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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • 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
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

• the present disclosure generally relates to compounds represented by general formula (I) or their salts, solvates, isotopically enriched analogs, tautomers, polymorphs, stereoisomers (including enantiomers) Isomers), or mixtures of stereoisomers, and their application in the treatment of tumors.
• Multiple myeloma is a malignant hematological cancer, accounting for about all tumors
• Thalidomide is the first generation of immunomodulatory drugs. It was used to treat morning sickness in pregnant women in the 1950s and 1960s, but it was forbidden to use it because it would cause malformed fetuses.
• Singhal et al. used thalidomide as a single agent for the treatment of refractory multiple myeloma patients for the first time, it showed good clinical effectiveness; subsequently, a large number of studies on thalidomide as a single agent or combined with dexamethasone A clinical trial of Metsone in the treatment of refractory or relapsed multiple myeloma.
• Thalidomide's immunomodulatory and anti-tumor activities have been discovered, and these drugs have attracted widespread attention.
• scientists have synthesized a series of phthalimide-replaced derivatives Pomalidomide and Lena with thalidomide as the lead compound.
• Degree amine Limalidomide
• Lenalidomide is a derivative with lower toxicity but higher activity. In 2006, it was approved by the FDA in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma.
• the third-generation immunomodulatory drug pomalidomide was approved for at least two drugs including lenalidomide and bortezomib Patients with relapsed/refractory multiple myeloma included in treatment.
• the detailed mechanism of action has not been clear until a study in 2010 used biochemical methods to affinity purify proteins that interact with thalidomide and identify the main targets of thalidomide and its analogs The point is Cereblon, and research in related fields is becoming increasingly active.
• immunomodulatory drugs can bind to the CRBN protein in cells, so that CRL4A eRBN ubiquitin ligase ubiquitinates and degrades the transcription factors IKZF1 and IKZF3. These two transcription factors are essential in the development and survival of B cells.
• Professor Harper discovered five endogenous ligase substrates through the ubiquitination analysis of the protein chip: GRINL1A, MBOAT7, OTUD7B, C6orfl41 and MEIS2.
• MEIS2 as a transcription factor, plays an important role in the normal development of the human body.
• MEIS2 myelodysplastic syndrome
• SILAC cell culture
• thalidomide drugs and their derivatives play a vital role in the treatment of multiple myeloma and other related malignant tumors, but the current reports of such compounds substituted by heteroatoms The biological activity needs to be further improved. Therefore, it is urgent to design and synthesize a series of thalidomide drugs with high activity in order to achieve better curative effect. Summary of the invention
• the present invention provides a compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer (including enantiomers) Isomer), or a mixture of stereoisomers:
• B, U, V, W are the same or different and each independently represents CH or N, where B, U, V, and W are not N at the same time;
• Y represents O or S;
• R represents SH, and L and Xi f exist;
• R represents S, L represents an optionally substituted linear or branched alkyl group, and ⁇ does not exist;
• R represents S(O) or S(0) 2
• L represents an optionally substituted linear or branched alkyl group or amino group, and Xi f is present;
• R represents S, S(O) or S(0) 2 ,
• L represents an optionally substituted linear or branched alkylene group, wherein the linear or branched alkylene group is optionally interrupted one or more times by one or more groups selected from: 0, C(O), S, S(O), S(0) 2 , C(0)N(Ri), N(R 2 )C(0), N(R 3 ), N(R 4 )C( 0) N(R 5 ), optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, or any combination thereof, wherein Ri , R 2, R 3, R 4 and 115 each independently represent H or Ci_ 3 ware group;
• Xi represents NReR ?, C(0)NR e R f , NHC(0)R 8 , NHC(0)NR 9 R IO ⁇ quaternary ammonium salt group, OR h , SH, optional substitution (especially optionally A straight or branched chain alkyl group substituted by one or more fluorines, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted heteroaryl group, wherein, Re, R 7 , R e , R f , R h , R 9 and R 10 each independently represent H, an optionally substituted linear or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group Group, an optionally substituted heterocyclic group or an optionally substituted heteroaryl group, provided that R 6 and R 7 are not H at the same time, and which represents a linear or branched alkyl group, an aryl group,
• Xi represents a group of the formula (Gi):
• B L U I , V I , ⁇ are the same or different and independently represent CH or N, where Bp Up Vi Wi is not N at the same time;
• Z represents S, S(O) or S(0) 2;
• Another object of the present invention is to provide a compound of formula (r) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer (including enantiomers) Structure), or a mixture of stereoisomers:
• A, B, U, V, W, Y are as defined in formula (I) herein;
• R represents S, S(O) or S(0) 2;
• L represents an optionally substituted linear or branched alkylene group, wherein the linear or branched alkylene group is optionally interrupted one or more times by one or more groups selected from: 0, C(O), S, S(O), S(0) 2 , S(0) 2 N(R I ), N(R 2 )S(O) 2 , C(0)N(Ri), N (R 2 )C(0), N(R 3 ), N(R 4 )C(0)N(R 5) , optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene group, or any combination thereof, wherein Ri, R 2, R 3, R 4 and 115 each independently represent H or C M alkyl; and
• X ! represents NHC O)! ⁇ or SR j , where and each independently represent optionally selected from ( ⁇ _ 6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino , Hydroxy, Ci_ 3 alkoxy, halo Ci_ 3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or cycloalkyl substituted with any combination of substituents, Or Xi means optionally selected from Ci_ 6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, Ci_ 3 alkoxy, halogenated Ci_ 3 alkoxy, methanesulfonyloxy , Cycloalkyl substituted with trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or any combination thereof; or
• NReRy represents H or Cw alkyl
• R 7 represents optionally selected from the group consisting of ⁇ _ 6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, Ci_ 3 alkoxy, halogen Substitute Ci_ 3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or any combination of substituents substituted cycloalkyl; or
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound of formula (I), compound of formula (r), or a pharmaceutically acceptable salt, solvate, or isotope thereof Enrichment of analogs, tautomers, polymorphs, stereoisomers (including enantiomers), or mixtures of stereoisomers, and at least one pharmaceutically acceptable carrier.
• the present invention also provides a kit or a kit, which comprises the compound of formula (I), compound of formula (r), or a pharmaceutically acceptable salt thereof, Solvates, isotopically enriched analogs, tautomers, polymorphs, stereoisomers (including enantiomers), or mixtures of stereoisomers, or the pharmaceutical composition of the present invention .
• the present invention also provides a compound of formula (I), or a compound of formula (r), or a pharmaceutically acceptable salt, solvate, isotope-enriched analog, Tautomers, polymorphs, stereoisomers (including enantiomers), or mixtures of stereoisomers, which are used as pharmaceuticals.
• the compound of formula (I), or compound of formula (r) according to the present invention or a pharmaceutically acceptable salt, solvate, isotope-enriched analog, or tautomer Forms, polymorphs, stereoisomers (including enantiomers), or mixtures of stereoisomers or the pharmaceutical composition of the present invention are used to treat cancer or tumors.
• the present invention also provides a compound of formula (I), compound of formula (r), or a pharmaceutically acceptable salt, solvate, isotope-enriched analog, and mutual Tautomers, polymorphs, stereoisomers (including enantiomers), or mixtures of stereoisomers or the use of the pharmaceutical composition of the present invention, which are used to prepare for treatment Cancer or tumor medicine.
• the present invention also provides a method of treating cancer or tumor, which comprises administering to a subject a therapeutically effective amount of the compound of formula (I) or the compound of formula (r), or Its pharmaceutically acceptable salts, solvates, isotopically enriched analogs, tautomers, polymorphs, stereoisomers (including enantiomers), or mixtures of stereoisomers, Or said pharmaceutical composition.
• Figure 1 shows the reported target proteins of small immunomodulatory molecules and their indications.
• Figure 2 is a study on the degradation of IKZF1 and IKZF3 proteins in MM1S cells by the compounds of the present invention. detailed description
• Embodiment 1 a compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereoisomer thereof Isomers (including enantiomers), or stereoisomers Body mixture:
• B, U, V, and W are the same or different and independently represent CH or N, where B, U, V, and W are not N at the same time;
• Y means 0 or S
• R represents SH, and L and Xi f exist;
• R represents S, L represents an optionally substituted linear or branched alkyl group, and ⁇ does not exist;
• R represents S(O) or S(0) 2
• L represents an optionally substituted linear or branched alkyl group or amino group, and Xi f is present;
• R represents S, S(O) or S(0) 2 ,
• L represents an optionally substituted linear or branched alkylene group, wherein the linear or branched alkylene group is optionally interrupted one or more times by one or more groups selected from: 0, C(O), S, S(O), S(0) 2 , C(0)N(Ri), N(R 2 )C(0), N(R 3 ), N(R 4 )C( 0) N(R 5 ), optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene or any combination thereof, wherein, R 2, R 3, R 4 and 115 each independently represent H or a group firing (firing preferably Ci_ 3-yl); and
• X ! represents NRgRy ⁇ C(0)NR e R f , NHC(0)R 8 , NHC(0)NR 9 Rio ⁇ quaternary ammonium salt group, OR h , SH, optional substitution (especially optionally substituted by One or more fluorine-substituted linear or branched alkyl groups, optionally substituted cycloalkyl groups, optionally substituted aryl groups, optionally substituted heterocyclic groups or optionally substituted heteroaryl groups, wherein, R 7 , R e , R f , R h , and R 1Q each independently represent H, an optionally substituted linear or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optional A substituted heterocyclic group or an optionally substituted heteroaryl group, provided that R 6 is not H at the same time, and 11 8 represents a linear or branched alkyl group, an aryl group, a heteroaryl group or
• Xi represents a group of the formula (Gi): Formula (GO
• Bi, Ui, Vi, ⁇ are the same or different and independently represent CH or N, where, Ui,: and Wi are not N at the same time;
• Z represents S, S(O) or S(0) 2;
• Embodiment 2 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, wherein the ring atoms B, U, V, and W in formula (I) are the same, and all are CH.
• Embodiment 3 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, wherein one of the ring atoms B, U, V, and W in formula (I) is N, and the rest are CH.
• Embodiment 4 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, wherein two of the ring atoms B, U, V, and W in formula (I) are N, and the rest are CH.
• Embodiment 5 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, wherein three of the ring atoms B, U, V, and W in formula (I) are N, and the rest are CH.
• Embodiment 6) It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, which are also compounds of formula (la):
• Embodiment 7 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, which are also compounds of formula Ob):
• Embodiment 8 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, which are also compounds of formula (Ic):
• Embodiment 9 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, which are also compounds of formula (Id): Formula (Id)
• Embodiment 10 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 1) ,, Or a mixture of stereoisomers, which are also compounds of formula (Ie):
• Embodiment 11 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 1)-10) Forms, stereoisomers, or mixtures of stereoisomers, where Y represents 0.
• Embodiment 12 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 1)-10) Forms, stereoisomers, or mixtures of stereoisomers, wherein Y in formula (I) represents S.
• Embodiment 13 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph as described in any one of embodiments 1)-11) Forms, stereoisomers, or mixtures of stereoisomers, where A in formula (I) represents cco).
• Embodiment 14 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 1)-11) Forms, stereoisomers, or mixtures of stereoisomers, where A in formula (I) represents CH 2 .
• Embodiment 15 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 1)-14) Forms, stereoisomers, or mixtures of stereoisomers, wherein R in formula (I) represents S, L represents an optionally substituted linear or branched alkyl group, and XiF is present. In a sub-embodiment, R represents S, and L represents an optionally substituted linear or branched C MO alkyl (especially ( ⁇ alkane) ⁇ ), and does not exist.
• R represents S
• L represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Neopentyl, tertpentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, or pentadecyl, and Xi f exists.
• Embodiment 16 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 1)-14) Form, stereoisomer, or mixture of stereoisomers, wherein R in formula (I) represents S(O) or S(0) 2 , and L represents an optionally substituted linear or branched alkyl group Or amino, and Xi F is present. In a sub-embodiment, R represents S(O) or S(0) 2 , L represents an optionally substituted linear or branched C MO alkyl (especially C MO alkyl) or amino group, and does not exist.
• R represents S(O) or S(0) 2
• L represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert Butyl, pentyl, isopentyl, neopentyl, p-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl Group, pentadecyl group or amino group, and Xi does not exist.
• Embodiment 17 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of Embodiments 1)-14) Forms, stereoisomers, or mixtures of stereoisomers, where R represents SH, and L and Xi f are present.
• Embodiment 18 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph as described in any one of the embodiments 1)-14) Forms, stereoisomers, or mixtures of stereoisomers, where
• R represents S, S(O) or S(0) 2;
• L represents an optionally substituted linear or branched C MO alkylene group, wherein the linear or branched C MO alkylene group is optionally interrupted by one or more groups selected from Times: 0, C(0), S, S(0), S(0) 2 , C(0)N(Ri), N(R 2 )C(0), N(R 3 ), N(R 4 ) C(0)N(R5 ) , optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene or any of them A combination, wherein Ri, R 2 , R 3 , R 4 and R 5 each independently represent an H or Ci- 3 alkyl group; and
• X ! represents NRgRy ⁇ C(0)NR e R f , NHC(0)R 8 , NHC(0)NR 9 Rio ⁇ 0R h , SH, quaternary ammonium salt group, optional substitution (especially optionally substituted by One or more fluorine-substituted linear or branched Cwo alkyl groups, optionally substituted cycloalkyl groups, selected substituted aryl groups, selected substituted heterocyclic groups or selected substituted heteroaryl groups ,
• R 6 , R 7 , Re, R f , R h , R 9 and R 1Q each independently represent H, optionally substituted linear or branched Cwo alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein with the proviso that, 117 are not simultaneously H, and wherein R 8 represents a linear or branched ⁇ _ 8 alkyl group, Aryl,
• Xi represents a group of the formula (Gi): Formula (GO
• Bi, Ui, Vi, ⁇ are the same or different and independently represent CH or N, where, Ui,: and Wi are not N at the same time;
• Z represents S, S(O) or S(0) 2 .
