EP3976038A1 - Heterocyclic compounds as prmt5 inhibitors - Google Patents
Heterocyclic compounds as prmt5 inhibitorsInfo
- Publication number
- EP3976038A1 EP3976038A1 EP20814821.3A EP20814821A EP3976038A1 EP 3976038 A1 EP3976038 A1 EP 3976038A1 EP 20814821 A EP20814821 A EP 20814821A EP 3976038 A1 EP3976038 A1 EP 3976038A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- optionally substituted
- compound
- pyrrolo
- quinolin
- ethyl
- 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.)
- Withdrawn
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 4
- 101150097768 prmt5 gene Proteins 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 85
- 101710084427 Protein arginine N-methyltransferase 5 Proteins 0.000 claims abstract description 30
- 102100034607 Protein arginine N-methyltransferase 5 Human genes 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 201000011510 cancer Diseases 0.000 claims abstract description 17
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 231
- -1 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl Chemical group 0.000 claims description 156
- VCVOSERVUCJNPR-UHFFFAOYSA-N cyclopentane-1,2-diol Chemical compound OC1CCCC1O VCVOSERVUCJNPR-UHFFFAOYSA-N 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 229910052731 fluorine Inorganic materials 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000000743 hydrocarbylene group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- UZXKVVXBQRGZOV-NOOVBMIQSA-N N1=CNC2=NC=3C=C(C=CC=3C=C21)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1=CNC2=NC=3C=C(C=CC=3C=C21)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O UZXKVVXBQRGZOV-NOOVBMIQSA-N 0.000 claims description 4
- LDRIAKCJFVBHCQ-PSAKCFHXSA-N N1=NNC2=NC=3C=C(C=CC=3C=C21)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1=NNC2=NC=3C=C(C=CC=3C=C21)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O LDRIAKCJFVBHCQ-PSAKCFHXSA-N 0.000 claims description 4
- UNLQFKFSCBSQMR-ZJQURUERSA-N N1C=CC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1C=CC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O UNLQFKFSCBSQMR-ZJQURUERSA-N 0.000 claims description 4
- ZPPUZQOUZYNMRP-ZJQURUERSA-N N1CCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1CCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O ZPPUZQOUZYNMRP-ZJQURUERSA-N 0.000 claims description 4
- WODPJZDGESQBBY-GLHSZLCASA-N N1CCC=2C1=NC1=CC(=CC=C1C=2)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 Chemical class N1CCC=2C1=NC1=CC(=CC=C1C=2)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 WODPJZDGESQBBY-GLHSZLCASA-N 0.000 claims description 4
- HAVQTSMXOFMEJS-NOOVBMIQSA-N N1N=CC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1N=CC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O HAVQTSMXOFMEJS-NOOVBMIQSA-N 0.000 claims description 4
- QYUHXYKQLUBPRR-JPAWQOSXSA-N N1N=CC=2C1=NC1=CC(=CC=C1C=2)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 Chemical class N1N=CC=2C1=NC1=CC(=CC=C1C=2)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 QYUHXYKQLUBPRR-JPAWQOSXSA-N 0.000 claims description 4
- YRVLRJRZAIDEJU-NOOVBMIQSA-N N1NCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1NCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O YRVLRJRZAIDEJU-NOOVBMIQSA-N 0.000 claims description 4
- ZVITYBOAZGMLFE-NOOVBMIQSA-N N1OCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1OCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O ZVITYBOAZGMLFE-NOOVBMIQSA-N 0.000 claims description 4
- OGZWHTPUKMWXCL-ZJQURUERSA-N N1OCCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N1OCCC=2C1=NC1=CC(=CC=C1C=2)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O OGZWHTPUKMWXCL-ZJQURUERSA-N 0.000 claims description 4
- FKFCLBYITBFCNF-NOOVBMIQSA-N N=1C=CN2C=NC=3C=C(C=CC=3C2=1)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N=1C=CN2C=NC=3C=C(C=CC=3C2=1)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O FKFCLBYITBFCNF-NOOVBMIQSA-N 0.000 claims description 4
- FCLAPPNPMKAIRP-NOOVBMIQSA-N N=1CCN2C=NC=3C=C(C=CC=3C2=1)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O Chemical class N=1CCN2C=NC=3C=C(C=CC=3C2=1)CC[C@@H]1[C@H]([C@H]([C@@H](C1)N1C=CC2=C1N=CN=C2)O)O FCLAPPNPMKAIRP-NOOVBMIQSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- JTZAMAGQUVDCAS-GECPAALWSA-N N1=CN=CC2=C1N(C=C2)[C@@H]1O[C@@H]([C@H]([C@H]1O)O)CCC=1C=CC=2C(=NC=3NCCCC=3C=2)C=1 Chemical class N1=CN=CC2=C1N(C=C2)[C@@H]1O[C@@H]([C@H]([C@H]1O)O)CCC=1C=CC=2C(=NC=3NCCCC=3C=2)C=1 JTZAMAGQUVDCAS-GECPAALWSA-N 0.000 claims description 3
- MZJTZFSKAMUKMJ-JPAWQOSXSA-N N=1C=CN2C=NC=3C=C(C=CC=3C2=1)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 Chemical class N=1C=CN2C=NC=3C=C(C=CC=3C2=1)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 MZJTZFSKAMUKMJ-JPAWQOSXSA-N 0.000 claims description 3
