5.90-5.79(m,1H),5.24(dd,J＝13.2,5.1Hz,1H),5.11(t,J＝14.7Hz,2H),4.35(dd,J＝55.6,16.5Hz,2H),3.59(d,J＝6.8Hz,2H),2.97-2.77(m,2H),2.44-2.32(m,1H),2.21(dd,J＝8.9,3.6Hz,1H)。
EXAMPLE 18 preparation of Compound 18
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Specific preparation referring to example 1, compound 18 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 18a (192.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ10.99(s,1H),7.75-7.42(m,7H),5.10(dd,J＝13.3,5.1Hz,1H),4.49-4.34(m,2H),4.27-4.09(m,2H),2.97-2.80(m,1H),2.58(d,J＝17.2Hz,1H),2.44-2.33(m,1H),1.97-1.92(m,1H)。
EXAMPLE 19 preparation of Compound 19
Specific preparation referring to example 1, compound 19 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 19a (138.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.35(s,1H),7.69(d,J＝7.2Hz,1H),7.48-7.41(m,2H),7.28-7.13(m,5H),5.19(dd,J＝12.4,3.2Hz,1H),4.25(dd,J＝62.7,16.5Hz,2H),3.21(t,J＝7.8Hz,2H),2.95–2.76(m,4H),2.32(dd,J＝12,3.2Hz,1H),2.16(d,J＝10.8Hz,1H)。
EXAMPLE 20 preparation of Compound 20
Specific preparation referring to example 1, compound 20 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 20a (110.2 mg,1.0 mmol).
1 H NMR(300MHz,CDCl 3 )δ8.16(s,1H),7.80(t,J＝4.3Hz,1H),7.44(d,J＝3.9Hz,2H),7.36-7.27(m,5H),5.20(dd,J＝13.1,5.2Hz,1H),4.30(dd,J＝49.0,16.6Hz,2H),2.91-2.73(m,2H),2.36-2.26(m,1H),2.24-2.12(m,1H)。
EXAMPLE 21 preparation of Compound 21
Specific preparation referring to example 1, compound 21 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 21a (124.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.66(d,J＝7.3Hz,1H),7.50(t,J＝7.6Hz,1H),7.33(dd,J＝9.9,8.1Hz,3H),7.23(d,J＝8.1Hz,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.31(dd,J＝55.8,17.6Hz,2H),3.00-2.81(m,1H),2.58(d,J＝17.3Hz,1H),2.47-2.37(m,1H),2.31(s,3H),2.06-1.94(m,1H)。
EXAMPLE 22 preparation of Compound 22
Specific preparation referring to example 1, compound 22 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 22a (138.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.04(s,1H),7.51(d,J＝7.3Hz,1H),7.40-7.20(m,4H),6.65(d,J＝7.5Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.35(dd,J＝56.0,17.3Hz,2H),3.03-2.80(m,1H),2.61(d,J＝18.1Hz,1H),2.48-2.40(m,1H),2.35(s,6H),2.09-2.01(m,1H)。
EXAMPLE 23 preparation of Compound 23
Specific preparation referring to example 1, compound 23 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 23a (140.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.01(s,1H),7.59(d,J＝7.0Hz,1H),7.51-7.39(m,3H),7.18(dd,J＝7.7,0.6Hz,1H),7.08-6.95(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.32(dd,J＝55.5,17.5Hz,2H),3.78(s,3H),2.99-2.78(m,1H),2.59(d,J＝17.5Hz,1H),2.48-2.38(m,1H),2.09-1.94(m,1H)。
EXAMPLE 24 preparation of Compound 24
Specific preparation referring to example 1, compound 24 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 24a (140.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.01(s,1H),7.71(d,J＝7.4Hz,1H),7.53(t,J＝7.6Hz,1H),7.42-7.28(m,2H),7.14-7.03(m,2H),6.93(t,J＝7.4Hz,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.33(dd,J＝52.1,17.6Hz,2H),3.81(s,3H),3.01-2.82(m,1H),2.69-2.34(m,2H),2.10-1.92(m,1H)。
EXAMPLE 25 preparation of Compound 25
Specific preparation referring to example 1, compound 25 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 25a (125.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.28(s,1H),7.75(t,J＝3.6Hz,1H),7.38(d,J＝4.0Hz,2H),7.31-7.18(m,4H),5.15(dd,J＝13.3,5.1Hz,1H),4.24(dd,J＝63.5,16.7Hz,2H),2.91-2.74(m,2H),2.35-2.19(m,1H),2.13(dd,J＝9.0,3.8Hz,1H),1.84(s,2H)。
EXAMPLE 26 preparation of Compound 26
Specific preparation referring to example 1, compound 26 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 26a (116.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.14(s,1H),7.72(d,J＝7.2Hz,1H),7.51(dd,J＝5.4,1.2Hz,1H),7.39(t,J＝7.7Hz,1H),7.32(dd,J＝3.6,1.2Hz,1H),7.26-7.24(m,1H),5.23(dd,J＝13.2,5.0Hz,1H),4.39(dd,J＝62.2,16.4Hz,2H),3.03-2.75(m,2H),2.44-2.22(m,1H)。
EXAMPLE 27 preparation of Compound 27
Specific preparation referring to example 1, compound 27 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 27a (144.6 mg,1.0 mmol).
