WO2022242696A1 - 一类精氨酸甲基转移酶抑制剂及其用途 - Google Patents
一类精氨酸甲基转移酶抑制剂及其用途 Download PDFInfo
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- WO2022242696A1 WO2022242696A1 PCT/CN2022/093688 CN2022093688W WO2022242696A1 WO 2022242696 A1 WO2022242696 A1 WO 2022242696A1 CN 2022093688 W CN2022093688 W CN 2022093688W WO 2022242696 A1 WO2022242696 A1 WO 2022242696A1
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- Prior art keywords
- substituted
- unsubstituted
- group
- alkyl
- ring
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- 101000757232 Homo sapiens Protein arginine N-methyltransferase 2 Proteins 0.000 title abstract description 4
- 229940123379 Methyltransferase inhibitor Drugs 0.000 title abstract 2
- 102000046485 human PRMT2 Human genes 0.000 title abstract 2
- 239000003697 methyltransferase inhibitor Substances 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- -1 cyano, amino Chemical group 0.000 claims description 215
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 144
- 229910052757 nitrogen Inorganic materials 0.000 claims description 87
- 125000003118 aryl group Chemical group 0.000 claims description 76
- 125000000623 heterocyclic group Chemical group 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- 229920006395 saturated elastomer Polymers 0.000 claims description 49
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000005842 heteroatom Chemical group 0.000 claims description 36
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 34
- 239000001301 oxygen Substances 0.000 claims description 34
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 34
- 229910052717 sulfur Inorganic materials 0.000 claims description 34
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 33
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 32
- 239000011593 sulfur Substances 0.000 claims description 32
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 30
- 125000006413 ring segment Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000004104 aryloxy group Chemical group 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 101710084434 Protein arginine N-methyltransferase 1 Proteins 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 4
- 229910052722 tritium Inorganic materials 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 150000003456 sulfonamides Chemical class 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 15
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical compound [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 297
- 238000006243 chemical reaction Methods 0.000 description 234
- 239000000243 solution Substances 0.000 description 165
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 129
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 88
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 79
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000007787 solid Substances 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
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- 230000002829 reductive effect Effects 0.000 description 56
- 239000012074 organic phase Substances 0.000 description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 45
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- 239000000706 filtrate Substances 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 38
- 238000000746 purification Methods 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 36
- 238000003756 stirring Methods 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000000543 intermediate Substances 0.000 description 34
- 239000000047 product Substances 0.000 description 33
- 238000004440 column chromatography Methods 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000000377 silicon dioxide Substances 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 235000019341 magnesium sulphate Nutrition 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 150000001299 aldehydes Chemical class 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000002994 raw material Substances 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
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- 239000012065 filter cake Substances 0.000 description 9
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- 230000005764 inhibitory process Effects 0.000 description 9
- 229910000160 potassium phosphate Inorganic materials 0.000 description 9
- 235000011009 potassium phosphates Nutrition 0.000 description 9
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- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
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- 101000924541 Homo sapiens Protein arginine N-methyltransferase 3 Proteins 0.000 description 7
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- 239000012298 atmosphere Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 6
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
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Definitions
- the invention relates to the fields of medicinal chemistry and medicine, in particular to a type I type PRMT inhibitor compound, its preparation method and its application in the field of disease treatment.
- type I PRMT is mainly responsible for catalyzing the asymmetric dimethylation of arginine
- changes in the level of asymmetric dimethylation in vivo are closely related to cardiovascular diseases, diabetes, renal failure, asthma and chronic non-obstructive diseases. relation. Therefore, it can be said that the abnormal expression of type I PRMT is related to the occurrence and development of various diseases. In summary, it is of great significance to develop new PRMT inhibitor molecules.
- the purpose of the present invention is to provide a novel PRMT inhibitor molecule.
- X 1 , X 2 , X 3 and X 4 are each independently selected from the following group: CR, NR or N; dotted lines are chemical bonds or none;
- Ring B is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted containing 1-3 members selected from oxygen, sulfur and A 3-12 membered heterocycle with a heteroatom in nitrogen, a substituted or unsubstituted -C 1 -C 6 alkyl-6-10 membered aryl, a substituted or unsubstituted C 3 -C 12 carbocycle, a substituted or Unsubstituted C 2 -C 10 acyl group, substituted or unsubstituted C 2 -C
- L is selected from the group consisting of: a chemical bond, or -O-, -(CHR 6 ) p -, -CHR 6 -O-, -CHR 6 -C(O)-, carbonyl, S, -NH-, -NHC(O )-, -NHS(O) 2 -, -NHC(O)NH-, -NHC(S)NH-, -COO-, -OS(O) 2 -, -COO-CH 2 -, -C(O )CH 2 -, -S(O) 2 -, or L is absent;
- R 1 and R 2 are each independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl;
- R 3 is a group selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or Unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkylamino, substituted or unsubstituted C 6 -C 10 aryl substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C 1 -C 6 alkyl-phenyl, substituted or unsubstituted C 3 -C 12 carbocycle, substituted or unsubstituted
- R 4 is a group selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or Unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkylamino, substituted or unsubstituted C 6 -C 10 aryl substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C 1 -C 6 alkyl-phenyl, substituted or unsubstituted C 3 -C 12 carbocycle, substituted or unsubstituted
- At least one of X 1 , X 2 , X 3 and X 4 is N.
- ring B when ring B is H, said m is 2, 3, 4, 5 or 6; and at least two R 4 on the same or adjacent ring atoms and the ring atoms to which they are connected together form Substituted or unsubstituted 5-11 membered carbocyclic or heterocyclic rings (the said rings are partially unsaturated rings, saturated rings or aromatic rings).
- the A ring is selected from the following group:
- the ring A is a substituted or unsubstituted group selected from the following group:
- a 3 ring and A 4 ring are each independently selected from the group consisting of substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-8 membered carbocyclic rings, substituted or unsubstituted saturated or partially unsaturated (non-aromatic) ) of 3-8 membered heterocycle;
- R is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkylamino, substituted or unsubstituted C 2 -C 6 acyl, substituted or unsubstituted C 2 -C 6 ester group, substituted or unsubstituted C 6 -C 10 aryloxy or heteroaryloxy group, substituted or unsubstituted C 6 -C 10 arylamino or heteroarylamino group, substituted or unsubstituted Substituted C 1 -C 6 amido, substituted or unsubstituted -C 1 -C 6 al
- the compound has the structure shown in the following formula V or formula VI:
- Ring B is selected from the group consisting of substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 1-3 members selected from oxygen, sulfur and nitrogen A 4-12 membered heterocycle, a substituted or unsubstituted C 3 -C 12 carbocycle in which the heteroatom is present;
- R 3 is a group selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 alkane substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkylamino, substituted or unsubstituted C 2 -C 6 acyl, substituted or unsubstituted C 2 - C 6 ester group, substituted or unsubstituted C 1 -C 4 alkyl-S(O) 2 -, substituted or unsubstituted C 1 -C 4 alkyl-SO-;
- the ring A is selected from the group consisting of substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-6 membered carbon rings, substituted or unsubstituted saturated or partially unsaturated ( Non-aromatic) 5-7 membered heterocyclic ring.