- TVZPCTRFMXFNPF-JPAWQOSXSA-N N=1CCN2C=NC=3C=C(C=CC=3C2=1)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 Chemical class N=1CCN2C=NC=3C=C(C=CC=3C2=1)CC[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=CC2=C1N=CN=C2 TVZPCTRFMXFNPF-JPAWQOSXSA-N 0.000 claims description 3
- HSXABXZICZHUFH-UHFFFAOYSA-N 1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridin-3-ol Chemical class N1CC(CC=2C=C3C(=NC1=2)C=CC=C3)O HSXABXZICZHUFH-UHFFFAOYSA-N 0.000 claims description 2
- ZCTBSFQMEZPPFF-JTQLQIEISA-N N1[C@@H](CC=2C1=NC1=CC=CC=C1C=2)CO Chemical class N1[C@@H](CC=2C1=NC1=CC=CC=C1C=2)CO ZCTBSFQMEZPPFF-JTQLQIEISA-N 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 142
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 126
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 110
- 239000000203 mixture Substances 0.000 description 105
- 239000000243 solution Substances 0.000 description 92
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 229910001868 water Inorganic materials 0.000 description 66
- 239000000543 intermediate Substances 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- 238000001914 filtration Methods 0.000 description 54
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- 239000000706 filtrate Substances 0.000 description 51
- 239000012267 brine Substances 0.000 description 49
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- 238000010898 silica gel chromatography Methods 0.000 description 39
- 239000011734 sodium Substances 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- 239000012300 argon atmosphere Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 239000000284 extract Substances 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 125000004093 cyano group Chemical group *C#N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 13
- 125000000304 alkynyl group Chemical group 0.000 description 13
- 125000000753 cycloalkyl group Chemical group 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 5
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- SSYDTHANSGMJTP-UHFFFAOYSA-N oxolane-3,4-diol Chemical compound OC1COCC1O SSYDTHANSGMJTP-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- QCHAVHXSBZARBO-UHFFFAOYSA-N (r)-monophos Chemical compound C1=CC2=CC=CC=C2C2=C1OP(N(C)C)OC1=C2C2=CC=CC=C2C=C1 QCHAVHXSBZARBO-UHFFFAOYSA-N 0.000 description 4
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 3
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
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- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 125000005423 trihalomethanesulfonamido group Chemical group 0.000 description 1
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001086 yeast two-hybrid system Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/14—Pyrrolo-pyrimidine radicals
Definitions
- the present disclosure relates to heterocyclic compounds, such as (1 R,2S,3R,5S)-3-(4- amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2-(2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)- cyclopentane-1 ,2-diol (1-7), as PRMT5 inhibitors, and pharmaceutical compositions comprising such compounds.
- the present disclosure also relates to the use of the compounds and compositions to treat cancer, infectious diseases, and other disorders.
- PRMT5 Protein arginine N-methyltransferase 5
- Skb1 Schizosaccharomyces pombe
- Hsl7 Sacharomyces cerevisiae
- PRMT5 catalyzes the transfer of methyl group from the essential co-factor S-adenosylmethionine to methylate the arginine N-guanidine group of various proteins.
- Substrate proteins for PRMT5 include histones, transcriptional elongation factors, kinases, and tumor suppressors, for example, histone H4, histone H3, and non-histone proteins such as FGF-216, NF-kB17, HOXA918, and p53.
- PRMT5 is involved in the transcriptional repression of a number of tumor suppressor genes including suppressor of tumorigenicity 7 (ST7), nonmetastatic 23 (NM23), retinoblastoma (Rb) family, and programmed cell death 4 (PDCD4).
- ST7 suppressor of tumorigenicity 7
- NM23 nonmetastatic 23
- Rb retinoblastoma
- PDCD4 programmed cell death 4
- PRMT5 has recently emerged as a promising drug target due to its frequent overexpression in a variety of malignancies including glioma, lung cancer, melanoma, mantle cell lymphoma, multiple endocrine neoplasia, prostate and gastric cancer, as well as its synthetic lethal relationship with methylthioadenosine phosphorylase (MTAP).
- MTAP methylthioadenosine phosphorylase
- PRMT5 localization differs between normal and tumor tissues and l between tumor subtypes. This is indicative that its compartment-specific functions likely regulate distinct molecular programs and are therefore associated with diverse phenotypic outcomes.
- the identification and development of small-molecules that inhibit PRMT5 activity will serve as therapeutic approach for the treatment of a variety of PRMT5-related diseases or disorders, such as cancer.
