US20230219938A1 - Compounds and their methods of use - Google Patents
Compounds and their methods of use Download PDFInfo
- Publication number
- US20230219938A1 US20230219938A1 US17/959,799 US202217959799A US2023219938A1 US 20230219938 A1 US20230219938 A1 US 20230219938A1 US 202217959799 A US202217959799 A US 202217959799A US 2023219938 A1 US2023219938 A1 US 2023219938A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- mmol
- compound
- heterocyclyl
- carbocyclyl
- 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.)
- Pending
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- 238000000034 method Methods 0.000 title claims abstract description 108
- 150000001875 compounds Chemical class 0.000 title claims description 201
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 198
- 125000000217 alkyl group Chemical group 0.000 claims description 453
- 125000000623 heterocyclic group Chemical group 0.000 claims description 285
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 262
- 125000003118 aryl group Chemical group 0.000 claims description 189
- 229910052739 hydrogen Inorganic materials 0.000 claims description 138
- 239000001257 hydrogen Substances 0.000 claims description 138
- 125000005843 halogen group Chemical group 0.000 claims description 136
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 94
- 150000003839 salts Chemical class 0.000 claims description 82
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 81
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 80
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 45
- 229910052805 deuterium Inorganic materials 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 125000004043 oxo group Chemical group O=* 0.000 claims description 43
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 229910052760 oxygen Inorganic materials 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000004429 atom Chemical group 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 208000012902 Nervous system disease Diseases 0.000 claims description 10
- 208000020016 psychiatric disease Diseases 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims 21
- 239000000203 mixture Substances 0.000 abstract description 225
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 46
- 206010015037 epilepsy Diseases 0.000 abstract description 36
- 201000010099 disease Diseases 0.000 abstract description 27
- 108010052164 Sodium Channels Proteins 0.000 abstract description 10
- 102000018674 Sodium Channels Human genes 0.000 abstract description 10
- 201000007547 Dravet syndrome Diseases 0.000 abstract description 9
- 208000036572 Myoclonic epilepsy Diseases 0.000 abstract description 9
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 abstract description 9
- 239000011734 sodium Substances 0.000 abstract description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 7
- 230000002159 abnormal effect Effects 0.000 abstract description 7
- 229910052708 sodium Inorganic materials 0.000 abstract description 7
- 230000001594 aberrant effect Effects 0.000 abstract description 5
- 230000002085 persistent effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 214
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 111
- 235000019439 ethyl acetate Nutrition 0.000 description 107
- 230000015572 biosynthetic process Effects 0.000 description 105
- 238000003786 synthesis reaction Methods 0.000 description 105
- 229910001868 water Inorganic materials 0.000 description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
- 238000005160 1H NMR spectroscopy Methods 0.000 description 81
- 239000007787 solid Substances 0.000 description 77
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
- 239000012043 crude product Substances 0.000 description 61
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 61
- -1 pentadienyl Chemical group 0.000 description 60
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- 239000007832 Na2SO4 Substances 0.000 description 51
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 51
- 229910052938 sodium sulfate Inorganic materials 0.000 description 51
- 239000012267 brine Substances 0.000 description 50
- 125000004432 carbon atom Chemical group C* 0.000 description 50
- 125000005842 heteroatom Chemical group 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- 239000000243 solution Substances 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 239000000741 silica gel Substances 0.000 description 48
- 229910002027 silica gel Inorganic materials 0.000 description 48
- 229910052796 boron Inorganic materials 0.000 description 42
- 239000004698 Polyethylene Substances 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 39
- 238000002953 preparative HPLC Methods 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 35
- 239000012074 organic phase Substances 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 31
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 29
- 239000003814 drug Substances 0.000 description 29
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 28
- 229940124597 therapeutic agent Drugs 0.000 description 28
- 208000014644 Brain disease Diseases 0.000 description 23
- 208000032274 Encephalopathy Diseases 0.000 description 23
- 230000001037 epileptic effect Effects 0.000 description 23
- 206010010904 Convulsion Diseases 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 125000000304 alkynyl group Chemical group 0.000 description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 20
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
- 208000035475 disorder Diseases 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- 239000003643 water by type Substances 0.000 description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 17
- 230000035772 mutation Effects 0.000 description 17
- 239000001301 oxygen Chemical group 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 238000011282 treatment Methods 0.000 description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- 229910052717 sulfur Chemical group 0.000 description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 14
- MXQOYLRVSVOCQT-UHFFFAOYSA-N bis(tri-t-butylphosphine)palladium (0) Substances [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 125000004076 pyridyl group Chemical group 0.000 description 14
- 239000011593 sulfur Chemical group 0.000 description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 14
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 125000001153 fluoro group Chemical group F* 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 239000003195 sodium channel blocking agent Substances 0.000 description 13
- 208000002877 Epileptic Syndromes Diseases 0.000 description 12
- 239000007821 HATU Substances 0.000 description 12
- HUOFUOCSQCYFPW-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(OC(F)(F)F)C=C1 HUOFUOCSQCYFPW-UHFFFAOYSA-N 0.000 description 12
- 229910002651 NO3 Inorganic materials 0.000 description 11
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 125000001715 oxadiazolyl group Chemical group 0.000 description 11
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 230000008901 benefit Effects 0.000 description 10
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 10
- 238000002648 combination therapy Methods 0.000 description 10
- 229940126142 compound 16 Drugs 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 208000024658 Epilepsy syndrome Diseases 0.000 description 9
- 208000002193 Pain Diseases 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229940125898 compound 5 Drugs 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 8
- 101000631760 Homo sapiens Sodium channel protein type 1 subunit alpha Proteins 0.000 description 8
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- 101000654381 Homo sapiens Sodium channel protein type 8 subunit alpha Proteins 0.000 description 8
- 102100028910 Sodium channel protein type 1 subunit alpha Human genes 0.000 description 8
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- 102100031371 Sodium channel protein type 8 subunit alpha Human genes 0.000 description 8
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- 125000000714 pyrimidinyl group Chemical group 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 7
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 7
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 7
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- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 7
- 239000002876 beta blocker Substances 0.000 description 7
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- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 6
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- GIYXAJPCNFJEHY-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) Chemical compound Cl.C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 GIYXAJPCNFJEHY-UHFFFAOYSA-N 0.000 description 6
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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 5
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- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 description 4
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Classifications
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- A61K31/42—Oxazoles
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D235/26—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- Sodium ion (Na+) channels primarily open in a transient manner and are quickly inactivated, thereby generating a fast Na+ current to initiate the action potential.
- the late or persistent sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons.
- INaL enhancement contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceutical compounds that selectively modulate sodium channel activity, e.g., abnormal INaL, are useful in treating such disease states.
- Described herein are fused heteroaryl compounds and compositions useful for preventing and/or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late sodium current (INaL).
- a disease, disorder, or condition e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late sodium current (INaL).
- a disease, disorder, or condition e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late sodium current (INaL).
- a disease, disorder, or condition e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late sodium current (INaL).
- the present disclosure features compounds of Formula (I):
- each of X, Y, and Z is independently N or CR′; M is O, C(R 2a )(R 2b ), or N(R 2c ); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ; R′ is hydrogen, alkyl, —OR c , or halogen; R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ; each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ; each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein each of X, Y, and
- the present disclosure provides a compound of formula (I-2):
- the present disclosure provides a compound of formula (I-3):
- the present disclosure provides a compound of formula (I-4):
- the present disclosure provides a compound of formula (I-5):
- the present disclosure provides a compound of formula (I-6):
- the present disclosure provides a compound of formula (I-7):
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.
- the present invention provides compounds and compositions useful for preventing and/or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL).
- a disease, disorder, or condition described herein e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL).
- exemplary diseases, disorders, or conditions include a neurological disorder (e.g., epilepsy or an epilepsy syndrome, a neurodevelopmental disorder or a neuromuscular disorder), a psychiatric disorder, pain, or a gastrointestinal disorder.
- Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
- the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
- Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
- HPLC high pressure liquid chromatography
- a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
- an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
- enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
- the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
- an enantiomerically pure compound can be present with other active or inactive ingredients.
- a pharmaceutical composition comprising enantiomerically pure R—compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R—compound.
- the enantiomerically pure R—compound in such compositions can, for example, comprise, at least about 95% by weight R—compound and at most about 5% by weight S—compound, by total weight of the compound.
- a pharmaceutical composition comprising enantiomerically pure S—compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S—compound.
- the enantiomerically pure S—compound in such compositions can, for example, comprise, at least about 95% by weight S—compound and at most about 5% by weight R—compound, by total weight of the compound.
- the active ingredient can be formulated with little or no excipient or carrier.
- Compound described herein may also comprise one or more isotopic substitutions.
- H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
- C may be in any isotopic form, including 12 C, 13 C, and 14 C;
- O may be in any isotopic form, including 16 O and 18 O; and the like.
- analogue means one analogue or more than one analogue.
- C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
- alkyl refers to a radical of a straight—chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C 1-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”).
- an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). Examples of C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.
- alkenyl refers to a radical of a straight—chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C 2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
- an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
- the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
- Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
- Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
- alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C 2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”).
- an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”).
- an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
- the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
- Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
- C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
- alkylene As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.
- aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
- an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
- an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
- Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
- Particularly aryl groups include pheny
- heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”).
- heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
- Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
- Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
- Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
- the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
- a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
- a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
- a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
- the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
- Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
- Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
- Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
- Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
- Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
- Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
- Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
- Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
- Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
- heteroaryls examples include the following:
- each Z is selected from carbonyl, N, NR 65 , O, and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 carbocyclyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
- “carbocyclyl” or “carbocyclic” refers to a radical of a non—aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”) and zero heteroatoms in the non—aromatic ring system.
- a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
- a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
- a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
- a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
- Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
- Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
- Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
- the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
- “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
- heterocyclyl or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”).
- the point of attachment can be a carbon or nitrogen atom, as valency permits.
- a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
- Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
- Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
- a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”).
- a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
- a heterocyclyl group is a 5-6 membered non—aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
- the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
- the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
- Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
- Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
- Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
- Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
- Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
- Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
- Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
- Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
- Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,. heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
- cyano refers to —CN
- halo or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
- haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
- nitro refers to —NO 2 .
- oxo refers to —C ⁇ O.
- substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
- a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
- a “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
- exemplary counterions include halide ions (e.g., F ⁇ , Cl ⁇ , Br ⁇ , I ⁇ ), NO 3 ⁇ , ClO 4 ⁇ , OH ⁇ , H 2 PO 4 ⁇ , HSO 4 ⁇ , SO 4 ⁇ 2 sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g.
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
- Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C( ⁇ O)R aa , —C( ⁇ O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C( ⁇ NR bb )R aa ,—C( ⁇ NR cc )OR aa , —C( ⁇ NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C( ⁇ S)N(R
- pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
- organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
- Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
- a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle—aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
- the subject is a human.
- the subject is a non-human animal.
- the terms “human,” “patient,” and “subject” are used interchangeably herein.
- the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).
- the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response.
- the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.
- An effective amount encompasses therapeutic and prophylactic treatment.
- a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
- a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
- the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
- the present invention features a compound of Formula (I):
- each of X, Y, and Z is independently N or CR′; M is O, C(R 2a )(R 2b ), or N(R 2c ); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ; R′ is hydrogen, alkyl, —OR c , or halogen; R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ; each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ; each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein each of X, Y, and
- X is CR′(e.g., CH).
- Y is CR′(e.g., CH).
- Z is CR′(e.g., CH).
- each of X, Y, and Z is independently CR′(e.g., CH).
- X is N. In some embodiments, X is N and Y is CR′(e.g., CH). In some embodiments, X is N and Z is CR′(e.g., CH). In some embodiments, X is N and each of X and Y is independently CR′(e.g., CH).
- Y is N. In some embodiments, Y is N and X is CR′(e.g., CH). In some embodiments, Y is N and Z is CR′(e.g., CH). In some embodiments, Y is N and each of X and Z is independently CR′(e.g., CH).
- Z is N. In some embodiments, Z is N and X is CR′(e.g., CH). In some embodiments, Z is N and Y is CR′(e.g., CH). In some embodiments, Z is N and each of X and Y is independently CR′(e.g., CH).
- M is O.
- M is C(R 2a )(R 2b ). In some embodiments, M is C(R 2a )(R 2b ) and each of R 2a and R 2b is independently hydrogen.
- M is N(R 2c ). In some embodiments, M is N(R 2c ) and R 2c is hydrogen or alkyl (e.g., methyl or ethyl).
- A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1 R 3 . In some embodiments, A is phenyl substituted by 1 R 3 in the para position.
- A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is nitrogen-containing heteroaryl. In some embodiments, A is pyridyl. In some embodiments, A is pyridyl substituted by 1 R 3 . In some embodiments, A is pyridyl is substituted by 1 R 3 in the para position.
- R 3 is alkyl or —OR c . In some embodiments, R 3 is —OR c . In some embodiments, R c is alkyl. In some embodiments, R c is alkyl substituted by one or more R 6 . In some embodiments, R 6 is halo. In some embodiemnts, R 3 is —OCH 3 , —OCF 3 , or —OCH 2 CF 3 . In some embodiemnts, R 3 is —OCF 3 .
- R 3 is alkyl. In some embodiments, R 3 is alkyl substituted with R 5 (e.g., 1 R 5 ). In some embodiments, R 5 is —OR c . In some embodiments, R 3 is —CH 2 OCH 3 .
- R 1 is hydrogen or alkyl. In some embodiments, R 1 is hydrogen.
- R 1 is alkyl. In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R 1 is unsubstituted C 1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R 4 . In some embodiments, R 1 is C 1-4 alkyl substituted with 1-4 R 4 .
- R 4 is deuterium, halo, —OR c , oxo, carbocyclyl, heteroaryl, —C(O)OR c , or —C(O)N(R d ) 2 .
- R4 is deuterium.
- R 1 is CD 3 or CD 2 CD 3 .
- R 4 is halo (e.g., fluoro).
- R 1 is —CH 2 CF 3 or CH 2 CHF 2 .
- R 4 is —OR c (e.g., —OH or —OCH 3 ).
- le is —CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(OH)CH 3 , CH 2 CH 2 CH 2 OH, or CH 2 CH 2 CH 2 OCH 3 .
- R 4 is carbocyclyl (e.g., cyclopropyl).
- R 1 is —CH 2 CH 2 -cyclopropyl or —CH 2 -cyclopropyl.
- R 4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl).
- R 1 is —CH 2 -tetrahydropyranyl or —CH 2 -tetrahydrofuranyl.
- R 4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R 4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R 7 . In some embodiments, R 1 is —CH 2 CH 2 -5-methyl-1,3,4-oxadiazole. In some embodiments, R 4 is —C(O)OR c (e.g., —C(O)OH). In some embodiments, R 1 is —CH 2 C(O)OH.
- R 4 is —C(O)N(R d ) 2 (e.g., C(O)—NH(CH 3 ) 2 , C(O)—NHCH(CH 3 ) 2 , C(O)—NH(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )CH 2 CF 3 , or C(O)—N-pyrrolidinyl).
- R 1 is —CH 2 C(O)NHCH(CH 3 ) 2 or —C(O)—N-pyrrolidinyl.
- the present invention features a compound of Formula (I-1):
- each of X, Y, and Z is independently N or CR′;
- M is O, C(R 2a )(R 2b ),) or N(R 2c );
- A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
- R′ is hydrogen, alkyl, —OR c , or halogen
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
- each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
- each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
- each R d is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R 6 ; or two R d , taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
- each R e is alkyl
- each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R 7 is independently alkyl, halo, oxo, —C(O)R c , or —C(O)OR c .
- the compound is not one of the following:
- the compound is not one of the following:
- each of X, Y, and Z is independently CR′(e.g., CH).
- M is O.
- M is C(R 2a )(R 2b )(e.g., CH 2 ).
- M is N(R 2c ) (e.g., NH, NCH 3 ).
- A is aryl (e.g., phenyl).
- A is phenyl substituted by 1 R 3 (e.g., wherein R 3 is in the para position).
- A is heteroaryl (e.g., pyridyl).
- A is pyridyl substituted by 1 R 3 (e.g., wherein R 3 is in the para position).
- R 3 is —OR c .
- R c is alkyl substituted by one or more R 6 .
- R 6 is halo (e.g., fluoro).
- R 3 is —OCF 3 .
- R 1 is alkyl (e.g., substituted with 1-4 R 4 ).
- R 4 is deuterium, halo, —OR c , oxo, carbocyclyl, heteroaryl, —C(O)OR c , or —C(O)N(R d ) 2 .
- R 4 is deuterium, fluoro, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, OH, C(O)N(CH 3 ) 2 , C(O)N(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )(CH 2 CF 3 ), or C(O)N-tetrahydropyrrolyl.
- R 4 is halo (e.g., fluoro).
- R 1 is —CH 2 CF 3 .
- the compound of Formula (I-1) is a compound of Formula (I-2):
- each of X, Y, and Z is independently N or CR′;
- M is O or C(R2a)(R 2b ) ;
- R′ is hydrogen, alkyl, —OR c , or halogen
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each of R 2a and R 2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
- each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
- each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
- each R d is independently hydrogen or alkyl optionally substituted with one or more halogen
- each R e is alkyl
- each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; and n is 0, 1, 2, 3, or 4.
- the compound is not one of the following:
- the compound of formula I-2 is a compound of formula I-3:
- the compound of formula I-2 is a compound of formula I-4:
- the compound of formula I-2 is a compound of formula I-5:
- the compound of formula I-2 is a compound of formula I-6:
- each of X, Y, and Z is CR′, wherein R′ is hydrogen.
- M is O.
- M is C(R 2a )(R 2b ).
- R 1 is alkyl, wherein alkyl is optionally substituted with one or more R 4 .
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)CH 3 , —C(O)OCH 3 , —SO 2 CH 3 , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 .
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —SO 2 CH 3 , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 .
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 .
- n 0.
- the compound of Formula (I-1) is a compound of Formula (I-7):
- each of X, Y, and Z is independently N or CR′;
- M is N(R 2c );
- R′ is hydrogen, alkyl, —OR c , or halogen
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each of R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
- each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
- each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
- each R d is independently hydrogen or alkyl optionally substituted with one or more halogen
- each R e is alkyl
- each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; and n is 0, 1, 2, 3, or 4.
- the compound is not one of the following:
- each of X, Y, and Z is CR, wherein R′ is hydrogen.
- R 1 is alkyl, wherein alkyl is optionally substituted with one or more R 4 .
- R 4 is halo
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 .
- n 0.
- the compound of Formula (I) is a compound of Formula (I-a):
- each of X, Y, and Z is independently N or CR′; M is O, C(R 2a )(R 2b ), or N(R 2c ); R′ is hydrogen, alkyl, —OR c , or halogen (e.g., hydrogen); R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ; each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ; each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ; each of R 4 and R 5 is independently de
- X is CR′(e.g., CH).
- Y is CR′(e.g., CH).
- Z is CR′(e.g., CH).
- each of X, Y, and Z is independently CR′(e.g., CH).
- M is Q.
- M is C(R 2a )(R 2b ). In some embodiments, M is C(R 2a )(R 2b ) and each of R 2a and R 2b is independently hydrogen.
- M is N(R 2c ). In some embodiments, M is N(R 2c ) and R 2c is hydrogen or alkyl (e.g., methyl or ethyl).
- n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.
- R 3a is alkyl or —OR c . In some embodiments, R 3a is alkyl (e.g., ethyl) substituted by one or more R 5 . In some embodiments, R 5 is —OR c . In some embodiments, R c is alkyl (e.g., methyl). In some embodiments, R 3a is —CH 2 CH 2 OCH 3 .
- R 3a is —OR c . In some embodiments, R c is alkyl. In some embodiments, R 3a is —OCH 3 .
- R 3a is alkyl. In some embodiments, R 3a is alkyl substituted with R 5 (e.g., 1 R 5 ). In some embodiments, R 5 is —OR c . In some embodiments, R 3a is —CH 2 OCH 3 .
- R 1 is hydrogen or alkyl. In some embodiments, R 1 is hydrogen.
- R 1 is alkyl. In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R 1 is unsubstituted C 1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R 4 . In some embodiments, R 1 is C 1-4 alkyl substituted with 1-4 R 4 (e.g., methyl, ethyl, propyl, or isopropyl).
- R 4 is deuterium, halo, —OR c , oxo, carbocyclyl, heteroaryl, —C(O)OR c , or —C(O)N(R d ) 2 .
- R4 is deuterium.
- R1 is CD 3 or CD 2 CD 3 .
- R 4 is halo (e.g., fluoro).
- R 1 is —CH 2 CF 3 or CH 2 CHF 2
- R 4 is —OR c (e.g., —OH or —OCH 3 ).
- le is —CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(OH)CH 3 , CH 2 CH 2 CH 2 OH, or CH 2 CH 2 CH 2 OCH 3 .
- R 4 is carbocyclyl (e.g., cyclopropyl).
- R 1 is —CH 2 CH 2 -cyclopropyl or —CH 2 -cyclopropyl.
- R 4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl).
- R 1 is —CH 2 — tetrahydropyranyl or —CH 2 — tetrahydrofuranyl.
- R 4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R 4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R 7 . In some embodiments, R 1 is —CH 2 CH 2 -5-methyl-1,3,4-oxadiazole.
- R 4 is —C(O)OR c (e.g., —C(O)OH). In some embodiments, R 1 is —CH 2 C(O)OH.
- R 4 is —C(O)N(R d ) 2 (e.g., C(O)—NH(CH 3 ) 2 , C(O)—NHCH(CH 3 ) 2 , C(O)—NH(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )CH 2 CF 3 , or C(O)—N-pyrrolidinyl).
- R 1 is —CH 2 C(O)NHCH(CH 3 ) 2 or —C(O)—N-pyrrolidinyl.
- the compound of Formula (I) is a compound of Formula (I-b):
- A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C
- A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1 R 3 . In some embodiments, A is phenyl substituted by 1 R 3 in the para position.
- A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is nitrogen-containing heteroaryl. In some embodiments, A is pyridyl. In some embodiments, A is pyridyl substituted by 1 R 3 . In some embodiments, A is pyridyl is substituted by 1 R 3 in the para position
- R 3 is alkyl or —OR c . In some embodiments, R 3 is —OR c . In some embodiments, R c is alkyl. In some embodiments, R c is alkyl substituted by one or more R 6 . In some embodiments, R 6 is halo. In some embodiemnts, R 3 is —OCH 3 , —OCF 3 , or —OCH 2 CF 3 . In some embodiemnts, R 3 is —OCF 3 .
- R 3 is alkyl. In some embodiments, R 3 is alkyl substituted with R 5 (e.g., 1 R 5 ). In some embodiments, R 5 is —OR c . In some embodiments, R 3 is —CH 2 OCH 3 .
- R 1 is hydrogen or alkyl. In some embodiments, R 1 is hydrogen.
- R 1 is alkyl. In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R 1 is unsubstituted C 1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R 4 . In some embodiments, R 1 is C 1-4 alkyl substituted with 1-4 R 4 (e.g., methyl, ethyl, propyl, or isopropyl).
- R 4 is deuterium, halo, —OR c , oxo, carbocyclyl, heteroaryl, —C(O)OR c , or —C(O)N(R d ) 2 .
- R4 is deuterium.
- R 1 is CD 3 or CD 2 CD 3 .
- R 4 is halo (e.g., fluoro).
- R 1 is —CH 2 CF 3 or CH 2 CHF 2 .
- R 4 is —OR c (e.g., —OH or —OCH 3 ).
- R 1 is —CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(OH)CH 3 , CH 2 CH 2 CH 2 OH, or CH 2 CH 2 CH 2 OCH 3 .
- R 4 is carbocyclyl (e.g., cyclopropyl).
- R 1 is —CH 2 CH 2 -cyclopropyl or —CH 2 -cyclopropyl.
- R 4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl).
- R 1 is —CH 2 — tetrahydropyranyl or —CH 2 — tetrahydrofuranyl.
- R 4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R 4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R 7 . In some embodiments, R 1 is —CH 2 CH 2 -5-methyl-1,3,4-oxadiazole.
- R 4 is —C(O)OR c (e.g., —C(O)OH). In some embodiments, R 1 is —CH 2 C(O)OH.
- R 4 is —C(O)N(R d ) 2 (e.g., C(O)—NH(CH 3 ) 2 , C(O)—NHCH(CH 3 ) 2 , C(O)—NH(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )CH 2 CF 3 , or C(O)—N-pyrrolidinyl).
- R 1 is —CH 2 C(O)NHCH(CH 3 ) 2 or —C(O)—N-pyrrolidinyl.
- the compound of Formula (I) is a compound of Formula (I-c):
- A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C
- A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1 R 3 . In some embodiments, A is phenyl substituted by 1 R 3 in the para position.
- A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is nitrogen-containing heteroaryl. In some embodiments, A is pyridyl. In some embodiments, A is pyridyl substituted by 1 R 3 . In some embodiments, A is pyridyl is substituted by 1 R 3 in the para position
- R 3 is alkyl or —OR c . In some embodiments, R 3 is —OR c . In some embodiments, R c is alkyl. In some embodiments, R c is alkyl substituted by one or more R 6 . In some embodiments, R 6 is halo. In some embodiemnts, R 3 is —OCH 3 , —OCF 3 , or —OCH 2 CF 3 . In some embodiemnts, R 3 is —OCF 3 .
- R 3 is alkyl. In some embodiments, R 3 is alkyl substituted with R 5 (e.g., 1 R 5 ). In some embodiments, R 5 is —OR c . In some embodiments, R 3 is —CH 2 OCH 3 .
- R 1 is hydrogen or alkyl. In some embodiments, R 1 is hydrogen.
- R 1 is alkyl. In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R 1 is unsubstituted C 1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R 4 . In some embodiments, R 1 is C 1-4 alkyl substituted with 1-4 R 4 (e.g., methyl, ethyl, propyl, or isopropyl).
- R 4 is deuterium, halo, —OR c , oxo, carbocyclyl, heteroaryl, —C(O)OR c , or —C(O)N(R d ) 2 .
- R4 is deuterium.
- R 1 is CD 3 or CD 2 CD 3 .
- R 4 is halo (e.g., fluoro).
- R 1 is —CH 2 CF 3 or CH 2 CHF 2 .
- R 4 is —OR c (e.g., —OH or —OCH 3 ).
- R 1 is —CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(OH)CH 3 , CH 2 CH 2 CH 2 OH, or CH 2 CH 2 CH 2 OCH 3 .
- R 4 is carbocyclyl (e.g., cyclopropyl).
- R 1 is —CH 2 CH 2 -cyclopropyl or —CH 2 -cyclopropyl.
- R 4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl).
- R 1 is —CH 2 — tetrahydropyranyl or —CH 2 — tetrahydrofuranyl.
- R 4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R 4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R 7 . In some embodiments, R 1 is —CH 2 CH 2 -5-methyl-1,3,4-oxadiazole.
- R 4 is —C(O)OR c (e.g., —C(O)OH). In some embodiments, R 1 is —CH 2 C(O)OH.
- R 4 is —C(O)N(R d ) 2 (e.g., C(O)—NH(CH 3 ) 2 , C(O)—NHCH(CH 3 ) 2 , C(O)—NH(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )CH 2 CF 3 , or C(O)—N-pyrrolidinyl).
- R 1 is —CH 2 C(O)NHCH(CH 3 ) 2 or —C(O)—N-pyrrolidinyl.
- the compound of Formula (I) is a compound of Formula (I-d):
- each of X, Y, and Z is independently N or CR′;
- R′ is hydrogen, alkyl, —OR c , or halogen (e.g., hydrogen);
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C
- X is CR′(e.g., CH).
- Y is CR′(e.g., CH).
- Z is CR′(e.g., CH).
- each of X, Y, and Z is independently CR′(e.g., CH).
- n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.
- R 3a is alkyl or —OR c . In some embodiments, R 3a is alkyl (e.g., ethyl) substituted by one or more R 5 . In some embodiments, R 5 is —OR c . In some embodiments, R c is alkyl (e.g., methyl). In some embodiments, R 3a is —CH 2 CH 2 OCH 3 .
- R 3a is —OR c . In some embodiments, R c is alkyl. In some embodiments, R 3a is —OCH 3 .
- R 3a is alkyl. In some embodiments, R 3a is alkyl substituted with R 5 (e.g., 1 R 5 ). In some embodiments, R 5 is —OR c . In some embodiments, R 3a is —CH 2 OCH 3 .
- R 1 is hydrogen or alkyl. In some embodiments, R 1 is hydrogen.
- R 1 is alkyl. In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R 1 is unsubstituted C 1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R 1 is C 1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R 4 . In some embodiments, R 1 is C 1-4 alkyl substituted with 1-4 R 4 (e.g., methyl, ethyl, propyl, or isopropyl).
- R 4 is deuterium, halo, —OR c , oxo, carbocyclyl, heteroaryl, —C(O)OR c , or —C(O)N(R d ) 2 .
- R4 is deuterium.
- R 1 is CD 3 or CD 2 CD 3 .
- R 4 is halo (e.g., fluoro).
- R 1 is —CH 2 CF 3 or CH 2 CHF 2 .
- R 4 is —OR c (e.g., —OH or —OCH 3 ).
- R 1 is —CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH(OH)CH 3 , CH 2 CH 2 CH 2 OH, or CH 2 CH 2 CH 2 OCH 3 .
- R 4 is carbocyclyl (e.g., cyclopropyl).
- R 1 is —CH 2 CH 2 -cyclopropyl or —CH 2 -cyclopropyl.
- R 4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl).