- X 5 , X 6 , X 7 and X 8 are each independently selected from the group consisting of C(R) 2 , NR, CR or N; the dotted lines are chemical bonds or none.
- the disease is selected from the group consisting of tumor, cardiovascular disease, neurodegenerative disease, malaria, AIDS, gout, diabetes, renal failure, chronic lung disease, oculopharyngeal muscular dystrophy , cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, alcoholic cirrhosis.
- C1-C6 alkoxy refers to a straight-chain or branched alkoxy group with 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc.
- C1-C12 alkoxycarbonyl refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including without limitation methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.
- 3-12 membered heterocyclic group refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, for example Dioxolyl, etc.
- 3-7 membered heterocyclyl has a similar meaning.
- the present invention provides a class of compounds with PRMT inhibitory activity, or pharmaceutically acceptable salts or deuterated products thereof:
- the compound of the present invention Since the compound of the present invention has excellent activity of inhibiting type I PRMT, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are the main active compounds.
- the pharmaceutical composition of the components can be used for treating, preventing and alleviating related diseases caused by abnormal activity or expression of PRMT.
- Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
- cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- gelatin such as talc
- solid lubricants such as stearic acid , magnesium stearate
- calcium sulfate such
- Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
- Step 1 Dissolve 1,2-dibromo-4,5-difluorobenzene (A-1) (2.0 g, 7.36 mmol) and methyl acrylate (1.90 g, 22.1 mmol, 1.99 mL) in dimethyl In methyl formamide (10 ml), add tetrabutylammonium bromide (2.37 g, 7.36 mmol), potassium carbonate (2.54 g, 18.4 mmol), and replace the reaction solution with nitrogen for 1 minute, add palladium acetate (33.03 mg , 147 micromoles). The reaction solution was stirred at 80°C for 16 hours.
- Step 3 Dimethyl 3,3'-(4,5-difluoro-1,2-phenylene)dipropionate (A-3) (1.0 g, 3.49 mmol) in xylene at 95 °C (5 ml) solution was slowly added dropwise to a suspension of NaH (209.59 mg, 5.24 mmol, 60% purity) in xylene (5 ml) under stirring condition, every 1 ml of 3,3'-(4 , 5-Difluoro-1,2-phenylene) Dimethyl dipropionate (A-3) Add a drop of absolute ethanol dropwise to the xylene solution. After the dropwise addition, the reaction temperature rose to 115° C., and the reaction was continued at this temperature for 1.5 hours. 6 reactions were set up in parallel.
- Step 5 Dissolve 2,3-difluoro-8,9-dihydro-5H-benzo[7]cyclopenten-7(6H)-one (A-5) (1.0 g, 5.10 mmol) in In tetrahydrofuran (10 ml), add lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 5.61 ml) at minus 70 degrees Celsius, react at minus 70 degrees Celsius for 1 hour under nitrogen protection, add N-phenylbis(trimethylsilyl)amide at minus 70 degrees Celsius Fluoromethanesulfonyl)imide (2.00 g, 5.61 mmol), the reaction solution was slowly raised to room temperature for 15 hours.
- Step 6 Add 2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yl triflate (A-6) (1.27 g, 3.87 mmol ) and bis-alcohol borate (1.08 g, 4.26 mmol) were dissolved in dioxane (20 ml) plus potassium acetate (1.14 g, 11.61 mmol), 1,1-bis(diphenyl Phosphorus) ferrocene palladium chloride (283.09 mg, 386.89 micromoles), the reaction solution was replaced with nitrogen for 1 minute. The reaction solution was stirred at 100 degrees Celsius under nitrogen protection for 16 hours.
- reaction solution was successively washed once with saturated aqueous sodium bicarbonate (200 ml), twice with 1M aqueous hydrochloric acid (200 ml), and once with saturated saline solution (200 ml).
- the organic phase was dried over magnesium sulfate and filtered off with suction.
- the filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, 13% ethyl acetate in petroleum ether) to give 1-(4,5-dihydro-1H-benzo[d]nitrogen as a white solid miscellaneous -3(2H)-yl)-2,2,2-trifluoroethanone (D-1) (16 g, 65.8 mmol, 88.0% yield).
- Step 2 Two reactions are set up in parallel, 1-(4,5-dihydro-1H-benzo[d]azepine -3(2H)-yl)-2,2,2-trifluoroethanone (D-1) (8.0 g, 32.9 mmol) was added to concentrated sulfuric acid (32 ml), stirred for 10 minutes to obtain a pale yellow solution . Potassium nitrate (2.66 g, 26.3 mmol) was added in portions at 0 °C over 20 min. The reaction was stirred at 0°C for 30 minutes. TLC detected that the starting material was completely consumed. The reaction solution was slowly poured into stirred ice water (50 mL), and extracted three times with ethyl acetate (50 mL).
- reaction solution was filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by column chromatography (silica, 30% ethyl acetate in petroleum ether) to obtain bright yellow solid 1-(7-amino-4,5-di Hydrogen-1H-benzo[d]azepine -3(2H)-yl)-2,2,2-trifluoroethanone (D-3) (6.6 g, 25.5 mmol, 85.4% yield, 99.7% purity).
- reaction solution was diluted with water (10 mL), and filtered with suction.
- the filtrate was extracted twice with ethyl acetate (10 mL).
- the organic layer was dried over magnesium sulfate, filtered with suction, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, 4% ethyl acetate in petroleum ether) to give yellow solid 2,2,2-trifluoro- 1-(7-(trifluoromethyl)-4,5-dihydro-1H-benzo[d]azepine -3(2H)-yl)ethanone (D-5) (180 mg, 578 ⁇ mol, 85.4% yield).
- Embodiment 1 (N1-((2-(4,5-dihydro-1H-benzo[d]azepine Synthesis of -3(2H)-yl)-6-methylpyridin-3-yl)methyl) -N1,N2-dimethylethane-1,2-diamine) (compound P110):
- Step 2 (2-((2-chloro-6-methylpyridin-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate tert-butyl ester (2 -2) (7.02 g, 21.4 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxabororin-2-yl)-1-(m-toluene base)-1,2,3,6-tetrahydropyridine (Intermediate B) (7.05 g, 23.6 mmol), and tripotassium phosphate (9.10 g, 42.9 mmol) in water (14 mL).
