CA2954060A1 - Inhibitors of lysine specific demethylase-1 - Google Patents
Inhibitors of lysine specific demethylase-1 Download PDFInfo
- Publication number
- CA2954060A1 CA2954060A1 CA2954060A CA2954060A CA2954060A1 CA 2954060 A1 CA2954060 A1 CA 2954060A1 CA 2954060 A CA2954060 A CA 2954060A CA 2954060 A CA2954060 A CA 2954060A CA 2954060 A1 CA2954060 A1 CA 2954060A1
- Authority
- CA
- Canada
- Prior art keywords
- optionally substituted
- compound
- pharmaceutically acceptable
- fluoro
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000004472 Lysine Substances 0.000 title claims abstract description 16
- 239000003112 inhibitor Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 282
- 238000000034 method Methods 0.000 claims abstract description 126
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 28
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- -1 substituted Chemical class 0.000 claims description 253
- 150000003839 salts Chemical class 0.000 claims description 107
- 229910052736 halogen Inorganic materials 0.000 claims description 87
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 22
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 21
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 claims description 20
- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 claims description 20
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 17
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims description 14
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 12
- 102000004190 Enzymes Human genes 0.000 claims description 10
- 108090000790 Enzymes Proteins 0.000 claims description 10
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 10
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- 150000003235 pyrrolidines Chemical class 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 238000013518 transcription Methods 0.000 claims description 4
- 230000035897 transcription Effects 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 2
- 125000005438 isoindazolyl group Chemical group 0.000 claims description 2
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical class NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 claims description 2
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical class NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 50
- 230000005764 inhibitory process Effects 0.000 abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 238000011282 treatment Methods 0.000 abstract description 12
- 201000010099 disease Diseases 0.000 abstract description 10
- 206010005003 Bladder cancer Diseases 0.000 abstract description 4
- 206010006187 Breast cancer Diseases 0.000 abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 4
- 206010060862 Prostate cancer Diseases 0.000 abstract description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 abstract description 4
- 201000005202 lung cancer Diseases 0.000 abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 abstract description 4
- 201000001441 melanoma Diseases 0.000 abstract description 4
- 201000005112 urinary bladder cancer Diseases 0.000 abstract description 4
- 230000001613 neoplastic effect Effects 0.000 abstract description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 157
- 238000002360 preparation method Methods 0.000 description 153
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 109
- 238000005160 1H NMR spectroscopy Methods 0.000 description 108
- 125000005843 halogen group Chemical group 0.000 description 92
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 88
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 description 68
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 68
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 63
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 61
- 125000002947 alkylene group Chemical group 0.000 description 55
- 210000004027 cell Anatomy 0.000 description 47
- 150000003857 carboxamides Chemical class 0.000 description 44
- 239000000243 solution Substances 0.000 description 43
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- 125000004432 carbon atom Chemical group C* 0.000 description 40
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 39
- 239000000126 substance Substances 0.000 description 38
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 36
- 150000003254 radicals Chemical class 0.000 description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 27
- 108010033040 Histones Proteins 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 125000004419 alkynylene group Chemical group 0.000 description 22
- 125000003118 aryl group Chemical group 0.000 description 22
- 102000010909 Monoamine Oxidase Human genes 0.000 description 17
- 108010062431 Monoamine oxidase Proteins 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 125000004452 carbocyclyl group Chemical group 0.000 description 15
- 235000018977 lysine Nutrition 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 102000006947 Histones Human genes 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 238000003556 assay Methods 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 125000003709 fluoroalkyl group Chemical group 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 13