• Embodiment 19 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 1)-14) Forms, stereoisomers, or mixtures of stereoisomers, where
• R represents S, S(O) or S(0) 2;
• L represents an optionally substituted linear or branched C MO alkylene group, wherein the linear or branched C MO alkylene group is optionally interrupted by one or more groups selected from Times: 0, C(O), S, S(O), S(0) 2 , C(0)N(Ri), N(R 2 )C(0), N(R 3 ), N(R 4) C (0) N ( R 5), optionally substituted with substituents selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy group or Ci_ 5 alkyl substituents arylene, optionally substituted with substituents selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy group, oxo group or Ci_ 5 alkyl substituents heterocyclylene , optionally substituted with halo, methan
• Xi represents NRgRy, C(0)NR e R f , NHC(0)R 8 , NHC(0)NR 9 Rio, OR h , SH, a quaternary ammonium salt group, optionally substituted by one or more fluorine Straight or branched Cwo alkyl, optionally selected from halogen, oxo, cyano, trifluoromethyl, amino, hydroxy, Ci_ 3 alkoxy, halo Ci_ 3 alkoxy, methanesulfonyl Cycloalkyl substituted with substituents of oxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, Ci_ 6 alkyl or any combination thereof, optionally selected from halogen, oxo, cyano, Trifluoromethyl, amino, hydroxy, Ci_ 3 alkoxy, halogenated Ci_ 3 alkoxy, methanesulfonyloxy, trifluoromethanesulfony
• Ci_ 6 alkyl optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heterocyclyl, optionally substituted 5- or 6-membered heteroaryl or any combination of substituents substituted hetero
• R 6 , R 7 , R e , R f , R h , R 9 and R 1Q each independently represent H, an optionally substituted linear or branched chain
• Embodiment 20 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, and stereo as described in embodiment 1) or 19) Isomers, or mixtures of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, C alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluene Sulfonyloxy or any combination of substituents substituted) group: straight or branched CVC 40 alkylene, *-((CH 2 ) nl O) ml -(CH 2 ) n2 -, *- ((CH 2) nl 0) ml - (CH 2) n2 -0- (CH 2) n3 -, * - (CH 2) nl -0- (CH 2) n2 -, * - ((CRiiR)
• R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are each independently selected from 11 and C M alkyl groups;
• R11, R12, Rl3, Rl4, Rl5, Rl6, Rl7, Rl8, Rl9 and R2 Q each independently represent H, linear or branched CrCn ) alkyl or C 3 -C 1 () cycloalkyl, wherein When in the same group L, R n , R 12 , R 13 , R 14 , or R 15 , R 16 , R 17 , R 18 , R 19 , R 2Q are not H at the same time; and nl, n2, n3, ml independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or An integer of 20.
• Embodiment 21 It relates to a compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents an optionally substituted linear or branched CrC % alkylene group.
• L represents optionally substituted with a substituent selected from halogen, Cw alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or any combination thereof
• Embodiment 22 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, and stereo as described in embodiment 20) or 21) Isomers, or mixtures of stereoisomers, where L represents the following optionally selected from halogen, Cw alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, or p-toluenesulfonyloxy or any combination group substituents: -CH 2-; - (CH 2 ) 2-; - (CH 2) 3-; - (CH 2) 4 - ;-( CH 2) 5-; - (CH 2 ) 6 -; -(CH 2 ) 7 -; -(CH 2 ) 8 -; -(CH 2 ) 9 -; -(CH 2 )i0-; -(CH 2 )n-; -(CH 2 ) i 2 - ;
• L represents -CH 2-; - (CH 2) 2 - ;-( CH 2) 3 - ;-( CH 2) 4 - ;-( CH 2) 5 - ;-( CH 2 ) 6 -;-(CH 2 ) 7 -;-(CH 2 ) 8 -;-(CH 2 ) 9 -;-(CH 2 )IO-; -(CH 2 )H-;- (CH2)12 -;-(CH2)13-;-(CH2)14-;-(CH2)15-;-(CH2)16-;-(CH2)17-;-(CH2)18-;-(CH2)19_; -(CH2)20-.
• Embodiment 23 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Cw alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy ((CH 2 ) nl O) ml -(CH 2 ) n2 -, *- ((CH 2 ) nl 0) ml -(CH 2 ) n2 -0-(CH 2 ) n3 -, *-(CH 2 ) nl -0-(CH 2 ) n2 -, *-((CRnRi 2 ) ni O) mi -(CRi3Ri4)
• Embodiment 24 It relates to the compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereo as described in embodiment 20) or 23) Isomers, or mixtures of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, C alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluene Sulfonyloxy or any combination of substituents substituted) group:
• Embodiment 25 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyl Oxy or any combination of substituents) *-(CH 2 ) nl -N(R 2i )-(CH 2 ) n2 -, where * represents the point of attachment to the group R; R 21 is selected from H and Ci_ 3 alkyl; nl and n2 each independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or An integer of 20.
• L represents the following optionally substituted (for example, optionally selected from halogen, Ci
• Embodiment 26 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, and stereo as described in embodiment 20) or 25) Isomers, or mixtures of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, C alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluene Sulfonyloxy or any combination of substituents substituted) groups: ⁇ (CHA-NH- CHA-, *- (CH 2 ) 2 -NH-(CH 2 ) I -, *-(CH 2 ) 2 -NH-(CH 2 ) 2 -, *-(CH 2 ) 2 -NH-(CH 2 ) 3 -, *-(CH 2 ) 2 -NH-(CH 2 ) 4 -, *- (CH 2 ) 2 -
• Embodiment 27 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyl Oxy or any combination of substituents) *-(CH 2 ) nl -N(R 22 )C(0)-(CH 2 ) n2 -, where * represents the point of attachment to the group R; R 22 Selected from H and Ci_ 3 alkyl; nl and n2 each independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, An integer of 18, 19, or 20.
• L represents the following optionally substituted (for example, optionally selected from hal
• Embodiment 28 It relates to the compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereo as described in embodiment 20) or 27).
• Embodiment 29 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Cw alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy Group or any combination of substituents) group *-(CH 2 ) nl -C(0)N(R 23 )-(CH 2 ) n2 -, where * represents the point of attachment to the group R; R 23 is selected from H and Ci_ 3 alkyl; nl and n2 each independently represent
• Embodiment 30 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, or stereo as described in embodiment 20) or 29) Isomers, or mixtures of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, C alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluene Substituted by a sulfonyloxy group or any combination thereof) group: *-(CH 2 ) 2 -C(0)NH-CH 2 -,
• Embodiment 31 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or Substituted by p-toluenesulfonyloxy or any combination of substituents) *-(CH 2 ) nl -N(R 24 )C(0)N(R 25 )-(CH 2)n2 -, where * means and The point of attachment of the group R; R 24 and R 25 are each independently selected from H and C M alkyl; nl, n2 each independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
• L represents the following optionally
• Embodiment 32 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, or stereo as described in embodiment 20) or 31).
• Embodiment 33 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents *-(012)...1-piperidanylene-(CH2) n2 -, where * denotes the point of attachment to the group R; the piperidylene is optional Ground through halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy or Cw alkyl (especially methyl, ethyl, propyl, isopropyl, butyl, sec-butyl Or tert-butyl) or any combination of substituents; nl and n2 each independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, or 20.
• Embodiment 34 It relates to the compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereo as described in embodiment 20) or 33). Isomers, or mixtures of stereoisomers, where L represents *-CH 2 -piperazinylene-CH 2 -, *-(CH 2 ) 2 -piperazinylene-(CH 2 ) 2 -, * -(CH 2 ) 2 -piperazinylidene-(CH 2 ) 3- , *-(CH 2 ) 2 -piperazinylidene-(CH 2 ) 4 -, *-(CH 2 ) 2 -piperazinide -(CH 2 ) 5 -, *-(CH 2 ) 3 -piperazinylidene-CH 2 -, *- (CH 2 ) 3 -piperazinylidene-(CH 2 ) 2 -, *- (CH 2 ) 3 -piperazinylid
• L represents *-CH 2 -piperazinyl-CH 2 -, *-(CH 2 ) 2 -piperazinyl-(CH 2 ) 2 -, *-(CH 2 ) 2 -piperazinyl-( CH 2 ) 3 -, *- (CH 2 ) 2 -piperazinylidene-(CH 2 ) 4 -, *-(CH 2 ) 2 -piperazinylidene-(CH 2 ) 5 -, *-(CH 2 ) 3 -piperazinylidene -CH 2 -, *-(CH 2 ) 3 -Piperazinylidene-(CH 2 ) 2 -, *-(CH 2 ) 3 -Piperazinylidene-(CH 2 ) 3 -, *-(CH 2 ) 4 -piperazinyl-CH 2 -, *-(CH 2 ) 4 -piperazinyl-CH 2 -, *-(CH 2 )
• Embodiment 35 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents *-(CH 2 ) nl -phenylene-(CH 2 ) n2 -, where * represents the point of attachment to the group R; the phenylene group is optionally halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy group or a Ci_ 5 alkyl (especially methyl, ethyl, propyl, isopropyl, butyl, sec-butyl Or tert-butyl) or any combination of substituents; nl and n2 each independently represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, or 20
• Embodiment 36 It relates to a compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereo as described in embodiment 20) or 35).
• Isomers, or mixtures of stereoisomers where L represents *-CH 2 -phenylene-CH 2 -, *-(CH 2 ) 2 -phenylene-(CH 2 ) 2 -, *-( CH 2 ) 2 -phenylene-(CH 2 ) 3 -, *- (CH 2 ) 2 -phenylene-(CH 2 ) 4 -, *-(CH 2 ) 2 -phenylene-(CH 2 ) 5 -, *-(CH 2 ) 3 -phenylene-CH 2 -, *-(CH 2 ) 3 -phenylene- (CH 2 ) 2 -, *-(CH 2 ) 3 -phenylene- (CH 2 ) 2 -, *-(CH 2 ) 3 -pheny
• L represents *-CH 2 -phenylene-CH 2 -, *-(CH 2 ) 2 -phenylene-(CH 2 ) 2 -, *-(CH 2 ) 2- Phenyl- (CH 2 ) 3 -, *-(CH 2 ) 2 -Phenyl-(CH 2 ) 4 -, *-(CH 2 ) 2 -Phenyl-(CH 2 ) 5 -, *- (CH 2 ) 3 -phenylene-CH 2 -, *- (CH 2 ) 3 -phenylene-(CH 2 ) 2 -, *-(CH 2 ) 3 -phenylene-(CH 2 ) 3 -, *-(CH 2 ) 4 -phenylene-CH 2 -, *-(CH 2 ) 4 -phenylene- (CH 2 ) 2 -, *-(CH 2 ) 4 -phenylene- (CH 2 ) 2 -, *-(CH 2 ) 4 -phenylene-
• Embodiment 37 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyl Oxy or any combination of substituents substituted) group *-(CH 2 ) nl -S-(CH 2 ) n2 -, where * represents the point of connection with the group R; nl and n2 each independently represent 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
• L represents the following optionally substituted (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, tri
• Embodiment 38 It relates to the compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereo as described in embodiment 20) or 37).
• L represents the following optionally substituted (for example, optionally selected from halogen, C alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluene Sulfonyloxy or any combination of substituents substituted) groups: *-(CH 2 ) I S(CH 2 ) I- , *- (CH 2 ) 2 S(CH 2 ) 2 -, *-( CH 2 ) 2 S(CH 2 ) I- , *-(CH 2 ) I S(CH 2 ) 2- , *-(CH 2 ) I S(CH 2 ) 3- , *-(CH 2 ) I S (CH 2 ) 4- , *-(CH 2 ) I S(CH 2 ) 4- , *
• Embodiment 39 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Cw alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy Group or any combination of substituents) group *-(CH 2 ) nl -S(0)-(CH 2 ) n2 -, where * represents the point of connection with the group R; nl and n2 are each independently Represents an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
• L represents the following optionally substituted (for example, optionally selected from halogen, Cw alkyl, methanesulfonyl
• Embodiment 40 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, or stereo as described in embodiment 20) or 39) Isomers, or mixtures of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, C alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluene Sulfonyloxy or any combination of substituents substituted) groups: *-(CH 2 ) I S(0)(CH 2 ) I- , *- (CH 2 ) 2 S(0)(CH 2 ) 2 -, *-(CH 2 ) 2 S(0)(CH 2 ) r , (9) -, *-(CH 2 ) 1 S(0)(CH 2 ) 3- , *- (CH 2 ) !
• Embodiment 41 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyl Oxy or any combination of substituents) group *-(CH 2 ) nl -S(0) 2 -(CH 2 ) n2 -, where * represents the point of connection with the group R; nl and n2 respectively It independently represents an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
• L represents the following optionally substituted (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfon
• Embodiment 42 It relates to the compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereo as described in embodiment 20) or 41).
• Embodiment 44 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents not substituted with a choice (for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyl Oxy or any combination of substituents substituted) group:
• a choice for example, optionally selected from halogen, Ci_ 5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyl Oxy or any combination of substituents substituted
• Embodiment 45 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 20) , Or a mixture of stereoisomers, where L represents the following optionally substituted (for example, optionally selected from halogen, Cw alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy Group or any combination of substituents substituted) group:
• Embodiment 46 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Form, stereoisomer, or mixture of stereoisomers, where Xi represents C(0)NH 2 , piperidine-1-carbonyl, N,N-diisopropylcarbamoyl, NHC(0)CH 3 , SH, adamantyl-0- (especially adamantane-1-yl-0- or adamantane-2-yl-0-), norbornyl-0-, 1,7,7 -trimethyl Base-bicyclo[2.2.1]heptyl-0- (especially (1 S,2R,4S)-1,7,7 -trimethylbicyclo[2.2.1]heptane-2-yl-0 -) Or OH.
• Xi represents C(0)NH 2 , piperidine-1-carbonyl, N,N-di
• Embodiment 47 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where Xi represents cyclohexyl-0- (for example, 2-isopropyl-5-methylcyclohexyl-0-), adamantine-1 -Base-0-, adamantane-2-yl-0-, adamantyl-NHC(O)-, 3,5-dimethyladamantan-1-yl-cis ( : (0)-, adamantane -2-yl-NHC(O)-, or NHC(0)CH 3 .