- XPhos-Pd-G2 (510 mg, 648 micromole) was added to the reaction system after several times of decompression and nitrogen replacement, and the reaction was heated in an oil bath at 85°C under the protection of nitrogen for 30 hours. The disappearance of raw materials was monitored by LCMS. After cooling to room temperature, the reaction solution was diluted with saturated brine (50 mL) and ethyl acetate (100 mL).
- Step 3 methyl (2-(methyl((6-methyl-1'-(m-tolyl)-1',2',3',6'-tetrahydro-[2,4'-linked Pyridin]-3-yl) methyl) amino) ethyl) tert-butyl carbamate (2-3) (7.84 g, 16.9 mmol) was dissolved in 250 ml of ethyl acetate, and 10% wet Pd was added under nitrogen protection ( OH) 2 /C (3.16 g). The system was replaced with a hydrogen balloon several times, and then stirred and reacted at room temperature for 36 hours under the protection of hydrogen. LCMS monitored the reaction to be complete.
- Step 4 Add methyl (2-(methyl((6-methyl-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methyl)amino)ethyl) Tert-butyl carbamate (2-4) (11.7 g, 25.1 mmol) was dissolved in methanol (70 mL), and HCl/1,4-dioxane (4M, 75 mL) was added dropwise with stirring. The reaction was stirred at room temperature under nitrogen protection for 16 hours, and the reaction was complete as monitored by LCMS. After concentrating the reaction solution, about 200 ml of methanol was added, and the mixture was spin-dried under reduced pressure, and the hydrochloric acid was removed twice.
- the concentrate was diluted with methanol, decolorized by heating with activated carbon, filtered at room temperature, washed with methanol, concentrated to about 100 ml, added isopropanol to replace methanol, and concentrated to 250 ml.
- the reaction emulsion was heated at 85°C for 30 minutes, stirred at 30°C for 10 hours, and cooled to room temperature. After filtration, the solid was washed successively with isopropanol (100 mL) and n-pentane (200 mL ⁇ 2), collected and dried in vacuo.
- Step 1 Add 2,6-dichloronicotinaldehyde (3-1) (25 g, 142 mmol) and bis(4-methoxybenzyl)amine (40.2 g, 156 mmol) in DMF (200 mL) Triethylamine (17.2 g, 170 mmol, 23.7 mL) was added to the solution. The reaction solution was stirred at 50°C for 16 hours, and the reaction was complete as monitored by LCMS. The mixture was poured into 200 mL of ice water and extracted with ethyl acetate (400 mL ⁇ 1, 200 mL ⁇ 2).
- Step 2 Add 6-(bis(4-methoxybenzyl)amino)-2-chloronicotinaldehyde (3-2) (800 mg, 2.02 mmol), 1-(m-tolyl) to the reaction flask in sequence -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (Intermediate B)( 1.02 g, 2.40 mmol, 70% purity), tetrahydrofuran (6 ml) and potassium phosphate aqueous solution (856 mg potassium phosphate was dissolved in 1 ml of water), the reaction system was decompressed-nitrogen replaced several times, and XPhos was added under nitrogen protection- Pd-G3 (37 mg, 43.71 micromole), heated in an oil bath at 70°C under nitrogen protection and stirred for 2.5 hours.
- Step 3 Add 6-(bis(4-methoxybenzyl)amino)-1'-(m-tolyl)-1',2',3',6'-tetrahydro-[2, 4'-bipyridyl]-3-carbaldehyde (3-3) (801 mg, 1.50 mmol) and ethyl acetate (50 ml), under nitrogen protection, add Pd(OH) 2 /C (450 mg, 10% Pd (OH) 2 /C). The reaction system was replaced with hydrogen, and then stirred and reacted at room temperature under a hydrogen atmosphere (hydrogen balloon) for 18 hours.
- Pd(OH) 2 /C 450 mg, 10% Pd (OH) 2 /C
- reaction solution was concentrated by filtration and purified by column chromatography (silica gel column, 0-25% ethyl acetate/petroleum ether gradient elution) to obtain a yellow viscous product (6-(bis(4-methoxybenzyl)amino)-2 -(1-(m-Tolyl)piperidin-4-yl)pyridin-3-yl)methanol (3-4) (695 mg, 1.23 mmol, 64.9% yield, 95% purity).
- Step 4 Compound (6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methanol (3-4) (440 mg, 818 micromoles) was added to 10 mL of dichloromethane, and Dess-Martin periodinane (347 mg, 818 micromoles) was added under ice-cooling, and the reaction solution was stirred at room temperature for 16 hours. The reaction was quenched by adding 20 mL of 10% aqueous sodium thiosulfate. After stirring for half an hour, 50 ml of saturated aqueous sodium bicarbonate solution was added, and extracted three times with dichloromethane.
- Step 6 Compound (2-((6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methane Base) (methyl) amino) ethyl) (methyl) tert-butyl carbamate (3-6) (60 mg, 84.7 micromole.) Add 1ML trifluoroacetic acid, then add trifluoromethanesulfonic acid (29 mg , 194 micromole). The reaction was stirred at room temperature under nitrogen protection for 16 hours.
- the reaction mixture was concentrated and purified by preparative HPLC (column: Boston Green ODS 150 ⁇ 30mm ⁇ 5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 0%-25%, 9min).
- the target product was freeze-dried to obtain a yellow solid product N 1 -((6-amino-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methyl)-N 1 ,N 2 -Dimethylethane-1,2-diamine (P226, Example 3) (22 mg, 58.7 ⁇ mol, 69.2% yield).
- Step 1 2-bromo-4-fluorobenzoic acid (4-1) (23 g, 105 mmol) was dissolved in tert-butanol (200 ml), and 4-dimethylaminopyridine (12.8 g , 105 mmol) and di-tert-butyl dicarbonate (68.8 g, 315 mmol, 3.0 eq.) (outgassing), reacted at 90 degrees Celsius for 2 hours under the protection of reaction liquid nitrogen. TLC detection of raw material consumption is complete, there is a new point generate. The reaction solution was diluted with water (100 mL), and extracted twice with ethyl acetate (150 mL).
- Step 2 Synthesis of lithium diisopropylamide: Diisopropylamine (5.15 g, 50.9 mmol, 7.19 ml) was dissolved in tetrahydrofuran (100 ml), and n-butyllithium (2.5M, 17.45 ml). After the dropwise addition was completed, the reaction solution was raised to room temperature and stirred for half an hour to obtain a yellow lithium diisopropylamide solution.
- Step 4 Mix tert-butyl 4-bromo-1H-indazole-5-carboxylate (4-4) (4.5 g, 15.14 mmol) and 3.4 dihydro-2H-pyran (3.82 g, 45.43 mmol, 4.15 ml) was dissolved in dichloromethane (60 ml), and p-toluenesulfonic acid monohydrate (288 mg, 1.51 mmol) was added. The reaction solution was stirred at 15 degrees Celsius for 1 hour. LC-MS detected that the raw material was completely consumed, and the target product was formed . The reaction solution was diluted with water (50 ml) and extracted twice with ethyl acetate (100 ml).