1 H NMR(300MHz,DMSO)δ10.99(s,1H),7.76(dd,J＝6.7,1.8Hz,1H),7.61-7.53(m,2H),7.50-7.41(m,2H),7.38-7.28(m,2H),5.13(dd,J＝13.2,5.1Hz,1H),4.33(dd,J＝43.7,17.7Hz,2H),3.00-2.79(m,1H),2.61-2.51(m,1H),2.47-22.38(m,1H),2.11-1.86(m,1H)。
EXAMPLE 28 preparation of Compound 28
Specific preparation referring to example 1, compound 28 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 28a (191.1 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.76(d,J＝6.3Hz,1H),7.67-7.48(m,4H),7.24(d,J＝8.4Hz,2H),5.13(dd,J＝13.2,4.9Hz,1H),4.32(dd,J＝53.0,17.6Hz,2H),2.97-2.80(m,1H),2.60-2.41(m,2H),2.08-1.92(m,1H)。
EXAMPLE 29 preparation of Compound 29
Specific preparation referring to example 1, compound 29 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 29a (128.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.73(d,J＝7.4Hz,1H),7.55(t,J＝7.6Hz,1H),7.49-7.40(m,2H),7.34-7.32(m,2H),7.24-7.20(m,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.35(dd,J＝54.4,17.6Hz,2H),3.00-2.83(m,1H),2.58(d,J＝17.6Hz,1H),2.48-2.38(m,1H),2.11-1.95(m,1H)。
EXAMPLE 30 preparation of Compound 30
Specific preparation referring to example 1, compound 30 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 30a (128.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.80(dd,J＝7.0,1.2Hz,1H),7.68-7.57(m,2H),7.41(dd,J＝14.2,7.7Hz,1H),7.16-7.09(m,3H),5.14(dd,J＝13.3,5.1Hz,1H),4.33(dd,J＝58.2,17.7Hz,2H),2.97-2.82(m,1H),2.58(d,J＝17.8Hz,1H),2.48-2.37(m,1H),2.00(dd,J＝9.0,3.5Hz,1H)。
EXAMPLE 31 preparation of Compound 31
Specific preparation referring to example 1, compound 31 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 31a (128.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.03(d,J＝18.7Hz,1H),7.75-7.27(m,7H),5.16(d,J＝13.3Hz,1H),4.46-4.23(m,2H),3.02-2.81(m,1H),2.70-2.29(m,2H),2.03(s,1H)。
EXAMPLE 32 preparation of Compound 32
Specific preparation referring to example 1, compound 32 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 32a (178.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ10.99(s,1H),7.81(dd,J＝6.8,1.6Hz,1H),7.69-7.55(m,5H),7.51(d,J＝7.8Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.35(dd,J＝60.3,17.7Hz,2H),2.97-2.83(m,1H),2.57(d,J＝17.7Hz,1H),2.49-2.37(m,1H),2.03-1.94(m,1H)。
EXAMPLE 33 preparation of Compound 33
Specific preparation referring to example 1, compound 33 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) in example 1 with compound 33a (178.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.93(d,J＝7.4Hz,1H),7.63(d,J＝7.6Hz,1H),7.54(dd,J＝15.5,7.9Hz,3H),7.24(s,1H),5.20(dd,J＝13.2,5.0Hz,1H),4.32(dd,J＝63.1,16.7Hz,2H),2.97-2.72(m,2H),2.43-2.26(m,1H),2.22(s,1H)。
EXAMPLE 34 preparation of Compound 34