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 13
- 229940002612 prodrug Drugs 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 108010077544 Chromatin Proteins 0.000 description 12
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000001413 cellular effect Effects 0.000 description 12
- 210000003483 chromatin Anatomy 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000004450 alkenylene group Chemical group 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 125000005884 carbocyclylalkyl group Chemical group 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 238000007069 methylation reaction Methods 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 244000201986 Cassia tora Species 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- NCAIGTHBQTXTLR-UHFFFAOYSA-N phentermine hydrochloride Chemical compound [Cl-].CC(C)([NH3+])CC1=CC=CC=C1 NCAIGTHBQTXTLR-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 230000011987 methylation Effects 0.000 description 7
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 150000001420 substituted heterocyclic compounds Chemical class 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- 101150041968 CDC13 gene Proteins 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZFWRIEYWTZJXOL-UHFFFAOYSA-N FC1=CC(=CC2=CN(N=C12)C)N Chemical compound FC1=CC(=CC2=CN(N=C12)C)N ZFWRIEYWTZJXOL-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- RNXYXIKLWRRZNU-UHFFFAOYSA-N Kynuramine Natural products NCCCC(=O)C1=CC=CC=N1 RNXYXIKLWRRZNU-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 229940098773 bovine serum albumin Drugs 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 125000001841 imino group Chemical group [H]N=* 0.000 description 6
- QLPVTIQQFGWSQQ-UHFFFAOYSA-N kynuramine Chemical compound NCCC(=O)C1=CC=CC=C1N QLPVTIQQFGWSQQ-UHFFFAOYSA-N 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 238000007745 plasma electrolytic oxidation reaction Methods 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 5
- 239000012981 Hank's balanced salt solution Substances 0.000 description 5
- 108010074870 Histone Demethylases Proteins 0.000 description 5
- 102000008157 Histone Demethylases Human genes 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 108010047956 Nucleosomes Proteins 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 4
- QBKXYSXQKRNVRQ-UHFFFAOYSA-N 4-bromo-3-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC=C1Br QBKXYSXQKRNVRQ-UHFFFAOYSA-N 0.000 description 4
- 101100477411 Dictyostelium discoideum set1 gene Proteins 0.000 description 4
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- 241000699660 Mus musculus Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 4
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- 150000007513 acids Chemical class 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
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- 238000001514 detection method Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 210000001623 nucleosome Anatomy 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 238000007833 oxidative deamination reaction Methods 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 4
- IWPBWVZEOVCZRX-UHFFFAOYSA-N 2-methyl-5-nitroindazole Chemical compound C1=C([N+]([O-])=O)C=CC2=NN(C)C=C21 IWPBWVZEOVCZRX-UHFFFAOYSA-N 0.000 description 3
- VCYPTGRYQJENCG-UHFFFAOYSA-N 4-bromo-3-fluoro-N'-(3-fluoro-4-methoxyphenyl)benzenecarboximidamide Chemical compound BrC1=C(C=C(C=C1)C(NC1=CC(=C(C=C1)OC)F)=N)F VCYPTGRYQJENCG-UHFFFAOYSA-N 0.000 description 3
- LIZZJCZQDJRGQO-UHFFFAOYSA-N 6-cyclopropylpyridin-2-amine Chemical compound NC1=CC=CC(C2CC2)=N1 LIZZJCZQDJRGQO-UHFFFAOYSA-N 0.000 description 3
- AFRBFDCKBJOMFE-UHFFFAOYSA-N 7-fluoro-4-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC=C(F)C2=C1C=NN2 AFRBFDCKBJOMFE-UHFFFAOYSA-N 0.000 description 3
- FOILNJNWYNCDHC-UHFFFAOYSA-N 7-fluoro-5-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC(F)=C2NN=CC2=C1 FOILNJNWYNCDHC-UHFFFAOYSA-N 0.000 description 3
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- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000005840 aryl radicals Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000000423 cell based assay Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
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- 238000005859 coupling reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- SIOIQIWIQSMQAG-UHFFFAOYSA-N ethyl 3-bromo-2-oxobutanoate Chemical compound CCOC(=O)C(=O)C(C)Br SIOIQIWIQSMQAG-UHFFFAOYSA-N 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Enzymes And Modification Thereof (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201462020758P | 2014-07-03 | 2014-07-03 | |
| US62/020,758 | 2014-07-03 | ||
| PCT/US2015/038661 WO2016004105A1 (en) | 2014-07-03 | 2015-06-30 | Inhibitors of lysine specific demethylase-1 |
Publications (1)
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| CA2954060A1 true CA2954060A1 (en) | 2016-01-07 |
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| EA201891526A3 (ru) * | 2014-07-03 | 2019-05-31 | Селджен Квонтисел Рисёрч, Инк. | Ингибиторы лизин-специфической деметилазы-1 |
| JP6525422B2 (ja) * | 2014-07-03 | 2019-06-05 | セルジーン クオンティセル リサーチ，インク． | リジン特異的なデメチラーゼ−１の阻害剤 |