• Xi represents cyclohexyl-0- (for example, 2-isopropyl-5-methylcyclohexyl-0-), adamantine-1 -Base-0-, adamantane
• Embodiment 48 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where ⁇ represents a linear or branched Cwo alkyl group optionally substituted with one or more fluorines.
• Embodiment 49 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 48) ,, Or a mixture of stereoisomers, where it means 0? 2 0? 3 or 0? 3 .
• Embodiment 50 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where ⁇ means optionally selected from halogen, cyano, Ci_ 3 alkyl, Ci_ 3 alkoxy, trifluoromethyl, methanesulfonyloxy , Trifluoromethanesulfonyloxy or p-toluenesulfonyloxy or Cw alkyl or any combination of substituents substituted cycloalkyl.
• Embodiment 51 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 50) , Or a mixture of stereoisomers, which represents cyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptane-2-yl or Adamantyl.
• Embodiment 52 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 50) , Or a mixture of stereoisomers, which represents cyclopropyl, 2,3-dihydro-111-indenyl, or 4-cyano-2,3-dihydro-1H-indenyl.
• Embodiment 53 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 50) , Or a mixture of stereoisomers, wherein it represents adamantyl-1-yl, adamantyl-2-yl, 3,5-dimethyladamantan-1-yl or (1 S, 2R, 4S)-1 ,7,7-Methylbicyclo[2.2.1]heptan-2-yl.
• Embodiment 54 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, wherein Xi represents a quaternary ammonium salt group of formula N + RJl b R c X, wherein R a , R b , and each independently represent Ci.
• X_ represents F, Cl ⁇ Br_, or 1_; or where R b and the N atom to which they are connected together form a five- to eight-membered heterocyclic group, and the ring atoms of the five- to eight-membered heterocyclic group may Optionally, it further includes a heteroatom selected from oxygen, nitrogen, and sulfur, R c represents a C UQ alkyl group, and X—represents F, Cl—, Br ⁇ or r.
• Embodiment 55 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 54) or a mixture of stereoisomers, wherein R a, R b, R c each independently represent C I-IQ not firing group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Base, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, ter-pentyl, hexyl, heptyl, octyl, nonyl, or decyl).
• C I-IQ not firing group e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Base, sec-buty
• Embodiment 56 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment 54) or a mixture of stereoisomers, wherein R a, Rb each independently represent not methyl, ethyl, propyl, isopropyl or butyl, Rc of the table is not ethyl, and X _ table is not cr.
• Embodiment 57 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 54) or a mixture of stereoisomers, wherein R a, R b, R c each represents an ethyl group, and X represents _ Cr; or wherein R a, R b, R c each represents a methyl group, and X represents _ cr.
• Embodiment 58 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where Xi represents a quaternary ammonium salt group of formula N + R a R b R ⁇ X_W, wherein R b and the N atom to which they are connected together form a five-membered to An eight-membered heterocyclic group, wherein the ring atoms of the five- to eight-membered heterocyclic group optionally further include heteroatoms selected from oxygen, nitrogen and sulfur, And X—represents F, cr, Br ⁇ or 1_.
• Embodiment 59 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer as described in embodiment 58) ,, Or a mixture of stereoisomers, where
• Embodiment 60 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where it represents an optional selected from halogen, halogenated Ci_ 3 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyl An aryl group substituted with a substituent of an oxy group, a Cw alkyl group, or any combination thereof.
• Embodiment 61 It relates to the compound of formula (I) or a salt, solvate, or isoposition thereof as described in embodiment 58) A prime-enriched analog, tautomer, polymorph, stereoisomer, or mixture of stereoisomers, which represents an optionally substituted phenyl or zeyl group.
• Embodiment 62 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, or stereoisomer as described in embodiment 58) , Or a mixture of stereoisomers, which represents phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 4-(bromomethyl)-2-fluorophenyl, or 3, 4, 5-Trifluorophenyl.
• Embodiment 63 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Type, stereoisomer, or mixture of stereoisomers, which represents an optionally substituted heterocyclic group or an optionally substituted heteroaryl group, wherein the substituent of the optionally substituted heterocyclic group is selected from: Ci_ 6 firing group (e.g.
• Ci_ 3-yl Su, oxo, chloro, amino, light group, Ci_ 3 firing group, on behalf of C l-3 alkoxy firing, firing substituting C l-3-yl ,
• the 5- or 6-membered heteroaryl group, or any combination thereof, and the substituent of the optionally substituted heteroaryl group are selected from: Ci_ 6 alkyl (such as Q_ 3 alkyl), halogen, cyano, amino, Hydroxyl, Ci_ 3 alkoxy, halogenated Ci_ 3 alkoxy, Alkyl;) phosphono, Ci_ 6 alkylsulfonyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted 5- or 6-membered
• Embodiment 64 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer, Or a mixture of stereoisomers, wherein the substituent of the optionally substituted 5- or 6-membered heterocyclic group is selected from the group consisting of Cw alkyl (for example, Q_ 3 alkyl), cyano, halogenated Q_ 3 alkyl, and amino , Hydroxy, or halogen or any combination thereof, the substituent of the optionally substituted 6-membered aryl group is selected from Ci_ 6 alkyl (for example, Ci_ 3 alkyl), halogenated Ci_ 3 alkyl, amino, hydroxy, or halogen or any combination thereof, and optionally substituted in the 5 - substituents selected from Q_ 6 alkyl group (e.g. Ci_ 3 alkyl), or 6-membered heteroaryl group, a halogenated Cg alkyl
• Embodiment 65 It relates to the compound of formula (I) or a salt, solvate, isotope-enriched analog, tautomer, polymorph, or stereoisomer as described in embodiment 63) or 64).
• Ci_ 3 alkyl halogen, oxo, cyano, amino, hydroxy, Q_ 3 alkoxy, halo Q_ 3 Alkoxy, Alkyl) phosphono, Ci_ 6 alkylsulfonyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl or Substituted in any combination) piperidinyl, optionally substituted (for example by Q_ 6 alkyl (for example 1-3 firing yl), Su, oxo, chloro, amino, light group, (1-3 ⁇ alkoxy burning, generation (firing ⁇ 1-3 alkoxy, C l-3 alkyl substituting, bis ( Ci_ 6 alkyl) phosphono, Ci_ 6 alkylsulfonyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted 5- or 6-membere
• Ci_ 6 alkyl e.g. Ci_ 3 alkyl
• halogen, oxo, cyano amino, hydroxy, Ci_ 3 alkoxy, halogenated Ci_ 3 alkoxy , Alkyl
• phosphono Ci_ 6 alkylsulfonyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl or Substituted by any combination thereof) 3, 8-diazabicyclo[3.2.1] octane-3-yl, optionally substituted (for example, by Ci_ 6 alkyl (for example, C 1-3 alkyl), prime, oxygen substituents, chloro group, amino group, light group, a C l-3 alkoxy firing, firing substituting C l-3 alkoxy, C l-3 Generation firing group, di (C l-6-yl firing) wins cool group, C 1-6 alkylcarbonyl, optionally substitute
• Ci_ 6 alkyl e.g. Ci_ 3 alkyl
• halogen cyano, amino, hydroxy, Ci_ 3 Alkoxy, halogenated Ci_ 3 alkoxy, Alkyl
• phosphono Ci_ 6 alkylsulfonyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl or Any combination thereof (substituted) pyrrolidinyl, optionally substituted (for example, Ci_ 6 alkyl (e.g., Ci_ 3 alkyl), halogen, chloro, amino, hydroxyl, C 1-3 alkoxy, substituted C 1 firing -3 alkoxy, C l-3 Generation firing group, di (C l-6-yl firing) wins cool group, Q_ 6 alkylsulfonyl group, an optionally substituted 6 membered aryl, optionally substituted 5 - or 6-membered heterocycly
• Embodiment 66 It relates to the compound of formula (I) as described in embodiment 63) or 64) or a salt, solvate, isotope enriched analog, tautomer, polymorph, and stereoisomer A structure, or a mixture of stereoisomers, which represents the following optionally substituted groups: 2-azabicyclo[3.2.1] octyl, 1,4-diazabicyclo[3.2.1] Octyl, tetrahydro-2H-pyranyl, azepanyl, azepanyl, isoindolyl, thiomorpholino, 5-azaspiro[2.4]heptyl, 6 -Azaspiro[2.5]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo [4.1.0] Heptyl, 5,7-dihydro-611-pyrrolo [3,4] pyr
• Embodiment 67 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analog, tautomer, polymorph, stereoisomer, Or a mixture of stereoisomers, where Xi represents morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, (N-methylpiperazinyl)piperidinyl, 3,5-dimethyl Piperazinyl, 1,4-diazepan-1-yl, 4-methyl-1,4-diazepan-1-yl, 1-methyl-1,4-diazepine Heptane-1-yl, 8-methyl-3,8-diazabicyclo [3.2.1] octane-3-yl, 5-methyl-2,5-diazabicyclo [2.2.
• Embodiment 68 It relates to the compound of formula (I) as described in embodiment 65) or 66) or its salt, solvate, isotope enriched analogue, tautomer, polymorph, stereoisomer A structure, or a mixture of stereoisomers, where X !
• Embodiment 69 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Wherein represents an optionally substituted cycloalkyl or an optionally substituted aryl group, wherein the substituent of the optionally substituted cycloalkyl group is selected from : Ci_ 6 alkyl group, halogen, Ci_ 3 alkoxycarbonyl group or any combination thereof, wherein the substituent of the optionally substituted aryl group is selected from the group consisting of: substituted C2_4 alkenyl, halogen or any combination thereof.
• Embodiment 70 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer, Or a mixture of stereoisomers, where Xi
• Embodiment 71 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Compounds, stereoisomers, or mixtures of stereoisomers, where X: represents NR 6 R 7 , where Re and R 7 each independently represent H or optionally substituted linear or branched Ci_ 1() alkane The condition is that Re and R 7 are not H at the same time.
• Embodiment 72 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer, Or a mixture of stereoisomers, where Xi represents NHCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , or N(CH(CH 3 ) 2 ) 2 .
• Embodiment 73 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Compounds, stereoisomers, or mixtures of stereoisomers, where X: represents NR 6 R 7 , where Re represents H, and R 7 represents substituted ethyl, where the substituent is 2,6-dichloro- 3-fluorophenyl.
• Embodiment 74 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph as described in any one of embodiments 18) to 45) Compound, stereoisomer, or mixture of stereoisomers, where represents NR 6 R 7 , wherein R 6 represents H or methyl, and R 7 represents optionally substituted cycloalkyl, optionally A substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group, wherein the substituent of the group represented by R 7 is optionally selected from the group consisting of: prime, Ci_ 5 alkyl, di(Ci_ 6 alkyl) saccharyl group, Ci_ 6 alkylcarbayl group, oxo group, optionally substituted 6-membered aryl group, optionally substituted 5- or 6-membered heterocyclic group, optionally substituted 5- or 6-membered Membered heteroaryl group, or cyano
• Embodiment 75 It relates to the compound of formula (I) or its salt, solvate, isotopic enrichment analogue, tautomer, polymorph, stereoisomer, Or a mixture of stereoisomers, where Xi represents NR 6 R 7 , where R 6 represents H or methyl, and R 7 represents pyrimidinyl, pyrrolidinyl (especially pyrrolidin-1-yl), pyridyl, Quinazolinyl, 6, 7-difluoroquinazolin-4-yl, phenyl, 3-chloro-4-methylphenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3, 4, 5 -Trifluorophenyl, 2-(dimethylphosphono)phenyl, 2-(isopropylsulfonyl)phenyl, 4-(pyrimidin-3-yl)pyrimidin-2-yl, indole Dolyl, 1-methyl-1H-in
• Embodiment 76 It relates to the compound of formula (I) or its salt, solvate, isotope enriched analogue, tautomer, polymorph as described in any one of embodiments 18) to 45) Compounds, stereoisomers, or mixtures of stereoisomers, where X: represents NR 6 R 7 , where Re represents H, methyl, ethyl, isopropyl or cyclohexyl, and R 7 represents optional substitution The following groups:
• Embodiment 77 It relates to the compound of formula (I) or its salt, solvate, isotopic enrichment analogue, tautomer, polymorph, stereoisomer, Or a mixture of stereoisomers, where R 7 represents
• Embodiment 78 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45)
• X represents NR 6 R 7 , wherein Re represents H, and R 7 represents a substituted thiazolyl group, wherein the substituent has the structural formula C(0)NHR A group of d , where R d represents a Cw alkyl group or 2-chloro-6-methylphenyl group.
• Embodiment 79 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where Xi represents NReR 7 , where Rg represents H, and R 7 represents pyrimidin-4-yl, pyridin-4-yl or quinazolin-4-yl ; Or where 1 represents NR 6 R 7 , where and represents a phenyl group.
• Embodiment 80 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where Xi represents Xi represents NHC(0)NR 9 R 1() , where R 9 represents H, and R 1() represents adamantyl, adamantine -1-yl, adamantan-2-yl, 3,5-dimethyladamantan-1-yl, phenyl, or 3-chloro-4-methylphenyl. .
• Embodiment 81 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where Xi represents C(0)NH 2 , piperidine-1-carbonyl, N,N-diisopropylcarbamoyl.
• Embodiment 82 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where Xi represents OH, adamantyl-0-, norbornyl-0-, or 1,7,7-trimethyl-bicyclo [2.2 .1] Heptyl-0- (for example, (1 S,2R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptyl-0-).
• Embodiment 83 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, which represent optionally substituted (for example, substituted by one or more fluorine) linear or branched Cwo alkyl groups.
• Xi table is not methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , P-pentyl, hexyl, heptyl, octyl, nonyl, decyl, CF 2 CF 3 or CF 3 .
• Embodiment 84 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Form, stereoisomer, or mixture of stereoisomers, where Xi represents NHC(0)R 8 , where Represents a straight-chain or branched C alkyl group, aryl group, heteroaryl group or heterocyclic group. In a sub-embodiment, Xi represents NHC(0)CH 3 .
• Embodiment 85 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Form, stereoisomer, or mixture of stereoisomers, where Xi represents NHC(0)NR 9 R 1Q , where and R 1Q each independently represent H, optionally substituted linear or branched Cwo alkane Group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocyclic group or optionally substituted heteroaryl group, wherein R C ⁇ PR 1Q is optionally not H at the same time.