- This disclosure relates to heterocyclic compounds comprising at least three ring systems, such as a compound of Formula 1 , certain optionally substituted (1 S,2R,3S,5R)-3-(2- (2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(2,3-dihydroimidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(imidazo[1 ,2-c]quinazolin-8-yl)eth
- Some embodiments include a compound represented by Formula 1 :
- (Rinqg A)) is an optionally substituted 4-amino-7F/-pyrrolo[2,3-d]pyrimidin-7-yl ;
- (Ring B) is an optionally substituted fused tricyclic heterocyclic ring system containing 1 , 2, 3, 4, or 5 ring N atoms, 0 or 1 ring 0 atom, and a fused benzene ring, wherein the fused benzene ring is directly attached to L;
- X is - 0-, -CH2-, or -CF2-;
- L is optionally substituted Ci-3 hydrocarbylene, optionally substituted -O-C1-2 hydrocarbylene-, optionally substituted -S-C1-2 hydrocarbylene-, or optionally substituted -NR A - C1-2 hydrocarbylene; and
- R A is H, Ci- 6 hydrocarbyl, C1-6 heteroaryl, C1-6 heterocycloalkyl, -C(O)- C1-6 alkyl,
- Some embodiments include use of a compound described herein, such as a subject compound in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other PRMT5 related disorders.
- a pharmaceutical composition comprising a therapeutically effective amount of a subject compound in combination with at least one pharmaceutically acceptable carrier.
- Some embodiments include a process for making a pharmaceutical composition comprising combining a subject compound and at least one pharmaceutically acceptable carrier.
- Some embodiments include a method of treating cancer, infectious diseases, and other PRMT5 related disorders comprising administering a subject compound to a patient in need thereof.
- Some embodiments include use of a subject compound in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other PRMT5 related disorders.
- kits containing a subject compound and a label with instructions to use the subject compound, or a composition or dosage form containing the subject compound, for the treatment of cancer, infectious diseases, and other PRMT5 related disorders.
- any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
- pharmaceutically acceptable salts such as sodium, potassium, and ammonium salts
- prodrugs such as ester prodrugs
- tautomers or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
- a compound of Formula 1 is a single enantiomer.
- a subject compound described herein contains one or more deuterium.
- a compound or chemical structural feature such as aryl when referred to as being“optionally substituted”, it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is“substituted”, meaning that the feature has one or more substituents.
- the term“substituent” is broad, and includes a moiety that occupies a position normally occupied by one or more hydrogen atoms attached to a parent compound or structural feature.
- a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g.
- a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0- 10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, Cl, Br, or I atom and N, S and P can be optionally oxidized.
- substituents include, but are not limited to, deuterium, tritium, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanes
- moiety or part of a molecule indicates the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.
- Ring A and Ring B The structures associated with some of the chemical names referred to herein, such as Ring A and Ring B, are depicted below. These structures may be unsubstituted, as shown below, or substituted with a substituent that may independently be in any position normally occupied by a hydrogen atom when the structure is unsubstituted. Unless a point of attachment is indicated by i , attachment may occur at any position normally occupied by a hydrogen atom.
- Ring A of Formula 1 comprises:
- each R is independently H, F, Cl, Br, I, -NR A R B , Ci-e hydrocarbyl, -OH, -CN, or -O-Ci-e alkyl; and wherein each R A and each R B are independently H, Ci-e hydrocarbyl, Ci -e heteroaryl, Ci - 6 heterocycloalkyl, -C(0)-Ci-e alkyl, -C(0)NH-CI- 6 alkyl, or -C(0)0Ci-e alkyl.
- Ring A is an optionally substituted 4-amino-7F/-pyrrolo[2,3-d]pyrimidin-7-yl.
- any or each of the substituents of Ring A may have a molecular weight of at least 15 g/mol, and up to: 50 g/mol, 60 g/mol, 70 g/mol, 80 g/mol, 90 g/mol, 100 g/mol, or 300 g/mol.
- Ring A may include -OH; -CN; halo, such as F, Cl, Br, I; hydrocarbyl, such as methyl, C 2 alkyl, C 2 alkenyl, C 2 alkynyl, C 3 alkyl, C 3 cycloalkyl, C 3 alkenyl, C 3 alkynyl, C 4 alkyl, C 4 cycloalkyl, C 4 alkenyl, C 4 alkynyl, C 5 alkyl, C 5 cycloalkyl, C 5 alkenyl, C 5 alkynyl, C 6 alkyl, C 6 cycloalkyl, Ce alkenyl, Ce alkynyl, phenyl, etc.; CN0-1O0-2F0-3H0-4; C2N0-1O0-3F0-5H0-6; C3N0-1O0-3F0- 7 HO- 8 ; C4N0-1O0-3F0-9H0-10; C5N0-1O
- Ring A is optionally substituted 4-amino-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl having 1 , 2, or 3 substituents, such as 4-amino-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl substituted with F, Cl, Br, Ci-e alkyl, -CO 2 H, , -CN, -CO-Ci-e-alkyl, -C(0)0-Ci- 6 -alkyl, C 1-6 alkyl-OH, OH, NH 2 , etc..
- Ring A is unsubstituted 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl.
- Ring A1 is represented by Formula A1 :
- R 1 is H or any substituent, such as R A , F, Cl, -CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc., wherein R A and R B are each H, Ci- 6 hydrocarbyl, Ci - 6 heteroaryl, Ci - 6 heterocycloalkyl, -C(0)-Ci- 6 alkyl, -C(0)NH-CI-6 alkyl, or -C(0)0Ci-s alkyl.
- R 1 may be H; F; Cl; -CN; CF 3 ; OH; NH 2 ; Ci-s alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n- propyl and isopropyl), cyclopropyl, any one of the butyl isomers, any one of the cyclobutyl isomers (e.g.
- R 1 may be H, F, Cl, or NH 2 .