| US20180284095A1 (en) | 2015-06-12 | 2018-10-04 | Oryzon Genomics, S.A. | Biomarkers associated with lsd1 inhibitors and uses thereof |
| WO2017013061A1 (en) | 2015-07-17 | 2017-01-26 | Oryzon Genomics, S.A. | Biomarkers associated with lsd1 inhibitors and uses thereof |
| CA3017411C (en) | 2016-03-15 | 2024-06-25 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for use in the treatment of solid tumors |
| EP3430015B9 (en) | 2016-03-16 | 2025-12-31 | Oryzon Genomics, S.A. | METHODS FOR DETERMINING THE ENGAGEMENT OF A KDM1A TARGET AND CORRESPONDING USEFUL CHEMOPROBE |
| US10150754B2 (en) | 2016-04-19 | 2018-12-11 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
| US20190256930A1 (en) | 2016-11-03 | 2019-08-22 | Oryzon Genomics, S.A. | Biomarkers for determining responsiveness to lsd1 inhibitors |
| AU2018309372B2 (en) | 2017-08-03 | 2024-08-15 | Oryzon Genomics, S.A. | Methods of treating behavior alterations |
| TWI794294B (zh) | 2017-09-13 | 2023-03-01 | 南韓商韓美藥品股份有限公司 | 吡唑衍生化合物及其用途 |
| CN113631164A (zh) | 2019-03-20 | 2021-11-09 | 奥莱松基因组股份有限公司 | 使用kdm1a抑制剂如化合物伐菲德司他治疗注意缺陷多动症的方法 |
| AU2020242302B2 (en) | 2019-03-20 | 2025-10-30 | Oryzon Genomics, S.A. | Methods of treating borderline personality disorder |
| JP2022546908A (ja) | 2019-07-05 | 2022-11-10 | オリゾン・ゲノミクス・ソシエダッド・アノニマ | Ｋｄｍ１ａ阻害剤を使用した小細胞肺がんの個別化された処置のためのバイオマーカーおよび方法 |
| AU2022254484A1 (en) | 2021-04-08 | 2023-11-09 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
| EP4419504A4 (en) * | 2021-10-18 | 2025-09-03 | Imago Biosciences Inc | KDM1A INHIBITORS FOR THE TREATMENT OF DISEASE |
| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
| JP2025516648A (ja) | 2022-05-09 | 2025-05-30 | オリゾン・ゲノミクス・ソシエダッド・アノニマ | Ｌｓｄ１阻害薬を用いるｎｆ１変異腫瘍の治療法 |
| KR20250109775A (ko) | 2022-11-24 | 2025-07-17 | 오리존 지노믹스 에스.에이. | 암 치료를 위한 lsd1 억제제 및 메닌 억제제의 조합 |
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| US5776954A (en) * | 1996-10-30 | 1998-07-07 | Merck & Co., Inc. | Substituted pyridyl pyrroles, compositions containing such compounds and methods of use |
| EP1466902A4 (en) * | 2001-12-28 | 2005-11-09 | Takeda Pharmaceutical | ANTAGONISTS OF THE ANDROGEN RECEPTOR |
| JP4316232B2 (ja) * | 2001-12-28 | 2009-08-19 | 武田薬品工業株式会社 | アンドロゲン受容体拮抗剤 |
| US7026311B2 (en) * | 2002-01-10 | 2006-04-11 | Abbott Gmbh & Co., Kg | Dibenzodiazepine derivatives, their preparation and use |
| NZ538339A (en) * | 2002-08-09 | 2007-01-26 | Astrazeneca Ab | Oxadiazoles as modulators of metabotropic glutamate receptor-5 |
| MXPA05005477A (es) * | 2002-11-21 | 2005-07-25 | Chiron Corp | Pirimidinas 2,4,6-trisustituidas como inhibidores de fosfotidilinositol (pi) 3-cinasa y su uso en el tratamiento del cancer. |
| US7320644B2 (en) * | 2005-02-22 | 2008-01-22 | American Axle & Manufacturing, Inc. | Universal joint with bearing retention device and method |
| US8592465B2 (en) | 2008-06-16 | 2013-11-26 | University Of Tennessee Research Foundation | Compounds for treatment of cancer |
| JP2012102018A (ja) * | 2009-03-03 | 2012-05-31 | Astellas Pharma Inc | アミド化合物 |
| PL2560949T3 (pl) * | 2010-04-20 | 2017-01-31 | Università Degli Studi Di Roma "La Sapienza" | Pochodne tranylocyprominy jako inhibitory demetylazy histonowej LSD1 i/lub LSD2 |
| EP2925307B1 (en) | 2012-11-30 | 2020-10-28 | McCord, Darlene E. | Hydroxytyrosol and oleuropein compositions for induction of dna damage, cell death and lsd1 inhibition |
| EP2969007B1 (en) | 2013-03-14 | 2019-05-08 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
| JP6525422B2 (ja) * | 2014-07-03 | 2019-06-05 | セルジーン クオンティセル リサーチ，インク． | リジン特異的なデメチラーゼ−１の阻害剤 |
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2015
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- 2015-06-30 CN CN201580047272.XA patent/CN106604997B/zh not_active Expired - Fee Related
- 2015-06-30 US US15/323,384 patent/US10414750B2/en active Active
- 2015-06-30 AU AU2015284197A patent/AU2015284197B2/en not_active Ceased
- 2015-06-30 WO PCT/US2015/038661 patent/WO2016004105A1/en not_active Ceased
- 2015-06-30 SG SG11201700007YA patent/SG11201700007YA/en unknown
- 2015-06-30 ES ES15815609T patent/ES2905280T3/es active Active
- 2015-06-30 BR BR112017000042-3A patent/BR112017000042B1/pt not_active IP Right Cessation
- 2015-06-30 MX MX2017000170A patent/MX391865B/es unknown
- 2015-06-30 EP EP15815609.1A patent/EP3164509B1/en not_active Not-in-force
- 2015-06-30 CA CA2954060A patent/CA2954060A1/en not_active Abandoned
- 2015-06-30 EA EA201790082A patent/EA201790082A1/ru unknown
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2016
- 2016-12-30 CL CL2016003423A patent/CL2016003423A1/es unknown
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2017
- 2017-01-01 IL IL249876A patent/IL249876B/en active IP Right Grant
- 2017-01-04 ZA ZA2017/00072A patent/ZA201700072B/en unknown
- 2017-01-16 CO CONC2017/0000363A patent/CO2017000363A2/es unknown
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|---|---|---|
| US10626103B2 (en) | Inhibitor of lysine specific demethylase-1 | |
| US10100046B2 (en) | Inhibitors of lysine specific demethylase-1 | |
| EP3137169B1 (en) | Inhibitors of lysine specific demethylase-1 |
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| Date | Code | Title | Description |
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