Specific preparation referring to example 1, compound 34 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 34a (160.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ10.98(s,1H),7.99-7.85(m,4H),7.73(d,J＝7.1Hz,1H),7.58-7.47(m,4H),7.40(dd,J＝8.6,1.6Hz,1H),5.12(dd,J＝13.2,5.0Hz,1H),4.37(dd,J＝53.0,17.6Hz,2H),2.94-2.82(m,1H),2.56(d,J＝17.8Hz,1H),2.47-2.37(m,1H),2.00-1.97(m,1H)。
EXAMPLE 35 preparation of Compound 35
Specific preparation referring to example 1, compound 35 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 35a (146.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.01(s,1H),7.69(d,J＝7.5Hz,1H),7.58-7.49(m,2H),7.48-7.43(m,1H),7.35(d,J＝7.7Hz,1H),7.22-7.15(m,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.36(dd,J＝55.5,17.5Hz,2H),2.97-2.85(m,1H),2.59(d,J＝17.3Hz,1H),2.49-2.38(m,1H),2.03-1.98(m,1H)。
EXAMPLE 36 preparation of Compound 36
Specific preparation referring to example 1, compound 36 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 36a (145.6 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ10.96(s,1H),8.44(d,J＝2.2Hz,1H),7.80(dd,J＝8.6,2.6Hz,1H),7.74(d,J＝7.5Hz,2H),7.68-7.64(m,1H),7.13(d,J＝8.6Hz,1H),5.12(dd,J＝13.3,4.9Hz,1H),4.32(dd,J＝53.3,17.8Hz,2H),3.00-2.76(m,1H),2.60(d,J＝8.6Hz,1H),2.45-2.36(m,1H),2.09-1.88(m,1H)。
EXAMPLE 37 preparation of Compound 37
Specific preparation referring to example 1, compound 37 was prepared by substituting only dimethyl disulfide 1a (94.2 mg,1.0 mmol) from example 1 with compound 37a (312.1 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ10.99(s,1H),7.87-7.28(m,8H),5.24-5.04(m,1H),4.39-4.20(m,2H),3.01-2.82(m,1H),2.49-2.27(m,2H),2.06-1.81(m,1H)。
EXAMPLE 38 preparation of Compound 38
Specific preparation referring to example 1, compound 38 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 3a (62.1 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.17(s,1H),7.90(d,J＝8.3Hz,1H),7.66-7.25(m,1H),7.62(d,J＝6.6Hz,1H),5.12-5.09(m,1H),3.17-3.12(m,2H),3.01-2.83(m,1H),2.62-2.52(m,2H),2.10-2.05(m,1H),1.32(t,J＝8.3Hz,3H)。
EXAMPLE 39 preparation of Compound 39
Specific preparation referring to example 1, compound 39 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 5a (76.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.13(s,1H),7.87-7.69(m,2H),7.63(d,J＝6.6Hz,1H),5.12(dd,J＝12.7,5.4Hz,1H),3.11(t,J＝7.2Hz,2H),2.95-2.81(m,1H),2.57(dd,J＝23.9,11.6Hz,2H),2.06(dd,J＝9.1,3.6Hz,1H),1.74-1.67(m,2H),1.03(t,J＝7.3Hz,3H)。
EXAMPLE 40 preparation of Compound 40
Specific preparation referring to example 1, compound 40 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 6a (90.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.13(s,1H),7.86-7.68(m,2H),7.63(d,J＝6.9Hz,1H),5.12(dd,J＝12.7,5.4Hz,1H),3.13(t,J＝7.3Hz,2H),2.96-2.82(m,1H),2.60(d,J＝18.7Hz,2H),2.16-2.01(m,1H),1.69-1.62(m,2H),1.51-1.42(m,2H),0.93(t,J＝7.3Hz,3H)。