- R 1 is —CH 2 — tetrahydropyranyl or —CH 2 — tetrahydrofuranyl.
- R 4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R 4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R 7 . In some embodiments, R 1 is —CH 2 CH 2 -5-methyl-1,3,4-oxadiazole.
- R 4 is —C(O)OR c (e.g., —C(O)OH). In some embodiments, R 1 is —CH 2 C(O)OH.
- R 4 is —C(O)N(R d ) 2 (e.g., C(O)—NH(CH 3 ) 2 , C(O)—NHCH(CH 3 ) 2 , C(O)—NH(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )CH 2 CF 3 , or C(O)—N-pyrrolidinyl).
- R 1 is —CH 2 C(O)NHCH(CH 3 ) 2 or —C(O)—N-pyrrolidinyl.
- the compound of Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d) is selected from:
- the compound of Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d) is selected from:
- a compound provided by the present invention is effective in the treatment of epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder.
- Compounds of the invention may also modulate all sodium ion channels, or may be specific to only one or a plurality of sodium ion channels, e.g., Na v 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, and/or 1.9.
- the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds.
- the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a hydrate of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g.
- Epilepsy is a CNS disorder in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness. Seizure symptoms will vary widely, from a simple blank stare for a few seconds to repeated twitching of their arms or legs during a seizure.
- Epilepsy may involve a generalized seizure or a partial or focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may cry out or make some sound, stiffen for several seconds to a minute a then have rhythmic movements of the arms and legs. The eyes are generally open, the person may appear not to be breathing and actually turn blue. The return to consciousness is gradual and the person maybe confused from minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain having abnormal electrical activity, symptoms may vary.
- Epilepsy includes a generalized, partial, complex partial, tonic clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.
- the compounds described herein may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance West syndrome.
- the epilepsy syndrome comprises an epileptic encephalopathy, such as Dravet syndrome, Angelman syndrome, CDKLS disorder, frontal lobe epilepsy, infantile spasms, West's syndrome, Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.
- an epileptic encephalopathy such as Dravet syndrome, Angelman syndrome, CDKLS disorder, frontal lobe epilepsy, infantile spasms, West's syndrome, Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.
- the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome.
- epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy
- the methods described herein further comprise identifying a subject having epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic syndrome
- the present invention features a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy,
- each of X, Y, and Z is independently N or CR′; M is O, C(R 2a )(R 2b ), or N(R 2c ); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ; R′ is hydrogen, alkyl, —OR c , or halogen; R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ; each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ; each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein each of X, Y, and
- a compound of the present invention may also be used to treat an epileptic encephalopathy, wherein the subject has a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C
- the methods described herein further comprise identifying a subject having a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKLS, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, S
- the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy.
- the methods described herein further comprise identifying a subject having a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- a neurodevelopmental disorder e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, vel
- the present invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a compound of Formula (I):
- a neurodevelopmental disorder e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy
- each of X, Y, and Z is independently N or CR′; M is O, C(R 2a )(R 2b ), or N(R 2c ); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ; R′ is hydrogen, alkyl, —OR c , or halogen; R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ; each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ; each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein each of X, Y, and
- the pain comprises neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder.
- the methods described herein further comprise identifying a subject having pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder) prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- pain e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder
- a compound described herein
- the present invention features a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder) comprising administering to a subject in need thereof a compound of Formula (I):
- pain e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder
- each of X, Y, and Z is independently N or CR′; M is O, C(R 2a )(R 2b ), or N(R 2c ); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ; R′ is hydrogen, alkyl, —OR c , or halogen; R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ; each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ; each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein each of X, Y, and
- the compounds described herein may be useful in the treatment of a neuromuscular disorder.
- the neuromuscular disorder comprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation.
- the methods described herein further comprise identifying a subject having a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- a neuromuscular disorder e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryn
- the present invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) comprising administering to a subject in need thereof a compound of Formula (I):
- a neuromuscular disorder e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation
- each of X, Y, and Z is independently N or CR′; M is O, C(R 2a )(R 2b ), or N(R 2c ); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ; R′ is hydrogen, alkyl, —OR c , or halogen; R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ; each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ; each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein each of X, Y, and
- a compound of the present invention may have appropriate pharmacokinetic properties such that they may active with regard to the central and/or peripheral nervous system.
- the compounds provided herein are used to treat a cardiovascular disease such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, and myocardial infarction.
- the compounds provided herein may be used in the treatment of diseases affecting the neuromuscular system resulting in itching, seizures, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and disease states related to diabetes, such as diabetic peripheral neuropathy.
- the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I):
- each of X, Y, and Z is independently N or CR′;
- M is O, C(R 2a )(R 2b ), or N(R 2c );
- A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
- R′ is hydrogen, alkyl, —OR c , or halogen
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
- each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ; each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
- each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
- each R d is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R 6 ;
- each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R 7 is independently alkyl, halo, or oxo.
- the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I-1):
- each of X, Y, and Z is independently N or CR′;
- M is O, C(R 2a )(R 2b ), or N(R 2c );
- A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R 3 ;
- R′ is hydrogen, alkyl, —OR c , or halogen
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each of R 2a , R 2b , and R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
- each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR c , —N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —C(O)N(R d ) 2 , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
- each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by one or more R 6 ;
- each R d is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R 6 ;
- each R e is alkyl
- each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R 7 is independently alkyl, halo, oxo, —C(O)R c , or —C(O)OR c .
- the compound is not one of the following:
- the neurological disorder is epilepsy.
- the neurological disorder is an epileptic encephalopathy.
- the epileptic encephalopathy comprises Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.
- each of X, Y, and Z is independently CR′(e.g., CH).
- X is N and each of Y and Z is independently CR′(e.g., CH).
- Z is N and each of X and Y is independently CR′(e.g., CH).
- M is O.
- M is C(R 2a )(R 2b ) (e.g., CH 2 ).
- M is N(R 2 ) (e.g., NH, NCH 3 ).
- A is aryl (e.g., phenyl).
- A is phenyl substituted by 1 R 3 (e.g., wherein R 3 is in the para position).
- A is heteroaryl (e.g., pyridyl).
- A is pyridyl substituted by 1 R 3 (e.g., wherein R 3 is in the para position).
- R 3 is —OR c .
- R c is alkyl substituted by one or more R 6 .
- R 6 is halo (e.g., fluoro).
- R 3 is —OCF 3 .
- R 1 is alkyl (e.g., substituted with 1-4 R 4 ).
- R 4 is deuterium, halo, —OR c , oxo, carbocyclyl, heteroaryl, —C(O)OR c , or —C(O)N(R d ) 2 .
- R 4 is deuterium, fluoro, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, OH, C(O)N(CH 3 ) 2 , C(O)N(CH 3 )(CH 2 CH 3 ), C(O)N(CH 3 )(CH 2 CF 3 ), or C(O)N— tetrahydropyrrolyl.
- R 4 is halo (e.g., fluoro).
- R 1 is —CH 2 CF 3 .
- the compound of Formula (I-1) is a compound of Formula (I-2):
- each of X, Y, and Z is independently N or CR′;
- M is O or C(R 2a )(R 2b );
- R′ is hydrogen, alkyl, —OR c , or halogen
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each of R 2a and R 2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
- each lea R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
- each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
- each R d is independently hydrogen or alkyl optionally substituted with one or more halogen
- each R e is alkyl
- each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; n is 0, 1, 2, 3, or 4.
- the compound of formula I-2 is a compound of formula I-3:
- the compound of formula I-2 is a compound of formula I-4:
- the compound of formula I-2 is a compound of formula I-5:
- the compound of formula I-2 is a compound of formula I-6:
- M is C(R 2a )(R 2b ).
- R 1 is alkyl, wherein alkyl is optionally substituted with one or more R 4 .
- n 0.
- the compound of Formula (I-1) is a compound of Formula (I-7):
- each of X, Y, and Z is independently N or CR′;
- M is N(R 2c );
- R′ is hydrogen, alkyl, —OR c , or halogen
- R 1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 4 ;
- each of R 2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R 4 ;
- each R 3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 5 ;
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R d ) 2 , —C(O)R c , —C(O)OR c , —S(O) 2 —R e , —S(O) 2 N(R d ) 2 , or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 ;
- each R c is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 6 ;
- each R d is independently hydrogen or alkyl optionally substituted with one or more halogen
- each R e is alkyl
- each R 6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R 7 is independently alkyl, oxo, halo, —C(O)R c , or —C(O)OR c ; and n is 0, 1, 2, 3, or 4.
- the compound is not one of the following:
- each of X, Y, and Z is CR′, wherein R′ is hydrogen.
- R 1 is alkyl, wherein alkyl is optionally substituted with one or more R 4 .
- each of R 4 and R 5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or —OR c , wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R 7 .
- n 0.
- the present disclosure provides a method comprises administering a pharmaceutical composition disclosed herein.
- the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.
- compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
- the pharmaceutical compositions may be administered alone or in combination with other therapeutic agents.
- Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.)
- compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
- agents having similar utilities for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
- compositions of the present invention are parenteral, particularly by injection.
- forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
- Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention.
- Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like.
- the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents;
- preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
- compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
- Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
- the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- compositions are preferably formulated in a unit dosage form.
- unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
- the compounds are generally administered in a pharmaceutically effective amount.
- each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein.
- the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
- these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a compound or composition described herein may be administered in combination with another agent or therapy.
- a subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy.
- diseases or conditions can relate to epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder.
- Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide.
- Cardiovascular related diseases or conditions that can benefit from a combination treatment of the sodium channel blockers of the invention with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.
- angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (
- Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.
- the co-administration of the sodium channel blockers of the invention with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving.
- Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction.
- beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Badorece), and timolol (Blocadren).
- Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure.
- examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.
- Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart.
- Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.
- Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure.
- diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (lnspra).
- Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing resistance to blood flow.
- ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).
- Vasodilators reduce pressure on the blood vessels by making them relax and expand.
- vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa.
- ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.
- Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.
- Antithrombotics inhibit the clotting ability of the blood.
- Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries.
- platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin).
- Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.
- Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots.
- anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.
- Thrombolytic agents act to break down an existing blood clot.
- examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).
- Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm.
- Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone.
- Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.
- Combinations with amiodarone and dronedarone are of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amioarone and dronedarone.
- Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clot for illation.
- antihypertensive agents include alpha-1-adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres), clonidine hydrochlor
- Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood.
- lipid lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).
- statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).
- the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder.
- secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder.
- Such patients can benefit from treatment of a combination therapy comprising administering to the patient ranolazine in combination with at least one therapeutic agent.
- Pulmonary disorder refers to any disease or condition related to the lungs.
- pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.
- COPD chronic obstructive pulmonary disease
- bronchitis bronchitis
- emphysema emphysema
- therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements.
- Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.
- metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.
- therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section “Cardiovascular Agent Combination Therapy” above.
- Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.
- Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.
- PAD peripheral arterial disease
- Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.
- GFD gastroesophageal reflux disease
- IBD inflammatory bowel disease
- pancreatitis pancreatitis
- therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, such as misoprostoL (Cytotec); sucralfate; and antacids.
- proton pump inhibitors such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole
- H2 blockers such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid);
- Patients presenting with an acute coronary disease event may exhibit conditions that benefit from administration of therapeutic agent or agents that are antibiotics, analgesics, antidepressant and anti-anxiety agents in combination with ranolazine.
- Antibiotics are therapeutic agents that kill, or stop the growth of, microorganisms, including both bacteria and fungi.
- Example of antibiotic agents include .beta.-Lactam antibiotics, including penicillins (amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor), cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, and monobactams; tetracyclines, such as tetracycline; macrolide antibiotics, such as
- Analgesics are therapeutic agents that are used to relieve pain.
- Examples of analgesics include opiates and morphinomimetics, such as fentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors.
- Antidepressant and anti-anxiety agents include those agents used to treat anxiety disorders, depression, and those used as sedatives and tranquillizers.
- Examples of antidepressant and anti-anxiety agents include benzodiazepines, such as diazepam, lorazepam, and midazolam; benzodiazepines; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine (Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane); paroxetine (Paxil, Seroxat, Aropax); traz
- one aspect of the invention provides for a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent.
- the composition comprises the sodium channel blockers of the invention and at least two therapeutic agents.
- the composition comprises the sodium channel blockers of the invention and at least three therapeutic agents, the sodium channel blockers of the invention and at least four therapeutic agents, or the sodium channel blockers of the invention and at least five therapeutic agents.
- the methods of combination therapy include co-administration of a single formulation containing the sodium channel blockers of the invention and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the sodium channel blocker of the invention and therapeutic agent or agents, and consecutive administration of a sodium channel blocker of the invention and therapeutic agent or agents, in any order, wherein preferably there is a time period where the sodium channel blocker of the invention and therapeutic agent or agents simultaneously exert their therapeutic effect.
- the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.
- protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
- the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
- the compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system.
- the compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods well known to those of skill in the art.
- A-6 A mixture of A-5 (800 mg, 2.55 mmol, 1 eq), [4-(trifluoromethoxy)phenyl]boronic acid (629.32 mg, 3.06 mmol, 1.2 eq), K 3 PO 4 (1.08 g, 5.09 mmol, 2 eq) and Pd(t-Bu 3 P) 2 (195.23 mg, 382.01 ⁇ mol, 0.15 eq) in dioxane (10 mL) and H 2 O (2 mL) was stirred at 85° C. for 16 hours.
- A-7 A mixture of A-6 (200 mg, 505.91 ⁇ mol, 1 eq) and N 2 H 4 .H 2 O (129.21 mg, 2.53 mmol, 125.45 ⁇ L, 5 eq) in EtOH (1 mL) was stirred at 90° C. for 48 hours. The mixture was concentrated to give the crude A-7 (150 mg, 393.39 ⁇ mol) as a solid.
- 1 H NMR (CDCl 3 , 400 MHz) ⁇ H 7.80 (d, 2H), 7.54 (d, 2H), 7.51-7.49 (m, 1H), 7.49-7.45 (m, 2H), 4.43 (t, 2H), 2.92 (t, 2H).
- A-15 A mixture of A-14 (120 mg, 294.59 ⁇ mol, 1 eq) and hydrazine (944.03 mg, 29.46 mmol, 1.07 mL, 100 eq) in EtOH (3 mL) was stirred at 100° C. for 14 hours . After cooling, the mixture was concentrated to afford A-15 (110 mg, 259.82 ⁇ mol) as a solid.
- LCMS R t 0.76 min using Method B, MS ESI calcd. for C 18 H 17 F 3 N 3 O 3 [M+H] + 380.1, found 379.9
- a mixture of A-22 (1000 mg, 3.72 mmol) and CDI (523.68 mg, 3.72 mmol) in THF (10 mL) was stirred at 20° C. for 16 hours . After cooling to r.t, the mixture was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE 0% to 50% to 100%) to afford A-23 (930 mg, 2.97 mmol) as a solid.
- 1 H NMR (CDCl3, 400 MHz) ⁇ H 9.76 (br s, 1H), 7.30-7.26 (m, 1H), 7.23 (s, 1H), 7.02 (d, 1H), 4.46 (q, 2H).
- A-29 A mixture of A-28 (150 mg, 0.38 mmol) and Pd/C (50 mg) in methanol (15 mL) was stirred under H 2 at 15° C. for 16 hours . The reaction mixture was filtered through Celite and the filtrate was concentrated to afford A-29 (100 mg, 0.37 mmol) as a solid.
- 1 H NMR (DMSO-d 6 400 MHz) ⁇ H 7.98 (d, 2H), 7.34 (d, 2H), 7.00 (d, 1H), 6.90 (d, 1H), 5.58 (s, 2H).
- a mixture of A-40 (200 mg, 0.44 mmol) and wet Pd/C (200 mg) in methanol (10 mL) was degassed and refilled with Hz. The reaction mixture was stirred under H 2 (50 psi) at 20° C. for 16 hours . The reaction mixture was diluted with MeOH (10 mL), filtered through a Celite pad and eluted with MeOH (10 mL). The filtrate was concentrated to give A-41 (160 mg, crude). LCMS R t 0.67 min using Method B, MS ESI calcd. for C 12 H 10 F 3 N 2 O 2 [M+H] + 271.1, found 270.9.
- the mixture was cooled to r.t., diluted with EtOAc (20 mL), filtered through silica gel and eluted with EtOAc (20 mL). The filtrate was concentrated to give the crude product.
- the crude product was purified by Prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water(10 mM NH 4 HCO 3 )-ACN]; B%: 51%-81%, 7 min) to give the product (134.4 mg, 0.3712 mmol, 45% yield) as a solid.
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Abstract
The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.
Description
- This application is a continuation of U.S. patent application Ser. No. 16/485,581, filed on Aug. 13, 2019; which is a 35 U.S.C. § 371 national stage filing of International Application Number PCT/US2018/018044, filed on Feb. 13, 2018; which claims priority to and the benefit of U.S. Provisional Patent Application No. 62/458,317, filed on Feb. 13, 2017, U.S. Provisional Patent Application No. 62/481,468, filed on Apr. 4, 2017, and U.S. Provisional Patent Application No. 62/545,549, filed on Aug. 15, 2017, each of which is incorporated herein by reference in its entirety.
- Sodium ion (Na+) channels primarily open in a transient manner and are quickly inactivated, thereby generating a fast Na+ current to initiate the action potential. The late or persistent sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g., Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceutical compounds that selectively modulate sodium channel activity, e.g., abnormal INaL, are useful in treating such disease states.
- Described herein are fused heteroaryl compounds and compositions useful for preventing and/or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late sodium current (INaL). In one aspect, the present disclosure features compounds of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; M is O, C(R2a)(R2b), or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R′ is hydrogen, alkyl, —ORc, or halogen; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a ring; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R7 is independently alkyl, halo, or oxo.
- In another aspect, the present disclosure provides a compound of formula (I-1):
- or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- In some embodiments, the present disclosure provides a compound of formula (I-2):
- or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- In some embodiments, the present disclosure provides a compound of formula (I-3):
- or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- In some embodiments, the present disclosure provides a compound of formula (I-4):
- or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- In some embodiments, the present disclosure provides a compound of formula (I-5):
- or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- In some embodiments, the present disclosure provides a compound of formula (I-6):
- or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- In some embodiments, the present disclosure provides a compound of formula (I-7):
- or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.
- In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- In another aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.
- Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims.
- As generally described herein, the present invention provides compounds and compositions useful for preventing and/or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include a neurological disorder (e.g., epilepsy or an epilepsy syndrome, a neurodevelopmental disorder or a neuromuscular disorder), a psychiatric disorder, pain, or a gastrointestinal disorder.
- Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
- Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
- As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
- In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R—compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R—compound. In certain embodiments, the enantiomerically pure R—compound in such compositions can, for example, comprise, at least about 95% by weight R—compound and at most about 5% by weight S—compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S—compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S—compound. In certain embodiments, the enantiomerically pure S—compound in such compositions can, for example, comprise, at least about 95% by weight S—compound and at most about 5% by weight R—compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
- Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like.
- The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.
- When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
- As used herein, “alkyl” refers to a radical of a straight—chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.
- As used herein, “alkenyl” refers to a radical of a straight—chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.
- As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.
- As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.
- As used herein,“aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
- As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
- In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
- Examples of representative heteroaryls include the following:
- wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65 is independently hydrogen, C1-C8 alkyl, C3-C10 carbocyclyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl.
- As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non—aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non—aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
- As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
- In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non—aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
- Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
- “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,. heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
- As used herein, “cyano” refers to —CN.
- As used herein, “halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
- As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms.
- As used herein, “nitro” refers to —NO2.
- As used herein, “oxo” refers to —C═O.
- In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
- A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F−, Cl−, Br−, I−), NO3 −, ClO4 −, OH−, H2PO4 −, HSO4 −, SO4 −2sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).
- Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRbb)Raa,—C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined above.
- These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
- Other definitions
- The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
- As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle—aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.
- Disease, disorder, and condition are used interchangeably herein.
- As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).
- As used herein, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.
- As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
- In one aspect, the present invention features a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; M is O, C(R2a)(R2b), or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R′ is hydrogen, alkyl, —ORc, or halogen; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a ring; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R7 is independently alkyl, halo, or oxo.
- In some embodiments, X is CR′(e.g., CH). In some embodiments, Y is CR′(e.g., CH). In some embodiments, Z is CR′(e.g., CH). In some embodiments, each of X, Y, and Z is independently CR′(e.g., CH).
- In some embodiments, X is N. In some embodiments, X is N and Y is CR′(e.g., CH). In some embodiments, X is N and Z is CR′(e.g., CH). In some embodiments, X is N and each of X and Y is independently CR′(e.g., CH).
- In some embodiments, Y is N. In some embodiments, Y is N and X is CR′(e.g., CH). In some embodiments, Y is N and Z is CR′(e.g., CH). In some embodiments, Y is N and each of X and Z is independently CR′(e.g., CH).
- In some embodiments, Z is N. In some embodiments, Z is N and X is CR′(e.g., CH). In some embodiments, Z is N and Y is CR′(e.g., CH). In some embodiments, Z is N and each of X and Y is independently CR′(e.g., CH).
- In some embodiments, M is O.
- In some embodiments, M is C(R2a)(R2b). In some embodiments, M is C(R2a)(R2b) and each of R2a and R2b is independently hydrogen.
- In some embodiments, M is N(R2c). In some embodiments, M is N(R2c) and R2c is hydrogen or alkyl (e.g., methyl or ethyl).
- In some embodiments, A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1 R3. In some embodiments, A is phenyl substituted by 1 R3 in the para position.
- In some embodiments, A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is nitrogen-containing heteroaryl. In some embodiments, A is pyridyl. In some embodiments, A is pyridyl substituted by 1 R3. In some embodiments, A is pyridyl is substituted by 1 R3 in the para position.
- In some embodiments, R3 is alkyl or —ORc. In some embodiments, R3 is —ORc. In some embodiments, Rc is alkyl. In some embodiments, Rc is alkyl substituted by one or more R6. In some embodiments, R6 is halo. In some embodiemnts, R3 is —OCH3, —OCF3, or —OCH2CF3. In some embodiemnts, R3 is —OCF3.
- In some embodiments, R3 is alkyl. In some embodiments, R3 is alkyl substituted with R5 (e.g., 1 R5). In some embodiments, R5 is —ORc. In some embodiments, R3 is —CH2OCH3.
- In some embodiments, R1 is hydrogen or alkyl. In some embodiments, R1 is hydrogen.
- In some embodiments, R1 is alkyl. In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R1 is unsubstituted C1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R4. In some embodiments, R1 is C1-4 alkyl substituted with 1-4 R4.
- In some embodiments, R4 is deuterium, halo, —ORc, oxo, carbocyclyl, heteroaryl, —C(O)ORc, or —C(O)N(Rd)2. In some embodiments, R4 is deuterium. In some embodiments, R1 is CD3 or CD2CD3.
- In some embodiments, R4 is halo (e.g., fluoro). In some embodiments, R1 is —CH2CF3 or CH2CHF2.
- In some embodiments, R4 is —ORc (e.g., —OH or —OCH3). In some embodiments, le is —CH2CH2OCH3, CH2CH2OH, CH2CH2CH(OH)CH3, CH2CH2CH2OH, or CH2CH2CH2OCH3.
- In some embodiments, R4 is carbocyclyl (e.g., cyclopropyl). In some embodiments, R1 is —CH2CH2-cyclopropyl or —CH2-cyclopropyl. In some embodiments, R4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl).
- In some embodiments, R1 is —CH2-tetrahydropyranyl or —CH2-tetrahydrofuranyl.
- In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R7. In some embodiments, R1 is —CH2CH2-5-methyl-1,3,4-oxadiazole. In some embodiments, R4 is —C(O)ORc (e.g., —C(O)OH). In some embodiments, R1 is —CH2C(O)OH.
- In some embodiments, R4 is —C(O)N(Rd)2 (e.g., C(O)—NH(CH3)2, C(O)—NHCH(CH3)2, C(O)—NH(CH3)(CH2CH3), C(O)N(CH3)CH2CF3, or C(O)—N-pyrrolidinyl). In some embodiments, R1 is —CH2C(O)NHCH(CH3)2 or —C(O)—N-pyrrolidinyl.
- In another aspect, the present invention features a compound of Formula (I-1):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of X, Y, and Z is independently N or CR′;
- M is O, C(R2a)(R2b),) or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3;
- R′ is hydrogen, alkyl, —ORc, or halogen;
- R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
- each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
- each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
- each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
- each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
- each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
- each Re is alkyl;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- and each R7 is independently alkyl, halo, oxo, —C(O)Rc, or —C(O)ORc.
- In some embodiments, the compound is not one of the following:
- and a pharmaceutically acceptable salt thereof.
- In some embodiments, the compound is not one of the following:
- and a pharmaceutically acceptable salt thereof.
- In some embodiments, each of X, Y, and Z is independently CR′(e.g., CH).
- In other embodiments, M is O.
- In certain embodiments, M is C(R2a)(R2b)(e.g., CH2).
- In some embodiments, M is N(R2c) (e.g., NH, NCH3).
- In certain embodiments, A is aryl (e.g., phenyl).
- In other embodiments, A is phenyl substituted by 1 R3 (e.g., wherein R3 is in the para position).
- In some embodiments, A is heteroaryl (e.g., pyridyl).
- In other embodiments, A is pyridyl substituted by 1 R3 (e.g., wherein R3 is in the para position).
- In certain embodiments, R3 is —ORc.
- In some embodiments, Rc is alkyl substituted by one or more R6.
- In other embodiments, R6 is halo (e.g., fluoro).
- In certain embodiments, R3 is —OCF3.
- In some embodiments, R1 is alkyl (e.g., substituted with 1-4 R4).
- In other embodiments, R4 is deuterium, halo, —ORc, oxo, carbocyclyl, heteroaryl, —C(O)ORc, or —C(O)N(Rd)2.
- In certain embodiments, R4 is deuterium, fluoro, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, OH, C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CF3), or C(O)N-tetrahydropyrrolyl.
- In some embodiments, R4 is halo (e.g., fluoro).
- In other embodiments, R1 is —CH2CF3.
- In some embodiments, the compound of Formula (I-1) is a compound of Formula (I-2):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of X, Y, and Z is independently N or CR′;
- M is O or C(R2a)(R2b);
- R′ is hydrogen, alkyl, —ORc, or halogen;
- R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
- each of R2a and R2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
- each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
- each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
- each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
- each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
- or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
- each Re is alkyl;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; and n is 0, 1, 2, 3, or 4.
- In some embodiments, the compound is not one of the following:
- and a pharmaceutically acceptable salt thereof.
- In some embodiments, the compound of formula I-2 is a compound of formula I-3:
- or a pharmaceutically acceptable salt thereof.
- In certain embodiments, the compound of formula I-2 is a compound of formula I-4:
- or a pharmaceutically acceptable salt thereof.
- In some embodiments, the compound of formula I-2 is a compound of formula I-5:
- or a pharmaceutically acceptable salt thereof.
- In some embodiments, the compound of formula I-2 is a compound of formula I-6:
- or a pharmaceutically acceptable salt thereof.
- In some embodiments of formula I-2, each of X, Y, and Z is CR′, wherein R′ is hydrogen.
- In some embodiments of formula I-2, M is O.
- In some embodiments of formula I-2, M is C(R2a)(R2b).
- In some embodiments of formula I-2, R1 is alkyl, wherein alkyl is optionally substituted with one or more R4.
- In some embodiments of formula I-2, each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)CH3, —C(O)OCH3, —SO2CH3, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7.
- In some embodiments of formula I-2, each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —SO2CH3, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7.
- In some embodiments of formula I-2, each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7.
- In some embodiments of formula I-2, n is 0.
- In some embodiments, the compound of Formula (I-1) is a compound of Formula (I-7):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of X, Y, and Z is independently N or CR′;
- M is N(R2c);
- R′ is hydrogen, alkyl, —ORc, or halogen;
- R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
- each of R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
- each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
- each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
- each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
- each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
- or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
- each Re is alkyl;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; and n is 0, 1, 2, 3, or 4.
- In some embodiments of formula I-7, the compound is not one of the following:
- and a pharmaceutically acceptable salt thereof.
- In some embodiments of formula I-7, each of X, Y, and Z is CR, wherein R′ is hydrogen.
- In some embodiments of formula I-7, R1 is alkyl, wherein alkyl is optionally substituted with one or more R4.
- In some embodiments, R4 is halo.
- In some embodiments of formula I-7, each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7.
- In some embodiments of formula I-7, n is 0.
- In some embodiments, the compound of Formula (I) is a compound of Formula (I-a):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; M is O, C(R2a)(R2b), or N(R2c); R′ is hydrogen, alkyl, —ORc, or halogen (e.g., hydrogen); R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4; each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen; or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with-OH, alkoxy, or alkyl optionally substituted with alkoxy; each Re is alkyl;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; each R7 is independently alkyl, halo, oxo, —C(O)Rc, or —C(O)ORc; and n is 0, 1, 2, 3, or 4.
- In some embodiments, X is CR′(e.g., CH). In some embodiments, Y is CR′(e.g., CH). In some embodiments, Z is CR′(e.g., CH). In some embodiments, each of X, Y, and Z is independently CR′(e.g., CH).
- In some embodiments, M is Q.
- In some embodiments, M is C(R2a)(R2b). In some embodiments, M is C(R2a)(R2b) and each of R2a and R2b is independently hydrogen.
- In some embodiments, M is N(R2c). In some embodiments, M is N(R2c) and R2c is hydrogen or alkyl (e.g., methyl or ethyl).