- Step 6 Add 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H- Indazole-5-carboxylic acid tert-butyl ester (4-6) (800 mg, 1.69 mmol) was dissolved in methanol (160 mL), and 10% Pd/C (150 mg) was added. The reaction solution was degassed under reduced pressure and replaced with hydrogen. The reaction solution was stirred at 50° C. for 32 hours under a hydrogen balloon atmosphere. LCMS detected the formation of the target product.
- Step 8 Add (1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidin-4-yl)-1H-indazol-5-yl)methanol ( 4-8) (200 mg, 493.18 micromol) was dissolved in dichloromethane (10 ml), and Dess-Martin reagent (220 mg, 518 micromol) was added. The reaction solution was reacted at 25 degrees Celsius for 6 hours. LC- MS detected that the starting material was completely consumed and the target product was formed.
- reaction solution was extracted with 10% sodium thiosulfate solution (20 ml), stirred at room temperature for 0.5 hours, the reaction solution was added with saturated sodium bicarbonate (50 ml), and extracted 3 times with dichloromethane (50 ml).
- Step 9 Adding 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidin-4-yl)-1H-indazole-5-carbaldehyde (4-9 ) (200 mg, 496 micromoles) and methyl (2-(methylamino) ethyl) tert-butyl carbamate (112 mg, 595 micromoles) were dissolved in dichloromethane (5 ml), and acetic acid ( 36 mg, 595 micromol). The reaction solution was stirred at 20°C for 2 hours. Sodium triacetoxyborohydride (315 mg, 1.49 mmol, 3 eq.) was added.
- Step 10 Methyl (2-(methyl((1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidin-4-yl)-1H- Indazol-5-yl)methyl)amino)ethyl)carbamate tert-butyl ester (4-10) (210 mg, 365 ⁇ mol) in methanol (2 mL) plus HCl/1,4-diox Hexacyclic (4M, 2.10 ml). The reaction was stirred at 25°C for 16 hours. LC-MS detected that the raw materials were completely consumed and the target product was formed.
- Step 1 tert-butyl 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (4-5) (1.95 g, 5.11 mmol), (2,3-Difluoro-6,9-dihydro-5H-benzo[7]cyclopent-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxo Borane (Intermediate A) (1.80 g, 5.88 mmol, 1.15 equiv), toluene (45 mL) and potassium phosphate (2.18 g, 10.3 mmol) were dissolved in water (6.5 mL) and added to the reaction flask , After replacing with nitrogen several times, chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1- biphenyl)] palladium (II
- Step 2 Crude product 4-(2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yl)-1-(tetrahydro-2H-pyran from the previous step -2-yl)-1H-indazole-5-carboxylic acid tert-butyl ester (5-1) was dissolved in ethyl acetate (50 ml), and under nitrogen atmosphere, palladium hydroxide/carbon (520 mg, 10% ). The reaction solution was replaced with hydrogen several times, and stirred at 30°C for 12h. LCMS detected consumption of starting material and formation of target product.
- Step 3 4-(2,3-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-1-(tetrahydro-2H-pyran -2-yl)-1H-indazole-5-carboxylic acid tert-butyl ester (5-2) (1.9 g, 3.94 mmol) was dissolved in methanol (30 mL) and THF (30 mL), and p-toluene monohydrate was added Sulfonic acid (297 mg, 1.56 mmol). The reaction solution was stirred at 30° C. for 3.5 days. LCMS detected the formation of the target product, and the raw material remained.
- reaction solution was quenched with saturated sodium bicarbonate solution (20 mL), and concentrated under reduced pressure to remove methanol.
- Ethyl acetate (100 mL) and water (50 mL) were added, the organic phase was separated and extracted twice with ethyl acetate (50 mL).
- the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified by thin layer chromatography (silica, 35% ethyl acetate in petroleum ether).
- Step 4 4-(2,3-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-1H-indazole-5-carboxylic acid tert Butyl ester (5-3) (424 mg, 1.06 mmol) was dissolved in dimethylformamide (10 ml), potassium carbonate (458 mg, 3.31 mmol) was added first, and iodine (459 mg, 1.81 mmol) was added The reaction solution was stirred for 16 hours at 15 to 20 degrees Celsius. LCMS detected 69% of the target product, and 30% of the raw material remained.
- Step 5 4-(2,3-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-iodo-1H-indazole-5 - tert-butyl carboxylate (5-4) (589 mg, 1.12 mmol) and 3,4-dihydropyran (420 mg, 4.99 mmol) were dissolved in dichloromethane (15 ml) in an ice bath At a temperature of 0-5 degrees Celsius, p-toluenesulfonic acid (50 mg, 263 micromoles, 0.23 eq.) was added. The reaction solution was stirred for 3 hours at 15-20 degrees Celsius.
- Step 6 Cast two reactions in parallel: tert-butyl 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3 -Iodo-1-(tetrahydro-2H-pyran-2--1)-indazole-5-carboxylic acid tert-butyl ester (5-5) (225 mg, 370 micromol, 1.0 eq.), 1, 4-Dioxane (5 mL) and potassium phosphate (236 mg, 1.11 mmol) were dissolved in water (1 mL).
- reaction solution was partitioned between saturated brine (50 mL) and ethyl acetate (50 mL), the organic layer was separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure.
- Step 9 4-(2,3-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole-5-carbaldehyde (5-8) (204 mg, 480 micromole), tert-butyl methyl (2-(methylamino)ethyl)carbamate Esters (186 mg, 987 micromoles) and acetic acid (62 mg, 1.03 mmoles, 2.15 eq.) were dissolved in dichloromethane (3 ml), stirred at 25°C for 2 hours, and triethoxycarbonyl hydroboration was added Sodium (340 mg, 1.60 mmol).
- reaction solution was stirred at 25°C for 14 hours.
- LCMS detected consumption of starting material and formation of target product.
- the reaction solution was partitioned between 5% sodium bicarbonate (15 mL) and dichloromethane, and the organic phase was separated. The aqueous phase was extracted 3 times with ethyl acetate (10 mL).
- Step 10 Hydrochloride-1,4-dioxane (4M, 5 mL) was added to (2-((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo [7] cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methyl)(methyl)amino ) ethyl) (methyl) tert-butyl carbamate (5-9) (202 mg, 338 micromole) in methanol solution. The reaction solution was stirred at 10-15 degrees Celsius for 12 hours. LCMS detected that the starting material was completely consumed and the target product was formed.