- R 1 may be H, F, Cl, or NH 2 .
- each R A1 may independently be H, or C1-12 hydrocarbyl, such as C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C a H2 a+i , or cycloalkyl having a formula C a H2 a -i , wherein a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, such as linear or branched alkyl with a formula: CH 3 , C2H5, C3H7, C4H9, C5H11 , OdH , C7H15, CSH I , C9H 19, C10H21 , etc., or cycloalkyl with a formula: C 3 H 5 , C4H7, C5H9, CeHn , C7HI 3 , C 3 Hi5, C9H 17, C10H 19, etc.
- R A1 may be H or C1-6 alkyl. In some embodiments, R A1 may be H or Ci- 3 alkyl. In some embodiments, R A1 may be H or CH 3 . In some embodiments, R A1 may be H.
- each R B1 may independently be H, or C1-12 hydrocarbyl, such as C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C a H2 a+i , or cycloalkyl having a formula C a H2 a -i , wherein a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, such as linear or branched alkyl with a formula: CH 3 , C2H5, C 3 H 7 , C4H9, C5H11 , OdHi 3 , C7H15, CeH ⁇ , C9H 19, C10H21 , etc., or cycloalkyl with a formula: C 3 H 5 , C4H7, C5H9, CeHn , C7HI 3 , CsHis, C9H 17, C10H 19, etc.
- R 2 is H or any substituent, such as R A , F, Cl, -CN, -OR A , CF 3 , -NO2, -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
- R 2 may be H, F, Cl, CN, CF 3 , OH, NH2, C1-6 alkyl, or Ci-e alkoxy.
- R 2 may be H, F, Cl, or NH2.
- R 2 may be H.
- R 3 is H or any substituent, such as R A , F, Cl, -CN, -OR A , CF 3 , -NO2, -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
- R 3 may be H, F, Cl, -CN, CF 3 , OH, NH 2 ,
- R 3 may be H, F, Cl, or NH . In some embodiments, R 3 may be H. [028] With respect to any relevant structural representation, such as Formula A1 , in some embodiments, both R A and R B are H. In some embodiments, R 1 , R 2 , and R 3 are all H. In some embodiments, R A , R B , R 1 , R 2 , and R 3 are all H.
- Ring B is an optionally substituted fused tricyclic heterocyclic ring system containing 1 , 2, 3, 4, or 5 ring N atoms, 0 or 1 ring 0 atom, and a fused benzene ring, wherein the fused benzene ring is directly attached to L.
- any or each of the substituents of Ring B may have a molecular weight of 15 g/mol to 50 g/mol, 50 g/mol to 100 g/mol, 50 g/mol to 75 g/mol, 75 g/mol to 100 g/mol, or 100 g/mol to 300 g/mol.
- Ring B may include halo, such as F, Cl, Br, or I; hydrocarbyl, such as methyl, C2 alkyl, C2 alkenyl, C2 alkynyl, C3 alkyl, C3 cycloalkyl, C3 alkenyl, C3 alkynyl, C4 alkyl, C4 cycloalkyl, C4 alkenyl, C4 alkynyl, C5 alkyl, C5 cycloalkyl, C5 alkenyl, C5 alkynyl, Ce alkyl, Ce cycloalkyl, Ce alkenyl, Ce alkynyl, or phenyl, etc.; CN0-1O0-2F0-3H0-4; C2 N 0- 10o-3 FO-5 H 0-6 i C3N0-1O0-3F0-7H0-8; C4N0-1O0-3F0-9H0-I0; C5N0-1O0-3F0-H Ho-12;
- Ring B is optionally substituted 2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8- yl, optionally substituted 1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 H-pyrazolo[3,4- b]quinolin-7-yl, optionally substituted 3H-imidazo[4,5-b]quinolin-6-yl, optionally substituted 3H- [1 ,2,3]triazolo[4,5-b]quinolin-6-yl, optionally substituted 2,3-dihydroimidazo[1 ,2-c]quinazolin-8- yl, optionally substituted imidazo[1 ,2-c]quinazolin-8-yl, optionally substituted (1aS,7bR)-1a
- Ring B is optionally substituted 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl having 0, 1 , 2, or 3, 4, 5, 6, 7, 8, or 9 substituents, such as 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl substituted with F, Cl, Br, C1-6 alkyl, -CO2H, -CN, -CO-Ci- 6 -alkyl, -C(0)0-Ci- 6 -alkyl, -C1-6 alkyl- OH, OH, NH2, etc.
- Ring B is 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl having 2 substituents. In some embodiments, Ring B is 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7- yl having 1 substituent. In some embodiments, Ring B is unsubstituted 2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl. In some embodiments, Ring B is 2,3-dihydro-1 H-pyrrolo[2,3- b]quinolin-7-yl having 2 substituents that are both methyl groups.
- Ring B is 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl having 2 substituents at a same ring carbon atom that are two methylene groups linked together and together with the ring carbon atom to which they are attached to form a spiro cyclopropyl.
- Ring B is 2,3-dihydro-1 H-pyrrolo[2,3- b]quinolin-7-yl having 1 substituent that is methyl.