- In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.
- In some embodiments, R3a is alkyl or —ORc. In some embodiments, R3a is alkyl (e.g., ethyl) substituted by one or more R5. In some embodiments, R5 is —ORc. In some embodiments, Rc is alkyl (e.g., methyl). In some embodiments, R3a is —CH2CH2OCH3.
- In some embodiments, R3a is —ORc. In some embodiments, Rc is alkyl. In some embodiments, R3a is —OCH3.
- In some embodiments, R3a is alkyl. In some embodiments, R3a is alkyl substituted with R5 (e.g., 1 R5). In some embodiments, R5 is —ORc. In some embodiments, R3a is —CH2OCH3.
- In some embodiments, R1 is hydrogen or alkyl. In some embodiments, R1 is hydrogen.
- In some embodiments, R1 is alkyl. In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R1 is unsubstituted C1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R4. In some embodiments, R1 is C1-4 alkyl substituted with 1-4 R4 (e.g., methyl, ethyl, propyl, or isopropyl).
- In some embodiments, R4 is deuterium, halo, —ORc, oxo, carbocyclyl, heteroaryl, —C(O)ORc, or —C(O)N(Rd)2. In some embodiments, R4 is deuterium. In some embodiments, R1 is CD3 or CD2CD3.
- In some embodiments, R4 is halo (e.g., fluoro). In some embodiments, R1 is —CH2CF3 or CH2CHF2
- In some embodiments, R4 is —ORc (e.g., —OH or —OCH3). In some embodiments, le is —CH2CH2OCH3, CH2CH2OH, CH2CH2CH(OH)CH3, CH2CH2CH2OH, or CH2CH2CH2OCH3.
- In some embodiments, R4 is carbocyclyl (e.g., cyclopropyl). In some embodiments, R1 is —CH2CH2-cyclopropyl or —CH2-cyclopropyl.
- In some embodiments, R4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl). In some embodiments, R1 is —CH2— tetrahydropyranyl or —CH2— tetrahydrofuranyl.
- In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R7. In some embodiments, R1 is —CH2CH2-5-methyl-1,3,4-oxadiazole.
- In some embodiments, R4 is —C(O)ORc (e.g., —C(O)OH). In some embodiments, R1 is —CH2C(O)OH.
- In some embodiments, R4 is —C(O)N(Rd)2 (e.g., C(O)—NH(CH3)2, C(O)—NHCH(CH3)2, C(O)—NH(CH3)(CH2CH3), C(O)N(CH3)CH2CF3, or C(O)—N-pyrrolidinyl). In some embodiments, R1 is —CH2C(O)NHCH(CH3)2 or —C(O)—N-pyrrolidinyl.
- In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):
- or a pharmaceutically acceptable salt thereof, wherein A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen; or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy; each Re is alkyl; each R7 is independently alkyl, halo, oxo, —C(O)Rc, or —C(O)ORc; and n is 0, 1, 2, 3, or 4.
- In some embodiments, A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1 R3. In some embodiments, A is phenyl substituted by 1 R3 in the para position.
- In some embodiments, A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is nitrogen-containing heteroaryl. In some embodiments, A is pyridyl. In some embodiments, A is pyridyl substituted by 1 R3. In some embodiments, A is pyridyl is substituted by 1 R3 in the para position
- In some embodiments, R3 is alkyl or —ORc. In some embodiments, R3 is —ORc. In some embodiments, Rc is alkyl. In some embodiments, Rc is alkyl substituted by one or more R6. In some embodiments, R6 is halo. In some embodiemnts, R3 is —OCH3, —OCF3, or —OCH2CF3. In some embodiemnts, R3 is —OCF3.
- In some embodiments, R3 is alkyl. In some embodiments, R3 is alkyl substituted with R5 (e.g., 1 R5). In some embodiments, R5 is —ORc. In some embodiments, R3 is —CH2OCH3.
- In some embodiments, R1 is hydrogen or alkyl. In some embodiments, R1 is hydrogen.
- In some embodiments, R1 is alkyl. In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R1 is unsubstituted C1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R4. In some embodiments, R1 is C1-4 alkyl substituted with 1-4 R4 (e.g., methyl, ethyl, propyl, or isopropyl).
- In some embodiments, R4 is deuterium, halo, —ORc, oxo, carbocyclyl, heteroaryl, —C(O)ORc, or —C(O)N(Rd)2. In some embodiments, R4 is deuterium. In some embodiments, R1 is CD3 or CD2CD3.
- In some embodiments, R4 is halo (e.g., fluoro). In some embodiments, R1 is —CH2CF3 or CH2CHF2.
- In some embodiments, R4 is —ORc (e.g., —OH or —OCH3). In some embodiments, R1 is —CH2CH2OCH3, CH2CH2OH, CH2CH2CH(OH)CH3, CH2CH2CH2OH, or CH2CH2CH2OCH3.
- In some embodiments, R4 is carbocyclyl (e.g., cyclopropyl). In some embodiments, R1 is —CH2CH2-cyclopropyl or —CH2-cyclopropyl.
- In some embodiments, R4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl). In some embodiments, R1 is —CH2— tetrahydropyranyl or —CH2— tetrahydrofuranyl.
- In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R7. In some embodiments, R1 is —CH2CH2-5-methyl-1,3,4-oxadiazole.
- In some embodiments, R4 is —C(O)ORc (e.g., —C(O)OH). In some embodiments, R1 is —CH2C(O)OH.
- In some embodiments, R4 is —C(O)N(Rd)2 (e.g., C(O)—NH(CH3)2, C(O)—NHCH(CH3)2, C(O)—NH(CH3)(CH2CH3), C(O)N(CH3)CH2CF3, or C(O)—N-pyrrolidinyl). In some embodiments, R1 is —CH2C(O)NHCH(CH3)2 or —C(O)—N-pyrrolidinyl.
- In some embodiments, the compound of Formula (I) is a compound of Formula (I-c):
- or a pharmaceutically acceptable salt thereof, wherein A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen; or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy; each Re is alkyl; each R7 is independently alkyl, halo, oxo, —C(O)Rc, or —C(O)ORc; and n is 0, 1, 2, 3, or 4.
- In some embodiments, A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1 R3. In some embodiments, A is phenyl substituted by 1 R3 in the para position.
- In some embodiments, A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is nitrogen-containing heteroaryl. In some embodiments, A is pyridyl. In some embodiments, A is pyridyl substituted by 1 R3. In some embodiments, A is pyridyl is substituted by 1 R3 in the para position
- In some embodiments, R3 is alkyl or —ORc. In some embodiments, R3 is —ORc. In some embodiments, Rc is alkyl. In some embodiments, Rc is alkyl substituted by one or more R6. In some embodiments, R6 is halo. In some embodiemnts, R3 is —OCH3, —OCF3, or —OCH2CF3. In some embodiemnts, R3 is —OCF3.
- In some embodiments, R3 is alkyl. In some embodiments, R3 is alkyl substituted with R5 (e.g., 1 R5). In some embodiments, R5 is —ORc. In some embodiments, R3 is —CH2OCH3.
- In some embodiments, R1 is hydrogen or alkyl. In some embodiments, R1 is hydrogen.
- In some embodiments, R1 is alkyl. In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R1 is unsubstituted C1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R4. In some embodiments, R1 is C1-4 alkyl substituted with 1-4 R4 (e.g., methyl, ethyl, propyl, or isopropyl).
- In some embodiments, R4 is deuterium, halo, —ORc, oxo, carbocyclyl, heteroaryl, —C(O)ORc, or —C(O)N(Rd)2. In some embodiments, R4 is deuterium. In some embodiments, R1 is CD3 or CD2CD3.
- In some embodiments, R4 is halo (e.g., fluoro). In some embodiments, R1 is —CH2CF3 or CH2CHF2.
- In some embodiments, R4 is —ORc (e.g., —OH or —OCH3). In some embodiments, R1 is —CH2CH2OCH3, CH2CH2OH, CH2CH2CH(OH)CH3, CH2CH2CH2OH, or CH2CH2CH2OCH3.
- In some embodiments, R4 is carbocyclyl (e.g., cyclopropyl). In some embodiments, R1 is —CH2CH2-cyclopropyl or —CH2-cyclopropyl.
- In some embodiments, R4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl). In some embodiments, R1 is —CH2— tetrahydropyranyl or —CH2— tetrahydrofuranyl.
- In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R7. In some embodiments, R1 is —CH2CH2-5-methyl-1,3,4-oxadiazole.
- In some embodiments, R4 is —C(O)ORc (e.g., —C(O)OH). In some embodiments, R1 is —CH2C(O)OH.
- In some embodiments, R4 is —C(O)N(Rd)2 (e.g., C(O)—NH(CH3)2, C(O)—NHCH(CH3)2, C(O)—NH(CH3)(CH2CH3), C(O)N(CH3)CH2CF3, or C(O)—N-pyrrolidinyl). In some embodiments, R1 is —CH2C(O)NHCH(CH3)2 or —C(O)—N-pyrrolidinyl.
- In some embodiments, the compound of Formula (I) is a compound of Formula (I-d):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; R′ is hydrogen, alkyl, —ORc, or halogen (e.g., hydrogen); R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen; or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy; each Re is alkyl; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and n is 0, 1, 2, 3, or 4.
- In some embodiments, X is CR′(e.g., CH). In some embodiments, Y is CR′(e.g., CH). In some embodiments, Z is CR′(e.g., CH). In some embodiments, each of X, Y, and Z is independently CR′(e.g., CH).
- In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.
- In some embodiments, R3a is alkyl or —ORc. In some embodiments, R3a is alkyl (e.g., ethyl) substituted by one or more R5. In some embodiments, R5 is —ORc. In some embodiments, Rc is alkyl (e.g., methyl). In some embodiments, R3a is —CH2CH2OCH3.
- In some embodiments, R3a is —ORc. In some embodiments, Rc is alkyl. In some embodiments, R3a is —OCH3.
- In some embodiments, R3a is alkyl. In some embodiments, R3a is alkyl substituted with R5 (e.g., 1 R5). In some embodiments, R5 is —ORc. In some embodiments, R3a is —CH2OCH3.
- In some embodiments, R1 is hydrogen or alkyl. In some embodiments, R1 is hydrogen.
- In some embodiments, R1 is alkyl. In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R1 is unsubstituted C1-6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted isopropyl). In some embodiments, R1 is C1-6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted with 1-4 R4. In some embodiments, R1 is C1-4 alkyl substituted with 1-4 R4 (e.g., methyl, ethyl, propyl, or isopropyl).
- In some embodiments, R4 is deuterium, halo, —ORc, oxo, carbocyclyl, heteroaryl, —C(O)ORc, or —C(O)N(Rd)2. In some embodiments, R4 is deuterium. In some embodiments, R1 is CD3 or CD2CD3.
- In some embodiments, R4 is halo (e.g., fluoro). In some embodiments, R1 is —CH2CF3 or CH2CHF2.
- In some embodiments, R4 is —ORc (e.g., —OH or —OCH3). In some embodiments, R1 is —CH2CH2OCH3, CH2CH2OH, CH2CH2CH(OH)CH3, CH2CH2CH2OH, or CH2CH2CH2OCH3.
- In some embodiments, R4 is carbocyclyl (e.g., cyclopropyl). In some embodiments, R1 is —CH2CH2-cyclopropyl or —CH2-cyclopropyl.
- In some embodiments, R4 is heterocyclyl (e.g., tetrahydropyranyl, tetrahydrofuranyl). In some embodiments, R1 is —CH2— tetrahydropyranyl or —CH2— tetrahydrofuranyl.
- In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl, pyrimidinyl). In some embodiments, R4 is heteroaryl (e.g., oxadiazolyl) substituted by 1-4 R7. In some embodiments, R1 is —CH2CH2-5-methyl-1,3,4-oxadiazole.
- In some embodiments, R4 is —C(O)ORc (e.g., —C(O)OH). In some embodiments, R1 is —CH2C(O)OH.
- In some embodiments, R4 is —C(O)N(Rd)2 (e.g., C(O)—NH(CH3)2, C(O)—NHCH(CH3)2, C(O)—NH(CH3)(CH2CH3), C(O)N(CH3)CH2CF3, or C(O)—N-pyrrolidinyl). In some embodiments, R1 is —CH2C(O)NHCH(CH3)2 or —C(O)—N-pyrrolidinyl.
- In any and all aspects, in some embodiments, the compound of Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d) is selected from:
- or a pharmaceutically acceptable salt thereof.
- In any and all aspects, in certain embodiments, the compound of Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d) is selected from:
- or a pharmaceutically acceptable salt thereof.
- Described herein are compounds and compositions thereof and their use to treat a disease, disorder, or condition relating to aberrant function of a sodium channel ion channel, e.g., abnormal late sodium (INaL) current. In some embodiments, a compound provided by the present invention is effective in the treatment of epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder. Compounds of the invention may also modulate all sodium ion channels, or may be specific to only one or a plurality of sodium ion channels, e.g., Nav 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, and/or 1.9.
- In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a hydrate of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g. a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-b), (I-c), or (I-d); such as a compound of Formula (I) named herein.
- The compounds described herein are useful in the treatment of epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness. Seizure symptoms will vary widely, from a simple blank stare for a few seconds to repeated twitching of their arms or legs during a seizure.
- Epilepsy may involve a generalized seizure or a partial or focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may cry out or make some sound, stiffen for several seconds to a minute a then have rhythmic movements of the arms and legs. The eyes are generally open, the person may appear not to be breathing and actually turn blue. The return to consciousness is gradual and the person maybe confused from minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain having abnormal electrical activity, symptoms may vary.
- Epilepsy, as described herein, includes a generalized, partial, complex partial, tonic clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.
- The compounds described herein may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance West syndrome.
- In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy, such as Dravet syndrome, Angelman syndrome, CDKLS disorder, frontal lobe epilepsy, infantile spasms, West's syndrome, Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.
- In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.
- In some embodiments, the methods described herein further comprise identifying a subject having epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- In one aspect, the present invention features a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; M is O, C(R2a)(R2b), or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R′ is hydrogen, alkyl, —ORc, or halogen; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a ring; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R7 is independently alkyl, halo, or oxo.
- A compound of the present invention (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)) may also be used to treat an epileptic encephalopathy, wherein the subject has a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.
- In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKLS, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- The compounds described herein may be useful in the treatment of a neurodevelopmental disorder. In some embodiments, the neurodevelopmental disorder comprises autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy. In some embodiments, the methods described herein further comprise identifying a subject having a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- In one aspect, the present invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; M is O, C(R2a)(R2b), or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R′ is hydrogen, alkyl, —ORc, or halogen; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a ring; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R7 is independently alkyl, halo, or oxo.
- The compounds described herein may be useful in the treatment of pain. In some embodiments, the pain comprises neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder. In some embodiments, the methods described herein further comprise identifying a subject having pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder) prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- In one aspect, the present invention features a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder) comprising administering to a subject in need thereof a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; M is O, C(R2a)(R2b), or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R′ is hydrogen, alkyl, —ORc, or halogen; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a ring; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R7 is independently alkyl, halo, or oxo.
- The compounds described herein may be useful in the treatment of a neuromuscular disorder. In some embodiments, the neuromuscular disorder comprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation. In some embodiments, the methods described herein further comprise identifying a subject having a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) prior to administration of a compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)).
- In one aspect, the present invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) comprising administering to a subject in need thereof a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR′; M is O, C(R2a)(R2b), or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3; R′ is hydrogen, alkyl, —ORc, or halogen; R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4; each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4; each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7; each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6; each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a ring; each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and each R7 is independently alkyl, halo, or oxo.
- In some embodiments, a compound of the present invention (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or (I-d)) may have appropriate pharmacokinetic properties such that they may active with regard to the central and/or peripheral nervous system. In some embodiments, the compounds provided herein are used to treat a cardiovascular disease such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, and myocardial infarction. In some embodiments, the compounds provided herein may be used in the treatment of diseases affecting the neuromuscular system resulting in itching, seizures, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and disease states related to diabetes, such as diabetic peripheral neuropathy.
- In one aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of X, Y, and Z is independently N or CR′;
- M is O, C(R2a)(R2b), or N(R2c);
- A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3;
- R′ is hydrogen, alkyl, —ORc, or halogen;
- R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
- each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
- each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5; each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
- each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
- each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6;
- or two Rd, taken together with the atoms to which they are attached, form a ring;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- and each R7 is independently alkyl, halo, or oxo.
- In another aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I-1):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of X, Y, and Z is independently N or CR′;
- M is O, C(R2a)(R2b), or N(R2c);
- A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3;
- R′ is hydrogen, alkyl, —ORc, or halogen;
- R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
- each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
- each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
- each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
- each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by one or more R6;
- each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6;
- or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
- each Re is alkyl;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- and each R7 is independently alkyl, halo, oxo, —C(O)Rc, or —C(O)ORc.
- In some embodiments, the compound is not one of the following:
- and a pharmaceutically acceptable salt thereof.
- In some embodiments, the neurological disorder is epilepsy.
- In some embodiments, the neurological disorder is an epileptic encephalopathy.
- In some embodiments, the epileptic encephalopathy comprises Dravet syndrome, infantile spasms, or Lennox-Gastaut syndrome.
- In some embodiments, each of X, Y, and Z is independently CR′(e.g., CH).
- In some embodiments, X is N and each of Y and Z is independently CR′(e.g., CH).
- In some embodiments, Z is N and each of X and Y is independently CR′(e.g., CH).
- In some embodiments, M is O.
- In some embodiments, M is C(R2a)(R2b) (e.g., CH2).
- In some embodiments, M is N(R2) (e.g., NH, NCH3).
- In some embodiments, A is aryl (e.g., phenyl).
- In some embodiments, A is phenyl substituted by 1 R3 (e.g., wherein R3 is in the para position).
- In some embodiments, A is heteroaryl (e.g., pyridyl).
- In some embodiments, A is pyridyl substituted by 1 R3 (e.g., wherein R3 is in the para position).
- In some embodiments, R3 is —ORc.
- In some embodiments, Rc is alkyl substituted by one or more R6.
- In some embodiments, R6 is halo (e.g., fluoro).
- In some embodiments, R3 is —OCF3.
- In some embodiments, R1 is alkyl (e.g., substituted with 1-4 R4).
- In some embodiments, R4 is deuterium, halo, —ORc, oxo, carbocyclyl, heteroaryl, —C(O)ORc, or —C(O)N(Rd)2.
- In some embodiments, R4 is deuterium, fluoro, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, OH, C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)N(CH3)(CH2CF3), or C(O)N— tetrahydropyrrolyl.
- In some embodiments, R4 is halo (e.g., fluoro).
- In some embodiments, R1 is —CH2CF3.
- In some embodiments, the compound of Formula (I-1) is a compound of Formula (I-2):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of X, Y, and Z is independently N or CR′;
- M is O or C(R2a)(R2b);
- R′ is hydrogen, alkyl, —ORc, or halogen;
- R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
- each of R2a and R2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
- each lea R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
- each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
- each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
- each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
- or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with-OH, alkoxy, or alkyl optionally substituted with alkoxy;
- each Re is alkyl;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; n is 0, 1, 2, 3, or 4.
- In some embodiments, the compound of formula I-2 is a compound of formula I-3:
- or a pharmaceutically acceptable salt thereof.
- In some embodiments, the compound of formula I-2 is a compound of formula I-4:
- or a pharmaceutically acceptable salt thereof.
- In some embodiments, the compound of formula I-2 is a compound of formula I-5:
- or a pharmaceutically acceptable salt thereof.
- In some embodiments, the compound of formula I-2 is a compound of formula I-6:
- or a pharmaceutically acceptable salt thereof.
- In some embodiments, each of X, Y, and Z is CR′, wherein R′ is hydrogen.
- In some embodiments, M is O.
- In some embodiments, M is C(R2a)(R2b).
- In some embodiments, R1 is alkyl, wherein alkyl is optionally substituted with one or more R4.
- In some embodiments, each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7.
- In some embodiments, n is 0.
- In some embodiments, the compound of Formula (I-1) is a compound of Formula (I-7):
- or a pharmaceutically acceptable salt thereof, wherein:
- each of X, Y, and Z is independently N or CR′;
- M is N(R2c);
- R′ is hydrogen, alkyl, —ORc, or halogen;
- R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
- each of R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
- each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
- each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
- each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
- each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
- or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
- each Re is alkyl;
- each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
- each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; and n is 0, 1, 2, 3, or 4.
- In some embodiments, the compound is not one of the following:
- and a pharmaceutically acceptable salt thereof.
- In some embodiments, each of X, Y, and Z is CR′, wherein R′ is hydrogen.
- In some embodiments, R1 is alkyl, wherein alkyl is optionally substituted with one or more R4.
- In some embodiments, each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7.
- In some embodiments, n is 0.
- In one aspect, the present disclosure provides a method comprises administering a pharmaceutical composition disclosed herein.
- In one aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein.
- Compounds provided in accordance with the present invention are usually administered in the foi'm of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.)
- The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
- One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
- Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents;
- preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
- The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
- In one aspect, the present disclosure provides a pharmaceutical composition comprising a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- A compound or composition described herein (e.g., for use in modulating a sodium ion channel, e.g., the late sodium (INaL) current) may be administered in combination with another agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. These diseases or conditions can relate to epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder.
- Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide.
- Cardiovascular Agent Combination Therapy
- Cardiovascular related diseases or conditions that can benefit from a combination treatment of the sodium channel blockers of the invention with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.
- Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.
- The co-administration of the sodium channel blockers of the invention with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving.
- Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by reducing its workload resulting in a decreased heart rate and less vigorous heart contraction. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).
- Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.
- Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.
- Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (lnspra).
- Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).
- Vasodilators reduce pressure on the blood vessels by making them relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.
- Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.
- Antithrombotics inhibit the clotting ability of the blood. There are three main types of antithrombotics--platelet inhibitors, anticoagulants, and thrombolytic agents.
- Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.
- Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.
- Thrombolytic agents act to break down an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).
- Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.
- Combinations with amiodarone and dronedarone are of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amioarone and dronedarone.
- Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is associated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clot for illation. Examples of antihypertensive agents include alpha-1-adrenergic antagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), metoprolol (Lopressor), and pindolol (Visken); central alpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenz Acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); combined alpha/beta-adrenergic antagonists, such as labetalol (Normodyne, Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, such as guanethidine (ismelin), reserpine (Serpasil); central nervous system-acting antihypertensives, such as clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents; ACE inhibitors, such as perindopril (Aceon) captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-II receptor antagonists, such as Candesartan (Atacand), Eprosartan (Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan (Micardis), Valsartan (Diovan); calcium channel blockers, such as verapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat, Procardia); diuretics; direct vasodilators, such as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), verapamil; and potassium channel activators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.
- Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood. Examples of lipid lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).
- In this invention, the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients can benefit from treatment of a combination therapy comprising administering to the patient ranolazine in combination with at least one therapeutic agent.
- Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.
- Examples of therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.
- Examples of metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.
- Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section “Cardiovascular Agent Combination Therapy” above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.
- Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.
- Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.
- Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump inhibitors, such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, such as misoprostoL (Cytotec); sucralfate; and antacids.
- Patients presenting with an acute coronary disease event may exhibit conditions that benefit from administration of therapeutic agent or agents that are antibiotics, analgesics, antidepressant and anti-anxiety agents in combination with ranolazine.
- Antibiotics are therapeutic agents that kill, or stop the growth of, microorganisms, including both bacteria and fungi. Example of antibiotic agents include .beta.-Lactam antibiotics, including penicillins (amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor), cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, and monobactams; tetracyclines, such as tetracycline; macrolide antibiotics, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, amikacin; quinolones such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramins, polymyxins; lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics, such as sulfisoxazole.
- Analgesics are therapeutic agents that are used to relieve pain. Examples of analgesics include opiates and morphinomimetics, such as fentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Given the ability of the sodium channel blockers of the invention to treat neuropathic pain via inhibition of the Nay 1.7 and 1.8 sodium channels, combination with analgesics are particularly envisioned. See U.S. Patent Application Publication 20090203707.
- Antidepressant and anti-anxiety agents include those agents used to treat anxiety disorders, depression, and those used as sedatives and tranquillizers. Examples of antidepressant and anti-anxiety agents include benzodiazepines, such as diazepam, lorazepam, and midazolam; benzodiazepines; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine (Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban).
- Accordingly, one aspect of the invention provides for a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises the sodium channel blockers of the invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises the sodium channel blockers of the invention and at least three therapeutic agents, the sodium channel blockers of the invention and at least four therapeutic agents, or the sodium channel blockers of the invention and at least five therapeutic agents.
- The methods of combination therapy include co-administration of a single formulation containing the sodium channel blockers of the invention and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the sodium channel blocker of the invention and therapeutic agent or agents, and consecutive administration of a sodium channel blocker of the invention and therapeutic agent or agents, in any order, wherein preferably there is a time period where the sodium channel blocker of the invention and therapeutic agent or agents simultaneously exert their therapeutic effect.
- In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope.
- The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.
- Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
- The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods well known to those of skill in the art.
- Exemplary general methods for analytical LCMS include Method A (Xtimate C18 (2.1 mm×30 mm, 3 μm); A=H2O (0.04% TFA) and B=CH3CN (0.02% TFA); 50° C.; 1.2 mL/min; 10-80% B over 0.9 minutes, then 80% B for 0.6 minutes) and Method B (Chromolith Flash RP-18 endcapped C18 (2 mm×25 mm); A=H2O (0.04% TFA) and B=CH3CN (0.02% TFA); 50° C.; 1.5 mL/min; 5-95% B over 0.7 minutes, then 95% B for 0.4 minutes).
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- DMF N,N-dimethylformamide
- THF tetrahydrofuran
- MeOH methanol
- CDI 1,1′-Carbonyldiimidazole
- DCM dichloromethane
- EtOH ethanol
- TsOH toluenesulfonic acid
- DMSO dimethyl sulfoxide
- Mel methyl iodide
- EtI ethyl iodide
- TFA trifluoroacetic acid
- TFAA trifluoroacetic anhydride
- LDA lithium diisopropylamide
- DIBAH diisobutylaluminum hydride
- Et3N trimethylamine
- Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
- AcN acetonitrile
- Pd(t-Bu3P)2 bis(tri-tent-butylphosphine)palladium(0)
- DIPEA N,N-diisopropylethylamine
- DIEA N,N-diisopropylethylamine
- HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
- 3-oxide hexafluorophosphate
- PPh3 triphenylphosphine
- DIAD diisopropyl azodicarboxylate
- DEAD diethyl azodicarboxylate
- m-CPBA meta-chloroperoxybenzoic acid
- AcN acetonitrile
- AcOH acetic acid
- BnOH benzyl alcohol
- TDA 4,4′-thiodianiline
- AcCl acetyl chloride
- MSCl methanesulfonyl chloride
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- Synthesis of A-2: To a solution of A-1 (5 g, 26.59 mmol, 1 eq) in THF (50 mL) was added CDI (5.17 g, 31.91 mmol, 1.2 eq), and the mixture was stirred at 20° C. for 1.5 hours. The mixture was poured into water (50 mL), acidized with 1 N HCl (40 mL), extracted with EtOAc (50 mL×2). The combined organic phase was washed with sat. Na2CO3 (40 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated to afford A-2 (6 g, crude) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.43-7.00 (m, 3H)
- Synthesis of A-3: To a solution of A-2 (3 g, 14.02 mmol, 1 eq), Cs2CO3 (9.13 g, 28.04 mmol, 2 eq) in DMF (30 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.88 g, 21.03 mmol, 1.5 eq), and the mixture was stirred at 20° C. for 16 hours. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 25% to 60%) to afford A-3 (1 g, 3.38 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.34 (dd, 1H), 7.22 (s, 1H), 7.14 (d, 1H), 4.40 (q, 2H)
- Synthesis of Compound 1: A mixture of A-3 (200 mg, 675.58 μmol, 1 eq), [2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (191.29 mg, 810.70 μmol, 1.2 eq), Pd(t-Bu3P)2 (51.79 mg, 101.34 μmol, 0.15 eq) and K3PO4 (286.81 mg, 1.35 mmol, 2 eq) in dioxane (5 mL) and H2O (0.3 mL) was stirred at 85° C. for 16 hours,
- The mixture was concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.04% NH3H2O) and B=CH3CN); 55-85% B over 10 minutes) to afford Compound 1 (173.90 mg, 426.48 μmol) as a solid. 1NMR (DMSO-d6 400 MHz) δH=7.54 (s, 1H), 7.47-7.38 (m, 2H), 7.28 (dd, 1H), 7.13 (s, 1H), 7.06 (d, 1H), 4.85 (d, 2H), 3.80 (s, 3H). LCMS Rt=1.41 min using Method A, MS ESI calcd. for C17H12F6NO4 [M+H]+ 408.1, found 407.9.
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- Synthesis of A-4: A mixture of A-2 (500 mg, 2.34 mmol, 1.00 eq), [4-(trifluoromethoxy)phenyl]boronic acid (577.32 mg, 2.80 mmol, 1.20 eq), Pd(t-Bu3P)2 (238.79 mg, 467.25 μmol, 0.20 eq) and K3PO4 (991.82 mg, 4.67 mmol, 2.00 eq) in dioxane (8.00 mL) and H2O (400.00 μL) was stirred at 80° C. for 16 hours. The mixture was then diluted with EtOAc (5 mL), filtered through silica gel, eluted with EtOAc (10 mL) and concentrated to give the crude product that was purified by flash chromatography on silica gel (PE:EtOAc =5:1 to 1:1) to afford A-4 (350.00 mg, 1.19 mmol) as a solid. 1NMR (DMSO-d6 400 MHz) δH=11.79 (br s, 1H), 7.76 (d, 2H), 7.44 (d, 2H), 7.40-7.36 (m, 2H), 7.34-7.31 (m, 1H).