EXAMPLE 41 preparation of Compound 41
Specific preparation referring to example 1, compound 41 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 7a (104.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.14(s,1H),7.82-7.68(m,2H),7.62(d,J＝6.9Hz,1H),5.12(dd,J＝12.8,5.4Hz,1H),3.12(t,J＝7.3Hz,2H),2.94-2.85(m,1H),2.58(dd,J＝23.3,11.4Hz,2H),2.11-2.01(m,1H),1.72-1.60(m,2H),1.50-1.26(m,4H),0.88(t,J＝7.2Hz,3H)。
EXAMPLE 42 preparation of Compound 42
Specific preparation referring to example 1, compound 42 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 8a (118.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.13(s,1H),7.79-7.72(m,2H),7.62(d,J＝6.8Hz,1H),5.11(dd,J＝12.7,5.4Hz,1H),3.12(t,J＝7.3Hz,2H),2.893-84(m,1H),2.62-2.53(m,2H),2.11-2.00(m,1H),1.71-1.60(m,2H),1.51-1.40(m,2H),1.32-1.25(m,4H),0.86(t,J＝7.0Hz,3H)。
EXAMPLE 43 preparation of Compound 43
Specific preparation referring to example 1, compound 43 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 16a (116.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.01(s,1H),7.57-7.47(m,3H),4.90(dd,J＝12.1,5.3Hz,1H),3.47-3.29(m,1H),2.91-2.56(m,3H),2.14-1.93(m,3H),1.83-1.67(m,2H),1.66-1.27(m,8H)。
EXAMPLE 44 preparation of Compound 44
Specific preparation referring to example 1, compound 44 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 14a (90.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝15.3Hz,1H),7.83(dd,J＝12.8,7.6Hz,2H),7.66(t,J＝7.6Hz,1H),4.98(dd,J＝12.3,5.3Hz,1H),2.98-2.58(m,3H),2.24-2.08(m,1H),1.42(s,6H),1.34(s,3H)。
EXAMPLE 45 preparation of Compound 45
Specific preparation referring to example 1, compound 45 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 45a (110.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.17(s,1H),7.72-7.51(m,7H),6.94(dd,J＝5.9,3.0Hz,1H),5.18(dd,J＝12.9,5.3Hz,1H),3.00-2.83(m,1H),2.61-2.54(m,2H),2.17-2.02(m,1H)。
EXAMPLE 46 preparation of Compound 46
Specific preparation referring to example 1, compound 46 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 21a (124.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.16(s,1H),7.68-7.60(m,2H),7.53(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),6.89(dd,J＝6.9,1.9Hz,1H),5.16(dd,J＝12.9,5.3Hz,1H),2.95-2.85(m,1H),2.69-2.52(m,1H),2.13-2.04(m,1H)。
EXAMPLE 47 preparation of Compound 47
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Specific preparation referring to example 1, compound 47 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 22a (138.2 mg,1.0 mmol).