- Example 11 Compound N, N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H-benzo[d] Synthesis of imidazol-5-yl]methyl]ethane-1,2-diamine (P406):
- Step 1 2-nitro-3-bromoaniline (11-1) (150 g, 691.18 mmol), N-iodosuccinimide (171 g, 760.05 mmol) and acetic acid (1500 mL) mixture Heat to reflux for about 2 hours, wait for the conversion of the reactant 11-1 and cool down, pour the reaction solution into 3600 ml of water, filter the precipitate, and dissolve it in ethyl acetate after vacuum drying, wash with water and saturated brine successively, extract with ethyl acetate, and combine The organic phase was dried with anhydrous magnesium sulfate; after filtration and concentration, silica gel column chromatography separated 178 g of brown solid 2-nitro-3-bromo-4-iodoaniline (11-2) 1 H NMR (400MHz, DMSO-d6) ⁇ (ppm)7.66(d,1H),6.70(d,1H),6.23(s,2H).
- Step 2 The compound 2-nitro-3-bromo-4-iodoaniline (11-2) (80.0 g, 233.29 mmol) was dissolved in tetrahydrofuran (640 ml)/ethanol (640 ml)/water (320 ml) The system was mixed and NH 4 Cl (187 g, 3.50 mol) was added. After the mixture was heated to 90° C., iron powder (52.1 g, 933.17 mmol) was slowly added in batches. Heating was continued for 2 hours until the reaction was complete.
- Step 3 Compound 3-bromo-4-iodo-o-phenylenediamine (11-3) (35.0 g, 111.85 mmol) was dissolved in tetrahydrofuran (350 ml), cooled in an ice-water bath, carbonyldiimidazole (27.2 g, 167.77 Millimoles). Gradually return to room temperature, and the reaction solution was stirred for about 2 hours until the reaction was complete.
- Step 4 Compound 4-bromo-5-iodo-1,3-dihydro-2H-benzo[d]imidazol-2-one (11-4) (28.0 g, 82.61 mmol) was carefully added to trichloroxy Phosphorus (130 ml), the mixture was heated to 100° C. for 3 hours, then heated to 120° C. for 16 hours, and the reaction was almost complete. After cooling to room temperature, it was distilled to half volume under pressure. Carefully pour it into 2 liters of ice water in batches and carefully adjust the pH value to 8 with potassium carbonate under stirring.
- Step 5 Compound 2-chloro-4-bromo-5-iodo-1H-benzo[d]imidazole (11-5) (30.0 g, 83.95 mmol, 2.05 mL) in isopropanol (150 mL) and THF (150 mL) was added morpholine (37.0 g, 424.70 mmol, 37.37 mL). The mixture was heated to 90°C for 4 days, cooled to room temperature after complete conversion of the raw materials, spinned off the organic solvent, and made a slurry in water (300 ml).
- Step 8 Compound 2-(4-morpholine)-4-(1-m-methylphenyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole-
- ethyl 5-carboxylate (11-8) (18.5 g, 41.43 mmol) in THF (600 mL) was added Pd(OH) 2 /C (7.0 g, 41.43 mmol, 10% purity), hydrogen
- react at 30°C for 16 hours under a hydrogen atmosphere (balloon) react at 30°C for 16 hours under a hydrogen atmosphere (balloon), the reaction is almost complete, filter, wash the filter cake with tetrahydrofuran (200 ml*2), and combine the filtrates to concentrate and dry to obtain the crude product 2-(4-morpholine)-4 -Ethyl(1-m-methylphenyl-4-piperidinyl)-3H-benzo[d]imidazole-5-carboxylate (11-9)
- Step 9 Compound 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-3H-benzo[d]imidazole-5-carboxylic acid ethyl ester (11-9 ) (19 g, 42.36 mmol) was dissolved in CH 3 CN (550 mL), cesium carbonate (69.0 g, 211.79 mmol) was added, and then SEM-Cl (19 g, 113.96 mmol, 20.17 mL) was added dropwise with stirring ). The reaction mixture was reacted at 30°C for 24 hours. The reaction is almost complete.
- Step 10 Under cooling in an ice-water bath, add the compound 2-(4-morpholine)-4-(1-methane) dropwise to a solution of aluminum lithium hydride (3.0 g, 79.05 mmol, 79.05 ml) in tetrahydrofuran (300 ml) Ethylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-carboxylate (11-10) (22.0 g, 38.01 mmol) in tetrahydrofuran (100 ml), gradually returned to room temperature after the dropwise addition, and heated to 30° C. for 1 hour. The reaction is basically complete.
- Step 13 Compound N-tert-butoxycarbonyl-N,N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H -Benzo[d]imidazol-5-yl]methyl]ethane-1,2-diamine (11-13) (10.6 g, 14.99 mmol) was dissolved in 50 mL of 1,4-dioxane, A solution of HCl/dioxane (50 mL) was added and stirred at 70°C for 2 hours, a white solid precipitated out.
- Example 12 Compound 5-((methyl(2-(methylamino)ethyl)amino)methyl)-4-(1-m-methylphenyl)piperidine-4- Base) the synthesis of indoline-2-ketone (P180):
- Step 1 Compound 4-bromoindolin-2-one (12-1) (2.00 g, 9.43 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.92 g, 9.43 mmol) and potassium phosphate (6.01 g, 28.30 mmol) were added To a mixture of 100 ml tetrahydrofuran and 20 ml water, Xphos Pd G3 (239 mg, 0.28 mmol) was added after nitrogen replacement. Nitrogen was replaced again, and then heated to 65° C. under nitrogen protection and stirred for 2 hours.
- Step 2 Compound 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-)indolin-2-one (12-2) (2.30 g, 7.32 mmol) was added To 50 ml of methanol, 10% palladium-carbon (460 mg, 0.43 mmol) was added after nitrogen replacement; then replaced with hydrogen, and stirred at room temperature under a hydrogen atmosphere (balloon) for 16 hours.
- Step 3 The crude product 4-(1-tert-butoxycarbonyl-piperidin-4-yl)-indolin-2-one (12-3) (3.70 g, 11.69 mmol) was dissolved in 100 mL of dichloromethane , added N-bromosuccinimide (2.29 g, 12.86 mmol, 1.1 eq) in batches, stirred at room temperature for 16 hours, and the reaction was almost complete.
- Step 6 Compound 5-bromo-4-(1-trimethylsilethoxycarbonyl-piperidin-4-yl)-indol-2-one (12-6) (2.00 g, 4.55 mmol), no Potassium water [2-(tert-butoxycarbonylmethylaminoethyl)(methyl)amino]methyl boron trifluoride (4.21 g, 13.65 mmol), potassium phosphate (2.90 g, 13.65 mmol), and Ruphos Add 40 ml of tetrahydrofuran and 4 ml of water to the mixture of Pd G2 (353 mg, 0.455 mmol), replace with nitrogen, heat to 80° C. for 16 hours under the protection of nitrogen, and the reaction is almost complete.