- Synthesis of Compound 2: To a solution of A-4 (50.00 mg, 169.37 μmoll, 1.00 eq), Cs2CO3 (110.37 mg, 338.74 μmol, 2.00 eq) in DMF (2.00 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (58.97 mg, 254.05 μmol, 1.50 eq), and the mixture was stirred at 15° C. for 16 hours. The mixture was then diluted with H2O (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product that was purified by Prep-TLC (silica gel, PE:EtOAc=5:1) to afford Compound 2 (34.80 mg, 89.83 μmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.59-7.54 (m, 2H), 7.39-7.30 (m, 4H), 7.21 (s, 1H), 4.47 (q, 2H). LCMS Rt=1.41 min using Method A, MS ESI calcd. for C16H10F6NO3 [M+H]+ 378.0, found 377.9.
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- Synthesis of A-5: To a solution of A-2 (3 g, 14.02 mmol, 1 eq) and Cs2CO3 (9.13 g, 28.04 mmol, 2 eq) in DMF (20 mL) was added ethyl 3-bromopropanoate (3.81 g, 21.03 mmol, 1.5 eq), and the mixture was stirred at 55° C. for 16 hours. The mixture was poured into water (20 mL), extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=10% to 20% to 50%) to afford A-5 (1 g, 2.81 mmol) as an oil. 1H NMR (DMSO-d6 400 MHz) δH=7.66 (s, 1H), 7.30 (s, 2H), 4.08-3.99 (m, 4H), 2.78 (t, 2H), 1.12 (t, 3H). LCMS Rt=0.80 min using Method B, MS ESI calcd. for C12H13BrNO4 [M+H+2]+ 316.0, found 315.7.
- Synthesis of A-6: A mixture of A-5 (800 mg, 2.55 mmol, 1 eq), [4-(trifluoromethoxy)phenyl]boronic acid (629.32 mg, 3.06 mmol, 1.2 eq), K3PO4 (1.08 g, 5.09 mmol, 2 eq) and Pd(t-Bu3P)2 (195.23 mg, 382.01 μmol, 0.15 eq) in dioxane (10 mL) and H2O (2 mL) was stirred at 85° C. for 16 hours. The mixture was concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 30%) to afford A-6 (1 g, 2.53 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.58 (d, 2H), 7.31 (d, 2H), 7.29-7.26 (m, 3H), 4.19-4.15 (m, 2H), 4.14-4.09 (m, 2H), 2.85 (t, 2H), 1.20 (t, 3H).
- Synthesis of A-7: A mixture of A-6 (200 mg, 505.91 μmol, 1 eq) and N2H4.H2O (129.21 mg, 2.53 mmol, 125.45 μL, 5 eq) in EtOH (1 mL) was stirred at 90° C. for 48 hours. The mixture was concentrated to give the crude A-7 (150 mg, 393.39 μmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.80 (d, 2H), 7.54 (d, 2H), 7.51-7.49 (m, 1H), 7.49-7.45 (m, 2H), 4.43 (t, 2H), 2.92 (t, 2H).
- Synthesis of Compound 3: To a mixture of A-7 (120 mg, 314.71 μmol, 1 eq) in THF (3 mL) was added the 1,1-dimethoxy-N,N-dimethyl-ethanamine (62.87 mg, 472.06 μmol, 69.02 μL, 1.5 eq) and the mixture was stirred at 50° C. for 16 hours. The mixture was concentrated to remove EtOH, and the residue was dissolved in toluene (3 mL), and TsOH.H2O (54.19 mg, 314.71 μmol, 1 eq) was added. The mixture was stirred at 110° C. for 16 hours . The mixture was concentrated, and the residue was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 38-68% B over 10 minutes) to afford Compound 3 (42.08 mg, 103.82 μmol) as a solid. 1H NMR (DMSO-d6+D2O 400 MHz) δH=7.76 (d, 2H), 7.54 (s, 1H), 7.45-7.38 (m, 4H), 4.23 (t, 2H), 3.28 (t, 2H), 2.31 (s, 3H). LCMS Rt=1.25 min using Method A, MS ESI calcd. for C19H15F3N3O4 [M+H]+ 406.1, found 406.0.
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- Synthesis of A-9: To a solution of A-8 (3 g, 13.27 mmol, 1.00 eq) and Cs2CO3 (8.65 g, 26.55 mmol, 2.00 eq) in DMF (20 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.62 g, 19.91 mmol, 1.5 eq), and the mixture was stirred at 15° C. for 16 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by flash chromatography on silica gel (PE:EtOAc=5:1 to 3:1) to afford A-9 (1.2 g, 3.90 mmol) as a solid. 1NMR (DMSO-d6 400 MHz) δH=7.69 (s, 1H), 7.55 (d, 1H), 7.41 (dd, 1H), 4.66 (q, 2H).
- Synthesis of A-10: A mixture of A-9 (500 mg, 1.62 mmol, 1 eq) in N2H4.H2O (5 mL) and DMSO (5 mL) was stirred at 130° C. for 20 hours. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product,which was purified by by flash chromatography on silica gel (EtOAc in PE=10% to 15% to 25%) to afford A-10 (70 mg, 238.04 μmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.25 (dd, 1H), 7.15 (d, 1H), 7.08 (s, 1H), 4.30 (q, 2H), 3.58 (s, 2H).
- Synthesis of Compound 4: A mixture of A-10 (70 mg, 238.04 μmol, 1 eq), [4-(trifluoromethoxy)phenyl]boronic acid (63.72 mg, 309.45 μmol, 1.3 eq), Pd(t-Bu3P)2 (24.33 mg, 47.61 μmol, 0.2 eq) and K3PO4 (101.06 mg, 476.08 μmol, 2 eq) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 80° C. for 12 hours in 20 mL sealed tube under N2. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-TLC (silica gel, PE:EtOAc=4:1) to afford Compound 4 (22.07 mg, 58.56 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.81 (d, 2H), 7.53 (s, 1H), 7.48 (d, 2H), 7.42-7.35 (m, 2H), 4.71 (q, 2H), 3.75 (s, 2H). LCMS Rt=1.26 min using Method A, MS ESI calcd. for C17H12F6NO2 [M+H]+ 376.1, found 375.8.
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- A mixture of A-2 (500 mg, 2.34 mmol, 1.00 eq), [4-(trifluoromethoxy)phenyl]boronic acid (577.32 mg, 2.80 mmol, 1.20 eq), Pd(t-Bu3P)2 (238.79 mg, 467.25 μmol, 0.20 eq) and K3PO4 (991.82 mg, 4.67 mmol, 2.00 eq) in dioxane (8.00 mL) and H2O (400.00 μL) was stirred at 80° C. for 16 hours . The mixture was diluted with EtOAc (5 mL), filtered through silica gel, eluted with EtOAc (10 mL) and concentrated to give the crude product, which was purified by flash chromatography on silica gel (PE:EtOAc=5:1 to 1:1) and Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 38-68% B over 10 minutes) to afford Compound 5 (23.72 mg, 78.54 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=11.79 (br s, 1H), 7.77 (d, 2H), 7.45 (d, 2H), 7.40-7.38 (m, 2H), 7.34-7.32 (m, 1H). LCMS Rt=1.14 min using Method A, MS ESI calcd. for C14H9F3NO3 [M+H]+ 296.0, found 295.7.
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- A mixture of A-3 (200 mg, 675.58 μmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (819.04 mg, 1.35 mmol, 2 eq), Pd(t-Bu3P)2 (51.79 mg, 101.34 μmol, 0.15 eq) and K3PO4 (286.81 mg, 1.35 mmol, 2 eq) in dioxane (10 mL) was stirred at 80° C. for 16 hours . The mixture was concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 54-84% B over 9.5 minutes) and Prep-TLC (silica gel, PE:EtOAc=4:1) to afford Compound 6 (104.91 mg, 267.46 μmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.32 (d, 1H), 7.82 (dd, 1H), 7.38-7.30 (m, 2H), 7.17 (s, 1H), 6.98 (d, 1H), 4.83 (q, 2H), 4.47 (q, 2H). LCMS Rt=1.23 min using Method A, MS ESI calcd. for C16H11F6N2O3 [M+H]+ 393.1, found 392.8.
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- Synthesis of 7-b: A mixture of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (5.00 g, 18.15 mmol), Pd(dppf)Cl2.CH2Cl2 (1.48 g, 1.82 mmol) and Et3N (5.51 g, 54.45 mmol) in EtOH (30 mL) was degassed, and refilled with CO. The reaction was stirred under CO (50 psi) for 16 hours at 80° C., at which point the desired product was observed by LCMS. The reaction mixture was diluted with EtOH (20 mL), and filtered through a Celite pad. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0%-5%) to afford compound 12-b (2.40 g, 8.93 mmol) as an oil. 1H NMR (400 MHz, CDCl3) δH=7.66-7.59 (m, 1H), 7.42 (d, 1H), 7.24-7.19 (m, 1H), 4.36 (q, 2H), 1.35 (t, 3H).
- Synthesis of 7-c: To a solution of 12-b (2.40 g, 8.93 mmol) in THF (30 mL) at −40° C. was added LiA1H4 (406.67 mg, 10.72 mmol) slowly. The reaction was stirred at -40° C. for 1 hour. The reaction was quenched with sat.NH4Cl (0.4 mL), diluted with EtOAc (30 mL).
- The solid formed was filtered through a Celite pad and eluted with EtOAc (30 mL). The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford compound 12-c (1.50 g, 6.62 mmol) as a solid. 1H NMR (400 MHz, CDCl3) δH=7.45-7.42 (m, 1H), 7.38 (d, 1H), 7.13-7.08 (m, 1H), 4.80 (d, 2H), 2.04 (t, 1H).
- Synthesis of 7-d: To a solution of compound 12-c (1.50 g, 6.62 mmol) in THF (20 mL) at 0° C. was added NaH (317.76 mg, 7.94 mmol, 60% purity) slowly. The mixture was stirred at 0° C. for 30 min. Then MeI (2.82 g, 19.86 mmol) was added. The reaction was stirred at 20° C. for 16 hours to give a mixture. The reaction mixture was quenched with sat.NH4Cl (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) to afford compound 12-d (1.40 g, 5.82 mmol) as an oil. 1H NMR (CDCl3 400 MHz) δH=7.43-7.32 (m, 2H), 7.09 (dd, 1H), 4.54 (s, 2H), 3.50 (s, 3H).
- Synthesis of 7-e: A mixture of 12-d (400.00 mg, 1.66 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (505.85 mg, 1.99 mmol), KOAc (325.82 mg, 3.32 mmol), X-Phos (197.84 mg, 415.00 μmol) and Pd2(dba)3 (152.01 mg, 166.00 umol) in dioxane (6 mL) was stirred under N2 at 80° C. for 16 hours. The mixture was cooled to r.t., concentrated to give the crude product. The crude product was purified by silica gel column (PE:EA=1:0 to 50:1) to afford compound 12-e (300.00 mg, 903.29 μmol) as an oil. LCMS Rt=0.99 min using Method B, MS ESI calcd. for C15H21BF3O4 [M+H]+ 333.1, found 332.7.
- A mixture of A-3 (100 mg, 0.34 mmol), 2-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (134.63mg, 0.41 mmol), K3PO4 (110.17mg, 0.52 mmol) and Pd(t-Bu3P)2 (19.92mg, 0.0400 mmo1) in 1,4-dioxane (2 mL) and water (0.2 mL) was stirred under N2 at 85° C. for 16 hours . The mixture was diluted with EtOAc (20 mL), filtered through silica gel and eluted with EtOAc (10 mL), and the filtrate was concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 53-83% B over 10 minutes) to afford Compound 7 (49.97 mg, 0.12 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.52-7.46 (m, 3H), 7.41 (s, 2H), 7.21 (dd, 1H), 4.85 (q, 2H), 4.36 (s, 2H), 3.25 (s, 3H). LCMS Rt=1.40 min using Method A, MS ESI calcd. for C18H14F6NO4 [M+H]+ 422.0822, found 422.0892.
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- To a solution of Compound 5 (500 mg, 1.69 mmol, 1 eq) in anhydrous DMF (5 mL) was added K2CO3 (468.16 mg, 3.39 mmol, 2 eq) and 2-bromoethanol (423.30 mg, 3.39 mmol, 240.51 μL, 2 eq). The resulting mixture was stirred at 60° C. under N2 for 16 hours . Saturated NH4Cl aqueous (10 mL) and EtOAc (20 mL) was added to the reaction mixture and the mixture was stirred for 5 mins. The aqueous phase was extracted with EtOAc (20 mL×2) and the combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to afford Compound 8 (250 mg, crude) as an oil. LCMS Rt=1.18 min using Method A, MS ESI calcd. for C16H13F3NO4 [M+H]+ 340.1, found 339.9.
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- To a solution of Compound 8 (150 mg, 442.13 μmol, 1 eq) in DMF (2 mL) was added NaH (21.22 mg, 530.56 μmol, 60% purity, 1.2 eq) at 0° C., then MeI (313.78 mg, 2.21 mmol, 137.62 μL,μL, 5 eq) was added to the mixture at 0° C. The resulting mixture was stirred at 15° C. for 12 hours . Saturated NH4Cl aqueous (10 mL) and EtOAc (10 mL) were added to the reaction suspension. The resulting mixture was stirred for 5 min. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini C18 (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 60-70%
- B over 8 minutes) to afford Compound 9 (51.05 mg, 144.50 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.75 (d, 2H), 7.71-7.63 (m, 2H), 7.44 (d, 2H), 7.23 (d, 1H), 4.46 (t, 2H), 3.95 (t, 2H), 3.90-3.83 (s, 3H). LCMS Rt=1.25 min using Method A, MS ESI calcd. for C17H15F3NO4 [M+H]+ 354.1, found 353.9.
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- To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs2CO3 (331.10 mg, 1.02 mmol, 2 eq) in DMF (10 mL) was added MeI (360.60 mg, 2.54 mmol, 158.16 μL 5 eq) and the mixture was stirred at 50° C. for 16 hours . The mixture was diluted with sat.NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 45-75% B over 10 minutes) to afford Compound 10 (49.15 mg, 156.52 μmol) as a solid. 1H NMR (DMSO-d6 +D20 400 MHz) δH=7.77 (d, 2H), 7.51 (d, 1H), 7.43-7.37 (m, 4H), 3.36 (s, 3H). LCMS Rt=1.21 min using Method A, MS ESI calcd. for C15H11F3NO3 [M+H]+ 310.1, found 309.9.
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- To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs2CO3 (331.10 mg, 1.02 mmol, 2 eq) in DMF (2 mL) was added the EtI (396.24 mg, 2.54 mmol, 203.20 μL, 5 eq) and the mixture was stirred at 50° C. for 16 hours . The mixture was diluted with sat.NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 48-78% B over 10 minutes) to afford Compound 11 (31.14 mg, 96.33 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.83 (d, 2H), 7.67 (s, 1H), 7.46 (d, 2H), 7.43 (d, 2H), 3.92 (q, 2H), 1.29 (t, 3H). LCMS Rt=1.24 min using Method A, MS ESI calcd. for C16H13F3NO3 [M+H]+ 324.1, found 323.8.
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- To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs2CO3 (331.10 mg, 1.02 mmol, 2 eq) in DMF (2 mL) was added bromomethylcyclopropane (137.19 mg, 1.02 mmol, 97.30 μL, 2 eq). The mixture was stirred at 60° C. under N2 for 16 hours . Saturated NH4Cl (10 mL) and EtOAc (20 mL) were added to the reaction mixture, and the aqueous phase was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini C18 (150 mm×25 mm,10 μm); A=H2O (0.04% NH3H2O) and B=CH3CN); 70-80% B over 8 minutes) to afford Compound 12 (60.27 mg, 172.54 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.85-7.81 (m, 2H), 7.73 (s, 1H), 7.47 (d, 2H), 7.44 (d, 2H), 3.79 (d, 2H), 1.35-1.26 (m, 1H), 0.55-0.48 (m, 2H), 0.46-0.40 (m, 2H). LCMS Rt=1.44 min using Method A, MS ESI calcd. for C18H15F3NO3 [M+H]+ 350.1, found 349.9.
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- To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs2CO3 (331.10 mg, 1.02 mmol, 2 eq) in DMF (2 mL) was added 2-bromopropane (124.99 mg, 1.02 mmol, 95.41 μL, 2 eq). The mixture was stirred at 60° C. under N2 for 16 hours . Saturated NH4Cl (10 mL) and EtOAc (20 mL) were added, and the mixture was stirred for 5 min. The aqueous phase was then extracted with EtOAc (20 mL×2) and the combined organic layers were washed with brine (20 mL×2), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini C18 (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 68-78% B over 8 minutes) to afford Compound 13 (48.72 mg, 144.44 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.83 (d, 2H), 7.67 (s, 1H), 7.46 (d, 2H), 7.42 (s, 2H), 4.57 (q, 1H), 1.50 (d, 6H). LCMS Rt=1.40 min using Method A, MS ESI calcd. for C17H15F3NO3 [M+H]+ 338.1, found 337.9.
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- To a mixture of Compound 5 (200 mg, 677.48 μmol, 1 eq) and K2CO3 (187.26 mg, 1.35 mmol, 2 eq) in DMF (5 mL) was added 3-bromopropan-l-ol (188.33 mg, 1.35 mmol, 122.29 μL, 2 eq). The reaction mixture was heated to 60° C. and stirred for 16 hours . The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated, and the residue was purified by Prep-HPLC (Phenomenex Gemini C18 (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 45-75% B over 8 minutes) to afford Compound 14 (53.43 mg, 150.93 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.81 (d, 2H), 7.63 (s, 1H), 7.47 (d, 2H), 7.43 (d, 2H), 4.61 (t, 1H), 3.94 (t, 2H), 3.48 (q, 2H), 1.92-1.82 (m, 2H). LCMS Rt=0.83 min using Method B, MS ESI calcd. for C17H15F3NO4 [M+H]+ 354.1, found 354.1
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- To a mixture of Compound 14 (150 mg, 424.58 μmol, 1 eq) in DMF (15 mL) was added NaH (20.38 mg, 509.49 μmol, 60% purity, 1.2 eq) at 0° C., and the mixture was stirred for 30 mins. MeI (301.32 mg, 2.12 mmol, 132.16 μL, 5 eq) was added, and the mixture was stirred at 15 ° C. for 16 hours . The mixture was diluted with sat. NH4Cl (40 mL) and extracted with EtOAc (40 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 35-65% B over 10 minutes) afford Compound 15 (28.92 mg, 78.73 μmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.76 (d, 2H), 7.67-7.62 (m, 2H), 7.43 (d, 2H), 7.21 (d, 1H), 4.37-4.31 (m, 2H), 3.85 (s, 3H), 3.53 (t, 2H), 2.14-2.05 (m, 2H). LCMS Rt=1.15 min using Method A, MS ESI calcd. for C18H17F3NO4 [M+H]+ 368.1, found 367.8
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- Synthesis of A-12: To a mixture of Compound 5 (500 mg, 1.69 mmol, 1 eq) and Cs2CO3 (1.10 g, 3.39 mmol, 2 eq) in DMF (15 mL) was added tert-butyl 2-bromoacetate (495.54 mg, 2.54 mmol, 375.41 1.5 eq). The reaction mixture was stirred at 55° C. for 16 hours . The mixture was then diluted with H2O (30 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated, and the residue purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) to afford A-12 (500 mg, 1.22 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.79 (d, 2H), 7.73 (s, 1H), 7.50-7.45 (m, 4H), 4.72 (s, 2H), 1.43 (s, 9H).
- Synthesis of Compound 16: A mixture of A-12 (500 mg, 1.22 mmol, 1 eq) in DCM (20 mL) and TFA (10 mL) was stirred at 15° C. for 16 hours . The mixture was concentrated to give the crude product (520 mg), which was purified by Prep-HPLC (Boston Green ODS (150 mm×30 mm, 5 μm) A=H2O (0.1% TFA) and B=CH3CN); 35-65% B over 8minutes) to afford Compound 16 (41.53 mg, 0.12 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=13.68-13.15 (m, 1H), 7.80 (d, 2H), 7.75 (s, 1H), 7.55-7.38 (m, 4H), 4.70 (s, 2H). LCMS Rt=1.22 min using Method A, MSESI calcd.for C16H9F3NO5 [M-H]+ 352.0511, found 352.0569.
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- To the mixture of Compound 16 (100.mg, 0.28 mmol), HATU (161.4 mg, 0.42 mmol) and DIEA (73.04mg, 0.57 mmol) in DMF (2 mL) was added pyrrolidine (24.16mg, 0.34 mmol) and the mixture was stirred at 15° C. for 16 hours . The mixture was diluted with sat. NH4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 40-70% B over 10 minutes) to afford Compound 17 (19.77 mg, 0.05 mmol) as a solid. 1H NMR (DMSO-d6+D20 400 MHz) δH=7.73 (d, 2H), 7.48 (s, 1H), 7.44-7.40 (m, 4H), 4.70 (s, 2H), 3.52 (t, 2H), 3.28 (t, 2H), 1.97-1.87 (m, 2H), 1.83-1.71 (m, 2H). LCMS Rt=1.26 min using Method A, MS ESI calcd. for C20H18F3N2O4 [M+H]+ 407.1, found 407.0.
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- To the mixture of Compound 16 (100 mg, 0.28 mmol), HATU (161.36 mg, 0.42 mmol) and DIEA (73.04mg, 0.57 mmol) in DMF (2 mL) was added propan-2-amine (20.08mg, 0.34 mmol) and the mixture was stirred at 15° C. for 16 hours . The mixture was diluted with NH4Cl (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 40-70% B over 10 minutes), to afford Compound 18 (17.87mg, 0.05 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.20 (d, 1H), 7.77 (d, 2H), 7.58 (s, 1H), 7.50-7.43 (m, 4H), 4.50 (s, 2H), 3.89-3.83 (m, 1H), 1.08 (d, 6H). LCMS Rt=1.25 min using Method A, MS ESI calcd. for C19H18F3N2O4 [M+H]+ 395.1, found 395.0.
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- To a mixture of Compound 5 (100 mg, 0.34 mmol), 2-cyclopropylethanol (43.76 mg, 0.51 mmol) and PPh3 (133.13 mg, 0.51 mmol) in THF (3 mL) under N2 was added DIAD (102.64 mg, 0.51 mmol) drop-wise at 0° C. The reaction mixture was then stirred at 15° C. for 16 hours . The reaction mixture was concentrated, and the residue was purified by Prep-HPLC C (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 72-82% B over 8 minutes) to afford Compund 19 (57.45 mg, 0.16 mmol) as an oil. 1H NMR (MeOD-d4 400 MHz) δH=7.72 (d, 2H), 7.46 (d, 1H), 7.43-7.39 (m, 1H), 7.38-7.32 (m, 3H), 4.03 (t, 2H), 1.71 (q, 2H), 0.80-0.68 (m, 1H), 0.46-0.38 (m, 2H), 0.03 (q, 2H). LCMS Rt=1.12 min using Method A, MS ESI calcd. for C19H17F3NO3 [M+H]+ 364.1, found 364.0.
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- A mixture of A-2 (200 mg, 0.93 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (566.47 mg, 1.87 mmol), Pd(t-BuP3)2 (95.51 mg, 0.19 mmol) and K3PO4 (257.92 mg, 1.87 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was stirred at 85° C. for 16 hours . The mixture was diluted with EtOAc (10 mL), filtered through silica gel, eluted with EtOAc (10 mL) and the filtrate concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 37-67% B over 10 minutes) to afford Compound 20 (48.55 mg, 0.16 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=11.80 (br s, 1H), 8.48 (d, 1H), 8.10 (dd, 1H), 7.38 (s, 2H), 7.34 (s, 1H), 7.07 (d, 1H), 5.04 (q, 2H). LCMS Rt=1.20 min using Method A, MS ESI calcd. for C14H10F3N2O3 [M+H]+ 311.1, found 310.8.
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- Synthesis of A-13: A mixture of A-8 (4 g, 17.70 mmol, 1 eq), [4-(trifluoromethoxy)phenyl]boronic acid (4.37 g, 21.24 mmol, 1.2 eq), Pd(t-Bu3P)2 (633.09 mg, 1.24 mmol, 0.07 eq) and K3PO4 (9.39 g, 44.24 mmol, 2.5 eq) in dioxane (200 mL) and H2O (40 mL) was stirred at 80° C. for 16 hours under N2. The mixture was then concentrated to a residue, and the residue was diluted with H2O (100 mL). The mixture was extracted with EtOAc (200 mL×2), and the combined organic phase was washed with water (50 mL×2) and brine (50 mL), dried over Na2SO4, filtered and concentrated to give a crude product that was purified by flash chromatography on silica gel (EtOAc in PE=20% to 30% to 50%) to afford A-13 (200 mg, 650.99 μmol). 1H NMR (DMSO-d6 400 MHz) δH=11.18 (br s, 1H), 7.85 (d, 2H), 7.61 (d, 1H), 7.51 (d, 2H), 7.37 (dd, 1H), 7.12 (d, 1H)
- Syntheis of A-14: A mixture of A-13 (200 mg, 650.99 μmol, 1 eq) and Cs2CO3 (424.21 mg, 1.30 mmol, 2 eq) in CH3CN (20 mL) was stirred at 20° C. for 0.5 hour. To the mixture was added ethyl 3-bromopropanoate (235.69 mg, 1.30 mmol, 2 eq), then the mixture was stirred at 55° C. for 4 hours . The mixture was filtered through Celite, eluted with EtOAc (30 mL), and the filtrate was concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE=10% to 20% to 40%) to afford A-14 (130 mg, 319.14 μmol) as an oil. 1H NMR (CDCl3, 400 MHz) δH=7.72-7.63 (m, 3H), 7.37 (d, 2H), 7.31 (dd, 1H), 7.22 (d, 1H), 4.13 (q, 2H), 4.10 (t, 2H), 2.80 (t, 2H), 1.22 (t, 3H).
- Synthesis of A-15: A mixture of A-14 (120 mg, 294.59 μmol, 1 eq) and hydrazine (944.03 mg, 29.46 mmol, 1.07 mL, 100 eq) in EtOH (3 mL) was stirred at 100° C. for 14 hours . After cooling, the mixture was concentrated to afford A-15 (110 mg, 259.82 μmol) as a solid. LCMS Rt=0.76 min using Method B, MS ESI calcd. for C18H17F3N3O3 [M+H]+ 380.1, found 379.9
- Synthesis of Compound 21: To a mixture of A-15 (110 mg, 289.98 μmol, 1 eq) in THF (4 mL) was added 1,1-dimethoxy-N,N-dimethyl-ethanamine (77.24 mg, 579.97 μmol, 84.79 μL, 2 eq), then the mixture was stirred at 55° C. for 4 hours. The mixture was concentrated to a residue, followed by addition of toluene (4 mL) and TsOH.H2O (11.03 mg, 58.00 μmol, 0.2 eq). The mixture was stirred at 110° C. for 16 hours . After cooling, the mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (30 mL×2). The combined organic phase was washed with water (10 mL×2) and brine (10 mL), dried over Na2SO4, filtered and concentrated to give a crude product that was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to afford Compound 21 (50.22 mg, 124.51 μmol) as a solid. 1H NMR (CDCl3 400 MHz) δH=7.57 (d, 2H), 7.36-7.28 (m, 3H), 7.22 (dd, 1H), 6.92 (s, 1H), 4.20 (t, 2H), 3.58 (s, 2H), 3.24 (t, 2H), 2.41 (s, 3H). LCMS Rt=1.17 min using Method A, MS ESI calcd. for C2oH17F3N3O3 [M+H]+ 404.1, found 403.9
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- Synthesis of A-18: A mixture of A-17 (2 g, 10.58 mmol, 1 eq) and CDI (2.06 g, 12.70 mmol, 1.2 eq) in THF (30 mL) was stirred at 50° C. for 2 hours . The mixture was then filtered through silica gel, and the filtrate was concentrated to provide the crude product A-18 (2.3 g, crude). 1H NMR (DMSO-d6 400 MHz) δH=12.82-11.26 (m, 1H), 8.04 (d, 1H), 7.71 (d, 1H).
- Synthesis of A-19: To a solution of A-18 (2.5 g, 11.63 mmol, 1 eq) and Cs2CO3 (7.58 g, 23.26 mmol, 2 eq) in DMF (20 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.40 g, 23.26 mmol, 2 eq), and the mixture was stirred at 20° C. for 16 hours. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (40 mL×2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=20% to 40% to 60%) to afford A-19 (700 mg, 2.36 mmol) as a solid. 1H NMR (DMSO-d6400 MHz) δH=8.16 (d, 1H), 8.13 (d, 1H), 4.90-4.82 (m, 2H).