1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),7.48(d,J＝6.9Hz,1H),7.32(t,J＝7.7Hz,1H),7.26(dd,J＝8.2,6.7Hz,1H),7.17(s,1H),6.57(d,J＝7.9Hz,1H),4.96(dd,J＝12.1,5.3Hz,1H),2.98-2.60(m,3H),2.35(s,6H),2.20-2.04(m,1H)。
EXAMPLE 48 preparation of Compound 48
Specific preparation referring to example 1, compound 48 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 23a (140.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.17(s,1H),7.90(d,J＝7.8Hz,1H),7.66-7.50(m,4H),7.12(d,J＝8.6Hz,2H),5.17(dd,J＝12.9,5.1Hz,1H),3.83(s,3H),3.01-2.83(m,1H),2.68-2.52(m,2H),2.17-2.05(m,1H)。
EXAMPLE 49 preparation of Compound 49
Specific preparation referring to example 1, compound 49 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 31a (128.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.16(s,1H),7.97-7.85(m,1H),7.77-7.62(m,3H),7.43(t,J＝8.8Hz,2H),6.92(dd,J＝6.4,2.5Hz,1H),5.16(dd,J＝12.9,5.3Hz,1H),2.99-2.86(m,1H),2.68-2.52(m,2H),2.20-2.01(m,1H)。
EXAMPLE 50 preparation of Compound 50
Specific preparation referring to example 1, compound 50 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 35a (146.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.14(s,1H),7.81(dd,J＝15.1,8.2Hz,1H),7.67(d,J＝4.4Hz,2H),7.54(t,J＝7.8Hz,1H),7.31(t,J＝8.4Hz,1H),6.99-6.85(m,1H),5.16(dd,J＝12.9,5.3Hz,1H),2.97-2.80(m,1H),2.64-2.55(m,2H),2.16-2.01(m,1H)。
EXAMPLE 51 preparation of Compound 51
Specific preparation referring to example 1, compound 51 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 27a (144.6 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.14(s,1H),7.97-7.86(m,3H),7.70-7.64(m,3H),7.05-6.97(m,1H),5.16(dd,J＝12.8,5.3Hz,1H),2.99-2.78(m,1H),2.71-2.56(m,2H),2.09-2.06(m,1H)。
EXAMPLE 52 preparation of Compound 52
Specific preparation referring to example 1, compound 52 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 32a (178.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.16(s,1H),8.00(s,1H),7.98-7.89(m,2H),7.79(t,J＝7.8Hz,1H),7.71(dd,J＝6.5,3.4Hz,2H),7.08-6.95(m,1H),5.17(dd,J＝12.9,5.3Hz,1H),2.95-2.86(m,1H),2.69-2.52(m,2H),2.09(dd,J＝9.1,3.7Hz,1H)。
EXAMPLE 53 preparation of Compound 53
Specific preparation referring to example 1, compound 53 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 33a (178.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.16(s,1H),7.86(dd,J＝26.4,8.3Hz,4H),7.78-7.66(m,2H),7.17(dd,J＝6.9,1.9Hz,1H),5.17(dd,J＝12.8,5.3Hz,1H),2.97-2.81(m,1H),2.71-2.52(m,2H),2.14-2.04(m,1H)。
EXAMPLE 54 preparation of Compound 54
Specific preparation referring to example 1, compound 54 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 54a (155.2 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.16(s,1H),8.28(d,J＝8.6Hz,2H),7.86-7.72(m,4H),7.39(d,J＝7.8Hz,1H),5.17(dd,J＝12.7,5.1Hz,1H),2.94-2.86(m,1H),2.64-2.53(m,2H),2.09-2.07(m,1H)。
EXAMPLE 55 preparation of Compound 55
Specific preparation referring to example 1, compound 55 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 36a (145.6 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.14(s,1H),8.57(d,J＝2.3Hz,1H),7.95(dd,J＝8.5,2.6Hz,1H),7.86(d,J＝6.6Hz,1H),7.80(t,J＝7.6Hz,1H),7.71-7.65(m,1H),7.59(d,J＝8.5Hz,1H),5.14(dd,J＝12.8,5.4Hz,1H),2.98-2.80(m,1H),2.61-2.52(m,2H),2.11-2.00(m,1H)。
EXAMPLE 56 preparation of Compound 56
Specific preparation referring to example 1, compound 56 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with diethyl diselenide 4a (216.1 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.14(s,1H),7.88-7.57(m,3H),5.13(dd,J＝12.8,5.4Hz,1H),3.14(q,J＝7.4Hz,2H),2.95-2.79(m,1H),2.59(d,J＝19.0Hz,2H),2.06(dd,J＝10.8,5.4Hz,1H),1.45(t,J＝7.4Hz,3H)。
EXAMPLE 57 preparation of Compound 57
Specific preparation referring to example 1, compound 57 was prepared by substituting lenalidomide (336.9 mg,1.3 mmol) in example 1 with pomalidomide (355.2 mg,1.3 mmol) and dimethyl disulfide 1a (94.2 mg,1.0 mmol) with compound 57a (312.1 mg,1.0 mmol).