- Step 7 Compound 2-trimethylsilylethyl-4-(5-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-2-
- a mixture of oxoindolin-4-yl)piperidine-1-carboxylate (12-7) (1.50 g, 2.41 mmol, 90% purity) and cesium carbonate (5.00 g, 15.35 mmol) was added to 20 mL Acetonitrile was stirred for 3 hours, 4-methoxybenzyl chloride (565 mg, 3.61 mmol, 0.49 ml) was added dropwise thereto, and after stirring at room temperature for 1 hour, the reaction was basically complete.
- Step 8 Compound 2-trimethylsilylethyl-4-(5-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-1- (4-Methoxybenzyl)-2,3-dioxoindolin-4-yl)piperidine-1-carboxylate (12-8) (2.10 g, 2.33 mmol, 77% purity) Dissolve in 30 ml of N,N-dimethylformamide, add cesium fluoride (1.77 g, 11.63 mmol, 0.43 ml), then heat to 65 degrees and stir for 5 hours, the reaction is almost complete.
- Step 9 Compound tert-butyl (2-(((1-(4-methoxybenzyl)-2,3-dioxo-4-(piperidin-4-yl)indoline-5-yl )methyl)(methyl)amino)ethyl)(methyl)carbamate (12-9) (1.30 g, 2.36 mmol), m-bromotoluene (605 mg, 3.54 mmol, 0.43 ml) and Add 20 milliliters of toluene to the mixture of cesium carbonate (1.54 g, 4.72 mmol), add RuPhos Pd G3 (200 mg, 0.24 mmol) after nitrogen replacement, then nitrogen replacement, and be heated to 100 degree stirring reaction for 16 hours, the reaction is basically completely.
- Step 10 Compound tert-butyl (2-(((1-(4-methoxybenzyl)-2,3-dioxo-4-(1-m-methylphenylpiperidin-4-yl) Indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-10) (190 mg, 0.30 mmol) was dissolved in 5 mL of ethanol and hydrazine hydrate was added (5.15 g, 87.44 mmol, 5.00 mL, 85% purity) and potassium hydroxide (332 mg, 5.93 mmol). The mixture was heated to 80° C. and stirred for 3 hours, and the reaction was almost complete.
- Step 11 Compound tert-butyl(2-(((1-(4-methoxybenzyl)-2-oxo-4-(1-m-methylphenylpiperidin-4-yl)indoline -5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-11) (220 mg, 0.32 mmol, 92% purity) was dissolved in 5 mL of trifluoroacetic acid, Then trifluoromethanesulfonic acid (200 mg, 1.33 mmol, 0.12 ml) was added dropwise with stirring, stirred at room temperature for 5 hours, then heated to 40°C for 30 hours, and the reaction was almost complete.
- reaction solution was concentrated, diluted with 5 ml of dichloromethane, and extracted with 0.5M dilute aqueous hydrochloric acid.
- the combined aqueous phases were adjusted to pH 12 with 1M aqueous sodium hydroxide solution and extracted with dichloromethane.
- the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the free base product 5-((methyl(2-(methylamino)ethyl)amino)methyl)-4-(1-m-methylphenyl )piperidin-4-yl)indolin-2-one (P180).
- Example 13 Compound N-((5-amino-3-(1-(m-methylphenyl)piperidin-4-yl)pyrazin-2-yl)methyl)-N,N'- Synthesis of dimethyl-1,2-ethylenediamine (P292):
- Step 1 Compound 2-cyano-3,5-dichloropyrazine (13-1) (145 g, 833.39 mmol) was dissolved in 1000 ml of N,N-dimethylformamide, then added dropwise at room temperature Diisopropylethylamine (109 g, 843.37 mmol, 146.90 mL). Then after cooling to 5-10 degrees, a solution of bis(4-methoxybenzyl)amine (217.50 g, 845.23 mmol) dissolved in 500 ml of N,N-dimethylformamide was added dropwise under stirring . Slowly warm up to room temperature and continue to stir for 3 hours, the reaction is almost complete.
- the reaction solution was poured into 5000 ml of ice-water mixture and stirred for 5 minutes, and a solid was precipitated. After filtration, the solid was dissolved in 4000 ml of ethyl acetate, then washed with saturated brine, the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated, and the crude product was beaten with 700 ml of methyl tert-butyl ether at 20 degrees for 16 hours, filtered The dried yellow solid compound 2-cyano-3-chloro-5-(bis(4-methoxybenzyl)amino)pyrazine (13-2) was directly used in the next reaction without further purification.
- Step 2 Compound 2-cyano-3-chloro-5-(bis(4-methoxybenzyl)amino)pyrazine (13-2) was dissolved in 600 ml of tetrahydrofuran and cooled to minus 78 degrees under nitrogen protection , DIBALH (1 mol/L, 548 ml) was added dropwise with stirring, and then the stirring reaction was continued for 2 hours until the reaction was substantially complete.
- Step 3 Compound 5-(bis(4-methoxybenzyl)amino)-3-chloro-pyrazine-2-carbaldehyde (13-3) (53.0 g, 133.21 mmol), N-tert-butoxycarbonyl -N,N'-Dimethylethylenediamine (30.0 g, 159.35 mmol) was dissolved in 1000 ml of dichloromethane, acetic acid (9.60 g, 159.86 mmol, 9.14 ml) was added to it, and then acetic acid was added in portions at room temperature Sodium borohydride (71.0 g, 335.00 mmol), continued to stir the reaction for 2 hours, then carefully added 1000 ml of saturated aqueous sodium carbonate solution to quench the reaction.
- Step 5 Compound tert-butyl (2-(((5-(bis(4-methoxybenzyl)amino)-3-(1-(m-methylphenyl)-1,2,3,6- Tetrahydropyridin-4-yl)pyrazin-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-5) (46.5 g, 65.78 mmol) was dissolved in Add palladium hydroxide/carbon (15 g, 21.36 mmol, 20% purity) to 600 ml of tetrahydrofuran under nitrogen protection, replace with hydrogen, and stir at room temperature in a hydrogen atmosphere (balloon) for 4 days.
- palladium hydroxide/carbon 15 g, 21.36 mmol, 20% purity
- Step 6 Compound tert-butyl(2-(((5-(bis(4-methoxybenzyl)amino)-3-(1-(m-methylphenyl)piperidin-4-yl)pyrazine -2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-6) (56 g, 78.99 mmol) was added with 300 ml of trifluoroacetic acid and then trifluoroacetic acid Methanesulfonic acid (30.0 g, 199.90 mmol, 17.65 ml), the reaction solution was stirred at room temperature for 16 hours, and the reaction was almost complete.
- reaction solution was concentrated under reduced pressure, 1 liter of water was added, and 2 liters of ethyl acetate was stirred until the solid was dissolved. After separation and extraction, the organic phase was extracted with 1M hydrochloric acid solution, and the aqueous phase was neutralized to pH 9 with 30% aqueous sodium hydroxide solution.