- Ring B is optionally substituted 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 0, 1 , 2, or 3, 4, 5, 6, 7, 8, 9, 10, or 1 1 substituents, such as 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl substituted with F, Cl, Br, Ci- 6 alkyl, -C0 2 H, -CN, -CO-Ci- 6 -alkyl, -C(0)0-Ci- 6 -alkyl, -Ci- 6 alkyl-OH, OH, NH 2 , etc.
- Ring B is 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 2 substituents. In some embodiments, Ring B is 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent. In some embodiments, Ring B is unsubstituted 1 , 2,3,4- tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
- Ring B is 1 , 2,3,4- tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent that is methyl or cyclopropyl. In some embodiments, Ring B is 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent that is methyl. In some embodiments, Ring B is 1 ,2,3,4- tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent that is cyclopropyl.
- Ring B is 3,4-dihydro-1 H-[1 ,2]oxazino[3,4-b]quinolin-8-yl. In some embodiments, Ring B is 1 ,3-dihydroisoxazolo[3,4-b]quinolin-7-yl. In some embodiments, Ring B is 3H- imidazo[4,5-b]quinolin-6-yl. In some embodiments, Ring B is 2,3,4,5-tetrahydro-1 H-azepino[2,3- b]quinolin-9-yl.
- Ring B is:
- each structure is optionally substituted;
- G is N or CR; the dashed line represents optionally with or without a bond;
- Y is -N(R A )-, N, C(R C ), -C(R C R D )-, or -C(R c R D )-C(R c R D )-;
- Z is a bond, -N(R A )-, N, C(R C ), or -C(R c R D )-;
- Ring B is represented by Formula 2 or 3:
- W and Z are linked by a single bond.
- Y and Z are linked by a double bond.
- WZ is -CH2-CH2-.
- WZ is - OCH2-,
- R 4 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
- R 4 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci- 6 alkyl, or Ci-e alkoxy.
- R 4 may be H, F, or Cl.
- R 4 may be H.
- R 5 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
- R 5 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci-e alkyl, or Ci-e alkoxy.
- R 5 may be H, F, or Cl.
- R 5 may be H.
- R 6 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
- R 6 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci-e alkyl, or Ci-e alkoxy.
- R 6 may be H, F, or Cl.
- R 6 may be H.
- R 7 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
- R 7 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci-e alkyl, or Ci-e alkoxy.
- R 7 may be H, F, or Cl.
- R 7 may be H.
- R A1 is H or Ci-i 2 hydrocarbyl.
- R A1 may be H or Ci-e alkyl.
- R A1 may be H or Ci- 3 alkyl.
- R A1 may be H or CH 3 .
- R A1 may be H.
- Z is a bond, -N(R A )-, or -C(R c R D )-. In some embodiments, Z is -C(R c R D )-. In some embodiments, Z is -N(R A )-. In some embodiments, Z is -N-. In some embodiments, Z is -CH 2 -. In some embodiments, Z is CH. In some embodiments, Z is a bond.
- W is a bond, -N(R A )-, N, -0-, C(R C ), or -C(R C R D )-.
- W is -C(R C R D )-.
- W is -N(R A )-.
- W is N.
- W is C(R C ).
- W is -CH-.
- W is CH 2 .
- W is a bond.
- W is -0-.
- G is N or CR. In some embodiments, G is N. In some embodiments, G is CR. In some embodiments, G is CH.
- both W and Z are a bond, and G is CH.
- X is -0-, -CH 2 - , or -CF 2 -. In some embodiments, X is -CF 2 -. In some embodiments, X is -0-. In some embodiments, X is -CH 2 -.
- L is C 1-3 hydrocarbylene.
- L is -0-Ci- 2 hydrocarbylene-.
- L is -S-Ci- 2 hydrocarbylene-. In some embodiments, L is -NR A -CI- 2 hydrocarbylene-. In some embodiments, L is -CH 2 -CH 2 -CH 2 -. In some embodiments, L is -CH 2 - CH 2 -.
- Some embodiments include a compound represented by Formula 4 or 5 below:
- Formula 4 and 5 may be unsubstituted as shown, or the 4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl may have 1 , 2, or 3 substituents, such as those described elsewhere herein, or may be substituted at any position, such as those described elsewhere herein.
- Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(2,3- dihydroimidazo[1 ,2-c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2- diol.
- Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(imidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-((1aS,7bR)-1a,7b- dihydro-1 H-cyclopropa[c]quinolin-5-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane- 1 ,2-diol.
- Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-((1aR,7bS)-1a,7b- dihydro-1 H-cyclopropa[c]quinolin-5-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane- 1 ,2-diol.
- Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(1 H-pyrazolo[3,4- b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.
- Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(2,3- dihydroimidazo[1 ,2-c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-
- Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(imidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.
- Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(1 H-pyrrolo[2,3- b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(3,4-dihydro-1 H- [1 ,2]oxazino[3,4-b]quinolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(1 ,3- dihydroisoxazolo[3,4-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2- diol.
- Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,3,4,5-tetrahydro-[1 ,2]oxazepino[3,4-b]quinolin-9-yl)ethyl)cyclopentane- 1 ,2-diol.
- Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(3H-imidazo[4,5- b]quinolin-6-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(3H- [1 ,2,3]triazolo[4,5-b]quinolin-6-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(2,3-dihydro-1 H- pyrazolo[3,4-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
- Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl)ethyl)cyclopentane-1 ,2- diol.
- Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(2,3,4,5-tetrahydro-1 H-azepino[2,3-b]quinolin-9-yl)ethyl)cyclopentane-1 ,2- diol.
- Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(1 H-pyrazolo[3,4- b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.
- Some embodiments include optionally substituted (2R,3R,4S,5R)-2-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl)ethyl)tetrahydrofuran-
- Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,2,3,4-tetrahydropyridazino[3,4-b]quinolin-8-yl)ethyl)cyclopentane-1 ,2- diol.
- Some embodiments include one of the compounds listed in Table 1 below, wherein each structure can be optionally substituted.
- Some embodiments include one of the compounds listed in Table 1a below, wherein each structure can be optionally substituted.
- Some embodiments include use of a subject compound in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other PRMT5 related disorders.
- a pharmaceutical composition comprising a subject compound may be adapted for oral, or parental, such as intravenous, intramuscular, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder.
- the dosage of a subject compound may vary depending on the route of administration, body weight, age, the type and condition of the disease being treated.
- a pharmaceutical composition provided herein may optionally comprise two or more subject compounds without an additional therapeutic agent, or may comprise an additional therapeutic agent (i.e., a therapeutic agent other than a compound provided herein).
- the compounds of the disclosure can be used in combination with at least one other therapeutic agent.
- Therapeutic agents include, but are not limited to antibiotics, antiemetic agents, antidepressants, and antifungal agents, anti-inflammatory agents, antiviral agents, and anticancer agents that are known in the art.
- the pharmaceutical composition may be used for the treatment of cancer, and other PRMT5-related diseases or disorders in patients.
- patient herein means a mammal (e.g., a human or an animal). In some embodiments, the patient has cancer.
- the pharmaceutical composition described herein can be prepared by combining a compound of Formula 1 with at least one pharmaceutical acceptable inert ingredient, such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc., selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety.
- a pharmaceutical acceptable inert ingredient such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc.
- the relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.
- Some embodiments include a method of treating a disease or disorder associated with PRMT5 comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutical composition comprising a compound of Formula 1 to a patient in need thereof.
- a therapeutically effective amount herein refers to an amount of a compound or a pharmaceutical composition of the present disclosure provided herein sufficient to be effective in inhibiting PRMT5 enzyme and thus providing a benefit in the treatment of cancer, infectious diseases and other PRMT5 associated disorders, to delay or minimize symptoms associated with cancer, infectious diseases and other PRMT5 associated disorders, or to ameliorate a disease or infection or cause thereof (e.g. 0.1-1000 mg).
- treatment refers to causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying causes of symptoms, postponing, preventing the further development of a disorder, or reducing the severity of symptoms that are otherwise expected to develop without treatment.
- Embodiment 1 A compound represented by a formula:
- (Ring A) is an optionally substituted 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl
- (Ring B) is an optionally substituted fused tricyclic heterocyclic ring system containing 1 , 2, 3, 4, or 5 ring N atoms, 0 or 1 ring 0 atom, and a fused benzene ring, wherein the fused benzene ring is directly attached to L;
- X is -0-, -CH 2 -, or -CF 2 -;
- L is optionally substituted C 1.3 hydrocarbylene, optionally substituted -0-Ci- 2 hydrocarbylene-, optionally substituted -S-Ci- 2 hydrocarbylene-, or optionally substituted -NR A -C I-2 hydrocarbylene-;
- R A is H, C hydrocarbyl, Ci-e heteroaryl, Ci-e heterocycloalkyl, -C(0)-Ci- 6 alkyl, -C(0)NH-CI- 6 alkyl, or -C(0)0Ci- 6 alkyl.
- Embodiment 2 The compound of embodiment 1 , wherein Ring A comprises:
- Ring B comprises: wherein each structure is optionally substituted
- G is N or CR
- Y is -N(R A )-, N, C(R c ), or -C(R c R D )-, or -C(R c R D )-C(R c R D )-;
- Z is a bond, -N(R A )-, N, C(R C ), or -C(R c R D )-;
- W is a bond, -N(R A )-, N, -0-, C(R C ), or -C(R C R D )-;
- dashed line represents optionally with or without a bond
- each R A and each R B are independently H, C1-6 hydrocarbyl, C1-6 heteroaryl, C1-6 heterocycloalkyl, -C(0)-Ci- 6 alkyl, -C(0)NH-Ci-e alkyl, or -C(0)0Ci-e alkyl; and wherein each R, each R A , each R B , each R c , and each R D are independently optionally halogenated.
- Embodiment 3 The compound of embodiment 1 or 2, wherein Ring A comprises unsubstituted 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl.
- Embodiment 4 The compound of embodiment 1 , 2, or 3, wherein the optionally substituted fused tricyclic heterocyclic ring system of Ring B is an optionally substituted fused tricyclic heteroaromatic ring system.
- Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains one ring N atom.
- Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains two ring N atoms.
- Embodiment 7. The compound of embodiment 1 , 2, or 3, wherein Ring B contains three ring N atoms.
- Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains four ring N atoms.
- Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains one ring 0 atom.