• Embodiment 86 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer as described in any one of embodiments 18) to 45) or 85) , Polymorphs, stereoisomers, or mixtures of stereoisomers, wherein Xi represents NHC(0)NR 9 R IO , wherein R 9 and Rio each independently represent H or the following optionally substituted groups: Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, ter-pentyl, hexyl, heptyl, octyl Base, nonyl, decyl, phenyl, naphthyl, pyrimidinyl, pyridyl, quinazolinyl, quin
• Embodiment 87 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, and interconversion as described in any one of the embodiments 18) to 45), 85) or 86) Isomers, polymorphs, stereoisomers, or mixtures of stereoisomers, where Xi represents NHC(O)NR 9 R I0> where R 9 represents H, and R 1Q represents adamantyl, adamantyl -1-yl, adamantan-2-yl, 3,5-dimethyladamantan-1-yl, phenyl, or 3-chloro-4-methylphenyl.
• Embodiment 88 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where ⁇ represents an optionally substituted cycloalkyl (for example, (: 3 -(: 12 cycloalkyl or C 3 -C 1Q cycloalkyl)).
• ⁇ represents an optionally substituted cycloalkyl (for example, (: 3 -(: 12 cycloalkyl or C 3 -C 1Q cycloalkyl)).
• the cycloalkyl group is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, oxo, Ci_ 3 alkyl, and Ci_ 3 alkane. Oxy, cyano, or trifluoromethyl substitution.
• Xi represents cyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [ 2.2.1] heptane-2 - group or an adamantyl group in a 'sub-described embodiment, the table is not Xi firing adamantan-1-yl, adamantyl firing - 2 - yl, 3, 5 - dimethyladamantane firing - 1-yl or (1 S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl.
• Embodiment 89 It relates to the compound of formula (I) or a salt thereof as described in any one of embodiments 18) to 45), Solvates, isotopically enriched analogs, tautomers, polymorphs, stereoisomers, or mixtures of stereoisomers, where Xi represents an optionally substituted aryl group (for example, 5 to 14 yuan) Aryl) .
• the aryl group optionally substituted with halo, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or Ci_ 3 alkyl.
• Xi represents phenyl, 4-fluorophenyl, 3,5-difluorophenyl, or 3,4,5-trifluorophenyl.
• Embodiment 90 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where represents an optionally substituted heterocyclic group (for example, a 3-membered-12-membered heterocyclic group).
• the heterocyclic group is optionally substituted with a Ci- 6 alkyl group, an oxo group, a di(Ci- 6 alkyl)phosphono group, a Ci- 6 alkylsulfonyl group, an optionally substituted 5- or 6- Member heteroaryl, halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy, oxo, Ci_ 3 alkoxy, cyano, trifluoromethyl, optionally substituted Aryl (for example, an optionally substituted 6-membered aryl group, such as phenyl or 4-fluorophenyl), an optionally substituted heterocyclic group (for example, an optionally substituted 5- or 6-membered heterocyclic group, such as piper Azinyl, N-methylpiperazinyl), amino or hydroxyl substitution.
• aryl for example, an optionally substituted 6-membered aryl
• the substituent of the optionally substituted 5- or 6-membered heterocyclic group is selected from C 1-6 alkyl or halogen
• the substituent of the optionally substituted 6-membered aryl group is selected from The C 1-6 alkyl group or element
• the substituent of the optionally substituted 5- or 6-membered heteroaryl group is selected from Ci- 6 alkyl or halogen.
• Xi represents the following optionally substituted heterocyclyl: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyridinyl, and triazole Group, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, two Oxanyl, 1,4-diazepan-1-yl, 3,8-diazabicyclo[3.2.1]octane-3-yl or 2,5-diazabicyclo[2.2 .2] Octane-2-yl, wherein the substituent can be selected from: halogen, methanesulfonyloxy,
• Embodiment 91 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Forms, stereoisomers, or mixtures of stereoisomers, where Xi represents an optionally substituted heteroaryl group (for example, a 5- to 10-membered heteroaryl group).
• the heteroaryl group is optionally substituted with a Ci- 6 alkyl group, an oxo group, a di(Ci- 6 alkyl)phosphono group, a Ci- 6 alkylsulfonyl group, an optionally substituted 6-membered aryl group , Optionally substituted 5- or 6-membered heterocyclic group, or optionally substituted 5- or 6-membered heteroaryl, halogen, methanesulfonyl Oxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy, oxo, Ci_ 3 alkoxy, cyano, or trifluoromethyl substituted.
• the substituent of the optionally substituted 5- or 6-membered heterocyclic group is selected from Ci- 6 alkyl or halogen
• the substituent of the optionally substituted 6-membered aryl group is selected from Ci- 6
• the alkyl group or halogen, and the substituent of the optionally substituted 5- or 6-membered heteroaryl group is selected from Ci- 6 alkyl group or halogen.
• Xi represents an optionally substituted quinazolinyl, an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, an optionally substituted thiazolyl, an optionally substituted quinolinyl, an optionally substituted The indolyl group, the optionally substituted benzothienyl group, or the optionally substituted benzofuranyl group, wherein the substituents are as defined above.
• Xi represents pyridyl, pyrimidinyl, thiazolyl, quinolinyl, 6, 7-difluoroquinazolin-4-yl, 3-cyano-quinolinyl, indolyl, 1 -Methyl-1H-indol-7-yl, benzothienyl, benzofuranyl, quinazolinyl, 6,7-difluoroquinazolin-4-yl, or 4-(pyridine-3- Base) pyrimidine-2-base.
• Embodiment 92 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 18) to 45) Form, stereoisomer, or mixture of stereoisomers, where Xi represents a group of formula (G0:
• a t represents (: 112 or (:(; 0;);
• the ring atoms,, Vi, Wi are the same, all are CH; or
• Ring atom One of them is N, the others are CH; or
• Ring atom Two of them are N and the rest are CH; or
• Z represents S, S(O) or S(0) 2 .
• Embodiment 93 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer as described in any one of embodiments 18) to 45) or 92) , Polymorphs, stereoisomers, or mixtures of stereoisomers, where Xi represents a group of formula (G 2 ): Formula (G 2 )
• Ai represents CH 2 or C(O)
• Yi represents O or S
• Z represents S, S(O) or S(0) 2 .
• Embodiment 94 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer as described in any one of embodiments 18) to 45) or 92) , Polymorphs, stereoisomers, or mixtures of stereoisomers, where Xi represents a group of formula (G 3 ):
• a t represents (: 112 or (: (0), Yi represents 0 or S, and Z represents S, S (O) or S (0) 2.
• Embodiment 95 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer as described in any one of embodiments 18) to 45) or 92) , Polymorphs, stereoisomers, or mixtures of stereoisomers, where Xi represents a group of formula (G 4 ):
• a ! represents CH 2 or C(O)
• Yi represents 0 or S
• Z represents S, SO) or S(0; h.
• Embodiment 96 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer as described in any one of embodiments 18) to 45) or 92) , Polymorphs, stereoisomers, or mixtures of stereoisomers, where Xi represents a group of formula (G 5 ): Formula (G 5 )
• Ai represents ( : 11 2 or ( : (0), Yi represents O or S, and Z represents S, S(O) or S(0) 2 .
• Embodiment 97 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer as described in any one of embodiments 18) to 45) or 92) , Polymorphs, stereoisomers, or mixtures of stereoisomers, where Xi represents a group of formula (G 6 ):
• A represents CH 2 or C(O)
• Yi represents 0 or S
• Z represents S, S(O) or S(0) 2 .
• Embodiment 98 It relates to the compound of formula (I) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments 92) to 97) the mixture type thereof, a stereoisomer thereof, or a stereoisomer thereof, wherein a t represents (: 112 or (:(; 0), Yi represents 0, and Z represents S.
• the present invention provides an embodiment A1): a compound of formula (I') or a salt, solvate, isotope-enriched analog, tautomer, polymorph, stereoisomer Isomers (including enantiomers), or mixtures of stereoisomers:
• A, B, U, V, W, Y are as defined in any one of the implementation schemes 1)-14);
• R means S, S(O) or S(0) 2;
• L represents an optionally substituted linear or branched alkylene group, wherein the linear or branched alkylene group is optionally interrupted one or more times by one or more groups selected from: 0, C(O), S, S(O), S(0) 2 , S(0) 2 N(R I ), N(R 2 )S(O) 2 , C(0)N(Ri), N (R 2 )C(0), N(R 3 ), N(R 4 )C(0)N(R 5 ), optionally substituted cycloalkylene, optionally substituted arylene, optionally substituted The heterocyclylene, optionally substituted heteroarylene or any combination thereof, wherein Ri, R 2 , R 3 ,
• R 4 and 115 each independently represent H or Ci_ 3 alkyl
• X ! represents NHC O)! ⁇ or SR j , where and each independently represent optionally selected from ( ⁇ _ 6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino , Hydroxy, Ci_ 3 alkoxy, halo Ci_ 3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or cycloalkyl substituted with any combination of substituents, Or Xi means optionally selected from Ci_ 6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, Ci_ 3 alkoxy, halogenated Ci_ 3 alkoxy, methanesulfonyloxy , Cycloalkyl substituted with trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or any combination thereof; or
• R 6 represents H or Ci_ 6 alkyl
• R 7 represents optionally selected from Ci_ 6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, Ci_ 3 alkoxy, Cycloalkyl substituted with halogenated Ci_ 3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or any combination thereof; or
• Embodiment A2 It relates to the compound of formula (I') or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, and stereoisomer as described in embodiment A1) Isomers, or mixtures of stereoisomers, where A represents CH 2 or C(O), and B, U, V, and W all represent CH.
• Embodiment A3 It relates to the compound of formula (1') or its salt, solvate, isotope enriched analogue, tautomer, polymorph, and stereoisomer as described in embodiment A1) Isomers, or a mixture of stereoisomers, where L represents an optionally substituted linear or branched C MO alkylene group, wherein the linear or branched C MO alkylene group is optionally substituted by one or more A group selected from the following interrupted one or more times: 0, C(O), S, S(O), S(0) 2 , S(0) 2 N(R I ), N(R 2 )S (0) 2 , C(0)N(R I ), N(R 2 )C(O), N(R 3 ), N(R 4 )C(O)N(R 5 ), optional from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, 5 alkyl substituted arylene group or p-toluene
• Embodiment A4 It relates to the compound of formula (1') or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, and stereoisomer as described in embodiment A1) Isomers, or mixtures of stereoisomers, where L represents the following optionally substituted groups: straight or branched CrQo alkylene, *-(CH 2 ) nl -N(R 22 )S(0) 2 -(CH 2 ) n2 -, *-(CH 2 ) nl -S(0) 2 N(R 23 )-(CH 2 ) n2 -, or *- ⁇ ! ⁇ ; ⁇ -phenylene-(CH 2 ) n2 -, where * represents the point of attachment to the group R, R 22 and R 23 are each independently selected from H and Ci_ 3 alkyl, nl, n2 each independently represent 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
• Embodiment A5 It relates to the compound of formula (1') or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, and stereoisomer as described in embodiment A1) Isomers, or a mixture of stereoisomers, where L represents the following optionally substituted group:
• Embodiment A6 It relates to the compound of formula (r) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment A1) ,, Or a mixture of stereoisomers, where L represents the following optionally substituted group:
• Embodiment A7) It relates to the compound of formula (r) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph as described in any one of the embodiments A1) to A6) Forms, stereoisomers, or mixtures of stereoisomers, in which:
• X ! represents the following optionally substituted groups:
• Adamantyl-C(0)NH-, adamantyl-S-, or norbornyl group wherein the substituent of the group is selected from Ci- 6 alkyl (for example, C 1-3 alkyl), oxo group, Su, chloro, methyl three gas, amino, light group, C l-3 alkoxy firing, generation of C l _ 3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy Sulfonyloxy or any combination thereof.
• Embodiment A8 It relates to the compound of formula (r) or its salt, solvate, isotope-enriched analogue, tautomer, polymorph, stereoisomer as described in embodiment A7) , Or a mixture of stereoisomers, where Xi represents adamantane-1-yl-CCO)NH-, 3-hydroxyadamantyl-CCO)NH-, 3-hydroxyadamantan-1-yl-C(; 0)NH-,
• 3-chloroadamantan-1-yl-C(0)NH- 4-chloroadamantan-1-yl-C(0)NH-, 2-chloroadamantan-1-yl-C(0)NH- , King Kong Alk-2-yl-C(0)NH-, adamantane-1-yl-S-, 3-hydroxyadamantyl-S-, 3-hydroxyadamantan-1-yl-S-, 3-chloroadamantyl Alkyl-1-yl-S-, 4-chloroadamantane-1-yl-S-, 2-chloroadamantane-1-yl-S-, adamantane-2-yl-S-, bicyclic [2.2.
• Embodiment A9 It relates to the compound of formula (r) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments A1) to A6) Forms, stereoisomers, or mixtures of stereoisomers, where
• NReRy represents H or ( ⁇ _ 3 alkyl, R 7 represents the following optionally substituted groups:
• Embodiment A10) It relates to the compound of formula (r) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorph as described in any one of embodiments A1) to A6) Types, stereoisomers, or mixtures of stereoisomers, wherein R7 represents ⁇ K adamantan-1-yl, 3-light fund pyrano-1-yl, 3-light fund pyrano-1-yl, 3- Chloroadamant-1-yl, 4-chloroadamantane-1-yl, 2-chloroadamantane-1-yl, adamantane-2-yl, bicyclo[2.2.1]heptane-2-yl, 1 ,7,7-trimethylbicyclo[2.2.1]heptane-2-yl, 7,7-dimethylbicyclo[2.2.1]heptane-1-yl, or 7,7-dimethyl Base-2 -oxobicyclo [2.2.1]
• Embodiment A11 It relates to the compound of formula (r) or its salt, solvate, isotope-enriched analogue, tautomer, and polymorphism as described in any one of embodiments A1) to A6).