- Synthesis of Compound 22: A mixture of A-19 (200 mg, 673.34 μmol, 1 eq) ,[4-(trifluoromethoxy)phenyl]boronic acid (207.99 mg, 1.01 mmol, 1.5 eq), Pd(t-Bu3P)2 (51.62 mg, 101.00 μmol, 0.15 eq) and K3PO4 (285.86 mg, 1.35 mmol, 2 eq) in dioxane (6 mL) and H2O (0.6 mL) was stirred at 90° C. for 16 hours . The mixture was concentrated and the crude product was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 63-73% B over 8 minutes) to afford Compound 22 (35.08 mg, 90.81 μmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.29 (d., 1H), 7.60-7.54 (m, 2H), 7.47 (d, 1H), 7.37 (d, 2H), 4.50 (q, 2H). LCMS Rt=1.33 min using Method A, MS ESI calcd. for C15H9F6N2O3 [M+H]+ 379.0, found 378.9.
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- Synthesis of A-21: A mixture of A-20 (5000 mg, 22.73 mmol), 2,2,2-trifluoroethanamine hydrochloride (4620 mg, 34.09 mmol) and DIEA (8811.82 mg, 68.18 mmol) in THF (30 mL) was stirred at 70° C. for 16 hours. After cooling to room temperature, the mixture was concentrated, then the mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE=0 to 30% to 100%) to give the product A-21 (6100 mg, 20.40 mmol). 1H NMR (CDCl3, 400 MHz) δH=8.28 (br s, 1H), 8.09 (dd, 1H), 7.12 (s, 1H), 6.94 (dd, 1H), 4.08-3.86 (m, 2H)
- Synthesis of A-22: A mixture of A-21 (2 g, 6.69 mmol), Fe (3.74 g, 66.88 mmol) and NH4Cl (3.58 g, 66.88 mmol) in ethanol (20 mL) and water (20 mL) was stirred at 75° C. for 2 hours . After cooling to r.t, the mixture was filtrated through Celite, and eluted with EtOAc (50 mL×2). The filtration was concentrated and diluted with EtOAc (50 mL), washed with (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product of A-22 (1.7 g, 6.32 mmol). LCMS Rt=0.74 min using Method B, MS ESI calcd. for C8H9BrF3N2 [M+H]+ 269.0, found 268.9.
- Synthesis of A-23: A mixture of A-22 (1000 mg, 3.72 mmol) and CDI (523.68 mg, 3.72 mmol) in THF (10 mL) was stirred at 20° C. for 16 hours . After cooling to r.t, the mixture was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 50% to 100%) to afford A-23 (930 mg, 2.97 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=9.76 (br s, 1H), 7.30-7.26 (m, 1H), 7.23 (s, 1H), 7.02 (d, 1H), 4.46 (q, 2H).
- Synthesis of Compound 23: A mixture of A-23 (400 mg, 1.36 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (558.34 mg, 2.71 mmol), Pd(dppf)Cl2.CH2Cl2 (221.42 mg, 0.27 mmol) and K2CO3 (374.73 mg, 2.71 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 90° C. for 16 hours . The mixture was concentrated to give a residue that was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 50-80% B over 10 minutes)to afford Compound 23 (44.78 mg, 0.12 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.80 (br s, 1H), 7.58 (d, 2H), 7.36-7.28 (m, 3H), 7.25-7.16 (m, 2H), 4.53 (q, 2H). LCMS Rt=1.19 min using Method A, MS ESI calcd. for C16H11F6N2O2 [M+H]+ 377.1, found 377.0.
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- Synthesis of A-24: To the mixture of the A-4 (1500 mg, 5.08 mmol) and K2CO3 (1402.39 mg, 10.16 mmol) in MeCN (5 mL) was added tert-butyl 3-bromopropanoate (1062.36 mg, 5.08 mmol), and the mixture was stirred at 50° C. for 16 hours . The mixture was cooled to r.t., diluted with sat.NH4Cl (50 mL), extracted with EtOAc (50 mL×2), and the combined phase was washed over brine (20 mL), dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=5% to 10% to 20%) to afford A-24 (1300 mg, 3.07 mmol) as an oil. 1H NMR (DMSO-d6 400 MHz) δH=7.83 (d, 2H), 7.72 (s, 1H), 7.47 (d, 2H), 7.43 (s, 2H), 4.10 (t, 2H), 2.75 (t, 2H), 1.31 (s, 9H).
- Synthesis of Compound 24: A mixture of A-24 (700 mg, 1.65 mmol) in TFA (5 mL, 1.65 mmol) and DCM (10 mL) was stirred at 15° C. for 16 hours . The mixture was concentrated, diluted with H2O (20 mL) and extracted with DCM (20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give a residue that was purified by Prep-HPLC (Phenomenex Synergi (150 mm×30 mm, 4 μm); A=H2O (0.1% TFA) and B=CH3CN); 45-75% B over 8 minutes) to afford Compound 24 (34.06 mg, 0.09 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=12.46 (br s, 1H), 7.82 (d, 2H), 7.72 (s, 1H), 7.47 (d, 2H), 7.43 (s, 2H), 4.09 (t, 2H), 2.76 (t, 2H). LCMS Rt=1.24 min using Method A, ESI calcd. for C17H13F3NO5 [M+H]+ 368.0668, found 368.0683
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- To the mixture of Compound 24 (150 mg, 0.41 mmol), HATU (232.79 mg, 0.61 mmol) and DIEA (105.37 mg, 0.82 mmol) in DMF (2 mL) was added N-methylmethanamine (22.09 mg, 0.49 mmol), and the mixture was stirred at 15° C. for 16 hours . The mixture was diluted with sat.NH4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give a residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 40-70% B over 10 minutes) to afford Compound 25 (77.68 mg, 0.20 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.83 (d, 2H), 7.73 (s, 1H), 7.47 (d, 2H), 7.44-7.39 (m, 2H), 4.07 (t, 2H), 2.92 (s, 3H), 2.83 (t, 2H), 2.80 (s, 3H). LCMS Rt=1.166 min using Method A, MS ESI calcd. for C19H18F3N2O4 [M+H]+ 395.1, found 395.0.
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- To the mixture of Compound 24 (150 mg, 0.4100 mmol), HATU (232.79 mg, 0.61 mmol) and DIEA (105.37 mg, 0.82 mmol) in DMF (2 mL) was added pyrrolidine (34.86 mg, 0.49 mmol) and the mixture was stirred at 15° C. for 16 hours . The mixture was diluted with sat.NH4Cl (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give a residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 43-73% B over 10 minutes) to afford Compound 26 (72.24 mg,0.17 mmol) as an oil. 1H NMR (DMSO-d6+D2O 400 MHz) δH=7.77 (d, 2H), 7.58 (s, 1H), 7.46-7.33 (m, 4H), 4.07 (t, 2H), 3.30 (t, 2H), 3.17 (t, 2H), 2.73 (t, 2H), 1.82-1.73 (m, 2H), 1.71-1.62 (m, 2H). LCMS Rt=1.20 min ung Method A, MS ESI calcd. for C21H20F3N2O4 [M+H]+ 421.1, found 421.0.
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- To a mixture of Compound 24 (150 mg, 0.41 mmol), HATU (232.94 mg, 0.61 mmol) and DIEA (105.53 mg, 0.82 mmol) in DMF (3 mL) was added propan-2-amine (28.97 mg, 0.49 mmol). The resulting mixture was stirred at 15° C. for 16 hours . To the stirred mixture was added saturated NH4Cl aqueous (15 mL) and EtOAc (15 mL), and the organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by Prep-HPLC (Xtimate C18 (250 mm×50 mm, 10 μm) A=H2O (0.05% NH4OH) and B=CH3CN); 50-80% B over 8 minutes) to afford Compound 27 (78.39 mg, 0.19 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.62-7.56 (m, 2H), 7.36 (d, 1H), 7.33-7.27 (m, 3H), 7.26-7.23 (m, 1H), 5.43 (d, 1H), 4.21 (t, 2H), 4.04-3.93 (m, 1H), 2.66 (t, 2H), 1.01 (d, 6H). LCMS Rt=1.30 mins using Method A, MS ESI calcd. for C20H20F3N2O4 [M+H]+ 409.1, found 409.0
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- To a solution of Compound 24 (150 mg, 0.41 mmol), HATU (232.94 mg, 0.61 mmol) and
- DIEA (105.53 mg, 0.82 mmol) in DMF (3 mL) was added N-ethylethanamine (35.85 mg, 0.49 mmol). The resulting mixture was stirred at 15° C. for 16 hours . To the stirring mixture was added saturated NH4Cl aqueous (15 mL) and EtOAc (15 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product that was purified by Prep-HPLC Xtimate C18 (250 mm×50 mm, 10 μm) A=H2O (0.05% NH4OH) and B=CH3CN); 58-88% B over 8 minutes) to afford Compound 28 (88.41 mg, 0.213 mmol) as an oil. 1H NMR (DMSO-d6 400 MHz) δH=7.82 (d, 2H), 7.73 (s, 1H), 7.47 (d, 2H), 7.42 (s, 2H), 4.10 (t, 2H), 3.29-3.21 (m, 4H), 2.82 (t, 2H), 1.05 (t, 3H), 0.96 (t, 3H). LCMS Rt=1.35 mins using Method A, MS ESI calcd. for C21H22F3N2O4 [M+H]+ 423.1, found 423.0.
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- Synthesis of A-26: To a solution of A-25 (10 g, 71.38 mmol) in methanol (200 mL) was added CH3ONa (3.85 g, 71.38 mmol) slowly at 15° C. The resulting solution was stirred at 15° C. for 30 min. Then Br2 (11.41 g, 71.38 mmol) was added to the solution dropwise 0° C. and the mixture was stirred at 15° C. for 16 hours . The reaction solution was quenched with glacial AcOH (1.25 mL) and concentrated to give the crude product of A-26 (22.00 g, crude) as a solid. The crude product was used in the next step without further purification. LCMS Rt=0.54 mins using Method B, MS ESI calcd. for C5H4BrN2O3 [M+H]+218.9, found 219.1.
- Synthesis of A-27: To a mixture of A-26 (10 g, 45.66 mmol) and K2CO3 (6.31 g, 45.66 mmol) in DMF (150 mL) was added bromomethylbenzene (3.9 g, 22.83 mmol). The resulting mixture was stirred at 60° C. for 16 hours . The reaction mixture was cooled to room temperature. Water (300 mL) and EtOAc (200 mL) was added to the reaction mixture. The organic layer was washed with brine (100 mL×2), dried over Na2SO4, filtered and concentrated to give a crude product that was purified by flash chromatography on silica gel (PE:EtOAc=PE to 10:1 to 5:1 to 3:1) to afford A-27 (2.95 g, 9.54 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.05 (s, 2H), 7.44-7.34 (m, 5H), 5.39 (s, 2H).
- Synthesis of A-28: A mixture of A-27 (950 mg, 3.07 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (759.45 mg, 3.69 mmol), Pd(t-Bu3P)2 (235.61 mg, 0.46 mmol) and K3PO4 (1304.9 mg, 6.15 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was stirred under N2 at 85° C. for 16 hours . The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give a crude product that was purified by flash chromatography on silica gel (PE:EtOAc=10:1 to 5:1 to 3:1) to afford A-28 (960 mg, 2.46 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.39 (d, 1H), 8.20-8.11 (m, 3H), 7.54-7.33 (m, 7H), 5.44 (s, 2H).
- Synthesis of A-29: A mixture of A-28 (150 mg, 0.38 mmol) and Pd/C (50 mg) in methanol (15 mL) was stirred under H2 at 15° C. for 16 hours . The reaction mixture was filtered through Celite and the filtrate was concentrated to afford A-29 (100 mg, 0.37 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.98 (d, 2H), 7.34 (d, 2H), 7.00 (d, 1H), 6.90 (d, 1H), 5.58 (s, 2H).
- Synthesis of Compound 29: A mixture of 2-amino-6-[4-(trifluoromethoxy)phenyl]-pyridin-3-ol (100 mg, 0.37 mmol) and CDI (62.57 mg, 0.44 mmol) in THF (5 mL) was stirred at 60° C. for 16 hours . The reaction mixture was cooled to room temperature and concentrated to give a crude product that purified by Prep-HPLC Xtimate C18 (250 mm×50 mm, 10 μm) A=H2O (0.05% NH4OH) and B=CH3CN); 30-60% B over 8 minutes) to afford Compound 29 (50.89 mg, 0.17 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=12.55 (br s, 1H), 8.11 (d, 2H), 7.76-7.69 (m, 2H), 7.47 (br d, 2H). LCMS=Rt=1.23 min using Method A, MS ESI calcd. for C13H8F3N2O3 [M+H]+ 297.0, found 296.9.
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- Synthesis of A-30: To a solution of Compound 14 (320 mg, 0.91 mmol) in DCM (10 mL) at 0° C. was added methanesulfonyl chloride (0.08 mL, 1.09 mmol). The reaction mixture was stirred at 15° C. for 1 hour to give a solution The reaction was quenched with sat.NH4Cl (30 mL), extracted with DCM (20 mL×3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give A-30 (420 mg, crude) as a solid. 1H NMR MeOD-d4 400 MHz) δH=7.75 (d, 2H), 7.49 (d, 1H), 7.44-7.40 (m, 1H), 7.38-7.30 (m, 3H), 4.34 (t, 2H), 4.08 (t, 2H), 3.05 (s, 3H), 2.31-2.22 (m, 2H).
- Synthesis of Compound 30: To the mixture of pyrrolidin-2-one (59.18 mg, 0.70 mmol) in DMF (3 mL) was added NaH (27.82mg, 0.70 mmol) at 0° C. and the mixture was stirred for 30 mins. Then A-30 (200.mg, 0.46 mmol) was added, and the mixture was stirred at 15° C. for 16 hours . The mixture was quenched by sat.NH4Cl (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 40-70% B over 10 minutes) to afford Compound 30 (12.42mg, 0.03 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.59 (d, 2H), 7.34-7.28 (m, 4H), 7.16 (s, 1H), 3.89 (t, 2H), 3.47-3.39 (m, 4H), 2.38 (t, 2H), 2.13-1.99 (m, 4H). LCMS Rt=1.16 min using Method A, MS ESI calcd. for C21H20F3N2O4 [M+H]+ 421.1, found 421.0.
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- To the mixture of oxazolidin-2-one (60.56 mg, 0.70 mmol) in DMF (3 mL) was added the NaH (27.82 mg, 0.70 mmol) at 0° C. and the mixture was stirred for 30 mins. Then A-30 (200 mg, 0.46 mmol) was added and the mixture was stirred at 15° C. for 16 hours . The mixture was quenched by sat.NH4Cl (10 mL), extracted with EtOAc (10 mL×2), and the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 20%) to afford Compound 31 (36.59 mg, 0.0843 mmol) as a solid. 1H NMR (DMSO-d6, 400 MHz) δH=7.83 (d, 2H), 7.71 (s, 1H), 7.48 (d, 2H), 7.44 (d, 2H), 4.29-4.16 (m, 2H), 3.91 (t, 2H), 3.61-3.49 (m, 2H), 3.26 (t, 2H), 2.06-1.91 (m, 2H). LCMS Rt=1.15 min using Method A, MS ESI calcd. for C20H18F3N2O5 [M+H]+ 423.1, found 423.0.
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- To a mixture of t-BuOK (47.71 mg, 0.43 mmol) and Compound 23 (80.00 mg, 0.21 mmol) in THF (10 mL) was added CH3I (150.86 mg, 1.06 mmol). The mixture was stirred at 20° C. for 16 hours . After cooling to r.t, the mixture was concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 68-78% B over 8 minutes) afford Compound 32 (20.18 mg, 0.05 mmol) as a solid. 1H NMR (CDCl3 400 MHz) δH=7.58 (d, 2H), 7.36 (dd, 1H), 7.31 (d, 2H), 7.23 (s, 1H), 7.09 (d, 1H), 4.53 (q, 2H), 3.49 (s, 3H). LCMS Rt=1.23 min using Method A, ESI calcd. for C17H13F6N2O2 [M+H]+ 391.0876, found 391.0818.
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- Synthesis of A-31: To a solution of A-28 (660 mg, 1.69 mmol) in Methanol (5 mL) was added NiCl2.6H2O (1025.74 mg, 5.07 mmol). To the resulting mixture was added NaBH4 (319.59 mg, 8.45 mmol) slowly and the mixture was stirred at 15° C. for 1 hour to give a suspension . Saturated NaHCO3 aqueous (10 mL) and DCM (20 mL) was added to the reaction mixture and filtered through Celite. The filtrate was separated, and the organic layer was washed with brine (10 mL×2), dried over anhydrous Na2SO4, filtered through silica gel (300-400 mesh) and concentrated to give A-31 (220 mg, 0.61 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.02 (d, 2H), 7.52 (d, 2H), 7.43-7.30 (m, 5H), 7.21-7.16 (m, 1H), 7.12-7.07 (m, 1H), 5.87 (s, 2H), 5.19 (s, 2H). LCMS Rt=0.768 mins in 1.5 mins chromatography, MS ESI calcd. for C19H16F3N2O2 [M+H]+ 361.1, found 361.0.
- Synthesis of A-32: To a solution of A-31 (200 mg, 0.56 mmol) in THF (10 mL) was added TEA (168.51 mg, 1.67 mmol) and TFAA (233.15 mg, 1.11 mmol) slowly. The resulting mixture was stirred at 15° C. for 16 hours to give a solution . Saturated NaHCO3 aqueous (10 mL) and EtOAc (20 mL) was added to the reaction mixture. After separation, the organic layer was washed with brine (10 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give A-32 (180 mg, 0.37 mmol) as a solid. LCMS Rt=0.97 min using Method B, MS ESI calcd. for C21H15F6N2O3 [M+H]+ 457.1, found 456.9.
- Synthesis of A-33: To a solution of A-32 (180 mg, 0.39 mmol) in DMF (5 mL) was added NaH (78.89 mg, 1.97 mmol). The resulting mixture was stirred at 15° C. for 10 mins. To the mixture was added 1,1,1-trifluoro-2-(trifluoromethylsulfonyl)ethane (255.72 mg, 1.18 mmol). The reaction mixture was stirred at 15° C. for 16 hours . Saturated NH4Cl aqueous (25 mL) and EtOAc (30 mL) were added to the reaction mixture. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-33 (100 mg, 0.22 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.08 (d, 2H), 7.53 (d, 2H), 7.44-7.38 (m, 4H), 7.37-7.32 (m, 1H), 7.30-7.20 (m, 2H), 6.74 (t, 1H), 5.23 (s, 2H), 4.34-4.20 (m, 2H). LCMS Rt=1.03 min using Method B, MS ESI calcd. for C21H17F6N2O2 [M+H]+ 443.1, found 443.4.
- Synthesis of A-34: To a solution of A-33 (100 mg, 0.23 mmol) in methanol (5 mL) was added Pd/C (50 mg, 0.2300 mmol). The resulting mixture was stirred at 15° C. under H2 balloon (15 psi) for 3 hours to give a suspension . The reaction mixture was filtered through Celite, and the filtrate was concentrated to give A-34 (86 mg, 0.22 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.03 (d, 2H), 7.37 (d, 2H), 7.12 (d, 1H), 6.97 (d, 1H), 6.51 (t, 1H), 4.29-4.19 (m, 2H). LCMS Rt=0.89 min using Method B, MS ESI calcd. for C14H11F6N2O2 [M+H]+353.1, found 353.3.
- Synthesis of Compound 33: To a solution of A-34 (86 mg, 0.24 mmol) in THF (4 mL) was added CDI (41.28 mg, 0.29 mmol) and the resulting mixture was stirred at 55° C. under N2 for 16 hours to give a colorless solution . The reaction solution was cooled to room temperature and concentrated to give a crude product that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 45-75% B over 10 minutes) to afford Compound 33 (35.88 mg, 0.09 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.20 (d, 2H), 7.94-7.85 (m, 2H), 7.50 (d, 2H), 4.79 (q, 2H). LCMS Rt=1.41 min using Method A, MS ESI calcd. for C13H9F6N203 [M+H]+ 379.0, found 378.9.
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- Synthesis of A-35: To a solution of A-18 (300 mg, 1.4 mmol) in DMF (7 mL) was added Cs2CO3 (909.77 mg, 2.79 mmol) and BnBr (286.38 mg, 1.67 mmol), and the mixture was stirred at 20° C. for 2 hours . The mixture was poured into water (15 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE=20% to 40% to 60%) to afford A-35 (370 mg, 0.93 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.12 (d, 1H), 7.96 (d, 1H), 7.45-7.40 (m, 2H), 7.40-7.31 (m, 3H), 5.04 (s, 2H). LCMS Rt=0.81 min using Method B, MS ESI calcd. for C13H10BrN2O2 [M+H+2]+307.0, found 306.7.
- Synthesis of Compound 34: A mixture of A-35 (300 mg, 0.98 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (242.96 mg, 1.18 mmol), Pd(t-Bu3P)2 (100.48 mg, 0.20 mmol) and K3PO4 (416.87 mg, 1.97 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 90° C. for 16 hours . After cooling to r.t., the mixture was concentrated to give the crude product, which was purified by by flash chromatography on silica gel (EtOAc in PE=15% to 40% to 70%) and Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 57-87% B over 8 minutes) to afford Compound 34 (43.43 mg, 0.11 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.32 (d, 1H), 8.03 (d, 1H), 7.81 (d, 2H), 7.52-7.45 (m, 4H), 7.40-7.29 (m, 3H), 5.12 (s, 2H). LCMS Rt=1.40 min using Method A, MS ESI calcd. for C20H14F3N2O3 [M+H]+ 387.1, found 387.0
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- To a mixture of A-4 (100 mg, 0.34 mmol), 2-pyrimidin-2-ylethanol (75.69 mg, 0.61 mmol) and PPh3 (159.75 mg, 0.61 mmol) in THF (3 mL) under N2 was added DEAD (106.19 mg, 0.61 mmol) drop-wise at 0° C. The reaction mixture was then stirred at 20° C. for 16 hours. The mixture was concentrated to give the crude product that was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 60-70% B over 8 minutes) to afford Compound 35 (65.01 mg, 0.1575 mmol) as an oil. 1H NMR (DMSO-d6+D20 400 MHz) δH=8.69 (d, 2H), 7.77 (d, 2H), 7.52 (s, 1H), 7.46 (d, 2H), 7.40 (d, 2H), 7.33 (t, 1H), 4.33 (t, 2H), 3.33 (t, 2H). LCMS Rt=1.26 min in using Method A, MS ESI calcd. for C20H15F3N3O3 [M+H]+ 402.1, found 402.0.
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- Synthesis of A-37: To a mixture of A-36 (5 g, 38.6 mmol) and K2CO3 (10.65 g, 77.2 mmol) in DMF (40 mL) was added bromomethylbenzene (5.04 mL, 42.46 mmol). The reaction mixture was heated to 60° C. and stirred for 16 hours . After cooling, the mixture was diluted with H2O (150 mL), and the mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated to afford A-37 (8000 mg, 36.42 mmol), which was used directly in next step. 1H NMR (CDCl3, 400 MHz) δH=8.14 (d, 1H), 7.44-7.34 (m, 5H), 7.26-7.21 (m, 2H), 5.11 (s, 2H).
- Synthesis of A-38: A mixture of A-37 (3 g, 13.66 mmol), [4-(trifluoromethoxy)phenyl]-boronic acid (3.09 g, 15.02 mmol), Pd(t-Bu3P)2 (1.0 g, 2.05 mmol) and K3PO4 (5.79 g, 27.31 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) under N2 was heated to 90° C. and stirred for 16 hours . After cooling, the reaction mixture was diluted with EtOAc (20 mL), filtered through a Celite pad, eluted with EtOAc (20 mL) and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-38 (4000 mg, 11.58 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.46 (d, 1H), 8.13 (d, 2H), 7.96 (d, 1H), 7.57 (dd, 1H), 7.52-7.32 (m, 7H), 5.25 (s, 2H).
- Synthesis of A-39: To a solution of A-38 (4 g, 11.58 mmol) in DCM (100 mL) was added m-CPBA (4.69 g, 23.17 mmol). The reaction mixture was stirred at 15° C. for 16 hours. The reaction was quenched with sat.NaHCO3 (200 mL), extracted with DCM (150 mL×3). The combined organic phase was washed with sat.NaHCO3 (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 40%) to afford A-39 (2000 mg, 5.54 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.27 (d, 1H), 7.92 (d, 2H), 7.61 (d, 1H), 7.49-7.36 (m, 7H), 7.21 (dd, 1H), 5.24 (s, 2H).
- Synthesis of A-40: To a mixture of A-39 (2 g, 5.54 mmol) in AcOH (20 mL) at 0° C. was added fuming HNO3 (20 mL) dropwise. The reaction mixture was then heated to 90° C. and stirred for 16 hours . The reaction mixture was concentrated, and the residue was treated with sat.NaHCO3 (100 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 50%) to afford A-40 (250 mg, 0.55 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.76 (s, 1H), 8.43-8.31 (m, 3H), 7.94 (d, 2H), 7.77 (d, 2H), 7.52 (d, 2H), 5.60 (s, 2H).
- Synthesis of A-41: A mixture of A-40 (200 mg, 0.44 mmol) and wet Pd/C (200 mg) in methanol (10 mL) was degassed and refilled with Hz. The reaction mixture was stirred under H2 (50 psi) at 20° C. for 16 hours . The reaction mixture was diluted with MeOH (10 mL), filtered through a Celite pad and eluted with MeOH (10 mL). The filtrate was concentrated to give A-41 (160 mg, crude). LCMS Rt=0.67 min using Method B, MS ESI calcd. for C12H10F3N2O2 [M+H]+ 271.1, found 270.9.
- Synthesis of Compound 36: To a solution of A-41 (160 mg, 0.59 mmol) in THF (5 mL) was added CDI (143.89 mg, 0.89 mmol). The reaction mixture was heated to 60° C. and stirred for 2 hours . The reaction mixture was concentrated, and the residue was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 25-55% B over 8 minutes) to afford Compound 36 (25.54 mg, 0.09 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=12.35 (br s, 1H), 8.56 (s, 1H), 8.17 (d, 2H), 7.72 (s, 1H), 7.46 (d, 2H). LCMS Rt=1.05 min using Method A, MS ESI calcd. for C13H8F3N2O3 [M+H]+ 297.0, found 296.9.
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- Synthesis of A-43: To a solution of A-42 (2 g, 8.42 mmol) in Toluene (20 mL) was added phenylmethanol (1 g, 9.27 mmol), tris[2-(2-methoxyethoxy)ethyl]amine (272.43 mg, 0.84 mmol), KOH (471.7 mg, 8.42 mmol) and K2CO3 (1162.4 mg, 8.42 mmol), and the mixture was stirred at for 4 hours. The mixture was filtered through Celite and eluted with EtOAc (30 mL×3). The filtrate was concentrated to give the crude product that was filtered through silica gel (˜20 g), The filtrate was concentrated to give the impure product, which was triturated from i-Pr2O (10 mL) to afford A-43 (2200 mg, 7.12 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.45 (d, 1H), 8.41 (d, 1H), 7.49 (d, 2H), 7.44-7.30 (m, 3H), 5.58 (s, 2H).
- Synthesis of A-44: A mixture of A-43 (1 g, 3.23 mmol), [4-(trifluoromethoxy)phenyl]-boronic acid (1 g, 4.85 mmol), K2CO3 (892.86 mg, 6.47 mmol) and Pd(dppf)Cl2.CH2Cl2 (396.25 mg, 0.49 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90° C. for 16 hours. After cooling to r.t., the mixture was diluted with PE (10 mL), filtered through silica gel (˜20 g) and eluted. The filtrate was concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE=10% to 15% to 20%) to afford A-44 (900 mg, 2.30 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.60 (d, 1H), 8.47 (d, 1H), 7.59 (d, 2H), 7.54 (d, 2H), 7.45-7.32 (m, 5H), 5.65 (s, 2H).
- Synthesis of A-45: A mixture of A-44 (400 mg, 1.02 mmol) and Pd/C (100 mg) in Methanol (10 mL) was stirred at 20° C. under H2 balloon (15 psi) for 2 hours . The mixture was filtered through Celite and eluted with MeOH (10 mL×2). The filtrate was concentrated to give the crude product A-45 (250 mg, 0.93 mmol) as a solid, which was used directly without any further purification. LCMS Rt=0.73 min using Method B, MS ESI calcd. for C12H10F3N2O2 [M+H]+271.0, found 270.9.
- Synthesis of Compound 37: A mixture of A-45 (300 mg, 1.11 mmol) and CDI (360.05 mg, 2.22 mmol) in THF (10 mL) was stirred at 60° C. for 16 hours . The mixture was filtered through silica gel and concentrated, and the residue was dissolved in MeOH (˜3 mL). The filtrate was concentrated to afford Compound 37 (47.80 mg, 0.16 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.26 (d, 1H), 7.84 (d, 2H), 7.75 (d, 1H), 7.49 (d, 2H). LCMS Rt=1.08 min using Method A, MS ESI calcd. for C13H8F3N2O3 [M+H]+ 297.0, found 296.9.
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- To a solution of Compound 16 (80 mg, 0.23 mmol) in DMF (3 mL) was added HATU (155 mg, 0.41 mmol), DIPEA (87.81 mg, 0.68 mmol) and N-methylmethanamine hydrochloride (22.16 mg, 0.27 mmol). The resulting mixture was stirred at 15° C. for 16 hours . Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give a residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 37-67% B over 10 minutes) to afford Compound 38 (26.69 mg, 0.07 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.77 (d, 2H), 7.61 (s, 1H), 7.49-7.44 (m, 4H), 4.85 (s, 2H), 3.10 (s, 3H), 2.86 (s, 3H). LCMS Rt=1.18 min using Method A, MS ESI calcd. for C18H16F3N2O4 [M+H]+ 381.1, found 381.0.