- Embodiment 10 The compound of embodiment 1 , 2, or 3, wherein Ring B is optionally substituted 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 3,3-dimethyl-2,3- dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 H-pyrazolo[3,4-b]quinolin-7-yl, optionally substituted 5-amino-2,3- dihydroimidazo[1 ,2-c]quinazolin-8-yl, optionally substituted 5-aminoimidazo[1 ,2-c]quinazolin-8-yl, optionally substituted (1aS,7bR)-2-amino-1 a,7b-dihydro-1 H-cyclopropa[c]quinolin-5-yl, optionally substituted (1aR,7b
- Embodiment 12 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 13 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 14 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 1 H-pyrazolo[3,4-b]quinolin-7-yl.
- Embodiment 15 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 5-amino-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-yl.
- Embodiment 16 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 5-aminoimidazo[1 ,2-c]quinazolin-8-yl.
- Embodiment 17 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (1 aS,7bR)-2-amino-1a,7b-dihydro-1 H-cyclopropa[c]quinolin-5-yl.
- Embodiment 18 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (1 aR,7bS)-2-amino-1a,7b-dihydro-1 H-cyclopropa[c]quinolin-5-yl.
- Embodiment 19 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 3,4-dihydro-1 H-[1 ,2]oxazino[3,4-b]quinolin-8-yl.
- Embodiment 20 The compound of embodiment 1 , 2, or 3, wherein Ring comprises optionally substituted 1 ,3-dihydroisoxazolo[3,4-b]quinolin-7-yl.
- Embodiment 21 The compound of embodiment 1 , 2, or 3, wherein Ring comprises optionally substituted (R)-3-methyl-3,4-dihydro-1 H-[1 ,2]oxazino[3,4-b]quinolin-8-yl
- Embodiment 22 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 3H-imidazo[4,5-b]quinolin-6-yl.
- Embodiment 23 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 24 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 25 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-cyclopropyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 26 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-cyclopropyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 27 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-ethyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 28 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-isopropyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 29 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-(tert-butyl)-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 30 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-allyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 31 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 2,2-dimethyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
- Embodiment 32 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted T,3'-dihydrospiro[cyclopropane-1 ,2'-pyrrolo[2,3-b]quinolin]-7'-yl.
- Embodiment 33 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
- Embodiment 34 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-methyl-1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
- Embodiment 35 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-methyl-1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
- Embodiment 36 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-cyclopropyl-1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
- Embodiment 37 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 2,3,4, 5- tetra hydro- 1 H-azepino[2,3-b]quinolin-9-yl.
- Embodiment 38 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 37, wherein X is -CH 2 -.
- Embodiment 39 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 37, wherein X is -0-.
- Embodiment 40 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 37, wherein X is -CF 2 -.
- Embodiment 41 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -CH2-CH2-.
- Embodiment 42 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -CH2-CH2-CH2-
- Embodiment 43 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -CH2O-.
- Embodiment 44 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -O-CH2-.
- Embodiment 45 A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted (1S,2R,3S,5R)-3-(2-(2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7- yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(2,3-dihydroimidazo[1 ,2-c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(imidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(
- Embodiment 46 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
- Embodiment 47 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
- Embodiment 48 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
- Embodiment 49 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, or 28, wherein each substituent, if present, of Ring A, Ring B, and L, has a molecular weight of 15 mg/ml_ to 200 mg/mL.
- Embodiment 50 A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:
- Embodiment 51 A method of treating cancer, infectious diseases, and other PRMT5- related diseases or disorders comprising administering a compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
- Embodiment 52 Use of a compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other PRMT5-related diseases or disorders.
- Embodiment 53 A pharmaceutical composition comprising a therapeutically effective amount of a compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.
- the compounds of the disclosure can be made using procedures known in the art.
- the following reaction schemes show typical procedures, but those skilled in the art will recognize that other procedures can also be suitable for using to prepare these compounds.
- For examples in Formula 1-3 and A1 wherein there is a substituent at any position of any of the structures, those skilled in the art will recognize that changes to the requisite reagents can be made at the appropriate steps in the synthetic methods outlined below.
- Reactions may involve monitoring for consumption of starting materials, and there are many methods for the monitoring, including but not limited to thin layer chromatography (TLC) and liquid chromatography mass spectrometry (LCMS).
- TLC thin layer chromatography
- LCMS liquid chromatography mass spectrometry
- mefa-chloroperoxybenzoic acid m-CPBA (or mCPBA)
- DIPEA Diisopropylethylamine
- DIEA Diisopropylethylamine
- iP ⁇ Net Diisopropylethylamine
- Lithium hexamethyldisilazide LiHMDS Methansulfonyl chloride: MeSC>2CI
- Triethylamine Et 3 N or TEA
- Trifluoroacetic acid TFA Trifluoromethanesulfonic anhydride: Tf20
- Analytical thin layer chromatography was performed on glass plates pre-coated with silica gel 60 F254 0.25 mm plates (EM Science), and visualized with UV light (254 nm) and/ or heating with commercial ethanolic phosphomolybdic acid preparative thin layer chromatography (TLC) was performed on glass-plates pre-coated with silica gel 60 F254 0.5 mm plates (20 x 20 cm, from commercial sources) and visualized with UV light (254 nm).
- NMR spectra and 13 C-NMR were recorded on a Varian Mercury- VX400 instrument operating at 400 MHZ.