1 H NMR(400MHz,DMSO)δ11.17(s,1H),7.77-7.48(m,7H),7.01(d,J＝7.9Hz,1H),5.17(dd,J＝12.9,5.3Hz,1H),2.96-2.87(m,1H),2.72-2.56(m,2H),2.11-2.06(m,1H)。
EXAMPLE 58 growth inhibition experiments of the Compounds of the invention on human mantle cell lymphoma (Mino cells)
Screening model: mino (Mino)
The screening method comprises the following steps:
Protocol id:147
protocol name suspension cells (3 days)
Instrument: spectraMAX 340
Materials: 96plate (core); cells; a Medium; MTS; DMSO (DMSO)
The process comprises the following steps:
detecting the survival rate of the human mantle cell lymphoma cell Mino cell by using an MTS method, namely sucking a culture medium of the human mantle cell lymphoma cell Mino cell growing in a logarithmic growth phase, lightly blowing and counting; inoculating 90ul in a 96-well plate at corresponding cell density; adding 10ul of the compound prepared by the method, wherein each compound is provided with a concentration gradient, each concentration is provided with three compound holes, and each concentration is respectively added into the corresponding hole; the final concentration of DMSO was 0.2%;5% CO 2 Culturing in an incubator at 37℃for 3days, and adding 20ul of MTS; after 3 hours incubation at 37 ℃, 490nm (L1) light absorbance was measured using spectromax 340, reference wavelength 690nm (L2), and (L1-L2) values were plotted against inhibitor concentration, and percent activity (%) = compound OD value-blast OD value/DMSO OD value-blast OD 100% was plotted to fit IC50 by formula.
Sample treatment:
the reference substances (lenalidomide, pomalidomide, CC-220 and CC-122) and the compound prepared by the invention are dissolved by DMSO, and the DMSO is preserved at low temperature, and the concentration of the DMSO in a final system is controlled within a range which does not influence the detection activity.
Data processing and result description:
primary screening the activity of the reference (lenalidomide, pomalidomide, CC-220, CC-122) and the compounds prepared according to the invention was tested at a single concentration, e.g. 20. Mu.g/ml (see Table 1). For samples exhibiting activity under certain conditions, such as% Inhibition greater than 50, the activity dose dependence, i.e., IC50/EC50 values, were tested, and the sample concentration was nonlinearly fitted by sample activity, calculated using Graphpad Prism 4, fitted using sigmoiddose-response (varible slope), and the bottom and top of the fitted curve set to 0 and 100 for most inhibitor screening models. In general, each sample was provided with a multiple well (n.gtoreq.2) in the test, and the results were expressed in terms of Standard deviation (Standard Deviation, SD) or Standard Error (SE) and are shown in Table 1.
EXAMPLE 59 growth inhibition experiments of the Compounds of the invention on human multiple myeloma cells (MM-1S cells) and human acute myelogenous leukemia cells (MV-4-11 cells) for 7days
Screening model: MM-1S (7 days); MV-4-11 (7 days)
The screening method comprises the following steps:
Protocol id:158
Protocol name:inhibitors-MTS(7days)
instrument: spectraMAX 340
Materials: 96plate (core); cells; a Medium; MTS; DMSO (DMSO)
The process comprises the following steps:
detecting the cell survival rate by using an MTS method, namely sucking a culture medium of cells growing in a logarithmic growth phase, lightly blowing and counting; 180ul of cells were seeded in 96-well plates at the corresponding cell densities; adding 20ul of the compound prepared by the method, wherein each compound is provided with a concentration gradient, each concentration is provided with three compound holes, and each concentration is respectively added into the corresponding hole; 5% CO 2 Culturing in an incubator at 37℃for 7days, and adding 20ul of MTS; after incubation at 37℃for 3 hours, the absorbance at 490nm (L1) was measured using SpectraMAX 340, the reference wavelength 690nm (L2), the (L1-L2) values plotted against the different concentrations of inhibitor, and the IC50 was fitted by formula.