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- To a mixture of Compound 16 (90 mg, 0.25 mmol), HATU (145.31 mg, 0.38 mmol) and DIPEA (65.85 mg, 0.51 mmol) in DMF (2 mL) was added the N-ethylethanamine (33.79 mg, 0.31 mmol) and the mixture was stirred at 15° C. for 16 hours . The mixture was diluted with sat.NH4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to a residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 45-75% B over 10 minutes) to afford Compound 39 (41.81 mg, 0.1024 mmol) as a solid. 1H NMR (DMSO-d6+D2O 400 MHz) δH=7.73 (d, 2H), 7.48-7.39 (m, 5H), 4.79 (s, 2H), 3.39 (q, 2H), 3.26 (q, 2H), 1.20 (t, 3H), 1.00 (t, 3H). LCMS Rt=1.25 min using Method A, MS ESI calcd. for C20H20F3N2O4 [M+H]+ 409.1, found 409.0.
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- To a solution of Compound 16 (80 mg, 0.23 mmol) in DMF (3 mL) was added HATU (155 mg, 0.41 mmol), DIPEA (87.81 mg, 0.68 mmol) and morpholine (23.68 mg, 0.27 mmol). The resulting mixture was stirred at 15° C. for 16 hours . Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 37-67% B over 10 minutes) to afford Compound 40 (8.33 mg, 0.02 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.76 (d, 2H), 7.60 (d, 1H), 7.51-7.41 (m, 4H), 4.91 (s, 2H), 3.72-3.66 (m, 2H), 3.60-3.54 (m, 4H), 3.47-3.41 (m, 2H). LCMS Rt=1.17 min using Method A, MS ESI calcd. for C20H18F3N2O5 [M+H]+ 423.1, found 423.0.
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- To a mixture of Compound 16 (90 mg, 0.25 mmol), HATU (145.31 mg, 0.38 mmol) and DIPEA (65.85 mg, 0.51 mmol) in DMF (2 mL) was added methanamine hydrochloride (20.64 mg, 0.31 mmol), and the mixture was stirred at 15° C. for 16 hours . The mixture was diluted with sat.NH4Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give a residue that purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 8-38% B over 9 minutes) to afford Compound 41 (27.35 mg, 0.0747 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.56 (d, 2H), 7.37-7.29 (m, 4H), 7.22 (d, 1H), 5.97 (br s, 1H), 4.50 (s, 2H), 2.87 (d, 3H). LCMS Rt=1.14 min using Method A, MS ESI calcd. for C17H14F3N2O4 [M+H]+ 367.1, found 367.0.
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- To a solution of Compound 16 (80 mg, 0.23 mmol) in DMF (3 mL) was added HATU (155 mg, 0.41 mmol), DIPEA (146.34 mg, 1.13 mmol) and ammonia hydrochloride (60.57 mg, 1.13 mmol). The resulting mixture was stirred at 15° C. for 16 hours. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 34-54% B over 10 minutes) to afford Compound 42 (22.9 mg, 0.07 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.85-7.75 (m, 3H), 7.61 (s, 1H), 7.50-7.43 (m, 4H), 7.36 (s, 1H), 4.52 (s, 2H). LCMS Rt=1.11 min using Method A, MS ESI calcd. for C16H12F3N2O4 [M+H]+ 353.1, found 352.9.
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- Synthesis of A-46: To a mixture of A-18 (300 mg, 1.4 mmol) and Cs2CO3 (681.91 mg, 2.09 mmol) in DMF (5 mL) was added CH3I (0.13 mL, 2.09 mmol). The mixture was stirred at 20° C. for 16 hours. The reaction was diluted with water (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 100%) to afford A-46 (110 mg, 0.33 mmol) as a solid. 1H NMR (CDCl3 400 MHz) δH=8.12 (d, 1H), 7.38 (d, 1H), 3.43 (s, 3H). LCMS Rt=0.63 min using Method B, MS ESI calcd. for C7H6BrN2O2 [M+H]+ 229.0, found 228.8.
- Synthesis of Compound 43: A mixture of A-46 (110 mg, 0.48 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (118.69 mg, 0.58 mmol), Pd(t-Bu3P)2 (49.09 mg, 0.10 mmol) and K3PO4 (203.93 mg, 0.96 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was stirred at 80° C. for 16 hours under N2. The mixture was filtered through silica gel and eluted with EtOAc (20 mL×2). The filtrate was concentrated and diluted with EtOAc (30 mL), washed with water (10 mL×2) and brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product that was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 55-66% B over 8 minutes) to afford Compound 43 (17.91 mg, 0.06 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.22 (d, 1H), 7.58 (d, 2H), 7.40-7.30 (m, 3H), 3.50 (s, 3H). LCMS Rt=1.17 min using Method A, MS ESI calcd. for C14H10F3N2O3 [M+H]+ 311.1, found 310.9.
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- Synthesis of A-47: To a mixture of A-47 (400 mg, 1.48 mmol) and K2CO3 (613.79 mg, 4.44 mmol) in MeCN (15 mL) was added bromomethylbenzene (329.14 mg, 1.92 mmol). The reaction mixture was stirred at 20° C. for 16 hours . The reaction mixture was diluted with EtOAc (10 mL), filtered through a Celite pad and eluted with EtOAc (10 mL). The residue was purified by by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 40%) to afford A-47 (150 mg, 0.4163 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.13 (s, 1H), 7.90 (d, 2H), 7.48-7.35 (m, 5H), 7.29-7.24 (m, 2H), 7.02 (s, 1H), 5.19 (s, 2H), 4.37 (s, 2H).
- Synthesis of A-48: To a mixture of A-47 (180 mg, 0.5 mmol) and pyridine (118.54 mg, 1.5 mmol) in DCM (5 mL) was added ethyl carbonochloridate (65.05 mg, 0.6 mmol). The reaction mixture was stirred at 20° C. for 2 hours . The reaction mixture was quenched with sat.NaHCO3 (20 mL), extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 40%) to afford A-48 (170 mg, 0.39 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=9.04 (s, 1H), 8.42-8.38 (m, 2H), 8.02 (d, 2H), 7.57 (d, 2H), 7.46-7.32 (m, 5H), 5.33 (s, 2H), 4.20 (q, 2H), 1.27 (t, 3H).
- Synthesis of A-49: To a solution of A-49 (170 mg, 0.39 mmol) in THF (5 mL) at 0° C. was added NaH (78.63 mg, 1.97 mmol). The reaction mixture was stirred at 0° C. for 20 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (456.27 mg, 1.97 mmol) was added. The reaction mixture was stirred at 50° C. for 1 hour . The reaction was quenched with sat.NH4Cl (20 mL), extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) to afford A-49 (180 mg, 0.3499 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.64 (s, 1H), 8.17 (d, 2H), 8.03 (s, 1H), 7.50-7.31 (m, 7H), 5.35 (s, 2H), 4.62-4.46 (m, 2H), 4.12-3.99 (m, 2H), 1.13-0.94 (m, 3H).
- Synthesis of A-50: A mixture of A-50 (180 mg, 0.35 mmol) and 10% wed Pd/C (200 mg, 0.19 mmol) in Methanol (10 mL) under N2 was degassed and refilled with Hz. The reaction mixture was stirred under H2 (15 psi, balloon) at 20° C. for 2 hours . The reaction mixture was diluted with EtOAc (10 mL), and filtered through a Celite pad to remove Pd/C, eluted with EtOAc (10 mL). The filtrate was concentrated to afford A-50 (120 mg, 0.28 mmol) as a oil. 1H NMR (DMSO-d6 400 MHz) δH=8.32 (s, 1H), 8.09 (d, 2H), 7.83 (s, 1H), 7.42 (d, 2H), 4.52-4.40 (m, 2H), 4.11 (q, 2H), 1.20-1.05 (m, 3H).
- Synthesis of A-51: To a mixture of A-50 (120 mg, 0.28 mmol) in methanol (10 mL) and water (2 mL) was added NaOH (113.13 mg, 2.83 mmol). The reaction mixture was stirred at 70° C. for 16 hours . The mixture was acidified with 2M HCl to pH=5-6, then concentrated to give the residue, which was treated with THF (20 mL) and filtered. The filtrate was concentrated to afford A-51 (120 mg, 0.34 mmol, crude) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.19 (s, 1H), 8.09 (d, 2H), 7.90 (s, 1H), 7.39 (d, 2H), 7.31 (s, 1H), 6.21 (t, 1H), 4.22-4.10 (m, 2H).
- Synthesis of Compound 44: A mixture of A-51 (120 mg, 0.34 mmol) and di(imidazol-1-yl)methanone (82.86 mg, 0.51 mmol) in THF (5 mL) was heated to 60° C. and stirred at 60° C. for 2 hours to give a solution . The reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 40%) to afford Compound 44 (82.61 mg, 0.21 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.69 (s, 1H), 8.21 (s, 1H), 8.18 (d, 2H), 7.53 (d, 2H), 4.91 (q, 2H). LCMS Rt=1.27 min using Method A, MS ESI calcd. for C15H9F6N2O3 [M+H]+ 379.1, found 378.9.
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- Synthesis of A-51: To a solution of A-4 (200 mg, 0.68 mmol) in DMF (4 mL) was added tert-butyl 2-bromopropanoate (169.98 mg, 0.81 mmol) and Cs2CO3 (441.45 mg, 1.35 mmol). The resulting mixture was stirred at 55° C. for 2 hours. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction mixture. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-51 (235 mg, 0.55 mmol) as an oil. 1H NMR (CDCl3, 400 MHz) δH=7.53 (d, 2H), 7.33-7.28 (m, 4H), 7.13 (s, 1H), 5.05 (q, 1H), 1.75 (d, 3H), 1.44 (s, 9H)
- Synthesis of A-52: To a solution A-51 (235 mg, 0.56 mmol) in DCM (4 mL) was added TFA (2 mL, 26.93 mmol). The resulting solution was stirred at 15° C. for 16 hours. The reaction solution was concentrated to give the crude product A-52 (200 mg, 0.54 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.80 (d, 2H), 7.66 (s, 1H), 7.50-7.44 (m, 4H), 5.23 (q, 1H), 1.70 (d, 3H)
- Synthesis of Compound 45: To a solution of A-52 (200 mg, 0.54 mmol) in DMF (4 mL) was added HATU (372.69 mg, 0.98 mmol), DIPEA (211.13 mg, 1.63 mmol) and pyrrolidine (46.47 mg, 0.65 mmol). The resulting mixture was stirred at 15° C. for 16 hours.
- Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 43-73% B over 10 minutes) to afford Compound 45 (77.94 mg, 0.19 mmol) as a solid. 1H NMR (CDCl3 DMSO-d6 400 MHz) δH=7.72 (d, 2H), 7.57 (d, 1H), 7.51-7.40 (m, 4H), 5.27 (q, 1H), 3.63-3.56 (m, 1H), 3.40-3.34 (m, 1H), 3.30-3.21 (m, 2H), 1.89-1.66 (m, 4H), 1.59 (d, 3H). LCMS Rt=1.27 min using Method A, MS ESI calcd. for C21H20F3N2O4 [M+H]+421.1, found 421.0.
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- To a solution of Compound 16 (140 mg, 0.40 mmol) in DMF (4 mL) was added HATU (226.04 mg, 0.59 mmol), DIPEA (153.66 mg, 1.19 mmol) and 2,2,2-trifluoroethanamine hydrochloride (107.42 mg, 0.79 mmol). The resulting mixture was stirred at 15° C. for 16 hours . Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) was added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Boston Green ODS (150 mm×30 mm, 5 μm) A=H2O (0.1% TFA) and B=CH3CN); 42-72% B over 10 minutes) to afford Compound 46 (54.91 mg, 0.12 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=9.02 (t, 1H), 7.77 (d, 2H), 7.60 (s, 1H), 7.50-7.43 (m, 4H), 4.67 (s, 2H), 4.02-3.92 (m, 2H). LCMS Rt=1.21 min using Method A, MS ESI calcd. for C18H13F6N2O4 [M+H]+ 435.1, found 435.0.
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- To the mixture of Compound 16 (180 mg, 0.51 mmol), HATU (290.62 mg, 0.76 mmol) and DIPEA (131.71 mg, 1.02 mmol) in DMF (2 mL) was added ethanamine hydrochloride (49.86 mg, 0.61 mmol) and the mixture was stirred at 20° C. for 16 hours . The mixture was diluted with sat. NH4Cl (30 mL), extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 um); A=H2O (0.05% NH4OH) and B=CH3CN); 50-80% B over 8 minutes) to afford Compound 47 (18.7 mg, 0.05 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.29 (t, 1H), 7.78 (d, 2H), 7.59 (s, 1H), 7.49-7.44 (m, 4H), 4.52 (s, 2H), 3.16-3.07 (m, 2H), 1.03 (t, 3H). LCMS Rt=1.17 min using Method A, MS ESI calcd. for C18H16F3N2O4 [M+H]+ 381.1, found 381.0.
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- Synthesis of A-53: To the mixture of A-18 (300 mg, 1.4 mmol) and Cs2CO3 (909.21 mg, 2.79 mmol) in DMF (5 mL) was added iodoethane (435.27 mg, 2.79 mmol) and the mixture was stirred at 20° C. for 16 hours . The mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 30%) to afford A-53 (160 mg, 0.66 mmol) as a solid. 1H NMR (DMSO-d6 400M Hz) δH=8.13-8.05 (m, 2H), 3.85 (q, 2H), 1.26 (t, 3H)
- Synthesis of Compound 48: A mixture of A-53 (90 mg, 0.37 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (90.75 mg, 0.44 mmol), Pd(t-Bu3P)2 (28.15 mg, 0.06 mmol), and K3PO4 (155.93 mg, 0.73 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was stirred under N2 at 90° C. for 16 hours . The mixture was cooled to r.t., diluted with EtOAc (10 mL), filtered with silica gel, eluted with EtOAc (15 mL) and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 um) A=H2O (10 mM NH4HCO3) and B=CH3CN); 35-65% B over 10 minutes) to afford Compound 48 (81.71 mg, 0.25 mmol) as a solid. 1H NMR (DMSO-d6 400M Hz) δH=8.31 (d, 1H), 8.10 (d, 1H), 7.88 (d, 2H), 7.51 (d, 2H), 3.92 (q, 2H), 1.31 (t, 3H). LCMS Rt=1.20 min using Method A, MS ESI calcd. for C15H12F3N2O3 [M+H]+ 325.1, found 324.9.
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- Synthesis of A-54: To the mixture of A-18 (300 mg, 1.4 mmol) and Cs2CO3 (909.21 mg, 2.79 mmol) in DMF (3 mL) was added the 2-(chloromethyl)pyrimidine (358.77 mg, 2.79 mmol) and the mixture was stirred at 20° C. for 16 hours . The mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE =20% to 50%) to afford A-54 (170 mg, 0.55 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.79 (d, 2H), 8.16 (d, 1H), 8.08 (d, 1H), 7.47 (t, 1H), 5.32 (s, 2H).
- Synthesis of Compound 49: A mixture of A-54 (90 mg, 0.29 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (71.95 mg, 0.35 mmol), Pd(t-Bu3P)2 (22.32 mg, 0.04 mmol), and K3PO4 (123.62 mg, 0.58 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was stirred under N2 at 90° C. for 16 hours . The mixture was cooled to r.t., diluted with EtOAc (10 ml), filtered with silica gel, eluted with EtOAc (15 mL) and the filtrate was concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 43-73% B over 10 minutes) to afford Compound 49 (69.86 mg, 0.18 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.79 (d, 2H), 8.36 (d, 1H), 8.11 (d, 1H), 7.81 (d, 2H), 7.51-7.44 (m, 3H), 5.39 (s, 2H). LCMS Rt=1.15 min using Method A, MS ESI calcd. for C18H12F3N4O3 [M+H]+ 389.1, found 389.0.
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- To the mixture of A-4 (200 mg, 0.68 mmol) and Cs2CO3 (441.45 mg, 1.35 mmol) in DMF (3 mL) was added 2-(chloromethyl)pyrimidine (174.19 mg, 1.35 mmol) and the mixture was stirred at 20° C. for 16 hours . The mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN) 50-80% B over 8 minutes) to afford Compound 50 (67.92 mg, 0.18 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.78 (d, 2H), 7.75 (d, 2H), 7.63 (d, 1H), 7.51-7.42 (m, 5H), 5.37 (s, 2H). LCMS Rt=1.22 min using Method A, MS ESI calcd. for C19H13F3N3O3 [M+H]+ 388.1, found 388.0.
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- To the mixture of A-4 (200 mg, 0.68 mmol) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (179.6 mg, 1.35 mmol) in ACN (3 mL) was added K2CO3 (187.27 mg, 1.35 mmol) and the mixture was stirred at 20° C. for 16 hours . The mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 58-68% B over 8 minutes) to afford Compound 51 (52.03 mg, 0.13 mmol) as a solid. 1H NMR (MeOD-d4 400 MHz) δH=7.70 (d, 2H), 7.52 (d, 1H), 7.48-7.44 (m, 1H), 7.40-7.34 (m, 3H), 5.40 (s, 2H), 2.52 (s, 3H). LCMS Rt=1.18 min using Method A, MS ESI calcd. for C18H13F3N3O4 [M+H]+ 392.1, found 391.9.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol) in THF (4 mL) was added methyl 3-hydroxypropanoate (105.44 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours to give a light yellow solution. The reaction solution was concentrated to give the crude product. The crude product was purified by silica gel column (PE:EtOAc=0% to 10% to 20%) to give the product of methyl 3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanoate (100 mg, 0.2616 mmol, 77% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δ=8.01 (d, 2H), 7.48 (d, 2H), 7.32 (d, 2H), 4.33 (t, 2H), 3.69 (s, 3H), 2.98 (t, 2H).
- To a solution of methyl 3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanoate (100 mg, 0.26 mmol) in Ethanol (5 mL) was added hydrazine (25.15 mg, 0.78 mmol). The resulting solution was stirred at 90° C. under N2 for 16 hours to give a yellow solution. The reaction solution was cooled to room temperature and concentrated to give the crude product (100 mg,0.1892 mmol) as a solid. The crude product was used to next step directly. LCMS Rt=0.752 min in 1.5 min chromatography, MS ESI calcd. for C16H14F3N4O4 [M+H]+ 383.1, found 383.0.
- To a solution of 3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanehydrazide (100 mg, 0.19 mmol) in THF (5 mL) was added 1,1-dimethoxy-N,N-dimethyl-ethanamine (37.8 mg, 0.28 mmol). The resulting mixture was stirred at 55° C. under N2 for 16 hours to give a yellow solution. The solution was concentrated to give a residue. Then the residue was re-dissolved in Toluene (5 mL) and TsOH.H2O (5.4 mg, 0.03 mmol) was added. The resulting mixture was stirred at 100° C. for 16 hours to give a brown solution. The reaction mixture was cooled to room temperature and concentrated to give the crude product. The crude product was purified by Prep-TLC (PE:EtOAc=1:1) to give the product (54.07 mg, 0.1322 mmol, 70% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.95 (d, 2H), 7.48 (s, 2H), 7.32 (d, 2H), 4.44 (t, 2H), 3.44 (t, 2H), 2.39 (s, 3H). LCMS Rt=1.197 min in 2.0 min chromatography, MS ESI calcd. for C18H14F3N4O4 [M+H]+ 407.1, found 407.0.
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- To a mixture of Compound 29 (100 mg, 0.34 mmol), tetrahydropyran-2-ylmethanol (117.65 mg, 1.01 mmol) and PPh3 (177.1 mg, 0.68 mmol) in THF (3 mL) was added DIAD (136.54 mg, 0.68 mmol) at 0° C. The mixture was allowed to warm to 25° C. and stirred for 16 hours under N2. The mixture was concentrated and purified by flash chromatography on silica gel (EtOAC in PE=0 to 30%) to give Compound 94, which was further purified by SFC (Chiralcel IC (250 mm×30 mm, 10 μm); A=CO2 and B=EtOH (0.1% NH3H2O); 38° C.; 60 mL/min; 20% B over 9 minutes; multiple injections) to afford Enantiomer 1, randomly assigned as Compound 54 (Rt=6.5 min) and Enantiomer 2, randomly assigned as Compound 55 (Rt=7.2 min). Compound 54 (36.04 mg, 0.09 mmol) 1H NMR (CDCl3, 400 MHz), δH=7.93 (d, 2H), 7.39 (d, 2H), 7.25 (d, 2H), 4.10-4.01 (m, 1H), 3.92-3.79 (m, 3H), 3.30 (dt, 1H), 1.85-1.77 (m, 1H), 1.68-1.60 (m, 1H), 1.58-1.51 (m, 1H), 1.48-1.32 (m, 3H). LCMS Rt=1.37 min using Method A, MS ESI calcd. for C19H18F3N2O4 [M+H]+ 395.1, found 395.0. Compound 55 (31.94 mg, 0.0810 mmol) 1H NMR (CDCl3+D2O 400 MHz) δH=8.00 (d, 2H), 7.47 (s, 2H), 7.32 (d, 2H), 4.18-4.09 (m, 1H), 4.00-3.87 (m, 3H), 3.38 (dt, 1H), 1.95-1.85 (m, 1H), 1.75-1.68 (m, 1H), 1.67-1.59 (m, 1H), 1.56-1.38 (m, 3H). LCMS Rt=1.34 min using Method A, MS ESI calcd. for C19H18F3N2O4 [M+H]+ 395.1, found 395.0.
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- To the mixture of Compound 5 (200 mg, 0.68 mmol), tetrahydropyran-4-ylmethanol (141.65 mg, 1.22 mmol) and PPh3 (319.86 mg, 1.22 mmol) in THF (5 mL) was added the DIAD (246.59 mg, 1.22 mmol) at 0° C. and the mixture was stirred under N2 at 20° C. for 16 hours. The mixture was diluted with H2O (20 mL), and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 56-86% B over 10 minutes) to afford Compound 56 (78.49 mg, 0.20 mmol) as a solid. 1H NMR (DMSO-d6+D2O 400 MHz) δH=7.75 (d, 2H), 7.52 (s, 1H), 7.44-7.36 (m, 4H), 3.83-3.69 (m, 4H), 3.22 (br t, 2H), 2.13-1.95 (m, 1H), 1.54-1.43 (m, 2H), 1.32-1.22 (m, 2H). LCMS Rt=1.29 min using Method A, MS ESI calcd. for C20H19F3NO4 [M+H]+ 394.1, found 394.1.
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- To a mixture of Compound 5 (150 mg, 0.51 mmol), DIAD (184.94 mg, 0.91 mmol) and tetrahydropyran-2-ylmethanol (106.24 mg, 0.91 mmol) in THF (5 mL) was added PPh3 (239.89 mg, 0.91 mmol). The mixture was stirred at 20° C. for 16 hours under N2. The mixture was concentrated, the residue was diluted with sat.NH4Cl (20 mL), extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give a residue, which was purified by Prep-HPLC Xtimate C18 (250 mm×50 mm, 10 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 50-80% B over 10 minutes) to afford Compound 57 as a solid. 1H NMR (CD3CN-d3 400 MHz) δH=7.71 (d, 2H), 7.44-7.34 (m, 4H), 7.32-7.26 (m, 1H), 3.92-3.79 (m, 3H), 3.77-3.68 (m, 1H), 3.38-3.30 (m, 1H), 1.87-1.75 (m, 1H), 1.75-1.64 (m, 1H), 1.59-1.43 (m, 3H), 1.42-1.28 (m, 1H). LCMS Rt=1.349 min using Method A, MS ESI calcd. for C20H19F3NO4 [M+H]+ 394.1, found 394.0. Compound 57 was purified by SFC (Chiralcel OJ (250 mm×30 mm, 5 μm); A=CO2 and B=MeOH (0.1% NH3H2O); 38° C.; 50 mL/min; 25% B over 9 minutes; multiple injections) to afford Enantiomer 1, randomly assigned as Compound 58 (Rt=7.05 min) and Enantiomer 2, randomly assigned as Compound 59 (Rt=7.95 min). Compound 58 (7.55 mg, 0.019 mmol) 1H NMR (CD3CN-d3 400 MHz) δH=7.71 (d, 2H), 7.45-7.34 (m, 4H), 7.31-7.26 (m, 1H), 3.94-3.80 (m, 3H), 3.76-3.67 (m, 1H), 3.38-3.28 (m, 1H), 1.87-1.79 (m, 1H), 1.69 (d, 1H), 1.55-1.43 (m, 3H), 1.38-1.29 (m, 1H). LCMS Rt=1.36 min using Method A, MS ESI calcd. for C20H19F3NO4 [M+H]+ 394.1, found 394.1. Compound 59 (10.33 mg, 0.025 mmol) 1H NMR (CD3CN-d3 400 MHz) δH=7.71 (d, 2H), 7.43-7.35 (m, 4H), 7.31-7.26 (m, 1H), 3.89-3.80 (m, 3H), 3.76-3.69 (m, 1H), 3.39-3.29 (m, 1H), 1.87-1.81 (m, 1H), 1.70 (d, 1H), 1.55-1.44 (m, 3H), 1.40-1.31 (m, 1H). LCMS Rt=1.36 min using Method A, MS ESI calcd. for C20H19F3NO4 [M+H]+ 394.1, found 394.0.
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- To a mixture of Compound 29 (100 mg, 0.34 mmol), tetrahydrofuran-3-ylmethanol (103.44 mg, 1.01 mmol) and PPh3 (177.1 mg, 0.68 mmol) in THF (3 mL) was added DIAD (136.54 mg, 0.68 mmol) at 0° C. The mixture was allowed to warm to 25° C. and stirred for 16 hours under N2. The mixture was concentrated to give Compound 60, which was purified by flash chromatography on silica gel (EtOAC in PE=0 to 30%) and SFC (ChiralCel OJ-H (150×4.6 mm, 5 μm); A=CO2 and B=iPrOH (0.05% DEA); 40° C.; 2.5 mL/min; from 5% to 40% of B in 5.5min and hold 40%, for 3 min, then 5% of B for 1.5 min) to afford Enantiomer 1, randomly assigned as Compound 61 (Rt=3.615 min) and Enantiomer 2, randomly assigned as Compound 62 (Rt=3.483 min). Compound 61 (22.50 mg, 0.060 mmol). 1H NMR (CDCl3, 400 MHz) δH=8.00 (d, 2H), 7.49 (s, 2H), 7.33 (d, 2H), 4.10-3.97 (m, 3H), 3.91-3.74 (m, 3H), 3.04-2.94 (m, 1H), 2.15-2.05 (m, 1H), 1.90-1.80 (m, 1H). LCMS Rt=1.28 min using Method A, MS ESI calcd. for C18H16F3N2O4 [M+H]+ 381.1, found 381.0. Compound 62 (15.4 mg,0.04 mmol). 1H NMR (CDCl3, 400 MHz), δH=8.00 (d, 2H), 7.49 (s, 2H), 7.33 (d, 2H), 4.10-3.97 (m, 3H), 3.93-3.74 (m, 3H), 3.06-2.94 (m, 1H), 2.15-2.04 (m, 1H), 1.91-1.79 (m, 1H). LCMS Rt=1.26 min using Method A, MS ESI calcd. for C18H16F3N2O4 [M+H]+381.1, found 381.0.
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- To a mixture of tetrahydrofuran-2-ylmethanol (103.44 mg, 1.01 mmol), Compound 29 (100 mg, 0.34 mmol) and PPh3 (177.1 mg, 0.68 mmol) in THF (3 mL) was added DIAD (136.54 mg, 0.68 mmol) at 0° C. The mixture was allowed to warm to 25° C. and stirred for 16 hours under N2. The mixture was concentrated to give Compound 63, which was purified by flash chromatography on silica gel (EtOAc in PE=0 to 30%) and SFC (Chiralcel IC (250 mm×30 mm, 10 pm); A=CO2 and B=EtOH (0.1% NH3H2O); 38° C.; 60 mL/min; 25% B over 9 minutes; multiple injections) to afford Enantiomer 1, randomly assigned as Compound 64 (Rt=5.8 min) and Enantiomer 2, randomly assigned as Compound 65 (Rt=7.2 min). Compound 64 (41.18 mg, 0.11 mmol) 1H NMR (CDCl3, 400 MHz), δH=8.00 (d, 2H), 7.47 (s, 2H), 7.32 (d, 2H), 4.60-4.51 (m, 1H), 4.15-4.07 (m, 1H), 4.02-3.91 (m, 2H), 3.85-3.77 (m, 1H), 2.16-1.90 (m, 3H), 1.86-1.77 (m, 1H). LCMS Rt=1.29 min using Method A, MS ESI calcd. for C18H16F3N2O4 [M+H]+ 381.1, found 381.0. Compound 65 (42.61 mg, 0.11 mmol) 1H NMR (CDCl3, 400 MHz), δH=8.03-7.96 (m, 2H), 7.47 (s, 2H), 7.32 (d, 2H), 4.60-4.51 (m, 1H), 4.15-4.06 (m, 1H), 4.02-3.90 (m, 2H), 3.86-3.76 (m, 1H), 2.16-1.90 (m, 3H), 1.86-1.74 (m, 1H). LCMS Rt=1.29 min using Method A, MS ESI calcd. for C18H16F3N2O4 [M+H]+381.1, found 381.0.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was added tetrahydropyran-3-ylmethanol (117.65 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 20° C. under N2 for 16 hours . The reaction solution was concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) and Prep-TLC (silica gel, PE:EtOAc=4:1) to afford A-58 (50 mg) as a solid. A-58 was purified by SFC (Chiralcel AD (250 mm×30 mm, 5 μm); A=CO2 and B=EtOH (0.1% NH3H2O); 38° C.; 50 mL/min; 30% B over 11 minutes; multiple injections) to afford Enantiomer 1, randomly assigned as Compound 66 (Rt=6.8 min) and Enantiomer 2, randomly assigned as Compound 67 (Rt=9.2 min). Compound 66 (14.37 mg, 0.04 mmol) 1H NMR (CDCl3 400 MHz) δH=8.00 (d, 2H), 7.48 (s, 2H), 7.33 (d, 2H), 4.01-3.80 (m, 4H), 3.56-3.35 (m, 2H), 2.43-2.30 (m, 1H), 1.96-1.85 (m, 1H), 1.82-1.72 (m, 1H), 1.69-1.59 (m, 1H), 1.49-1.37 (m, 1H). LCMS Rt=1.32 min using Method A, MS ESI calcd. for C19H18F3N2O4 [M+H]+ 395.1, found 395.0. Compound 67 (15.66 mg, 0.04 mmol) 1H NMR (CDCl3, 400 MHz) δH=8.00 (d, 2H), 7.48 (s, 2H), 7.33 (d, 2H), 4.00-3.81 (m, 4H), 3.55-3.46 (m, 1H), 3.41 (dd, 1H), 2.43-2.31 (m, 1H), 1.96-1.86 (m, 1H), 1.82-1.72 (m, 1H), 1.69-1.59 (m, 1H), 1.49-1.37 (m, 1H). LCMS Rt=1.33 min using Method A, MS ESI calcd. for C19H18F3N2O4 [M+H]+395.1, found 395.1.