- NMR spectra were obtained as CDCh solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm for the proton and 77.00 ppm for carbon), CD3OD (3.4 and 4.8 ppm for the protons and 49.3 ppm for carbon), DMSO-d 6 (2.49 ppm for proton), or internally tetramethylsilane (0.00 ppm) when appropriate.
- Other NMR solvents were used as needed.
- Step 1 Synthesis of (3aR,6R,6aR)-2,2-dimethyl-6-vinyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4- one
- step 6 compound 2-1 was prepared from compound 1-5 using intermediate 15 as the coupling partner.
- LC-MS: m/e 619 [M+H] + .
- step 7 compound 2-3 was prepared from compound 2-2.
- LC-MS : m/e 459 [M+H] + .
- Step 5 [102] To a solution of 33.1 g (92.7 mmol) of bromo(methyl)triphenyl-lambda5-phosphane in 200 mL of THF was added 85 ml. (85.0 mmol) of 1 M t-BuOK solution in THF. Then the mixture was stirred at O °C for 1 h, a solution of 10.0 g (30.9 mmol) of compound 3-4 in 10 mL of THF was introduced. The mixture was stirred at 0 °C for additional 1 h and then quenched by addition of 300 mL of saturated NH CI solution.
- step 3 compound 33 was converted to intermediate rac-34.
- LC-MS: m/e 279 [M+H] + .
- step 1 compound 35 was prepared from m-bromoaniline similarly.
- LC-MS: m/e 290 [M+H] + .
- step 2 compound 36 was prepared from compound 35 similarly.
- LC-MS: m/e 417 [M+FI] + .
- step 3 compound 37 was prepared from compound 36 similarly.
- LC-MS: m/e 445 [M+H] + .
- step 1 step 2
- Step 3 [186] To a stirred solution of 490 mg (1.63 mmol) of compound 84 in 10 mL of ethyl alcohol were added 326 mg (6.52 mmol) of hydrazine hydrate dropwise at RT. The mixture was stirred at 60 °C overnight under nitrogen atmosphere. The mixture was filtered; the filter cake was washed with three 20 mL portions of EtOH and dried to give intermediate 85.
- LC-MS: m/e 264 [M+H] + .
- Step 1 [191] Following the procedure described in Scheme 15, step 2, compound 90 was prepared from 5-aminovaleric acid and phthalic anhydride.
- LC-MS: m/e 248 [M+H] + .
- step 3 compound 91 was prepared from compound 90.
- LC-MS: m/e 401 [M+H] + .
- step 2 compound 92 was prepared from compound 91.
- LC-MS: m/e 429 [M+H] + .
- step 3 intermediate 93 was prepared from compound 92.
- LC-MS: m/e 263 [M+H] + .
- step 1 compound 94 was prepared from compound 6-methylpiperidin-2-one.
- LC-MS: m/e 132 [M+H] + .
- step 3 compound 96 was prepared from compound 95.
- LC-MS: m/e 415 [M+H] + .
- step 3 compound 97 was prepared from compound 96.
- LC-MS: m/e 443 [M+H] + .
- step 1 compound 99 was prepared from delta-valerolactone and m-bromoaniline.
- LC-MS: m/e 272 [M+H] + .
- Step 3 [202] Following the procedure described in Scheme 16, step 3, compound 101 was prepared from compound 100.
- LC-MS: m/e 373 [M+H] + .
- step 5 compound 103 was prepared from compound 102.
- LC-MS: m/e 311 [M+FI] + .
- step 2 compound 104 was prepared from compound 103.
- LC-MS: m/e 441 [M+FI] + .
- step 3 compound 105 was prepared from compound 104.
- LC-MS: m/e 469 [M+FI] + .
- step 4 intermediate 106 was prepared from compound 105.
- LC-MS: m/e 303 [M+H] + .
- step 2 compound 112 was prepared from aminocaproic acid and phthalic anhydride.
- LC-MS: m/e 262 [M+H] + .
- step 3 compound 113 was prepared from compound 112.
- LC-MS: m/e 463 [M+FI] + .
- step 3 compound 114 was prepared from compound 113.
- LC-MS: m/e 491 [M+FI] + .
- step 3 compound 115 was treated with hydrazine in butanol to give compound 114.
- LC-MS: m/e 361 [M+H] + .
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Abstract
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US201962854435P | 2019-05-30 | 2019-05-30 | |
US202062966337P | 2020-01-27 | 2020-01-27 | |
PCT/US2020/034711 WO2020243178A1 (en) | 2019-05-30 | 2020-05-27 | Heterocyclic compounds as prmt5 inhibitors |
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JP (1) | JP2022534998A (en) |
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CN (1) | CN114126614A (en) |
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CA2969295A1 (en) * | 2016-06-06 | 2017-12-06 | Pfizer Inc. | Substituted carbonucleoside derivatives, and use thereof as a prmt5 inhibitor |
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- 2020-05-27 AU AU2020283505A patent/AU2020283505A1/en not_active Abandoned
- 2020-05-27 WO PCT/US2020/034711 patent/WO2020243178A1/en unknown
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CA3141855A1 (en) | 2020-12-03 |
EP3976038A4 (en) | 2023-07-12 |
AU2020283505A1 (en) | 2021-12-23 |
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