Sample treatment: sample processing the sample processing procedure is described above with reference to example 58.
Data processing and result description: the data processing procedure was as described above with reference to example 58 and the results are shown in table 1.
TABLE 1 comparative (lenalidomide, pomalidomide Pomalidoamide, CC-220, CC-122) and cytotoxicity test data for the compounds of the invention
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In Table 1, the cytotoxicity test data shows that lenalidomide is used as a control group of 57 compounds provided by the invention, the IC50 value of the lenalidomide is greater than 20 mu m on Mino cell line, the IC50 value of the lenalidomide is 0.081 mu m on MM.1S cell line, the IC50 value of the lenalidomide is greater than 20 mu m on MV-4-11 cell line, which indicates that lenalidomide does not show a certain proliferation inhibition activity on Mino and MV-4-11 cell lines and a certain proliferation inhibition activity on MM.1S cell line;
pomalidomide is used as a control group of 57 compounds provided by the invention, the IC50 value of the pomalidomide on a Mino cell line is 0.18 mu m, the IC50 value of the pomalidomide on a MM.1S cell line is 0.026 mu m, the IC50 value of the pomalidomide on a MV-4-11 cell line is more than 2.24 mu m, and the pomalidomide shows a certain proliferation inhibition activity on the Mino cell line, the MV-4-11 cell line and the MM.1S cell line;
CC-220 was used as a control group of 57 compounds provided by the present invention, the IC50 value on Mino cell line was 0.010. Mu.M, the IC50 value on MM.1S cell line was 0.002. Mu.M, and the IC50 value on MV-4-11 cell line was 3.68. Mu.M, indicating that CC-220 showed a certain proliferation inhibitory activity on Mino cell line, MV-4-11 cell line and MM.1S cell line;
CC-122 is used as a control group of 57 compounds provided by the invention, the IC50 value of the compound is 0.11 mu m on a Mino cell line, the IC50 value of the compound is 0.017 mu m on an MM.1S cell line, the IC50 value of the compound is more than 1.64 mu m on an MV-4-11 cell line, and the compound shows a certain proliferation inhibition activity on the Mino cell line, the MV-4-11 cell line and the MM.1S cell line;
of the 57 small molecule compounds provided by the invention, compounds 1, 6, 7, 8, 9, 10, 11, 18, 19, 22, 23, 24, 25, 26, 27, 28, 32, 33, 34 all show certain proliferation inhibition activity on Mino cell lines, MV-4-11 cell lines and MM.1S cell lines; the compounds 2, 3, 4, 5, 15, 16, 17, 20, 21, 29, 30, 31, 35, 36, 37, 39, 40, 41, 42, 48, 54, 56 selectively show a certain proliferation inhibition activity on Mino cell lines, MV-4-11 cell lines and MM.1S cell lines, so that the lenalidomide/pomalidomide analogue compounds provided by the invention can be used for preparing drugs for treating or preventing multiple myeloma, leukemia and lymphoma.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.

Claims (8)

1. Lenalidomide/pomalidomide analogues or pharmaceutically acceptable salts or stereoisomers thereof, which are characterized by the following structures:
2. a pharmaceutical composition comprising the lenalidomide/pomalidomide analog of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is formulated as an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, transdermal patch, or excipient.
4. Use of lenalidomide/pomalidomide analogue or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 in the preparation of a medicament for the treatment and/or prophylaxis of an anti-tumour.
5. Use of a pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment and/or prophylaxis of antitumor agents.
6. The use according to claim 4 or 5, wherein the tumour is multiple myeloma, leukemia, lymphoma, myelofibrosis, myelodysplastic syndrome.
7. The use according to claim 4, wherein the lenalidomide/pomalidomide analogue or a pharmaceutically acceptable salt or stereoisomer thereof is used for inhibiting the growth of multiple myeloma, leukemia, lymphoma.
8. The use according to claim 7, wherein the cells of multiple myeloma are multiple myeloma cells MM-1S cells, the cells of leukemia are human acute myelogenous leukemia cells MV-4-11 cells, and the cells of lymphoma are human mantle cell lymphoma cells.
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