TWI753016B - Menin-mll相互作用之稠合二環抑制劑 - Google Patents

Info

Publication number

TWI753016B

TWI753016B TW106131464A TW106131464A TWI753016B TW I753016 B TWI753016 B TW I753016B TW 106131464 A TW106131464 A TW 106131464A TW 106131464 A TW106131464 A TW 106131464A TW I753016 B TWI753016 B TW I753016B

Authority

TW

Taiwan

Prior art keywords

compound

group

mmol

leukemia

alkyl

Prior art date

2016-09-14

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• 239000003112 inhibitor Substances 0.000 title abstract description 8
• 125000002619 bicyclic group Chemical group 0.000 title abstract description 5
• 230000003993 interaction Effects 0.000 title description 15
• 150000001875 compounds Chemical class 0.000 claims abstract description 335
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
• 201000011510 cancer Diseases 0.000 claims abstract description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
• 201000003793 Myelodysplastic syndrome Diseases 0.000 claims abstract description 16
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 7
• 239000000203 mixture Substances 0.000 claims description 141
• 125000000217 alkyl group Chemical group 0.000 claims description 110
• 229910052739 hydrogen Inorganic materials 0.000 claims description 91
• 239000001257 hydrogen Substances 0.000 claims description 90
• 150000003839 salts Chemical class 0.000 claims description 90
• 125000001424 substituent group Chemical group 0.000 claims description 90
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 75
• 238000000034 method Methods 0.000 claims description 64
• -1 isothiazolyl oxazolyl Chemical group 0.000 claims description 38
• 238000011282 treatment Methods 0.000 claims description 38
• 229910052736 halogen Inorganic materials 0.000 claims description 32
• 208000032839 leukemia Diseases 0.000 claims description 32
• 125000001153 fluoro group Chemical group F* 0.000 claims description 31
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 150000002367 halogens Chemical class 0.000 claims description 25
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 23
• 229910052760 oxygen Inorganic materials 0.000 claims description 23
• 125000004076 pyridyl group Chemical group 0.000 claims description 23
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 21
• 229910052717 sulfur Inorganic materials 0.000 claims description 21
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 17
• KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 16
• CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 16
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 16
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 15
• 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 15
• 125000004432 carbon atom Chemical group C* 0.000 claims description 14
• 125000005843 halogen group Chemical group 0.000 claims description 13
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 9
• 125000002883 imidazolyl group Chemical group 0.000 claims description 9
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 8
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
• 230000014509 gene expression Effects 0.000 claims description 7
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
• 206010000830 Acute leukaemia Diseases 0.000 claims description 6
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 6
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 6
• 101150029107 MEIS1 gene Proteins 0.000 claims description 6
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 6
• 201000009277 hairy cell leukemia Diseases 0.000 claims description 6
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
• 208000003747 lymphoid leukemia Diseases 0.000 claims description 6
• 208000025113 myeloid leukemia Diseases 0.000 claims description 6
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
• 101150033506 HOX gene Proteins 0.000 claims description 5
• 101100237041 Homo sapiens MEIS1 gene Proteins 0.000 claims description 5
• 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 5
• 125000003566 oxetanyl group Chemical group 0.000 claims description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
• 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 208000005017 glioblastoma Diseases 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• KPPVNWGJXFMGAM-UUILKARUSA-N (e)-2-methyl-1-(6-methyl-3,4-dihydro-2h-quinolin-1-yl)but-2-en-1-one Chemical compound CC1=CC=C2N(C(=O)C(/C)=C/C)CCCC2=C1 KPPVNWGJXFMGAM-UUILKARUSA-N 0.000 claims description 3
• 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
• 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
• 208000006404 Large Granular Lymphocytic Leukemia Diseases 0.000 claims description 3
• 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 3
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
• 201000008717 T-cell large granular lymphocyte leukemia Diseases 0.000 claims description 3
• 208000024207 chronic leukemia Diseases 0.000 claims description 3
• 150000004677 hydrates Chemical class 0.000 claims description 3
• 201000001441 melanoma Diseases 0.000 claims description 3
• 201000000050 myeloid neoplasm Diseases 0.000 claims description 3
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
• 206010006187 Breast cancer Diseases 0.000 claims 1
• 208000026310 Breast neoplasm Diseases 0.000 claims 1
• 206010009944 Colon cancer Diseases 0.000 claims 1
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
• 210000001744 T-lymphocyte Anatomy 0.000 claims 1