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- To the mixture of Compound 5 (200 mg, 0.68 mmol), tetrahydrofuran-3-ylmethanol (124.54 mg, 1.22 mmol) and PPh3 (319.86 mg, 1.22 mmol) in THF (5 mL) was added DIAD (246.59 mg, 1.22 mmol). The mixture was stirred under N2 at 20° C. for 16 hours. The mixture was diluted with sat.NH4Cl (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 55-85% B over 8 minutes) to afford Compound 68 (48.85 mg, 0.13 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.82 (d, 2H), 7.72 (s, 1H), 7.47 (d, 2H), 7.44 (d, 2H), 3.89 (d, 2H), 3.85-3.79 (m, 1H), 3.71 (dd, 1H), 3.63 (q, 1H), 3.52 (dd, 1H), 2.87-2.75 (m, 1H), 2.04-1.90 (m, 1H), 1.76-1.62 (m, 1H). LCMS Rt=1.244 min using Method A, MS ESI calcd. for C19H17F3NO4 [M+H]+ 380.1, found 380.2. The product was purified by SFC (Chiralcel AD (250 mm×30 mm, 5 μm); A=CO2 and B=MeOH (0.1% NH3H2O); 38° C.; 50 mL/min; 30% B over 12 minutes; multiple injections) to afford Enantiomer 1, randomly assigned as Compound 69 (Rt=6.5 min) and Enantiomer 2, randomly assigned as Compound 70 (Rt=10.5 min). Compound 69 (12.76 mg, 0.03 mmol) 1H NMR (DMSO-d6 400 MHz) δH=7.85-7.79 (m, 2H), 7.72 (s, 1H), 7.52-7.39 (m, 4H), 3.89 (d, 2H), 3.82 (dt, 1H), 3.71 (dd, 1H), 3.63 (q, 1H), 3.51 (dd, 1H), 2.87-2.75 (m, 1H), 2.02-1.91 (m, 1H), 1.72-1.61 (m, 1H). LCMS Rt=1.25 min using Method A, MS ESI calcd. for C19H17F3NO4 [M+H]+ 380.1, found 380.0. Compound 70 (12.37 mg, 0.03 mmol) 1H NMR (DMSO-d6 400 MHz) δH=7.86-7.79 (m, 2H), 7.73 (s, 1H), 7.52-7.41 (m, 4H), 3.89 (d, 2H), 3.82 (dt,), 3.72 (dd, 1H), 3.64 (q, 1H), 3.52 (dd, 1H), 2.88-2.75 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.60 (m, 1H). LCMS Rt=1.26 min using Method A, MS ESI calcd. for C19H17F3NO4 [M+H]+ 380.1, found 379.9.
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- Synthesis of Compound 71b: To a suspension of NaH (453.66 mg, 11.34 mmol) in THF (50 mL) was added 2,2,2-trifluoroethanol (1.13 g, 11.34 mmol) at 0° C., and the mixture was stirred at 20° C. for 1 hour. Then to the mixture was added 71a (2 g, 10.31 mmol), and the mixture was stirred at 20° C. for another 4 hours . The mixture was quenched with sat.NH4Cl (50 mL), and the mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford Compound 71b (1500 mg, 5.47 mmol) as an oil. 1H NMR (CDCl3, 400 MHz) δH=8.00 (d, 1H), 7.58 (dd, 1H), 4.81 (q, 2H).
- Synthesis of Compound 71c: A mixture of Compound 71b (1500 mg, 5.47 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2780.26 mg, 10.95 mmol), Pd(dppf)Cl2. CH2Cl2 (447.05 mg, 0.55 mmol) and KOAc (1074.49 mg, 10.95 mmol) in 1,4-dioxane (100 mL) was stirred at 90° C. for 16 hours . After cooling to r.t., the mixture was concentrated to a residue that was diluted with H2O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0 to 5% to 30%) column to afford Compound 71c (3800 mg, 11.835 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.26 (s, 1H), 7.72 (dd, 1H), 4.87 (q, 2H), 1.35 (s, 12H)
- Synthesis of A-60: To a solution of A-59 (240 mg, 1.12 mmol) in THF (4 mL) was added ethanol (154.28 mg, 3.35 mmol), PPh3 (585.58 mg, 2.23 mmol) and then DIAD (451.45 mg, 2.23 mmol). The resulting mixture was stirred at 20° C. under N2 for 16 hours . The reaction solution was concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-60 (180 mg, 0.74 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.33-7.20 (m, 2H), 4.01 (q, 2H), 1.44 (t, 3H).
- Synthesis of Compound 71: A mixture of A-59 (100 mg, 0.41 mmol), Compound 71c (198.15 mg, 0.62 mmol), K3PO4 (174.69 mg, 0.82 mmol) and Pd(t-Bu3P)2 (31.54 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80° C. under N2 for 16 hours . The reaction mixture was cooled to room temperature, filtered through Celite and eluted with EtOAc (10 mL×2). The filtrate was concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 71 (125.91 mg, 0.35 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.50 (d, 1H), 8.08 (dd, 1H), 7.51-7.41 (m, 2H), 4.91 (q, 2H), 4.07 (q, 2H), 1.49 (t, 3H). LCMS Rt=1.26 min using Method A, MS ESI calcd. for C15H12F4N3O3 [M+H]+ 358.1, found 358.0.
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- To the mixture of Compound 5 (150 mg, 0.51 mmol), DIAD (184.94 mg, 0.91 mmol) and tetrahydropyran-3-ylmethanol (106.24 mg, 0.91 mmol) in THF (5 mL) was added PPh3 (239.89 mg, 0.91 mmol). The mixture was stirred at 20° C. for 16 hours under N2. The mixture was concentrated, and the residue was diluted with sat.NH4Cl (20 mL), and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered, and the filtrate was concentrated to give a residue that was purified by Prep-HPLC (Xtimate C18 (250 mm×50 mm, 10 μm) A=H2O (10 mM % NH3HCO3) and B=CH3CN); 55-85% B over 11.3 minutes) to afford Compound 72 (52.87 mg, 0.13 mmol) as an oil. 1H NMR (CD3CN 400 MHz) δH=7.73 (d, 2H), 7.42-7.35 (m, 4H), 7.33-7.27 (m, 1H), 3.83-3.69 (m, 4H), 3.43 (dt, 1H), 3.34-3.26 (m, 1H), 2.24-2.15 (m, 1H), 1.89-1.80 (m, 1H), 1.73-1.64 (m, 1H), 1.58-1.46 (m, 1H), 1.46-1.34 (m, 1H). LCMS Rt=1.293 min using Method A, MS ESI calcd. for C20H19F3NO4 [M+H]+ 394.1, found 394.1. Compound 72 was purified by SFC (Chiralcel 0J-3 150×4.6 mm 3 μm Mobile phase: A: CO2 B:ethanol (0.05% DEA)) to give Compound 73 (11.22 mg, 0.0285 mmol) (Peakl, Rt=3.171 min in SFC, compound 73) as a solid and Compound 74 (8.6 mg, 0.0219 mmol) (Peak2, Rt=3.378 min in SFC) as a solid. Stereochemistry of compound 73 and 74 was randomly assigned.
- 1H NMR (CD3CN-d3 400 MHz) δH=7.73 (d, 2H), 7.43-7.36 (m, 4H), 7.33-7.28 (m, 1H), 3.82-3.70 (m, 4H), 3.48-3.40 (m, 1H), 3.30 (dd, 1H), 2.24-2.17 (m, 1H), 1.90-1.78 (m, 1H), 1.72-1.64 (m, 1H), 1.57-1.48 (m, 1H), 1.44-1.35 (m, 1H). LCMS Rt=1.30 min, MS ESI calcd. for C20H19F3NO4 [M+H]+ 394.1, found 394.2
- 1H NMR CD3CN-d3 400 MHz 6=7.78-7.69 (m, 2H), 7.47-7.33 (m, 4H), 7.33-7.26 (m, 1H), 3.82-3.69 (m, 4H), 3.48-3.40 (m, 1H), 3.30 (dd, 1H), 2.25-2.16 (m, 1H), 1.90-1.80 (m, 1H), 1.72-1.64 (m, 1H), 1.56-1.46 (m, 1H), 1.45-1.38 (m, 1H). LCMS Rt=1.334 min in 2.0 min chromatography, MS ESI calcd. for C20H19F3NO4 [M+H]+ 394.1, found 394.1.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was added MeOH (32.41 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours to give a solution . The solution was concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 75 (45.57 mg, 0.15 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.02 (d, 2H), 7.48 (s, 2H), 7.33 (d, 2H), 3.55 (s, 3H). LCMS Rt=1.26 min using Method A, MS ESI calcd. for C14H10F3N2O3 [M+H]+ 311.1, found 310.9.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was added EtOH (46.69 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hrs. The solution was then concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0 to 20% to 50%) to afford Compound 76 (86.45 mg, 0.27 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.18 (d, 2H), 7.84-7.74 (m, 2H), 7.49 (d, 2H), 3.94 (q, 2H), 1.37 (t, 3H). LCMS Rt=1.32 min using Method A, MS ESI calcd. for C15H12F3N2O3 [M+H]+ 325.1, found 324.9.
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- Synthesis of A-61: To a mixture of A-18 (400 mg, 1.86 mmol) and Cs2CO3 (1212.28 mg, 3.72 mmol) in DMF (5 mL) was added 2-bromopropane (457.64 mg, 3.72 mmol). The mixture was stirred at 50° C. for 16 hours . The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE=0 to 20% to 50%) to afford A-60 (200 mg, 0.70 mmol) as a solid, 1H NMR (CDCl3, 400 MHz) δH=8.10 (d, 1H), 7.47 (d, 1H), 4.57 (spt, 1H), 1.56-1.50 (m, 6H). LCMS Rt=0.73 min using Method B, MS ESI calcd. for C9H10BrN2O2 [M+H]+257.0, found 256.7.
- Synthesis of Compound 77: A mixture of A-60 (200 mg, 0.78 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (192.25 mg, 0.93 mmol), Pd(t-Bu3P)2 (79.52 mg, 0.16 mmol) and K3PO4 (330.33 mg, 1.56 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. for 16 hours . After cooling, the mixture was filtered through silica gel and eluted with EtOAc (20 mL×2). The filtrate was concentrated and diluted with EtOAc (30 mL), washed with water (10 mL×2) and brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 55-85% B over 8 minutes) to give Compound 77 (24.22 mg, 0.07 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.19 (d, 1H), 7.57 (d, 2H), 7.46 (d, 1H), 7.36 (d, 2H), 4.63 (spt, 1H), 1.60 (d, 6H). LCMS Rt=1.23 min using Method A, MS ESI calcd. for C16H14F3N2O3 [M+H]+ 339.1, found 338.9.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was added propan-2-ol (60.87 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours . The reaction solution was concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 78 (49.62 mg, 0.15 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.17 (d, 2H), 7.82-7.73 (m, 2H), 7.49 (d, 2H), 4.62 (spt, 1H), 1.58 (d, 6H). LCMS Rt=1.34 min using Method A, MS ESI calcd. for C16H14F3N2O3 [M+H]+ 339.1, found 338.9.
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- Synthesis of A-62: To a solution of Compound 29 (200 mg, 0.68 mmol) in THF (5 mL) was added tert-butyl 2-hydroxyacetate (267.71 mg, 2.03 mmol), PPh3 (354.21 mg, 1.35 mmol) and DIAD (273.07 mg, 1.35 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours . The reaction solution was concentrated, and the residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-61 (270 mg, 0.66 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.97 (d, 2H), 7.49 (s, 2H), 7.30 (d, 2H), 4.62 (s, 2H), 1.49 (s, 9H).
- Synthesis of A-63: To a solution of A-61 (270 mg, 0.66 mmol) in DCM (4 mL) was added TFA (2 mL, 26.93 mmol). The resulting mixture was stirred at 15° C. for 16 hours . The reaction solution was concentrated to afford A-62 (220 mg, 0.62 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.17 (d, 2H), 7.91-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.48 (d, 2H), 4.67 (s, 2H).
- Synthesis of Compound 79: To a solution of A-62 (110 mg, 0.31 mmol) in DMF (3 mL) was added HATU (177.11 mg, 0.47 mmol), DIPEA (120.4 mg, 0.93 mmol) and pyrrolidine (26.5 mg, 0.37 mmol). The resulting mixture was stirred at 15° C. for 16 hours. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) was added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated, and the residue was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 49-69% B over 8 minutes) to afford Compound 79 (21.73 mg, 0.05 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.94 (d, 2H), 7.47 (q, 2H), 7.29 (d, 2H), 4.70 (s, 2H), 3.61 (t, 2H), 3.54 (t, 2H), 2.09 (quin, 2H), 1.92 (quin, 2H). LCMS Rt=1.21 min using Method A, MS ESI calcd. for C19H17F3N304 [M+H]+ 408.1, found 407.9.
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- Synthesis of Compound 80: To a solution of Compound 16 (100 mg, 0.28 mmol) in DMF (3 mL) was added HATU (161.46 mg, 0.42 mmol), DIPEA (109.76 mg, 0.85 mmol) and 2,2,2-trifluoro-N-methyl-ethanamine hydrochloride (50.8 mg, 0.34 mmol). The resulting mixture was stirred at 15° C. for 16 hours. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 55-75% B over 10.5 minutes) to afford Compound 80 (55.77 mg, 0.12 mmol) as a solid 1H NMR (CDCl3, 400 MHz) δH=7.74 (m, 2H), 7.65-7.40 (m, 5H), 5.00 (s, 1.6H), 4.91 (s, 0.4H), 4.47 (m, 0.4H), 4.19 (m, 1.6H), 3.25 (s, 2.4H), 2.96 (s, 0.6H). Note that rotamers were observed in the 1H NMR spectrum of this compound. LCMS Rt=1.25 min using Method A, MS ESI calcd. for C19H15F6N2O4 [M+H]+ 449.0931, found 449.0990.
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- To the mixture of Compound 5 (150 mg, 0.51 mmol), DIAD (184.94 mg, 0.91 mmol) and pyrimidin-5-ylmethanol (100.71 mg, 0.91 mmol) in THF (5 mL) was added PPh3 (239.89 mg, 0.91 mmol) and the mixture was stirred at 20° C. for 16 hours under N2. The mixture was concentrated, the residue was diluted with NH4Cl (20 mL) extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give a residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 40-70% B over 10 minutes) to afford Compound 84 as a solid. 1H NMR (DMSO-d6 400 MHz) δH=9.14 (s, 1H), 8.92 (s, 2H), 7.81-7.74 (m, 3H), 7.51-7.44 (m, 4H), 5.19 (s, 2H). LCMS Rt=1.19 min using Method A, MS ESI calcd. for C19HDF3N3O3 [M+H]+ 388.1, found 388.0.
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- To the a mixture of Compound 15 (100 mg, 0.28 mmol), HATU (161.46 mg, 0.42 mmol) and DIPEA (73.17 mg, 0.57 mmol) in DMF (2 mL) was added N-methylethanamine (20.08 mg, 0.34 mmol) and the mixture was stirred at 20° C. for 16 hours . The mixture was diluted with sat. NH4Cl (10 mL), extracted with EtOAc (10 mL×2), and the combined organic phase was washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue that was purified by Prep-HPLC Xtimate C18 (250 mm×50 mm, 10 μm) A=H2O (10 mM NH3HCO3) and B=CH3CN); 50-70% B over 7 minutes) to afford Compound 85 (25.86 mg 0.0656 mmol) as a solid. 1H NMR (DMSO-d6+D2O 400 MHz) δH=7.72 (d, 2H), 7.52-7.35 (m, 5H), 4.79 (d, 2H), 3.40 (d, 0.9 H), 3.28 (d, 1H), 3.03 (s, 1.7H), 2.79 (s, 1.3H), 1.18 (t, 1.3H), 0.98 (t, 1.7H). Note that rotamers were observed in the 1H NMR spectrum of this compound. LCMS Rt=1.21 min using Method A, MS ESI calcd. for C19H18F3N2O4 [M+H]+ 395.1, found 395.0.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was added 2,2-difluoroethanol (83.1 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours . The reaction solution was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 86 (77.26 mg, 0.21 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.03-7.97 (m, 2H), 7.53 (d, 2H), 7.33 (d, 2H), 6.30 (tt, 1H), 4.37 (dt, 2H). LCMS Rt=1.25min using Method A, MS ESI calcd. for C15H10F5N2O3 [M+H]+ 361.1, found 361.0.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was added 2-pyrimidin-2-ylethanol (125.73 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours . The reaction solution was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 87 (84.69 mg, 0.21 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.62 (d, 2H), 7.95 (d, 2H), 7.44 (s, 2H), 7.30 (d, 2H), 7.10 (t, 1H), 4.53 (t, 2H), 3.56 (t, 2H). LCMS Rt=1.20 min using Method A, MS ESI calcd. for C19H14F3N4O3 [M+H]+ 403.1, found 403.1.
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- To a solution of A-62 (110 mg, 0.31 mmol) in DMF (3 mL) was added HATU (177.11 mg, 0.47 mmol), DIPEA (120.4 mg, 0.93 mmol), and then N-methylmethanamine hydrochloride (30.38 mg, 0.37 mmol). The resulting mixture was stirred at 20° C. for 16 hours . Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) was added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give a residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN); 47-67% B over 8 minutes) to afford Compound 88 (34.39 mg, 0.09 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.15 (d, 2H), 7.87 (d, 1H), 7.79 (d, 1H), 7.47 (d, 2H), 4.86 (s, 2H), 3.14 (s, 3H), 2.86 (s, 3H). LCMS Rt=1.16 min using Method A, MS ESI calcd. for C17H15F3N3O4 [M+H]+ 382.1, found 382.0.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200 mg, 0.68 mmol) in THF (5 mL) was added PPh3 (354.21 mg, 1.35 mmol), 4-hydroxybutan-2-one (178.48 mg, 2.03 mmol) and then DIAD (273.07 mg, 1.35 mmol). The resulting solution was stirred at 20° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (200 mg, 0.5231 mmol) as a solid. 1H NMR (CDCl3 400 MHz) δH=8.00 (d, 2H), 7.47 (d, 2H), 7.32 (d, 2H), 4.28 (t, 2H), 3.11 (t, 2H), 2.23 (s, 3H). LCMS Rt=0.881 min in 1.5 min chromatography, MS ESI calcd. for C17H14F3N2O4 [M+H]+ 367.1, found 367.0.
- To a solution of 3-(3-oxobutyl)-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-2-one (200 mg, 0.55 mmol) in THF (20 mL) was added NaBH4 (41.31 mg, 1.09 mmol). The resulting mixture was stirred at 15° C. for 0.5 h to give a suspension. Saturated NH4Cl aqueous (20 mL) and EtOAc (30 mL) was added to the reaction suspension. After separated, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product .
- The product was purified by SFC (AD (250 mm×30 mm, 5 μm; A=CO2 and B =EtOH (0.1% NH3H2O); 38° C.; 50 mL/min; 20% B; 10 min run; 15 injections, Rt of peak 1=8.0 min, Rt of Peak 2=8.6 min) to give Compound 99 (3.02 mg, 0.0079 mmol) (Peak 1, Rt=3.250 min in SFC) as a solid and Compound 100 (10.09 mg, 0.0274 mmol) (Peak 2: Rt=3.381 min in SFC) as a solid. The stereochemistry of compound 99 and compound 100 was randomly assigned
- Compound 99 1H NMR (CDCl3, 400 MHz) δH=7.96 (d, 2H), 7.56-7.48 (m, 2H), 7.34 (d, 2H), 4.29-4.11 (m, 2H), 3.86-3.70 (m, 1H), 3.67-3.56 (m, 1H), 2.10-1.99 (m, 1H), 1.90-1.76 (m, 1H), 1.25 (d, 3H). LCMS Rt=1.201 min in 2.0 min chromatography, MS ESI calcd. for C17H16F3N2O4[M+H]+ 369.1, found 369.0.
- Compound 100 1H NMR (CDCl3, 400 MHz) δH=7.95 (d, 2H), 7.55-7.46 (m, 2H), 7.33 (d, 2H), 4.28-4.10 (m, 2H), 3.81-3.69 (m, 1H), 3.63-3.52 (m, 1H), 2.09-1.97 (m, 1H), 1.88-1.75 (m, 1H), 1.24 (d, 3H). LCMS Rt=1.226 min in 2.0 min chromatography, MS ESI calcd. for C17H16F3N2O4 [M+H]+ 369.1, found 369.0.
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- Synthesis of A-66: To a solution of Compound 29 (150 mg, 0.51 mmol) in THF (4 mL) was added 3-[tert-butyl(dimethyl)silyl]oxypropan-1-ol (289.2 mg, 1.52 mmol), PPh3 (265.65 mg, 1.01 mmol) and DIAD (204.8 mg, 1.01 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours . The reaction solution was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-66 (180 mg, 0.38 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.02 (d, 2H), 7.49-7.43 (m, 2H), 7.31 (d, 2H), 4.13 (t, 2H), 3.77 (t, 2H), 2.17-2.08 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).
- Synthesis of Compound 90: To a solution of A-66 (40 mg, 0.09 mmol) in methanol (2 mL) was added HCl/dioxane (2 mL, 0.09 mmol). The resulting solution was stirred at 15° C. for 16 hours . The reaction was concentrated to give a residue that was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to afford Compound 90 (21.59 mg, 0.06 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.17 (d, 2H), 7.83-7.74 (m, 2H), 7.49 (d, 2H), 4.58 (t, 1H), 3.96 (t, 2H), 3.52 (q, 2H), 1.97 (quin, 2H). LCMS Rt=1.16 min using Method A, MS ESI calcd. for C16H14F3N2O4 [M+H]+ 355.1, found 355.0.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was added 1,1,1,2,2-pentadeuterio-2-deuteriooxy-ethane (52.78 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours . The reaction solution was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 91 (49.41 mg, 0.15 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.18 (d, 2H), 7.84-7.74 (m, 2H), 7.49 (d, 2H). LCMS Rt=1.29 min using Method A, MS ESI calcd. for C15H7D5F3N2O3 [M+H]+ 330.1108, found 330.1104.
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- Synthesis of A-67: To a mixture of A-18 (173.22 mg, 1.4 mmol) and PPh3 (439.18 mg, 1.67 mmol) in THF (3 mL) under N2 was added DEAD (291.6 mg, 1.67 mmol) drop-wise at 0° C. The reaction mixture was then stirred at 20° C. for 16 hours . The mixture was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=0 to 50% to 100%) to afford A-67 (250 mg, 0.26 mmol) as a solid. LCMS Rt=0.67 min using Method B, MS ESI calcd. for C12H10BrN4O2 [M+H+2]+323.0, found 322.9.
- Synthesis of Compound 92: A mixture of A-67 (250 mg, 0.78 mmol), K3PO4 (330.55 mg, 1.56 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (192.38 mg, 0.93 mmol) and Pd(t-Bu3P)2 (79.57 mg, 0.16 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. for 16 hours under N2. After cooling, the mixture was filtered through silica gel and eluted with EtOAc (20 mL×2). The filtrate was concentrated and diluted with EtOAc (30 mL), washed with water (10 mL×2) and brine (10 mL), dried over Na2SO4, filtered and concentrated to give a residue that was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H2O (0.05% NH4OH) and B=CH3CN); 53-63% B over 8 minutes) to afford Compound 92 (50.95 mg, 0.12 mmol) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.65 (d, 2H), 8.17 (d, 1H), 7.54 (d, 2H), 7.40 (d, 1H), 7.35 (d, 2H), 7.17 (t, 1H), 4.44 (t, 2H), 3.50 (t, 2H). LCMS Rt=1.15 min using Method A, MS ESI calcd. for C19H14F3N403 [M+H]+ 403.1, found 403.0.
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- To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was added trideuterio(deuteriooxy)-methane (36.53 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C. under N2 for 16 hours . The reaction solution was concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 93 (68.88 mg, 0.22 mmol) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.19 (d, 2H), 7.84-7.74 (m, 2H), 7.49 (d, 2H). LCMS Rt=1.23 min using Method A, MS ESI calcd. for C14H7D3F3N2O3 [M+H]+ 314.0826, found 314.0815.
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- To the mixture of 5-bromo-3H-1,3-benzoxazol-2-one (300 mg, 1.4 mmol) and Cs2CO3 (913.37 mg, 2.8 mmol) in DMF (5 mL) was added iodoethane (437.26 mg, 2.8 mmol) and the mixture was stirred at 20° C. for 16 hours. The mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=20% to 50%) to give the product of 5-bromo-3-ethyl-1,3-benzoxazol-2-one (220 mg, 0.908 mmol, 645% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.24 (dd, 1H), 7.13 (d, 1H), 7.08 (d, 1H), 3.87 (q, 2H), 1.39 (t, 3H).
- A mixture of 5-bromo-3-ethyl-1,3-benzoxazol-2-one (200 mg, 0.83 mmol), 3-fluoro (4,4,5,5-tetram ethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (397.92 mg, 1.24 mmol), K3PO4 (350.81 mg, 1.65 mmol), and Pd(t-Bu3P)2 (63.33 mg, 0.12 mmol) in 1,4-Dioxane (3 mL) and Water (0.3 mL) was stirred at 90° C. for 16 hours under N2 to give a mixture. The mixture was cooled to r.t., diluted with EtOAc (20 mL), filtered through silica gel and eluted with EtOAc (20 mL). The filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 51%-81%, 7 min) to give the product (134.4 mg, 0.3712 mmol, 45% yield) as a solid. 1H NMR DMSO-d6 400 MHz 6=8.41 (d, 1H), 8.25 (dd, 1H), 7.74 (d, 1H), 7.54-7.41 (m, 2H), 5.14 (q, 2H), 3.91 (q, 2H), 1.30 (t, 3H). LCMS Rt=1.254 min in 2.0 min chromatography, MS ESI calcd. for C16H13F4N2O3 [M+H]+ 357.1, found 357.0.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (400 mg, 1.35 mmol) in THF (5 mL) was added PPh3 (710.79 mg, 2.71 mmol), and 4-hydroxybutan-2-one (358.16 mg, 4.06 mmol), then DIAD (547.98 mg, 2.71 mmol). The resulting solution was stirred at 20° C. under N2 for 16 hours to give a solution. The mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (column: Waters Xbridge 150*25 5 u, mobile phase: water (10 mM NH4HCO3)-CAN, B%: 55%-75%, 7 min) to give the product (150 mg, 0.410 mmol, 30% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=7.82 (d, 2H), 7.69 (s, 1H), 7.47 (d, 2H), 7.42 (s, 2H), 4.04 (t, 2H), 3.00 (t, 2H), 2.13 (s, 3H).
- To a solution of 3-(3-oxobutyl)-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one (150 mg, 0.41 mmol) in methanol (2 mL) was added NaBH4 (31.07 mg, 0.82 mmol). The resulting mixture was stirred at 20° C. for 0.5 h to give a suspension. Saturated NH4Cl aqueous (10 mL) and EtOAc (10 mL) was added to the reaction suspension. After separation, the organic layer was washed with brine (5 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the product (120 mg).
- The product was purified by SFC (AD (250 mm×30 mm, 5 μm), A=CO2 and B=EtOH (0.1% NH3H2O); 38° C.; 50 mL/min; 20% B; 9 min run; 12 injections, Rt of peak 1=6.7 min,
- Rt of Peak 2=7.8 min) to give compound 97 (29.78 mg, 0.0811 mmol) (Peakl, Rt=3.090 min in SFC) as oil and compound 98 (31.57 mg, 0.086 mmol) (Peak2, Rt=3.301 min in SFC) as oil.