• U represents ( ⁇ _ 3 alkyl, represents optionally substituted piperidinyl, wherein the substituted piperazine optionally substituted group given port
• the group is selected from: C 1-6 alkyl (for example, C 1-3 alkyl), element, oxo, chloro, amino, hydroxy, Ci_ 3 alkoxy, halogenated Ci_ 3 alkoxy, halogenated Ci_ 3 alkyl, di(C M alkyl) phosphono, Ci_ 6 alkylsulfonyl or any combination thereof.
• the compounds of formula (I), (la), Ob), (Ic), (Id), and formula (I') of the present invention can have a stereo configuration, and therefore can be different in more than one stereo
• the present invention also relates to compounds having a stereoconfiguration in a substantially pure isomeric form, such as greater than about 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures.
• These isomers can be prepared by conventional methods in the art such as asymmetric synthesis (eg chiral intermediates) or chiral resolution.
• Another aspect of the present invention also provides a pharmaceutical composition, which comprises as an active ingredient the compound of formula (I) or the compound of formula (r) of the present invention, or a pharmaceutically acceptable compound thereof Salts, racemates, enantiomers, diastereomers, solvates or polymorphs, and pharmaceutically acceptable carriers.
• the pharmaceutical composition of the present invention further includes at least one additional drug for treating or preventing cancer or tumor.
• the cancer or tumor includes but is not limited to multiple myeloma, myelodysplastic syndrome (MDS), previously treated myelodysplastic syndrome, plasma cell myeloma, transplantation-related cancer , Myelofibrosis, plasma cell myeloma, bone marrow disease, neutropenia; leukemia, acute myeloid leukemia, anemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, acute myeloid leukemia (AML), CD20 positive ; Primary lymphoma, B-cell lymphoma, recurrent B-cell non-Hodgkin’s lymphoma, recurrent diffuse large B-cell lymphoma, recurrent primary mediastinal (thymus) large B-cell, recurrent transforming non-Hodgkin’s lymphoma Hodgkin's lymphoma, refractory B-cell non-Hodgkin’s lymphoma,
• MDS myel
• the pharmaceutical composition of the present invention containing the active ingredient can be administered according to a suitable route of administration (including but not limited to nasal cavity administration, inhalation administration, topical administration, oral administration, oral mucosal administration, Rectal, pleural, intraperitoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous) are prepared into Suitable preparation forms such as spray preparations, patches, tablets, capsules, dragees, troches, powders, granules, powder injections, or liquid preparations (such as suspensions, solutions, emulsions or syrups).
• a suitable route of administration including but not limited to nasal cavity administration, inhalation administration, topical administration, oral administration, oral mucosal administration, Rectal, pleural, intraperitoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous
• Suitable preparation forms such as spray preparations, patches, tablets, capsules, dragees, tro
• the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, Solvates or polymorphs, which are used as medicaments.
• the compound of formula (I), or compound of formula (r), or a pharmaceutically acceptable salt, racemate, enantiomer, Diastereomers, solvates or polymorphs which are used to prevent and/or treat cancer or tumors.
• the cancer or tumor includes, but is not limited to, multiple myeloma, myelodysplastic syndrome (MDS), previously treated myelodysplastic syndrome, plasma cell myeloma, transplantation-related cancer, bone marrow fibers Myeloma, plasma cell myeloma, bone marrow disease, neutropenia; leukemia, acute myeloid leukemia, anemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, acute myeloid leukemia (AML), CD20 positive; primary Lymphoma, B-cell lymphoma, recurrent B-cell non-Hodgkin’s lymphoma, recurrent diffuse large B-cell lymphoma, recurrent primary mediastinal (thymus) large B-cell, recurrent transforming non-Hodgkin’s Lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell
• Another aspect of the present invention provides a compound of formula (I), or a compound of formula (r), or a pharmaceutically acceptable salt, racemate, enantiomer, or non-
• enantiomers, solvates or polymorphs for the preparation of drugs for the prevention and/or treatment of cancer or tumors.
• the cancer or tumor includes, but is not limited to, multiple myeloma, myelodysplastic syndrome (MDS), previously treated myelodysplastic syndrome, plasma cell myeloma, transplantation-related cancer, and bone marrow fibers Myeloma, plasma cell myeloma, bone marrow disease, neutropenia; leukemia, acute myeloid leukemia, anemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, acute myeloid leukemia (AML), CD20 positive; primary Lymphoma, B-cell lymphoma, recurrent B-cell non-Hodgkin’s lymphoma, recurrent diffuse large B-cell lymphoma, recurrent primary mediastinal (thymus) large B-cell, recurrent transforming non-Hodgkin’s lymphoma Lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory
• Another aspect of the present invention also provides a method for treating or preventing cancer or tumor, which comprises administering to a subject a therapeutically effective amount of the compound of formula (I), or compound of formula (r), or Its pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, solvates or polymorphs, or the pharmaceutical composition of the present invention.
• the cancer or tumor is selected from the group consisting of: multiple myeloma, myelodysplastic syndrome (MDS) , Previous treatment of myelodysplastic syndrome, plasma cell myeloma, transplant-related cancer, myelofibrosis, plasma cell myeloma, bone marrow disease, neutropenia; leukemia, acute myeloid leukemia, anemia, chronic granulocyte Leukemia, B-cell chronic lymphocytic leukemia, acute myeloid leukemia (AML), CD20 positive; primary lymphoma, B-cell lymphoma, recurrent B-cell non-Hodgkin’s lymphoma, recurrent diffuse large B-cell lymphoma Tumors, recurrent primary mediastinal (thymus) large B-cells, recurrent transforming non-Hodgkin’s lymphoma, refractory B-
• MDS myelodysplastic syndrome
• the compound of formula (I), or compound of formula (I'), or a pharmaceutically acceptable salt or external elimination thereof according to the present invention Rotate, enantiomer, diastereomer, solvate or polymorph, or said pharmaceutical composition, by at least one selected from nasal administration, inhalation administration, topical administration, Oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, percutaneous administration, epidural administration, intrathecal administration Drug and intravenous administration are administered to the subject.
• halogen atom or halogen used alone or in combination refer to fluorine, chlorine, bromine or iodine, and preferably F, C1 or Br.
• alkyl used alone or in combination refers to a straight or branched chain alkyl group.
• C x -C y alkyl or “C xy alkyl” (x and y are each an integer) refers to a straight or branched chain alkyl group containing x to y carbon atoms.
• Cy alkyl used alone or in combination in the present invention refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms.
• Cwo alkyl group preferably present invention is Ci_ 9 alkyl, more preferably Ci_ 8 alkyl group, further more preferably C 2-8 alkyl, more preferably Cw alkyl group, even more preferably an alkyl group Cw, Cw alkyl , Or ( ⁇ _ 4 alkyl.
• Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Neopentyl, tertpentyl, hexyl, heptyl, octyl, nonyl and decyl.
• Q_ 3 alkyl in the present invention refers to an alkyl group containing 1 to 3 carbon atoms, and representative examples thereof include Methyl, ethyl, n-propyl and isopropyl.
• the "alkyl” is optionally substituted, and the substituent is preferably one or more selected from halogen, cyano, Ci_ 3 Alkyl group, Ci_ 3 alkoxy group, trifluoromethyl group, heterocyclic group or a combination of substituents.
• alkylene (which is used interchangeably with “alkylene chain”), used alone or in combination, refers to a straight or branched bivalent chain composed of carbon and hydrogen atoms.
• C x -C y alkylene (X and y are each an integer) refers to a linear or branched alkylene group containing x to y carbon atoms.
• the CrC % alkylene group of the present invention is preferably C1-C29 alkylene group, C1-C28 alkylene group, C1-C27 alkylene group, C1-C26 alkylene group, C1-C25 alkylene group, C1-C24 alkylene group group, C1-C23 alkylene firing group, C1-C22 alkylene firing group, C1-C21 alkylene firing group, C1-C20 alkylene firing group, C1-C19 alkylene group firing, Ci_ C l8 firing alkylene group, C l -C l7 alkylene Alkylene group, C l -C l6 alkylene group, C l -C l5 alkylene group, C l -C l
• Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene , Neopentylene, terpentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, decylene Tetraalkyl, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, eicosylene, arachidylene Dialkyl, trichenylene, tetracosene, pentadecylene, hexadecylene, heptadecylene, octadecylene, and 29 Alkyl,
• the "alkylene” is optionally substituted, and the substituent is preferably one or more selected from halogen, cyano, Ci_ 3 alkyl, Ci_ 3 alkoxy, trifluoromethyl , Heterocyclic group or a combination of substituents.
• aryl used alone or in combination refers to an aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally one or more fused rings, such as phenyl and naphthyl. Or fluorenyl.
• the "aryl group” is an optionally substituted aryl group.
• a substituted aryl group refers to an aryl group substituted 1-3 times by a substituent, wherein the substituent is preferably selected from Ci_ 6 alkyl (for example, Ci_ 3 alkyl), halogenated alkenyl, halogenated Q_ 3 alkoxy, Cyano, Ci_ 3 alkoxy, halogenated Ci_ 3 alkyl (trifluoromethyl), heterocyclic, halogen, amino or hydroxyl.
• arylene used alone or in combination refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene Group or naphthylene or fluorenylene.
• the "arylene group” is an optionally substituted arylene group.
• a substituted arylene group refers to an arylene group substituted 1-3 times by a substituent, wherein the substituent is selected from the group consisting of ⁇ _ 3 alkyl, halogenated alkenyl, halogenated Q_ 3 alkoxy, cyano, Q_ 3 Alkoxy, halogenated Ci_ 3 alkyl (trifluoromethyl), heterocyclic group, halogen, amino or hydroxyl.
• alkoxy used alone or in combination refers to a linear or branched alkoxy group, the structural formula of which is -O-alkyl.
• the alkyl moiety of the alkyloxy group may contain 1-10 carbon atoms.
• Representative examples of "alkyloxy” include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, 2 -Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc.
• Ci_ 3 alkoxy refers to a straight or branched chain alkoxy group containing 1 to 3 carbon atoms.
• Representative examples of Ci_ 3 alkoxy include but are not limited to methoxy, ethoxy, n-propoxy and isopropoxy. Preferably methoxy and Ethoxy.
• cycloalkyl used alone or in combination refers to having 3 to 12 carbon atoms (for example, 3-12, 3-11, 3-10, 3-8, 3-7, 3-6 carbon atoms) saturated and partially unsaturated (that is, having one or more double bonds, but not fully conjugated) monocyclic or bicyclic or polycyclic cyclic hydrocarbon groups.
• C 3 -C 1Q cycloalkyl refers to a saturated and partially unsaturated (that is, one or more double bonds, but not fully conjugated) monocyclic or bicyclic or polycyclic rings with 3 to 10 carbon atoms Cycloalkyl.
• cycloalkyl includes monocyclic, bicyclic, or tricyclic alkyl groups, which have 3 to 12 carbon atoms.
• monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• Bicyclic and tricyclic cycloalkyls include bridged cycloalkyls, fused rings and spirocycloalkyls, such as but not limited to decalin, octahydrocyclopentadiene, octahydro-1H-indenyl, 2,3-di Hydrogen-111-indenyl, spirocyclic group, adamantyl group, noradamantyl group, norbornyl group (system named bicyclo[2.2.1]heptyl group).
• the "cycloalkyl” is optionally mono- or poly-substituted, for example, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, Or 2, 6-disubstituted cyclohexyl.
• the substituent of the substituted "cycloalkyl” is preferably one or more selected from halogen, cyano, ⁇ _ 3 alkyl, ⁇ _ 3 alkoxy, halo ⁇ _ 3 alkyl ( For example, trifluoromethyl), amino, hydroxyl, heterocyclic group or any combination of substituents.
• cycloalkylene used alone or in combination means having 3 to 12 carbon atoms (for example, 3-12, 3-11, 3-10, 3-8 , 3-7, 3-6 carbon atoms) saturated and partially unsaturated (that is, with one or more double bonds, but not fully conjugated) monocyclic or bicyclic or polycyclic cyclic hydrocarbon divalent groups.
• C 3 -C 10 cycloalkylene refers to a saturated and partially unsaturated (that is, one or more double bonds, but not fully conjugated) monocyclic or bicyclic or polycyclic ring with 3 to 10 carbon atoms Divalent cyclic hydrocarbon group.
• cycloalkylene includes monocyclic, bicyclic or tricyclic hydrocarbon divalent groups having 3 to 12 carbon atoms.
• Representative examples of monocyclic cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, And cyclooctyl.
• Bicyclic and tricyclic cycloalkylene groups include bridged cycloalkylene, fused ringylene, and spirocycloalkylene, such as but not limited to decahydronaphthylene, octahydrocyclopentadienylene, and octahydro-1H -Indenylidene, 2,3-dihydro-111-indenylidene, spirocyclylene, adamantylene, noradamantyl, norbornylene (system named bicyclo[2.2.1] heptane Alkylene).
• the "cycloalkylene” is optionally mono- or poly-substituted, for example, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- , Or 2,6-disubstituted cyclohexyl.
• the substituent of the substituted "cycloalkyl” is preferably one or more selected from halogen, cyano, Ci_ 3 alkyl, Ci_ 3 alkoxy, and halogenated Ci_ 3 alkyl (for example, trifluoromethyl) , Amino, hydroxy, heterocyclic group or any combination of substituents.
• C xy spirocycloalkyl or "C xy spirocyclic group” (x and y are each an integer) used alone or in combination refer to a spiro ring containing x to y carbon atoms alkyl.
• C 7-12 spirocycloalkyl used alone or in combination in the present invention refers to a spirocycloalkyl group containing 7 to 12 carbon atoms.
• C 7-n spirocycloalkyl include, but are not limited to, spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl , Spiro [4.5] decane Base or spiro [5.5] Undecyl.
• C 7-12 spirocycloalkyl is optionally further selected from halogen, cyano, Ci_ 3 alkyl, Q_ 3 alkoxy, halogenated Q_ 3 alkyl (such as trifluoromethyl), amino One or more of the substituents of, oxo, hydroxy, heterocyclyl, or any combination thereof.
• heteroaryl used alone or in combination refers to containing one or more (for example, 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3 A) 5- to 10-membered monocyclic or bicyclic aromatic ring groups independently selected from heteroatoms of oxygen, nitrogen and sulfur.