• 208000029742 colonic neoplasm Diseases 0.000 claims 1
• 201000007270 liver cancer Diseases 0.000 claims 1
• 208000014018 liver neoplasm Diseases 0.000 claims 1
• 201000005202 lung cancer Diseases 0.000 claims 1
• 208000020816 lung neoplasm Diseases 0.000 claims 1
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
• 239000003550 marker Substances 0.000 claims 1
• 201000002528 pancreatic cancer Diseases 0.000 claims 1
• 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
• 101001045846 Homo sapiens Histone-lysine N-methyltransferase 2A Proteins 0.000 abstract description 49
• 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 abstract description 48
• 102100030550 Menin Human genes 0.000 abstract description 42
• 101710169972 Menin Proteins 0.000 abstract description 41
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 24
• 201000010099 disease Diseases 0.000 abstract description 20
• 239000008177 pharmaceutical agent Substances 0.000 abstract description 7
• 241000124008 Mammalia Species 0.000 abstract description 6
• 230000006916 protein interaction Effects 0.000 abstract description 5
• 238000011321 prophylaxis Methods 0.000 abstract description 3
• 238000002560 therapeutic procedure Methods 0.000 abstract description 3
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 213
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 190
• 239000000543 intermediate Substances 0.000 description 153
• 238000002360 preparation method Methods 0.000 description 117
• 239000000243 solution Substances 0.000 description 96
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 78
• 239000012071 phase Substances 0.000 description 69
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 65
• 239000012453 solvate Substances 0.000 description 64
• 239000000047 product Substances 0.000 description 61
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 53
• 235000011114 ammonium hydroxide Nutrition 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
• 235000019439 ethyl acetate Nutrition 0.000 description 44
• 239000012044 organic layer Substances 0.000 description 44
• 239000003643 water by type Substances 0.000 description 42
• 230000005526 G1 to G0 transition Effects 0.000 description 41
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 39
• 235000019341 magnesium sulphate Nutrition 0.000 description 39
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• 239000002585 base Substances 0.000 description 36
• 239000005457 ice water Substances 0.000 description 34
• 239000011541 reaction mixture Substances 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• 230000001788 irregular Effects 0.000 description 32
• 238000003756 stirring Methods 0.000 description 30
• 239000012267 brine Substances 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 29
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
• 238000005481 NMR spectroscopy Methods 0.000 description 27
• 229910052757 nitrogen Inorganic materials 0.000 description 27
• 238000000746 purification Methods 0.000 description 27
• 239000007787 solid Substances 0.000 description 27
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
• 239000007858 starting material Substances 0.000 description 26
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
• 239000000377 silicon dioxide Substances 0.000 description 25
• 238000002953 preparative HPLC Methods 0.000 description 24
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
• 239000002904 solvent Substances 0.000 description 23
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
• 238000010898 silica gel chromatography Methods 0.000 description 22
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• 239000001301 oxygen Chemical group 0.000 description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 229910052731 fluorine Inorganic materials 0.000 description 18
• 239000011737 fluorine Substances 0.000 description 18
• 0 *Cc([s]c1nc(*)n2)cc1c2II* Chemical compound *Cc([s]c1nc(*)n2)cc1c2II* 0.000 description 17
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 17
• 238000012360 testing method Methods 0.000 description 17
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• 125000004434 sulfur atom Chemical group 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• 125000004429 atom Chemical group 0.000 description 14
• 229910000027 potassium carbonate Inorganic materials 0.000 description 14
• 230000002265 prevention Effects 0.000 description 14
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• 229910002027 silica gel Inorganic materials 0.000 description 14
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 13
• 239000002253 acid Substances 0.000 description 13
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
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• 150000003840 hydrochlorides Chemical class 0.000 description 11
• 239000002244 precipitate Substances 0.000 description 11
• DZSVALSILXNFGI-UHFFFAOYSA-N 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine Chemical compound N1=CN=C2SC(CC(F)(F)F)=CC2=C1Cl DZSVALSILXNFGI-UHFFFAOYSA-N 0.000 description 10
• 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 10
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• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
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• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
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• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
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