- Test example 1 PRMT1 enzyme activity test method
- Compounds were prepared in 100% DMSO to the final desired highest inhibitor concentration in a 100X reaction, then transferred to one well in a 384-well Echo plate (Echo-qualified 384-well polypropylene microplate 2.0, clear, flat bottom) and Dilute with 3-fold dilutions of 100% DMSO in the next well, and so on, with a total of 10 concentrations in terms of Precision. 100% DMSO was added to two empty wells as no compound control wells and no enzyme control wells in the same 384-well Echo plate.
- the final concentrations of the components were as follows: 0.5 nM for PRMT1, 0.25 uM for 3 H-SAM, 0.1 uM for peptide, and 1% DMSO concentration. After 120 minutes of incubation, the assay was terminated by the addition of non-radiolabeled SAM (5uL) to a final concentration of 125uM, which diluted 3H-SAM to a level at which its incorporation into the peptide substrate was no longer detectable. Then 25 ⁇ L of the reaction solution in the 384-well assay plate was transferred to a 384-well assay plate (Streptavidin FlashPlate HTS PLUS, high capacity, 384 wells).
- the difference is that MV-4-11 cells are used, and the cell culture medium is IMDM+10% FBS; the third step of the test method is 250 cells per well;
- A stands for IC 50 ⁇ 50nM
- the test method of PRMT1 is as in Test Example 1.
- the test and curve fitting of PRMT5 and PRMT7 refer to the test of PRMT1 and the data processing method is carried out with optimized parameters.
- the test method of PRMT3 is as follows:
- Compounds were prepared in 100% DMSO to the final desired highest inhibitor concentration in a 100X reaction, then transferred to one well in a 384-well Echo plate (Echo-qualified 384-well polypropylene microplate 2.0, clear, flat bottom) and Dilute with 3-fold dilutions of 100% DMSO in the next well, and so on, with a total of 10 concentrations in terms of Precision. Add 100% DMSO to two empty wells as a control well without compound and a control well without enzyme in the same 384-well Echo plate.
- Curve fitting copy the original data from Reader, and calculate the inhibition rate value in Excel by equation (1).
- Equation (1): Inh% (RFUmax-RFUcmpd)/(RFUmax-RFUmin)*100, where the Max signal is obtained through the action of the enzyme and the substrate, and the Min signal is obtained through the substrate.
- IC50 values were obtained by fitting the data with equation (2) using the XLFit plug-in version 45.4.0.8 in Excel.
- Equation (2): Y Bottom+(Top-Bottom)/(1+((IC50/X)*HillSlope)), where Y represents the percentage of inhibition and X represents the compound concentration.
- Test example 4 RKO in cell western experimental method
- Patent_ID RKO ICW_EC30 Patent_ID RKO ICW_EC30 P001 B P118 A P003 A P122 C P004 B P130 B P005 B P131 B P007 A P136 B P008 B P137 B P009 B P141 B P014 B P142 B P015 B P143 B P021 A P147 B P022 A P148 B P023 A P149 B P025 A P153 A P039 B P157 B P044 B P158 A P049 A P165 B
- Patent_ID RKO ICW_EC30 Patent_ID RKO ICW_EC30 P050 B P167 A P051 B P170 B P052 B P171 B P053 B P179 B P054 A P184 C P056 B P185 B P057 B P186 B P069 B P187 A P074 B P198 A P075 B P202 B P078 A P206 B P079 A P207 A P080 B P208 B P081 A P225 A P083 A P226 A P085 A P236 B P088 B P240 B P089 A P243 B P094 A P250 B P095 A P251 B P106 B P252 B P107 B P258 A P112 B P323 C P114 A P325 B
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Abstract
Description
化合物 | PRMT3 | PRMT4 | PRMT5 | PRMT6 | PRMT7 | PRMT8 |
P207 | B | A | C | A | C | A |
P023 | A | A | C | A | C | A |
P118 | B | B | C | A | C | A |
Patent_ID | RKO ICW_EC30 | Patent_ID | RKO ICW_EC30 |
P001 | B | P118 | A |
P003 | A | P122 | C |
P004 | B | P130 | B |
P005 | B | P131 | B |
P007 | A | P136 | B |
P008 | B | P137 | B |
P009 | B | P141 | B |
P014 | B | P142 | B |
P015 | B | P143 | B |
P021 | A | P147 | B |
P022 | A | P148 | B |
P023 | A | P149 | B |
P025 | A | P153 | A |
P039 | B | P157 | B |
P044 | B | P158 | A |
P049 | A | P165 | B |
Patent_ID | RKO ICW_EC30 | Patent_ID | RKO ICW_EC30 |
P050 | B | P167 | A |
P051 | B | P170 | B |
P052 | B | P171 | B |
P053 | B | P179 | B |
P054 | A | P184 | C |
P056 | B | P185 | B |
P057 | B | P186 | B |
P069 | B | P187 | A |
P074 | B | P198 | A |
P075 | B | P202 | B |
P078 | A | P206 | B |
P079 | A | P207 | A |
P080 | B | P208 | B |
P081 | A | P225 | A |
P083 | A | P226 | A |
P085 | A | P236 | B |
P088 | B | P240 | B |
P089 | A | P243 | B |
P094 | A | P250 | B |
P095 | A | P251 | B |
P106 | B | P252 | B |
P107 | B | P258 | A |
P112 | B | P323 | C |
P114 | A | P325 | B |
Claims (15)