• heteroaryl groups include but are not limited to furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, Imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, Indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2, 1,3] oxa Azolyl, benzo[2, 1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, is
• heteroaryl groups can be unsubstituted or substituted.
• a substituted heteroaryl group refers to a heteroaryl group substituted 1-3 times by a substituent, wherein the substituent is preferably selected from Ci_ 3 alkyl, Ci_ 3 alkoxy, cyano, trifluoromethyl, heterocyclic, Halogen, amino or hydroxyl.
• heteroarylene used alone or in combination means containing one or more (for example, 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) 5- to 10-membered monocyclic or bicyclic divalent aromatic ring groups independently selected from heteroatoms of oxygen, nitrogen and sulfur.
• heteroarylene groups include, but are not limited to, furanylene, oxazolyl, isoxazolyl, oxadiazolyl, thienylene, thiazolyl, isothiazolyl, Thiadiazole, pyrrolylene, imidazolylidene, pyrazolylidene, triazolylidene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindylene Dole, benzofuranyl, isobenzofuranyl, benzothienylene, indazolylidene, benzimidazolylidene, benzoxazolylidene, benzisoxanyl, phenylene Thiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2, 1,3] oxadiazolyl, benzol[2, 1,3] thiadiazolyl, phenylene
• the heteroarylene group can be unsubstituted or substituted.
• the substituted heteroarylene group refers to a heteroarylene group substituted 1-3 times by a substituent, wherein the substituent is preferably selected from Q_ 3 alkyl, Q_ 3 alkoxy, cyano, trifluoromethyl, and heterocycle Group, halogen, amino or hydroxyl.
• heterocyclic group or “heterocyclic group” used alone or in combination means containing one or more (for example, containing 1 to 5 or 1 to 4) independently selected from sulfur, 3- to 12-membered monocyclic, bicyclic or tricyclic ring with heteroatoms of oxygen and nitrogen The saturated or partially unsaturated (that is, with one or more double bonds, but not fully conjugated) cyclic hydrocarbon group.
• heterocyclyl may preferably refer to a 3- to 6-membered monocyclic saturated or partially unsaturated ring containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen (ie, having one Or multiple double bonds, but not fully conjugated) cyclic hydrocarbon group.
• Representative examples include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyridinyl, triazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl Hydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, 1,4-diaza Cycloheptane-1-yl, 3,8-diazabicyclo[3.2.1]octane-3-yl, 2,5-diazabicyclo[2.2.2]octane-2-yl, and nitrogen Heterospiro ring group (especially 3-azaspiro [5.5] undecane-3-yl).
• the heterocyclic group may be unsubstituted or substituted as clearly defined, wherein the substituent may preferably be selected from Ci_ 6 alkyl (for example, Ci_ 3 alkyl), Ci_ 3 alkoxy, cyano, and trifluoromethyl , Heterocyclic group, halogen, amino or hydroxyl.
• heterocyclylene used alone or in combination refers to those containing one or more (for example, containing 1 to 5 or 1 to 4) independently selected from sulfur, oxygen and nitrogen Heteroatomic 3- to 12-membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated (ie, having one or more double bonds, but not fully conjugated) cyclic hydrocarbon divalent group.
• heterocyclylene may preferably refer to a 3- to 6-membered monocyclic saturated or partially unsaturated ring containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen (ie, having One or more double bonds, but not fully conjugated) A cyclic hydrocarbon divalent group.
• heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, pyridinylene, Triazolyl, tetrahydrofuranylene, tetrahydropyranyl, tetrahydrothiophenylene, tetrahydrothiopyranyl, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, sub Morpholinyl, thiomorpholinylene, dioxanyl and dioxanyl.
• the heterocyclylene may be unsubstituted or substituted as clearly defined, wherein the substituent may preferably be selected from Ci_ 3 alkyl, Ci_ 3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen , Amino or hydroxyl.
• the term "quaternary ammonium salt group" used alone or in combination refers to a quaternary ammonium salt group represented by the formula N + R a R b R ⁇ X_, wherein R a , R b , R c each independently represents an alkyl group, and X_ represents F, Cl ⁇ Br_, or r; or wherein RjP R b and the N atom to which they are connected together form a four- to eight-membered heterocyclic group (especially five- to eight-membered A heterocyclic group, or a five-membered to six-membered heterocyclic group), the ring atoms of the five-membered to eight-membered heterocyclic group may optionally further include a heteroatom selected from oxygen, nitrogen and sulfur, R c represents C MO ⁇ Base, and X—represents F, cr, Br ⁇ or r.
• heterocyclic group in the five- to eight-membered heterocyclic group may be as defined above, and the heteroatom of the heterocyclic group may optionally further include an oxygen atom, a nitrogen atom, and/or a sulfur atom.
• exemplary heterocyclic groups include but are not limited to piperidinyl, morpholinyl, imidazolyl, triazolyl, piperazine
• heterocyclic quaternary ammonium salt groups include but are not limited to
• amantadine has a definition known to those skilled in the art.
• An example of “amantadine” may be adamantan-1-amine (its corresponding English chemical name is adamantan-1-amine or Tricyclo[3.3.1.1 3 ' 7 ]decan-l-amine; CAS: 768-94 -5), has the following structural formula:
• the salt of the compound of formula I, or the salt of the compound of formula (r), or a pharmaceutically acceptable salt thereof refers to a non-toxic inorganic or organic acid and/or Base addition salt.
• examples include: sulfate, hydrochloride, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrophosphate, pyrophosphate Salt, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate or p-toluenesulfonate, etc.
• “Pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, such as fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents or encapsulating materials,
• the compound useful in the present invention is carried or transported into the patient's body or administered to the patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body.
• the carrier is compatible with the other ingredients of the formulation (including the compound useful in the present invention) and is not harmful to the patient, and the carrier must be "acceptable.”
• pharmaceutically acceptable carrier materials include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose And cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil ; Glycols, such as propylene glycol; Polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; Esters, such as ethyl oleate and ethyl laurate; Agar; Buffers, such as
• treatment refers to the administration of a compound of formula I, or a compound of formula (r), or a pharmaceutically acceptable salt thereof according to the present invention to a subject, or contains formula I as an active ingredient
• the beneficial or expected clinical results of the present invention include, but are not limited to: alleviation of symptoms, alleviation of disease severity, stabilization of disease state, delay or delay of disease progression, improvement or alleviation of disease, and alleviation of disease.
• the "therapeutically effective amount" of the compound of the present invention depends on the age, sex, and weight of the patient, the patient's current medical condition, and the cancer progression of the patient being treated. Those skilled in the art can determine the appropriate dosage based on these and other factors.
• room temperature in the present invention refers to the ambient temperature, such as a temperature of 20-30°C.
• Umemoto test unit Ll 2, 8 -difluoro-5-(trifluoromethyl)-5H-dibenzo[B,D]thiophene-5 -piper trifluoromethanesulfonate [00170]
• target compound sulfur group substituted pomalidomide alkyl carbon chain carboxylic acid series compound
• reaction solution was cooled to room temperature, and 3-(4-amino-1-oxoisoindoline-2-yl)piperidine-2,6-dione (namely lenalidomide) (8.0 g, 30.9 mmol), and finally, tert-butyl nitrite (4.78 g, 46.4 mmol) is slowly added dropwise, after the dropping, the temperature is raised to 80 ° C again and stirred for 8h. After the reaction, the reaction solution was cooled to room temperature, water (200 mL) was added, and ethyl acetate was extracted (2 x 200 mL).
• the eluent (v/v): acetonitrile/(water+0.05% TFA) 10% -100%, to obtain the corresponding tert-butanol ester intermediate product;
• the corresponding tert-butanol ester intermediate product was added to a 10 mL egg-shaped flask, 88% formic acid (3 mL) was added, and the mixture was stirred at room temperature for 12 h.
• the reaction solvent was evaporated under reduced pressure, and water was added to freeze-dry to obtain the corresponding target compound.
• step 1 The Boc-protected alkylation intermediate product obtained in step 1 was added to a 10 mL reaction flask, followed by anhydrous methylene chloride (2 mL) and trifluoroacetic acid (2 mL), and stirred at room temperature for 12 h.
• the reaction solvent was evaporated under reduced pressure, and the crude product was separated by a reversed-phase C18 column.
• the eluent (v/v): acetonitrile/(water+0.05% TFA) 10% -100%.
• the solvent was evaporated under reduced pressure and lyophilized to obtain the corresponding Target compound.
• reaction was quenched with saturated sodium bicarbonate, extracted with DCM, dried over anhydrous sodium sulfate and concentrated to obtain a colorless oil, added 2 mL of acetonitrile, separated on a C18 reverse phase column, eluent: 10%-100% (vl: v2 ) Acetonitrile: water, remove the solvent under reduced pressure to obtain the sulfoxide and sulfone target compounds.
• NHR 4 R 5 represents a linear or branched secondary or primary alkyl amine or a nitrogen-containing heterocyclic substrate.
• n can be an integer in the range of 1-20.
• Example 1 Preparation of 3-(4-(benzylthio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (SIAIS171088)
• the compound SIAIS 171 132 was prepared under appropriate conditions understandable in the art, except that the brominated substrate used was tert-butyl (5-bromopentyl) carbamate.
• the target compound SIAIS171 132 (light yellow solid, 95 mg, total yield of two steps 73%) was obtained.
• the compound SIAIS 171 136 is prepared under appropriate conditions understandable in the art, except that the brominated substrate used is tert-butyl (8-bromooctyl) carbamate.
• the target compound SIAIS171 136 (white solid, 100 mg, total yield of two steps 68%) was obtained.
• the compound SIAIS1210073 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was methyl iodide.
• the target compound SIAIS 1210073 (yellow solid, 58 mg, yield 55%) was obtained.
• the compound SIAIS1210071 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was methyl iodide.
• the target compound SIAIS 1210071 (white solid, 134 mg, yield 64%) was obtained.
• the compound SIAIS1213073 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was bromoethane.
• the target compound SIAIS 1213073 (orange solid, 15 mg, yield 45%) was obtained.
• ⁇ NMR (500 MHz, DMSO) 5 10.99 1.0 Hz, 1H), T59-T50 (m, 2H), 5.12 13.3, 5.1 Hz, 1H), 4.36 (d, J 17.3 Hz, 1H), 4.22 (d, 17.4
• the compound SIAIS1213071 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1-bromopropane.
• the target compound SIAIS1213071 (light yellow solid, 15 mg, yield 43%).
• the compound SIAIS1213075 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 2-bromopropane.
• the target compound SIAIS1213075 (light yellow solid, 12 mg, yield 34%) was obtained.
• Example 7 Preparation of 3-(1-oxo-4-(pentylthio)isoindoline-2-yl)piperidine-2,6-dior (SIAIS1213195)
• the compound SIAIS1213195 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1-bromopentane.
• the target compound SIAIS1213195 (light yellow solid, 29 mg, yield 76%) was obtained.
• Example 8 Preparation of 3-(1-oxo-4-(pentylthio)isoindoline-2-yl)piperidine-2,6-dione (SIAIS1216025)
• the compound SIAIS1216025 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1-bromooctane.
• the target compound SIAIS 1216025 (white solid, 22.4 mg, yield 58%) was obtained.
• the compound SIAIS1216189 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 3-bromo-1-propanol.
• the target compound SIAIS1216189 (light yellow solid, 20 mg, yield 60%) was obtained.
• the compound SIAIS 1220069 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 5-bromo-1-pentanol.
• the target compound SIAIS1220069 (white solid, 16 mg, yield 44%) was obtained.
• the compound SIAIS264006 was prepared according to the method of Scheme 9 under appropriate conditions understandable in the art, except that the halogenated substrate used was 8-bromo-1-octanol.
• the target compound SIAIS264006 (white solid, 40 mg, yield 55%) was obtained.
• the compound SIAIS1213145 was prepared according to the method of Scheme 9 under appropriate conditions understandable in the art, and The same is that the halogenated substrate used is 2-iodoacetamide.
• the target compound SIAIS1213145 (white solid, 14
• the compound SIAIS1216133 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1,6-dibromohexane.
• the target compound SIAIS1216133 (white solid, 339 mg, yield 38%) was obtained.
• the compound SIAIS1216135 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1,7-dibromoheptane.
• the compound SIAIS1216137 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1,8-dibromooctane.
• the target compound SIAIS1216137 (white solid, 351 mg, yield 38%) was obtained.
• the compound SIAIS 1220013 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1,10-dibromodecane.
• the target compound SIAIS1220013 was obtained (light yellow solid, 329 mg, yield 33%) o ! H NMR (500 MHz, DMSO) 5 11.01 7.5 Hz,
• Example 13 Preparation of 3-(4-(methylsulfonyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (SIAIS1210083)
• Example 14 3-(4-((5-morpholinopentyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione( SIAIS1216061)
• the compound SIAIS1216061 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((5-bromopentyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216049) and morpholine.
• the hydrochloride of the target compound SIAIS 1216061 was obtained (light yellow solid, 7.3 mg, yield 34%) o i fi NMR (500 MHz, DMSO) 5 11.02 (s, 1H), 10.44 7.0 Hz, 1H),
• Example 15 3- (1-oxo- 4 -(( 5- (piperazin-1-yl)pentyl)thio)isoindoline- 2 -yl)piperidine- 2 , 6 -Diketone (SIAIS1216063)
• compound SIAIS 1216063 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((5-bromopentyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1216049) and piperazine. Obtain the target compound SIAIS1216063 hydrochloride (light yellow solid, 12 mg, yield 56%) o !
• Example 16 3-(4-((5-(methylamino)pentyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS1216141)
• compound SIAIS1216141 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((5-bromopentyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216049) and methylamine hydrochloride.
• the hydrochloride (white solid, 5 mg, yield 13%) of the target compound SIAIS1216141 was obtained.
• Example 17 3-( 4 -(( 5 -(( 2- (diethylamino)ethyl)amino)pentyl)sulfanyl)-1-oxoisoindole- 2 _ Base) piperidine-2,6-dione (SIAIS1220035)
• the compound SIAIS 1220035 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((5-bromopentyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216049) and N1, N1- diethyl-ethane-1,2 - diamine.