- 一种如下式I所示的化合物,或其药学上可接受的盐或氘代产物:X 1、X 2、X 3和X 4各自独立地选自下组:CR、NR或N;虚线为化学键或无;A环选自下组:取代或未取代的饱和或部分不饱和(非芳香)的4-8元碳环、取代或未取代的饱和或部分不饱和(非芳香)的4-8元杂环;B环选自下组:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳环、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的3-12元的杂环、取代或未取代的-C 1-C 6烷基-6-10元芳基、取代或未取代的C 3-C 12碳环、取代或未取代的C 2-C 10酰基、取代或未取代的C 2-C 10酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;m和n各自独立地选自下组:0、1、2、3、4、5或6;L选自下组:化学键,或-O-、-(CHR 6) p-、-CHR 6-O-、-CHR 6-C(O)-、羰基、S、-NH-、-NHC(O)-、-NHS(O) 2-、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2-、-COO-CH 2-、-C(O)CH 2-、-S(O) 2-,或L不存在;p选自下组:1、2或3;R 1和R 2各自独立地选自下组:H、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基;R 3为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 3-C 12碳环、取代或未取代的C 2-C 10酰基、取代或未取代的C 2-C 10酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;R为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的4-7元的杂环、取代或未取代的-C 1- C 6烷基-苯基、取代或未取代的C 3-C 12碳环、取代或未取代的C 2-C 10酰基、取代或未取代的C 2-C 10酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;或两个位于相邻环原子上的R与其相连的环原子共同构成取代或未取代的5-11元碳环或杂环,所述的环为部分不饱和或饱和的;较佳地,所述的碳环或杂环为5-9元碳环或杂环,更优选为5-7元碳环或杂环(所述的碳环或杂环为饱和、部分不饱和或芳香性的);R 4为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 3-C 12碳环、取代或未取代的C 2-C 10酰基、取代或未取代的C 2-C 10酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;或两个位于相同或相邻环原子上的R 4与其相连的环原子共同构成取代或未取代的3-11元碳环或杂环,所述的环为部分不饱和环、饱和环或芳香性环;R 6为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、酰基磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基;除非特别说明,上述各式中,所述的取代指对应基团上的氢原子被一个或多个选自下组的取代基所取代:氘、氚、卤素、羟基、羧基、巯基、苄基、氧(=O)、C 1-C 12烷氧基羰基、C 1-C 6醛基、氨基、C 1-C 6酰胺基、硝基、氰基、未取代或卤代的C 1-C 6烷基、C 2-C 10烯基、C 1-C 6烷氧基、C 1-C 6烷基-胺基、C 1-C 6烷基-磺酰胺基、C 1-C 6烷基-脲基、C 1-C 6烷基-S-、C 6-C 10芳基、五元或六元杂芳基、五元或六元非芳香性杂环基、五元或六元非芳香性杂环基-(CH 2)-、-O-(C 6-C 10芳基)、-O-(五元或六元杂芳基)、-NH-(C 6-C 10芳基)、-NH-(五元或六元杂芳基)、C 1-C 12烷氨基羰基、未取代或卤代的C 2-C 10酰基、磺酰基(-SO 2-OH)、磺酰胺基(-SO 2-NH 2)、磷酰基(-PO 3-OH)、未取代或卤代的C 1-C 4烷基-S(O) 2-、未取代或卤代C 1-C 4烷基-SO-、 各式中,杂环或杂芳环中具有1-3个选自下组的杂原子:N、S或O;各个芳基、杂芳基、杂环基可以各自独立地被1-3个选自下组的取代基取代:氘、氚、卤素、羟基、羧基、巯基、C 1-C 6烷基、C 1-C 6烷氧基。
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的R 3为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-10元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的 C 3-C 8碳环、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;和/或R为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-10元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 3-C 8碳环、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;或两个位于相邻环原子上的R与其相连的碳原子共同构成取代或未取代的5-9元碳环或杂环,所述的环为部分不饱和、饱和或芳香性的;和/或
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的B环选自下组:H,或取代或未取代的苯基、取代或未取代的5-10元杂芳环、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的3-12元的杂环、取代或未取代的C 3-C 12碳环。
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的R 3为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-10元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 1-C 6酰胺基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;和/或R为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 1-C 6酰胺基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;或两个位于相邻环原子上的R与其相连的环原子共同构成取代或未取代的5-7元碳环或杂环;和/或R 4为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 8碳环、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 10酯基、取代或未取代的C 1-C 6酰胺基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;或两个位于相邻环原子上的R 4与其相连的碳原子共同构成取代或未取代的5-9元碳环或杂环,所述的环为部分不饱和或饱和的。
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的B环选自下组:取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的4-12元的杂环、取代或未取代的C 3-C 12碳环。
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的化合物具有如下式III所示的结构:其中,A环选自下组:取代或未取代的饱和或部分不饱和(非芳香)的4-8元碳环、取代或未取代的饱和或部分不饱和(非芳香)的4-8元杂环;B环选自下组:取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的3-12元的杂环、取代或未取代的C 3-C 12碳环;较佳地,R 3为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;较佳地,R 4为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-7元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 3-C 8碳环、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-。
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的化合物具有如下式IV所示的结构:其中,A 1环选自下组:取代或未取代的饱和或部分不饱和(非芳香)的5-8元碳环、取代或未取代的饱和或部分不饱和(非芳香)的5-8元杂环;A 2环选自下组:取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 3-C 12碳环;且A 2环和A 1环稠合;A 3环和A 4环各自独立地选自下组:取代或未取代的饱和或部分不饱和(非芳香)的5-8元碳环、取代或未取代的饱和或部分不饱和(非芳香)的3-8元杂环;m为0、1、2、3或4;R 5选自下组:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 6-C 10芳氧基或杂芳氧基、取代或未取代的C 6-C 10芳胺基或杂芳胺基,取代或未取代的C 1-C 6酰胺基、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;且R 5可以位于A 1环、A 2环、A 3环或A 4环上。
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的化合物具有如下式V或式VI所示的结构:其中,C环为取代或未取代的苯基、取代或未取代的5-7元杂环基、或取代或未取代的5-6元杂芳基;A环选自下组:取代或未取代的饱和或部分不饱和(非芳香)的5-6元碳环、取代或未取代的饱和或部分不饱和(非芳香)的4-8元杂环;B环选自下组:取代或未取代的C 6-C 10芳基、取代或未取代的5-12元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的4-12元的杂环、取代或未取代的C 3-C 12碳环;较佳地,R 3为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-;较佳地,R 4为选自下组的基团:H、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 1-C 6烷胺基、取代或未取代的C 6-C 10芳基、取代或未取代的5-7元杂芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的-C 1-C 6烷基-苯基、取代或未取代的C 3-C 8碳环、取代或未取代的C 2-C 6酰基、取代或未取代的C 2-C 6酯基、取代或未取代的C 1-C 4烷基-S(O) 2-、取代或未取代的C 1-C 4烷基-SO-。
- 如权利要求1所述的化合物,或其药学上可接受的盐或氘代产物,其特征在于,所述的化合物为实施例P1-P448中任一化合物。
- 一种药物组合物,其特征在于,所述的药物组合物含有治疗有效量的如权利要求1所述的式I化合物、或其可药用的盐,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
- 如权利要求1所述的式I化合物、或其可药用盐在制备治疗或预防与PRMT相关的疾病的药物组合物中的用途;较佳地,所述的PRMT为I型PRMT。
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WO2023156386A3 (en) * | 2022-02-16 | 2023-09-28 | Duke Street Bio Limited | Pharmaceutical compound |
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EP4342878A1 (en) | 2024-03-27 |
BR112023024167A2 (pt) | 2024-02-06 |
TW202313554A (zh) | 2023-04-01 |
JP2024521741A (ja) | 2024-06-04 |
KR20240013180A (ko) | 2024-01-30 |
CA3219927A1 (en) | 2022-11-24 |
AU2022275898A1 (en) | 2024-01-18 |
CN115368246A (zh) | 2022-11-22 |
CN117377649A (zh) | 2024-01-09 |
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