• the target compound SIAIS 1220035 was obtained as a hydrochloride (white solid, 20 mg, yield 43%).
• Example 18 3-( 4 -(( 6 -morpholinohexyl)sulfanyl)-1-oxoisoindoline- 2 -yl)piperidine- 2 , 6 -dione ( SIAIS1220027)
• the compound SIAIS 1220027 was prepared according to the method of Scheme 11 under appropriate conditions understood in the art, except that the substrate used was 3-(4-((6-bromohexyl)thio)-1- oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216133) and morpholine.
• the hydrochloride (white solid, 17 mg, yield 39%) of the target compound SIAIS1220027 was obtained.
• Example 19 3-(4-((7-morpholinoheptyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS1220031 )
• the compound SIAIS 1220031 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216135) and morpholine.
• Example 20 3-(4-((8-morpholinooctyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione( SIAIS1216143)
• the compound SIAIS1216143 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-bromooctyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216137) and morpholine.
• the target compound SIAIS1216143 hydrochloride (light yellow solid, 16 mg, yield 68%) was obtained.
• Example 21 3- (l-oxo- 4 -(( 8 _(piperazin-1-yl)octyltonyl)isoindoline- 2 -yl)piperidine- 2 , 6- Dione (SIAIS1216145)
• the compound SIAIS1216145 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-bromooctyl)thio)-1 -Oxoiso [ 1innoline-2-yl)piperidine-2,6-dione (SIAIS1216137) and piperazine.
• Example 22 3-(4-((8-(3,5-dimethylpiperazin-1-yl)octyl)sulfanyl)-1-oxoisoindoline-2-yl )Piperidine-2,6-dione (SIAIS1220057)
• compound SIAIS1220057 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((8-bromooctyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1216137) and 2, 6 - dimethyl piperazine.
• the substrate used for rice was 3-(4-((8-bromooctyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1216137) and 2, 6 - dimethyl piperazine.
• Obtain the target compound SIAIS 1220057 hydrochloride (white solid, 30 mg, yield 60%) o !
• Example 23 3-(1-oxo-4-((8-(piperidin-1-yl)octylonyl)isoridolin-2-yl)piperidine-2, 6- Dione (SIAIS1220009)
• compound SIAIS 1220009 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((8-bromooctyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216137) and piperidine.
• the target compound SIAIS1220009 hydrochloride (white solid, 38 mg, yield 81%) was obtained. 4 NMR (500 MHz, DMSO) 5 11.71 (s, 1H), 11.02 (s, 1H), 7.63 (d, 7.4 Hz, 1H),
• Example 24 3-(4-((8-(4,4-difluoropiperidin-1-yl)octyl)thio)-1-oxoisoindoline-2-yl) Piperidine-2,6-dione (SIAIS1220055)
• the compound SIAIS 1220055 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-bromooctyl)thio)- 1-oxoiso [ 1innoline-2-yl)piperidine-2,6-dione (SIAIS 1216137) and 4,4-dihaloperidine.
• the target compound SIAIS 1220055 hydrochloride (white solid, 12 mg, yield 40%) was obtained.
• Example 25 3-(4-((8-(l,4-diazepan-1-yl)octyl)thio)-1-oxoisoindoline-2- Base) piperidine-2,6-dione (SIAIS1220017)
• compound SIAIS 1220017 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-bromooctyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216137) and homopiperazine.
• the target compound SIAIS 1220017 was obtained as a hydrochloride (white solid, 33 mg, yield 67%).
• the compound SIAIS 1220019 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-bromooctyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216137) and 1- (piperidin--4-- yl) piperazine.
• the target compound SIAIS 1220019 hydrochloride (white solid, 39 mg, yield 70%) was obtained.
• Example 27 3-(4-((8-(methylamino)octyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS1216151)
• SIAIS1216151 3-(4-((8-(methylamino)octyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
• Example 28 3-(4-((8-((2-(Diethylamino)ethyl)amino)octyl)sulfanyl)-1-oxoisoindole-2-yl ) Piperidine-2,6-dione (SIAIS1220037)
• compound SIAIS 1220037 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((8-bromooctyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1216137) and N1, N1- diethyl-ethane-1,2 - diamine.
• the target compound SIAIS 1220037 hydrochloride (white solid, 16 mg, yield 36%) was obtained.
• Example 29 3-(4-((8-(4-methylpiperazin-1-yl)octyl)thio)-1-oxoisoindolin-2-yl)piperidine -2,6-dione (SIAIS1220011)
• the compound SIAIS 1220011 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-bromooctyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1216137) and 1-methylpiperazine.
• the hydrochloride (white solid, 12 mg, yield 80%) of the target compound SIAIS 1220011 was obtained.
• compound SIAIS 1220065 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((9-bromononyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1220059) and morpholine.
• the target compound SIAIS 1220065 hydrochloride (white solid, 7 mg, yield 17%) was obtained.
• Example 31 3- (4 - ((10- morpholino-decyl) thio) -1-oxo-isoindoline _ _ 2-yl) piperidine _ 2, 6 - dione ( SIAIS1220023)
• compound SIAIS 1220023 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((10-bromodecyl)thio)- 1-oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1220013) and morpholine.
• the target compound SIAIS 1220023 was obtained as a hydrochloride (light yellow solid, 24 mg, yield 60%).
• Example 32 3-(4-((11-morpholinoundecyl)sulfanyl)-1-oxoisoindolin-2-yl)piperaz-2,6-dione (SIAIS1220045)
• the compound SIAIS 1220045 was prepared under appropriate conditions understandable in the art. The difference is that the substrate used for ten meters is 3-(4-((11-bromoundecyl)sulfur Base) -1-oxoisoB-innosing Lin-2-yl) piperidine-2, 6-di unitary (SIAIS1220015) and morpholine.
• the target compound SIAIS 1220045 hydrochloride (white solid, 35 mg, yield 85%) was obtained. o !
• Example 33 3-(4-((5-(Diethylamino)pentyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-di Ketone (SIAIS1216139)
• the compound SIAIS1216139 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((5-bromopentyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1216049).
• the target compound SIAIS1216139 was obtained as a hydrochloride (light yellow solid, 21 mg, yield 71%). !
• Example 34 3-(4-((6-(Diethylamino)hexyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dior (SIAIS1220029)
• compound SIAIS1220029 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((6-bromohexyl)thio)-1- oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216133).
• the target compound SIAIS 1220029 hydrochloride (white solid, 23 mg, yield 53%) was obtained.
• Example 35 3-(4-((7-(Diethylamino)heptyl)sulfanyl)-1-oxoisoindolin-2-yl)piperidin-2,6-di Ketone (SIAIS1220033)
• the compound SIAIS 1220033 was prepared under appropriate conditions understood in the art, the difference is that the substrate used is 3-(4-((7-bromoheptyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216135).
• the target compound SIAIS 1220033 hydrochloride (white solid, 18 mg, yield 40%) was obtained.
• Example 36 3-(4-((8-(Diethylamino)octyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-di Ketone (SIAIS1216147)
• compound SIAIS1216147 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((8-bromooctyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216137).
• the target compound SIAIS1216147 was obtained as a hydrochloride (white solid, 16 mg, yield 70%).
• Example 37 3-(4-((9-(Diethylamino)nonyl)sulfanyl)-1-oxoisoindolin-2-yl)piperidine-2,6-di Ketone (SIAIS1220067)
• the compound SIAIS1220067 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((9-bromononyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS 1220059).
• the target compound SIAIS 1220067 hydrochloride (white solid, 19 mg, yield 79%) was obtained.
• Example 38 3-(4-((10-(Diethylamino)decyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-di Ketone (SIAIS1220025)
• the compound SIAIS1220025 was prepared under appropriate conditions understandable in the art. The difference is that the substrate used is 3-(; 4-(; (; 10-bromodecyl)sulfanyl )-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS1220013).
• the target compound SIAIS 1220025 was obtained as the hydrochloride (light yellow solid, 23 mg, yield 59%).
• Example 3 9 3 - (4 _ ((ll- ( diethylamino) undec embankment yl) thio) -1-oxo-isoindoline _ _ 2-yl) piperidine _ 2, 6 -Dione (SIAIS1220047)
• Example 40 3-(4-((5-(dimethylamino)pentyl)sulfanyl)-1-oxoisoindolin-2-yl)piperidine-2,6-di Ketone (SIAIS1216089)
• the compound SIAIS1216089 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((5-aminopentyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS171132).
• the target compound SIAIS1216089 hydrochloride (light yellow solid, 7 mg, yield 54%) was obtained. !
• Example 41 3-(4-((8-(dimethylamino)octyl)sulfanyl)-1-oxoisoindolin-2-yl)piperidine-2,6-two Ketone (SIAIS1216149)
• the compound SIAIS1216149 was prepared under appropriate conditions understandable in the art. The difference is that the substrate used is 3-(; 4-(; (; 8-aminooctyl) thiol. )-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS171136).
• the target compound SIAIS1216149 hydrochloride (white solid, 14 mg, yield 63%) was obtained. !
• Example 42 3-(4-((8-(4-methyl-1,4-diazepan-1-yl)octyl)thio)-1-oxoisoindyl Dolin-2-yl)piperidine-2,6-dione (SIAIS1220051)
• the compound SIAIS1220051 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-(1,4-diaza heterocycle Heptan-1-yl)octyl)thio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (SIAIS 1220017).
• the target compound SIAIS 1220051 hydrochloride (white solid, 12 mg, yield 62%) was obtained.
• Example 43 3-(4-((8-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)octyl)crane)-1-oxoisoindyl Dolin-2-yl)piperidine-2,6-dione (SIAIS1220049)
• the compound SIAIS1220049 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(1-oxo- 4 -(( 8- ( 4- (piperidine) (Azin-1-yl)piperidin-1-yl)octyl)thio)isoindoline- 2 -yl)piperidine-2,6-dione (SIAIS 1220019).
• the target compound SIAIS 1220049 hydrochloride (white solid, 5 mg, yield 63%) was obtained.
• the compound SIAIS 1227123 was prepared according to the method of Scheme 9 under appropriate conditions understandable in the art. The same is that the used generation substrate is 1,3-bis(bromomethyl)benzene.
• the target compound SIAIS 1227123 (light yellow oil, 357 mg, yield 39%) was obtained.
• Example 44 Preparation of 3-(4-(tert-butylsulfanyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (SIAIS1213167)
• Example 46 Preparation of N-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)thio)pentan Base) acetamide
• Example 48 Preparation of 3,3'-((octane-1,8-bis*bis(thiodiyl))bis(1-oxoisoindoline-4,2-bis*)) Di(piperidine-2,6-dione) (SIAIS1216137B)
• the compound SIAIS1216137B was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 1,8-dibromooctane.
• the target compound SIAIS1216137B (white solid, 10 mg, yield 12%) was obtained.
• Example 49 Preparation of 3,3'-((Nonyl-1,9-diylbis(thiodiyl))bis(1-oxoisoindoline-4,2-diyl)) Di(piperidine-2,6-dione) (SIAIS1220059B)
• the compound SIAIS1220059B was prepared according to the method of Scheme 9 under appropriate conditions understandable in the art, except that the halogenated substrate used was 1,9-dibromononane.
• the target compound SIAIS1220059B (white solid, 12 mg, yield 13%) was obtained.
• Step 1 Preparation of 3-(5-(benzylthio)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (SIAIS1213173)
• Step 2 Preparation of 3-(5-mercapto-1-oxoisoindoline-2-yl)piperidine-2,6-dione (SIAIS1213175)
• the compound SIAIS1213111 was prepared according to the method of Scheme 9 and under appropriate conditions understandable in the art, except that the substrate used was 3-(5-mercapto-1-oxoisoindoline- 2-yl)piperazine-2,6-dione (SIAIS1213175) and methyl iodide.
• the target compound SIAIS1213111 (gray solid, 7 mg, yield 12%) was obtained.
• the compound SIAIS1213163 was prepared with reference to the method of Example 49, except that the substrate used was 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-di Ketones and tert-butyl mercaptan.
• the target compound SIAIS1213163 (yellow solid, 19 mg, yield 56%) was obtained.
• the compound SIAIS1220141 was prepared under appropriate conditions understandable in the art, with the difference that the substituted substrate used was 1,4-bis(bromomethyl)benzene.
• Example 5 4 Preparation of 3-( 4 -(( 4- (morpholinomethyl)benzyl)thio)-1-oxoisoindoline- 2 -yl)piperidine- 2 , 6 -Dione (SIAIS1220167)
• the compound SIAIS1220167 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((4-(bromomethyl)benzyl) Sulfuryl)-1-oxoisoH-innoline-2-yl)piperazin-2,6-dione (SIAIS1220141) and morpholine.
• the compound SIAIS1220165 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((4-(bromomethyl)benzyl)sulfur Base)-1-oxoisoH-innoline-2-yl)piperazin-2,6-dione (SIAIS1220141) and piperidine.
• the hydrochloride (white solid, 12 mg, yield 52%) of the target compound SIAIS1220165 was obtained.
• Example 56 Preparation of 3-(1-oxo-4-((7-(pyrrolidin-1-yl)heptyl)sulfanyl-indolin-2-yl)piperidine-2,6 -Er (SIAIS1220161)
• the compound SIAIS1220161 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio) -1 -OxoisoH-innoline-2-yl)piperidine-2,6-dione (SIAIS1216135) and tetrahydropyrrole.
• the hydrochloride of the target compound SIAIS1220161 pale yellow solid, 14 mg, yield 45% was obtained.
• Example 57 Preparation of 3-(1-oxo-4-((7-(piperidin-1-yl)heptyl)thio)isoindolin-2-yl)piperidine-2, 6-diketone (SIAIS1220105)
• compound SIAIS1220105 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216135) and piperidine.
• the target compound SIAIS1220105 hydrochloride (light yellow solid, 14 mg, yield Rate 63%).
• Example 58 Preparation of 3-(4-((7-(azeppan-1-yl)heptyl)sulfanyl)-1-oxoisoindoline-2-yl)piperidine -
• the compound SIAIS1220163 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216135) and azepane.
• the target compound SIAIS1220163 hydrochloride pale yellow solid, 14 mg, yield 67%) was obtained.
• ⁇ NMR (500 MHz, DMSO) 5 11.02 (s, 1H), 10.22 (s, 1H), T63 ( ( ⁇ , 7 75,
• Example 59 Preparation of 3-(4-((7-(diisopropylamino)heptyl)sulfanyl)-1-oxoisoindoline-2-yl)piperidine-
• the compound SIAIS1220107 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216135) and diisopropylamine.
• the hydrochloride (white solid, 2 mg, yield 8%) of the target compound SIAIS1220107 was obtained. !
• Example 60 Preparation of 3-(4-((7-(( ⁇ -1-yl)amino)heptyl)thio)-1-oxoisoindoline-2-yl)piperidine -2,6-dione (8 181220155)
• the compound SIAIS1220155 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1 -Oxoiso [ 1innoline-2-yl)piperidine-2,6-dione (SIAIS1216135) and amantadine-1-amine.
• the target compound SIAIS 1220155 hydrochloride (white solid, 6 mg, yield 22%) was obtained.
• ⁇ NMR (500 MHz, DMSO) 5 11.01 (s, 1H), 8.42 (s, 2H), T63 (d, J 7.3 Hz,
• Example 61 Preparation of 3-(4-((7-((3,5-dimethyladamantan-1-yl)amino)heptyl)thio)-1-oxoisoindoline -2-yl)piperidine-2,6-dione (SIAIS1220157)
• the compound SIAIS1220157 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216135) and 3, 5 - dimethyl adamantane-1-amine.
• the target compound SIAIS1220157 hydrochloride (white solid, 10 mg, yield 34%) was obtained.
• Example 62 Preparation of 3-(4-((7-((adamantan-2-yl)aminoephedyl)thio)-1-oxoisoindolin-2-yl)piperidine- 2,6-Diketone (8 181220159)
• the compound SIAIS1220159 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216135) and adamantane -2-- amine.
• the hydrochloride (white solid, 7 mg, yield 25%) of the target compound SIAIS1220159 was obtained.
• Example 63 Preparation of 3-(4-((8-((adamantan-1-yl)amino)octyl)thio)-1-oxoisoindoline-2-yl pyridine- 2, 6 -dione (SIAIS1220087) [00373] According to the method of Scheme 11, compound SIAIS1220087 was prepared under appropriate conditions understandable in the art, except that the substrate used for rice was 3-(4-((8-bromooctyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216137) and adamantane-1-amine.
• Example 64 Preparation of 3-(4-((8-((adamantan-2-yl)amino)octyl)thio)-1-oxoisoindoline-2-yl)piperidine -2, 6 -dione (SIAIS1220089)
• the compound SIAIS1220089 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((8-bromooctyl)thio)-1 - oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216137) and adamantane -2-- amine.
• the target compound SIAIS 1220089 hydrochloride (white solid, 14 mg, yield 50%) was obtained.
• Example 65 Preparation of 3,3'-(((piperazine-1,4-diylbis(octane-8,1-diyl))bis(thiodiyl))bis(1-oxygen) (Isoindoline-4,2-diyl))bis(piperidine-2,6-dione) (SIAIS1220061)
• the compound SIAIS 1220061 was prepared under appropriate conditions understandable in the art.
• the difference is that the substrate used is different in that the substrate used is 3-(4-((8- Bromooctyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS1216137) and piperazine (0.5 equivalent).
• the target compound SIAIS 1220061 (white solid, 30 mg, yield 70%) was obtained.
• Example 66 Preparation of 3-(1-oxo-4-((4,4,5,5,5-pentafluoropentyl)thio)isoindolin-2-yl)piperidine- 2,6-Diketone (SIAIS1220133)
• the compound SIAIS 1220133 was prepared by referring to the method of step 3 in Example 44, except that 4, 4, 5, 5, 5-pentafluoropentane-1-thiol was used instead of tert-butyl mercaptan.
• the target compound SIAIS1220133 (brown solid, 4 mg, yield 8%) was obtained.
• Example 67 Preparation of 3-(1-oxo-4-((9-((4,4,5,5,5-pentafluoropentyl)thio)nonyl)thio)isoindyl Dolphen-2-yl)piperidine-2,6-dione (8 181220131)
• SIAIS 1220131 the difference lies in the use of 3-(4-((8-bromooctyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS1216137) And 4,4,5,5,5-pentafluoropentane-1-thiol as raw materials.
• the target compound SIAIS1220131 (white solid, 8 mg, yield 27%) was obtained.
• Example 68 Preparation of 3-(1-oxo-4-((9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)thio)iso Indoline-2-yl)piperidine-2,6-n
• Steps 1 and 2 [00384] Add 4, 4, 5, 5, 5-pentafluoropentyl-1-thiol (194.2 mg, 1 mmol), potassium carbonate (414.6 mg, 3 mmol) and DMF (5 mL) into 100 mL single In the bottle, add 1,9-dibromononane (582.5 mg, 3 mmol) under stirring at 50 ° C and react for 3 h.
• compound SIAIS1220145 was prepared under appropriate conditions understandable in the art, except that the halogenated substrate used was 9-((4, 4, 5, 5, 5-pentafluoropentane Group) sulfoxide group) 1 bromononane (SIAIS1220139) to obtain the target compound SIAIS1220145 (white solid, 17 mg, yield 50%). !
• Example 69 Preparation of 3-(1-oxo-4-((9-((4,4,5,5,5-pentafluoropentyl)sulfo)nonyl)thio)isoindyl Dolin-2-yl)piperidine-2,6-dione (SIAIS1220147)
• the compound SIAIS 1220147 was prepared with reference to the method of Example 68, except that the halogenated substrate used in step 3 was 9-((4,4,5,5,5-pentafluoropentyl)sulfone)1 -Bromononane (81 ⁇ 181220140) (white solid, 8 mg, yield 20%).
• Example 72 Preparation of 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)thio)-N ,N-Diisopropylheptanamide (SIAIS1220117)
• the compound SIAIS 1220117 was prepared with reference to the method of Example 71, except that diisopropylamine was used instead of piperidine.
• the target compound SIAIS1220117 (white solid, 13 mg, yield 8%) was obtained.
• Example 75 Preparation of 1-(3-chloro-4-methylphenyl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1- Oxoisoindoline-4 -yl)
• Example 76 Preparation of 3-(1-oxo-4-((8-(2-oxopiperidin-1-yl)octyl)thio)isoindolin-2-yl)piper Pyridine-
• Example 77 3-(4-((6-((( ⁇ -1-yl)amino)hexyl)thio)-1-oxoisoindole-2-yl)piperidine- 2,6-Diketone (SIAIS1220177)
• the compound SIAIS1220177 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((6-bromohexyl)thio)-1- oxo-isopropyl [1 primer noise Lin 2-yl) -2,6-piperidine steep pay (SIAIS1216133) and adamantane-1-amine.
• the hydrochloride of the target compound SIAIS1220177 was obtained as a pale yellow solid, 7 mg, yield 28%.
• Example 78 3-(4-((6-((adamantan-2-yl)amino))sulfanyl)-1-oxoisoindoline-2-yl)piperidine-2, 6-Diketone (SIAIS1220179)
• compound SIAIS1220179 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((6-bromohexyl)sulfanyl)-1- Oxo iso [ 1 Yinnolin-2-yl) called steep-2,6-dione (SIAIS1216133) and adamantane-2-amine.
• the hydrochloride of the target compound SIAIS1220179 was obtained as a pale yellow solid, 22 mg, and the yield was 87%.
• the compound SIAIS1221003 was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((4-(bromomethyl)benzyl) sulfur (Base)-1-oxoisoH-innoline-2-yl)piperazin-2,6-dione (SIAIS1220141) and adamantane-1-amine.
• Example 80 3-(4-((4-((adamantan-2-ylamino)methyl)sulfanyl)-1-oxoisoindoline-2-yl)piperidine- 2,6- ⁇ H(SIAIS1221005)
• the compound is prepared under appropriate conditions understandable in the art, except that the substrate used is 3-(4-((4-(bromomethyl)benzyl)thio) -1-oxoiso n-innoline-2-yl) piperidone-2, 6-dione (SIAIS 1220141) and adamantane-2-amine.
• Example 81 3-(4-((6-((adamantan-1-ylmethyl)amino)hexyl)thio)-1-oxoisoindoline-2-yl)piperidine -2,6- ⁇ M(SIAIS1221013)
• the compound was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((6-bromohexyl)thio)-1-oxo Isoindolin-2-yl) piperazine-2,6-dione (SIAIS1216133) and 1-adamantane methylamine.
• the hydrochloride of the target compound SIAIS1221013 was obtained as a white solid, 23 mg, yield 88%.
• Example 82 3-(4-((7-(adamantan-1-ylthio)heptyl)thio)-1-oxoisoindoline-2-yl)piperidine-2 ,6-Diketone (SIAIS1221025)
• the compound is prepared under appropriate conditions understandable in the art, except that the substrate used is 3- ( 4 -(( 7 -bromoheptyl)thio)-1-oxy Substitute isoindoline_ 2 _ yl) piperazine_ 2 , 6 _ dione (siAismu 35 ) and adamantane-1-thiol.
• the substrate used is 3- ( 4 -(( 7 -bromoheptyl)thio)-1-oxy
• Example 83 3-(4-((7-(((adamantan-1-yl)methyl)amino)heptyl)thio)-1-oxoisoindoline-2-yl ) Piperidine-2,6-dione (81 181220171)
• the compound was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1-oxy Substituting isoindoline-2-yl) piperazine-2,6-dione (SIAIS1216135) and 1-adamantane methylamine.
• the target compound SIAIS1220171 was obtained as the hydrochloride salt, white solid, 16 mg, yield 59%.
• Example 84 N- (adamantan-1-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4 -Yl)thio)heptanamide (SIAIS1220195)
• Example 85 N-(3,5-Dimethyladamantan-1-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxy (Isoindoline-4-yl)thio)heptanamide (SIAIS1220197)
• the compound SIAIS 1220197 was prepared with reference to the method of Example 71, except that 3,5-dimethyladamantane-1-amine was used instead of piperidine.
• Target compound SIAIS1220197 white solid, 21 mg, yield 75%.
• Example 86 N- (adamantane-2-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4 -Yl)thio)heptanamide (SIAIS1220199)
• the compound SIAIS 1220199 was prepared with reference to the method of Example 71, except that adamantane-2-amine was used instead of piperidine.
• the target compound SIAIS1220199 was obtained, white solid, 21 mg, yield 78%.
• Example 87 3-(4-((6-(cyclohexylamino)hexyl)thio)-1-oxoisoindolin-2-yl)piperidin-2,6-dione ( SIAIS1220183)
• the compound is prepared under appropriate conditions understandable in the art, except that the substrate used is 3-(4-((6-bromohexyl)thio)-1-oxo Isoindolin-2-yl)piperazine-2,6-dione (SIAIS1216133) and cyclohexylamine.
• the hydrochloride of the target compound SIAIS1220183 was obtained as a white solid, 18 mg, and the yield was 78%.
• Example 88 3-(4-((7-(Cyclohexylamino)heptyl)thio)-1-oxoisoindolin-2-yl)piperazin-2,6-dione (SIAIS1220185)
• the compound is prepared under appropriate conditions understandable in the art, except that the substrate used is 3- ( 4 -(( 7 -bromoheptyl)thio)-1-oxy Substitute isoindoline _ 2 _ yl) piperazine _ 2 , 6 _ dione (SIAISm 6 l 35 ) and aniline to obtain the target compound SIAIS1220187, white solid, 8 mg, yield 35%.
• H NMR 500 MHz , CDC1 3 ) 5 8.69 (s, 1H), T75 (d, 6.7 Hz, 1H), T59 (d, 6.9 Hz, 2H), T53 (d, 6.9 Hz, 1H),
• Example 90 3-(4-((7-(Methyl(phenyl)amino)heptyl)thio)-1-oxoisoindolin-2-yl)piperidine-2, 6-diketone (SIAIS1220189)
• the compound was prepared under appropriate conditions understandable in the art, except that the substrate used was 3-(4-((7-bromoheptyl)thio)-1-oxy Substitute isoindolin-2-yl) piperazine-2,6-dione (SIAIS1216135) and N-methylaniline to obtain the target compound SIAIS1220189, white solid, 13 mg, yield 54%. !
• Example 91 3-(4-((7-(Azacyclooctane-1-yl)heptyl)thio)-1-oxoisoindolin-2-yl)piperidine -2,6- Dione (SIAIS1220193)
• the compound was prepared under appropriate conditions understandable in the art, except that the substrate used was 3- ( 4 _(( 7 -bromoheptyl)thio) -1-oxy Substitute isoindoline_ 2 _ yl) piperazine_ 2 , 6 _dione (SIAISm 6 l 35 ) and azetidine to obtain the hydrochloride of the target compound SIAIS1220193, pale yellow solid, 22 mg, yield 92%.
• Example 92 3-(1-oxo-4-((7-(((lR,2S,4R)-l,7,7-trimethylbicyclo[2.2.1]heptane- 2-yl)amino)heptyl)thio)#indoline-2-yl)piperidine-2,6-:
• the compound is prepared under appropriate conditions understandable in the art, except that the substrate used is 3-(4-((7-bromoheptyl)thio)-1-oxy Substitute isoindolin-2-yl) piperazine-2,6-dione (SIAIS1216135) and norbornamine to obtain the target compound SIAIS1221019 hydrochloride, white solid, 14 mg, yield 54%. ! H NMR (500 MHz, DMSO) 5 10.99 (s, 1H), 8.64 (s, 1H), 8.22 7.5 Hz, 1H),
• Example 93 3-(4-((7-(3-azaspiro[5.5]undec-3-yl)heptyl)sulfanyl)-1-oxoisoindoline-2 -Yl) piperidine-2,6-dione (81 181221015)
• Example 94 3-(4-((7-(3,5-dimethylpiperidin-1-yl)heptyl)sulfanyl)-1-oxoisoindolin-2-yl ) _ Steep-2,6-dione (81 181221021)
• the compound is prepared under appropriate conditions understandable in the art, except that the substrate used is 3-(4-((7-bromoheptyl)thio)-1-oxy (Substituted isoindolin-2-yl) piperidine-2,6-dione (SIAIS1216135) and

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