- Compound 97 1H NMR DMSO-d6 400 MHz δ=7.81 (d, 2H), 7.60 (s, 1H), 7.47 (d, 2H), 7.42 (s, 2H), 4.63 (d, 1H), 3.98-3.89 (m, 2H), 3.71-3.64 (m, 1H), 1.85-1.66 (m, 2H), 1.10 (d, 3H). LCMS Rt=1.228min in 2.0 min chromatography, MS ESI calcd. for C18H17F3NO4 [M+H]+ 368.1, found 368.0.
- Compound 98 1H NMR DMSO-d6 400 MHz 6=7.81 (d, 2H), 7.60 (s, 1H), 7.47 (d, 2H), 7.42 (s, 2H), 4.64 (d, 1H), 3.97-3.91 (m, 2H), 3.70-3.64 (m, 1H), 1.84-1.67 (m, 2H), 1.10 (d, 3H). LCMS Rt=1.230 min in 2.0 min chromatography, MS ESI calcd. for C18H17F3NO4 [M+H]+ 368.1, found 368.0.
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- A mixture of 3-benzyloxy-6-bromo-2-nitro-pyridine (1.9 g, 6.15 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (1.52 g, 7.38 mmol), K3PO4 (2.61 g, 12.29 mmol) and Pd(t-Bu3P)2 (471.17 mg, 0.92 mmol) in 1,4-Dioxane (20 mL) and Water (2 mL) was stirred at 80° C. under N2 for 16 hours to give a suspension. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (1000 mg, 2.56 mmol, 42% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.36 (d, 1H), 8.17-8.07 (m, 3H), 7.53-7.31 (m, 7H), 5.42 (s, 2H).
- To a solution of 3-benzyloxy-2-nitro-6-[4-(trifluoromethoxy)phenyl]pyridine (1 g, 2.56 mmol) in Methanol (50 mL) was added Pd/C (200 mg, 1.89 mmol). The resulting mixture was stirred at 20° C. under molecular hydrogen (512.36 mg, 253.64 mmol) (15 psi) for 3 hours to give a black suspension. The reaction mixture was filtered through Celite. The filtrate was concentrated to give the crude product (690 mg, 2.55 mmol,) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.98 (d, 2H), 7.35 (d, 2H), 7.01 (d, 1H), 6.91 (d, 1H), 5.59 (s, 2H).
- To a solution of 2-amino-6-[4-(trifluoromethoxy)phenyl]pyridin-3-ol (690 mg, 2.55 mmol) in THF (30 mL) was added di(imidazol-1-yl)methanone (496.87 mg, 3.06 mmol). The resulting mixture was stirred at 60° C. for 16 hours to give a solution. The reaction mixture was cooled to room temperature and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=20% to 40% to 50%) to give the product of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (700 mg, 2.3633 mmol, 92.548% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=12.55 (br s, 1H), 8.10 (d, 2H), 7.78-7.66 (m, 2H), 7.46 (d, 2H).
- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol) in THF (5 mL) was added tetrahydropyran-4-ylmethanol (117.65 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 25° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (42.79 mg, 0.11 mmol,) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.00 (d, 2H), 7.48 (s, 2H), 7.33 (d, 2H), 4.00 (dd, 2H), 3.92 (d, 2H), 3.40 (t, 2H), 2.35-2.23 (m, 1H), 1.71-1.63 (m, 2H), 1.56-1.48 (m, 2H). LCMS Rt=1.28 min in 2.0 min chromatography, MS ESI calcd. for C19H18F3N2O4 [M+H]+395.1, found 395.0.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol) in THF (5 mL) was added oxetan-3-ylmethanol (89.24 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 25° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (84.3 mg, 0.23 mmol, 68% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.99 (d, 2H), 7.49 (s, 2H), 7.33 (d, 2H), 4.90-4.84 (m, 2H), 4.71 (t, 2H), 4.34 (d, 2H), 3.66-3.54 (m, 1H). LCMS Rt=1.22 min in 2.0 min chromatography, MS ESI calcd. for C17H14F3N2O4 [M+H]+ 367.1, found 367.0.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol) in THF (5 mL) was added pyrimidin-5-ylmethanol (111.52 mg, 1.01 mmol), PPh3 (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 25° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (98.9 mg, 0.25 mmol, 75% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=9.14 (s, 1H), 8.96 (s, 2H), 8.16 (d, 2H), 7.85-7.78 (m, 2H), 7.48 (d, 2H), 5.17 (s, 2H). LCMS Rt=1.17 min in 2.0 min chromatography, MS ESI calcd. for C18H12F3N4O3 [M+H]+ 389.1, found 389.0.
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- To a solution of (2S)-tetrahydrofuran-2-carboxylic acid (2 g, 17.22 mmol) in THF (3 mL) was added the BH3.SMe2 (2.58 mL, 25.84 mmol) at 0° C., then the mixture was stirred at 20° C. for 16 hours to give a colorless solution. 2N NaOH (10 mL) was added to the mixture slowly at 0° C. Then the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product (400 mg, 3.92 mmol, 23% yield) as colorless oil. 1H NMR CDCl3, 400 MHz δH=4.06-3.99 (m, 1H), 3.92-3.84 (m, 1H), 3.83-3.75 (m, 1H), 3.73-3.62 (m, 1H), 3.57-3.45 (m, 1H), 2.13-2.05 (m, 1H), 1.98-1.87 (m, 3H), 1.70-1.59 (m, 1H).
- To the mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100.00 mg, 0.34 mmol), [(2S)-tetrahydrofuran-2-yl]methanol (103.79 mg, 1.02 mmol) and PPh3 (177.70 mg, 0.68 mmol) in THF (5.00 mL) was added the DIAD (136.99 mg, 0.68 mmol) at 0° C. and the mixture was stirred under N2 at 20° C. for 16 hours to give a mixture. The mixture was diluted with H2O (20 mL), extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 □m), A=H2O (10 mM NH4HCO3) and B=CH3CN; 60-90% B over 6.6 minutes) to give the product (40.86 mg, 0.11 mmol, 32% yield) as oil.
- Note: the Specific rotation was +19.79 (c=1, CHCl3, 27.5° C.). 1H NMR DMSO-d6 400 MHz δH=7.80 (d, 2H), 7.66 (s, 1H), 7.47 (d, 2H), 7.43 (s, 2H), 4.30-4.20 (m, 1H), 3.97-3.87 (m, 2H), 3.78-3.70 (m, 1H), 3.66-3.59 (m, 1H), 2.08-1.75 (m, 3H), 1.71-1.59 (m, 1H). LCMS Rt=1.48 min in 2.0 min chromatography, MS ESI calcd. for C19H17F3NO4 [M+H]+ 380.1, found 380.1.
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- To a solution of (2R)-tetrahydrofuran-2-carboxylic acid (2 g, 17.22 mmol) in THF (20 mL) was added the BH3.SMe2 (2.58 mL, 25.84 mmol) at 0° C., then the mixture was stirred at 20° C. for 16 hours to give the colorless solution. 2N NaOH (10 mL) was added to the mixture slowly at 0° C. Then the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product (450.00 mg, 4.41 mmol, 26% yield) as colorless oil. 1H NMR (CDCl3, 400 MHz) δH=4.07-3.97 (m, 1H), 3.94-3.85 (m, 1H), 3.84-3.76 (m, 1H), 3.72-3.63 (m, 1H), 3.55-3.46 (m, 1H), 2.02-1.87 (m, 4H), 1.72-1.65 (m, 1H).
- To the mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (150.00 mg, 0.51 mmol), [(2R)-tetrahydrofuran-2-yl]methanol (155.68 mg, 1.52 mmol) and PPh3 (266.55 mg, 1.02 mmol) in THF (5 mL) was added the DIAD (205.49 mg, 1.02 mmol) at 0° C. and the mixture was stirred under N2 at 20° C. for 16 hours to give the mixture. The mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 56-86% B over 6 minutes) to give the product (28.34 mg, 0.07 mmol, 15% yield) as oil.
- Note: the Specific rotation was −14.51 (c=1, CHCl3, 27.7° C.). 1H NMR DMSO-d6 400 MHz δH=7.80 (d, 2H), 7.66 (s, 1H), 7.47 (d, 2H), 7.43 (s, 2H), 4.29-4.21 (m, 1H), 3.98-3.87 (m, 2H), 3.79-3.71 (m, 1H), 3.67-3.58 (m, 1H), 2.08-1.74 (m, 3H), 1.70-1.60 (m, 1H). LCMS Rt=1.35 min in 2.0 min chromatography, MS ESI calcd. for C19H17F3NO4 [M+H]+ 380.1, found 379.8.
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- To a solution of 2,2-difluorocyclopropanecarboxylic acid (1 g, 8.19 mmol) in Ether (30 mL) was added LiA1H4 (466.33 mg, 12.29 mmol) slowly at 0° C. over 10 mins. After the addition, the resulting colorless suspension was allowed to warm to 25° C., and stirred for a further 18 hours to give a suspension. The reaction mixture was then cooled in an ice-bath, and then 2M NaOH (1 mL) was added in a dropwise manner to quench the reaction, followed by H2O (1 mL). The mixture was filtered, and rinsed with Et2O (10 mL×2). The filtrate was concentrated to give a residue. Then the residue was re-dissolved in DCM (20 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated at 5-10° C. to give the crude product (800 mg, 7.40 mmol, 90% yield) as oil. 1H NMR (CDCl3, 400 MHz) δH=3.82-3.74 (m, 1H), 3.71-3.63 (m, 1H), 1.98-1.76 (m, 1H), 1.53-1.41 (m, 1H), 1.22-1.11 (m, 1H).
- To a solution of (2,2-difluorocyclopropyl)methanol (232 mg, 2.15 mmol) and 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200 mg, 0.68 mmol) in THF (4 mL) was added PPh3 (354.21 mg, 1.35 mmol) and DIAD (273.07 mg, 1.35 mmol). The resulting mixture was stirred at 20° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give compound 53 (150 mg) as a solid.
- Compound 53 1H NMR (CDCl3+D2O 400 MHz) δH=8.00 (d, 2H), 7.51 (s, 2H), 7.33 (d, 2H), 4.31-4.22 (m, 1H), 4.09-4.00 (m, 1H), 2.35-2.21 (m, 1H), 1.61 (m, 2H). LCMS Rt=1.31 min using Method A, MS ESI calcd. for C17H12F5N2O3 [M+H]+ 387.1, found 387.0.
- The product was purified by SFC (Column: OJ (250 mm×30 mm, 5 μm); A=CO2 and B=Neu-ETOH; 35° C.; 50 mL/min; 20% B; 10 min run; 13 injections, Rt of Peak 1=7.7 min, Rt of Peak 2=8.5 min) to give the compound 106 (24.52 mg, 0.06 mmol) (Peak 1, Rt=2.749 min in SFC) as a solid and compound 107 (Peak 2, Rt=2.959 min in SFC) (˜80 mg, ee %=80%).
- The impure compound 107 was purified again by SFC (Column: OJ (250 mm×30 mm, 5 μm); A=CO2 and B=0.1%NH3H2O ETOH; 35° C.; 50 mL/min; 25% B; 9 min run; 8 injections, Rt of Peak 1=7.17 min, Rt of Peak 2=7.8 min) to give the product of 3-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-2-one (39.28 mg, 0.10 mmol, 14.95% yield, 99.29% purity) (Peak 2, Rt=2.959 min in SFC) as a solid.
- Compound 106: 1H NMR CDCl3+D2O 400 MHz δ=8.00 (d, 2H), 7.51 (s, 2H), 7.33 (d, 2H), 4.26 (dd, 1H), 4.04 (dd, 1H), 2.36-2.20 (m, 1H), 1.62-1.46 (m, 2H). LCMS Rt=1.27 min in 2.0 min chromatography, MS ESI calcd. for C17H12F5N2O3 [M+H]+ 387.1, found 387.0.
- Compound 107: 1H NMR CDCl3 +D2O 400 MHz 6=8.00 (d, 2H), 7.51 (s, 2H), 7.33 (d, 2H), 4.26 (dd, 1H), 4.04 (dd, 1H), 2.36-2.19 (m, 1H), 1.62-1.46 (m, 2H). LCMS Rt=1.32 min in 2.0 min chromatography, MS ESI calcd. for C17H12F5N2O3 [M+H]+ 387.1, found 387.0.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300 mg, 1.02 mmol), tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol), PPh3 (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20 mL) was stirred at 20° C. under N2 for 16 hours. The mixture was concentranted and purified by flash chromatography on silica gel (EtOAc in PE=10% to 25%) to afford the product (430 mg, 0.90 mmol, 88% yield) as an oil. LCMS Rt=0.95 min in 1.5 min chromatography, MS ESI calcd. for C24H25F3N2O5Na [M+Na]+ 501.2, found 501.2.
- A mixture of tert-butyl(3S)-3-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol yl]methyl]pyrrolidine-1-carboxylate (430 mg, 0.90 mmol) in 4 M HCl/dioxane (10 mL, 0.90 mmol) was stirred at 20° C. for 16 hours. The mixture was concentrated to afford the crude product (400 mg, 0.96 mmol) as oil. LCMS Rt=0.75 min in 1.5 min chromatography, MS ESI calcd. for C19H18F3N2O3 [M+H]+ 379.1, found 379.0.
- A mixture of 3-[[(3S)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol) and Et3N (0.17 mL, 1.21 mmol) in CH2Cl2 (20 mL) was stirred at 20° C. for 16 h. The reaction mixture was concentrated and purified by prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 45-75% B over 6 minutes) to give the product (35.75 mg, 0.09 mmol, 35% yield, 100%) as a solid. 1H NMR (MeOD-d4 400 MHz) δH=7.74 (d, 2H), 7.51 (dd, 1H), 7.46-7.40 (m, 1H), 7.39-7.32 (m, 3H), 3.99 (dd, 2H), 3.75-3.33 (m, 4H), 2.97-2.78 (m, 1H), 2.23-2.08 (m, 1H), 2.06-2.01 (m, 3H), 1.98-1.75 (m, 1H). LCMS Rt=1.19 min in 2.0 min chromatography, MS ESI calcd. for C21H20F3N2O4 [M+H]+ 421.1, found 421.1.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300 mg, 1.02 mmol), tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol), PPh3 (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20 mL) was stirred at 20° C. under N2 for 16 hours. The mixture was concentrated and purified by flash chromatography on silica gel (EtOAc in PE=10% to 25%) to afford the product (330 mg, 0.69 mmol, 68% yield) as an oil. LCMS Rt=1.16 min in 1.5 min chromatography, MS ESI calcd. for C24H25F3N2O5Na [M+Na]+ 501.2, found 501.2.
- A mixture of tert-butyl(2R)-2-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]methyl]pyrrolidine-1-carboxylate (330 mg, 0.69 mmol) in 4M HCl/dioxane (10 mL, 0.69 mmol) was stirred at 20° C. for 16 hours. The mixture was concentrated to give the product (280 mg, 0.67 mmol, 98% yield) as a solid. LCMS Rt=0.76 min in 1.5 min chromatography, MS ESI calcd. for C19H18F3N2O3 [M+H]+ 379.1, found 379.0.
- A mixture of 3-[[(2R)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol) and Et3N (0.17 mL, 1.21 mmol) in DCM (25 mL) was stirred at 20° C. for 16 hours. The mixture was concentrated and purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 47-77% B over 6 minutes) to give the product (47.32 mg, 0.11 mmol, 46% yield) as a solid. 1H NMR (MeOD, 400 MHz) δH=7.79-7.66 (m, 3H), 7.45-7.30 (m, 4H), 4.57-4.47 (m, 1H), 4.08-3.93 (m, 2H), 3.65-3.56 (m, 1H), 3.54-3.45 (m, 1H), 2.18-1.94 (m, 7H). LCMS Rt=1.23 min in 2.0 min chromatography, MS ESI calcd. for C21H20F3N2O4 [M+H]+ 421.1, found 421.1.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300 mg, 1.02 mmol), tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol), PPh3 (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20 mL) was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (20 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 25%) to give the impure product (600 mg, 1.25 mmol) as oil. LCMS Rt=0.96 min in 1.5 min chromatography, MS ESI calcd. for C24H25F3N2O5Na [M+Na]+ 501.2, found 501.1.
- A mixture of tert-butyl (3R)-3-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]methyl]pyrrolidine-1-carboxylate (600 mg, 1.25 mmol) in 4M HCl/dioxane (10 mL) was stirred at 20° C. for 16 hours. The mixture was concentrated to give the crude product (600 mg, 1.45 mmol) as oil. The product was used directly without any further purification. LCMS Rt=0.75 min in 1.5 min chromatography, MS ESI calcd. for C19H18F3N203 [M+H]+ 379.1, found 379.0.
- A mixture of 3-[[(3R)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol) and Et3N (0.17 mL, 1.21 mmol) in DCM (20 mL) was stirred at 20° C. for 16 hours to give a mixture. From LCMS, desired MS was observed, and no starting material was remained. The reaction was diluted with sat.NH4Cl (20 mL), and the mixture was extracted with DCM (15 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN, 45%-55% B over 8 minutes) to give the impure product. The impure product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (11.95 mg, 0.03 mmol, 12% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=7.74 (d, 2H), 7.53-7.48 (m, 1H), 7.45-7.40 (m, 1H), 7.39-7.31 (m, 3H), 3.98 (dd, 2H), 3.73-3.32 (m, 4H), 2.97-2.79 (m, 1H), 2.19-2.07 (m, 1H), 2.05-2.00 (m, 3H), 1.96-1.77 (m, 1H). LCMS Rt=1.22 min in 2 min chromatography, MS ESI calcd. for C21H20F3N2O4 [M+H]+ 421.1, found 421.1.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300 mg, 1.02 mmol), tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol), PPh3 (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20 mL) was stirred at 25° C. under N2 for 16 hours. The reaction was quenched with sat.NH4Cl (20 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 25%) to afford the crude product (400 mg, 0.84 mmol, 83% yield) as oil. 1H NMR (CDCl3, 400 MHz) δH=7.62-7.39 (m, 3H), 7.22-6.98 (m, 4H), 4.25-4.15 (m, 1H), 3.98-3.79 (m, 2H), 3.43-3.18 (m, 2H), 1.95-1.77 (m, 4H), 1.30 (s, 9H).
- A mixture of tert-butyl(2S)-2-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]methyl]pyrrolidine-1-carboxylate (400 mg, 0.84 mmol) in 4 M HCl/dioxane (10 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated to afford the crude product (300 mg, 0.68 mmol, 82% yield) as oil. LCMS Rt=0.75 min in 1.5 min chromatography, MS ESI calcd. for C19H18F3N2O3 [M+H]+ 379.1, found 379.0.
- A mixture of 3-[[(2S)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol) and Et3N (0.17 mL, 1.21 mmol) in CH2Cl2(20 mL) was stirred at 25° C. for 16 hours to give a solution. The reaction was quenched with sat.NH4Cl (20 mL), and the mixture was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=30% to 80%) to give impure product. The impure product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3), and B=CH3CN; 47-77% B over 6 minutes) to give the product (12.41 mg, 0.03 mmol, 12% yield) as a solid. 1H NMR MeOD-d4 400 MHz δH=7.79-7.67 (m, 3H), 7.47-7.30 (m, 4H), 4.57-4.46 (m, 1H), 4.08-3.91 (m, 2H), 3.64-3.44 (m, 2H), 2.20-1.93 (m, 7H). LCMS Rt=1.25 min in 2.0 min chromatography, MS ESI calcd. for C21H20F3N2O4 [M+H]+ 421.1, found 421.1.
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- A mixture of 3-[[(2S)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), Et3N (0.17 mL, 1.21 mmol) and methyl carbonochloridate (45.56 mg, 0.48 mmol) in CH2Cl2 (10 mL) was stirred at 25° C. for 16 hours. The reaction was quenched with sat NH4Cl (10 mL), and the mixture was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 57-77% B over 6 minutes) to give the product (71.61 mg, 0.16 mmol, 68% yield) as a solid. 1H NMR DMSO-d6 +D20 400 MHz δH=7.80-7.71 (m, 2H), 7.59-7.38 (m, 5H), 4.30-4.17 (m, 1H), 3.99-3.83 (m, 2H), 3.40-3.17 (m, 5H), 2.02-1.73 (m, 4H). LCMS Rt=1.30 min in 2.0 min chromatography, MS ESI calcd. for C21H20F3N2O5 [M+H]+ 437.1, found 437.0.
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- A mixture of 3-[[(2S)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), Et3N (0.17 mL, 1.21 mmol) and methanesulfonyl chloride (55.23 mg, 0.48 mmol) in CH2Cl2 (10 mL) was stirred at 25° C. for 16 hours. The reaction was quenched with sat.NH4Cl (10 mL), and the mixture was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 um), A=H2O (10 mM NH4HCO3) and B=CH3CN; 55-75% B over 6 minutes) to give the product (47.27 mg, 0.10 mmol, 43% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.78 (d, 2H), 7.61 (s, 1H), 7.48-7.38 (m, 4H), 4.13-4.07 (m, 1H), 3.97-3.86 (m, 2H), 3.31-3.20 (m, 2H), 2.86 (s, 3H), 2.05-1.79 (m, 4H). LCMS Rt=1.26 min in 2.0 min chromatography, MS ESI calcd. for C20H20F3N2O5S [M+H]+ 457.1, found 457.0.
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- To the mixture of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid (500 mg, 1.42 mmol), (3R)-pyrrolidin-3-ol (184.97 mg, 2.12 mmol) and HATU (1.61 g, 4.25 mmol) in DMF (10 mL) was added the DIPEA (0.74 mL, 4.25 mmol). And the mixture was stirred at 25° C. for 16 hours. The mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=20% to 50% to 100%) to give the impure product (300 mg, ˜50% yield) as a solid.
- A part of the impure product (100 mg) was triturated from i-Pr2O (2 mL) to give the product (55 mg, 0.13 mmol, 55% yield) as a solid. 1H NMR DMSO-d6+D20 400 MHz δH=7.72 (d, 2H), 7.49-7.37 (m, 5H), 4.79-4.61 (m, 2H), 4.43-4.25 (m, 1H), 3.69-3.23 (m, 4H), 2.09-1.70 (m, 2H). LCMS Rt=1.17 min in 2.0 min chromatography, MS ESI calcd. for C20H18F3N205 [M+H]+ 423.1, found 423.1.
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- To the mixture of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid (500 mg, 1.42 mmol), (3S)-pyrrolidin-3-ol (184.97 mg, 2.12 mmol) and HATU (1.61 g, 4.25 mmol) in DMF (10 mL) was added the DIPEA (0.74 mL, 4.25 mmol). The mixture was stirred at 25° C. for 16 hours to give the solution. The mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=20% to 50% to 100%) to give the impure product (300 mg, ˜50% yield) as a solid.
- The impure product (100 mg) was purified by Prep-HPLC (Xtimate C18 (150 mm×25 mm 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 35-65% B over 9 minutes) to give the product (43.95 mg, 0.10 mmol, 44% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.72 (d, 2H), 7.54-7.34 (m, 5H), 4.80-4.60 (m, 2H), 4.41-4.26 (m, 1H), 3.71-3.24 (m, 4H), 2.07-1.72 (m, 2H). LCMS Rt=1.22 min in 2.0 min chromatography, MS ESI calcd. for C20H18F3N2O5 [M+H]+ 423.1, found 423.1.
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- A mixture of 3-[[(2R)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (90 mg, 0.22 mmol), Et3N (0.15 mL, 1.08 mmol) and methyl carbonochloridate (41.01 mg, 0.43 mmol) in DCM (25 mL) was stirred at 20° C. for 16 hours. The reaction was diluted with sat.NH4Cl (15 mL), extracted with DCM (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 59-79% B over 6 minutes) to give the product (38.68 mg, 0.09 mmol, 41% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.81-7.70 (m, 2H), 7.55-7.34 (m, 5H), 4.29-4.16 (m, 1H), 3.97-3.85 (m, 2H), 3.41-3.13 (m, 5H), 2.02-1.70 (m, 4H). LCMS Rt=1.30 min in 2 min chromatography, MS ESI calcd. for C21H20F3N2O5 [M+H]+ 437.1, found 437.1.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100 mg, 0.34 mmol), 2-pyrimidin-5-ylethanol (126.15 mg, 1.02 mmol) and PPh3 (177.7 mg, 0.68 mmol) in THF (6 mL) was added DIAD (136.99 mg, 0.68 mmol) and the mixture was stirred under N2 at 20° C. for 16 hours to give a mixture. The mixture was concentrated to dryness, diluted with H2O (10 mL), and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered. And the filtrate was concentrated to give the crude product. The crude product was purified by Prep-HPLC (Kromasil (150 mm×25 mm, 10 μm), A=H2O (0.05% NH3 H2O) and B=CH3CN; 48-78% B over 7 minutes) to give the product (49.53 mg, 123.4 μmol, 36% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=9.02 (s, 1H), 8.73 (s, 2H), 7.78 (d, 2H), 7.60 (s, 1H), 7.48 (d, 2H), 7.42 (s, 2H), 4.20 (t, 2H), 3.11 (t, 2H). LCMS Rt=1.17 min in 2 min chromatography, MS ESI calcd. for C2oH15F3N3O3 [M+H]+ 402.1, found 402.1.
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- A mixture of 3-[[(2R)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), Et3N (0.17 mL, 1.21 mmol) and methanesulfonyl chloride (55.23 mg, 0.48 mmol) in DCM (25 mL) was stirred at 20° C. for 16 hours. The reaction was diluted with sat.NH4Cl (15 mL), and extracted with DCM (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 55-75% B over 6 minutes) to give the product (22.24 mg, 48.7 μmol, 20% yield, 100%) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.77 (d, 2H), 7.59 (s, 1H), 7.46-7.34 (m, 4H), 4.13-4.07 (m, 1H), 3.98-3.86 (m, 2H), 3.31-3.17 (m, 2H), 2.83 (s, 3H), 2.04-1.78 (m, 4H). LCMS Rt=1.25 min in 2 min chromatography, MS ESI calcd. for C20H20F3N2O5S [M+H]+ 457.1, found 457.1.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (500 mg, 1.69 mmol) in THF (20 mL) was added tert-butyl 2-hydroxyacetate (669.28 mg, 5.06 mmol), PPh3 (885.52 mg, 3.38 mmol) and DIAD (682.68 mg, 3.38 mmol). The resulting mixture was stirred at 25° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (680 mg, 1.66 mmol, 98% yield) as a solid. 1H NMR CDCl3, 400 MHz δH=7.97 (d, 2H), 7.49 (s, 2H), 7.30 (d, 2H), 4.62 (s, 2H), 1.49 (s, 9H).
- To a solution of tert-butyl 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]acetate (690 mg, 1.68 mmol) in DCM (10 mL) was added TFA (5.11 mL). The resulting mixture was stirred at 25° C. for 3 hours to give a solution. The reaction solution was concentrated to give the crude product (586 mg, 1.65 mmol, 98% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.17 (d, 2H), 7.92-7.79 (m, 2H), 7.48 (d, 2H), 4.67 (s, 2H).
- To a solution of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]acetic acid (195 mg, 0.55 mmol) in DMF (5 mL) was added HATU (313.96 mg, 0.83 mmol), DIPEA (0.48 mL, 2.75 mmol) and then piperidine (56.25 mg, 0.66 mmol). The resulting mixture was stirred at 25° C. for 16 hours to give a solution. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction mixture and stirred for 5 minutes. After separated, the organic layer was washed with water (20 mL×2), brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (120.57 mg, 0.28 mmol, 52% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.15 (d, 2H), 7.88 (d, 1H), 7.80 (d, 1H), 7.49 (d, 2H), 4.86 (s, 2H), 3.59-3.51 (m, 2H), 3.46-3.41 (m, 2H), 1.67-1.58 (m, 4H), 1.50-1.42 (m, 2H). LCMS Rt=1.21 min in 2.0 min chromatography, MS ESI calcd. for C20H19F3N3O4 [M+H]+ 422.1, found 422.1.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100 mg, 0.34 mmol), 2-pyrazin-2-ylethanol (126.15 mg, 1.02 mmol) and PPh3 (177.7 mg, 0.68 mmol) in THF (6 mL) was added the DIAD (136.99 mg, 0.68 mmol), and the mixture was stirred under N2 at 20° C. for 16 hours to give the mixture. The mixture was concentrated to dryness, diluted with H2O (10 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Kromasil (150 mm×25 mm 10 μm), A=H2O (0.05% NH3.H2O) and B=CH3CN; 50-80% B over 7 minutes) to give the product (41.28 mg, 102.9 μmol, 30% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.64 (d, 1H), 8.52-8.49 (m, 1H), 8.47 (d, 1H), 7.77 (d, 2H), 7.54 (s, 1H), 7.48 (d, 2H), 7.41 (s, 2H), 4.28 (t, 2H), 3.26 (t, 2H). LCMS Rt=1.19 min in 2 min chromatography, MS ESI calcd. for C20H15F3N3O3 [M+H]+ 402.1, found 402.0.
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- A mixture of 6-bromo-2-nitro-pyridin-3-ol (3 g, 13.7 mmol), Fe (7657.88 mg, 136.99 mmol) and NH4C1 (7329.1 mg, 136.99 mmol) in Ethanol (100 mL) and Water (100 mL) was stirred at 75° C. for 2 hours to give a black suspension. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the crude product (2.5 g, 13.22 mmol, 96.55% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=9.71 (s, 1H), 6.74 (d, 1H), 6.50 (d, 1H), 5.92 (br s, 2H).
- A mixture of 2-amino-6-bromo-pyridin-3-ol (2.5 g, 13.23 mmol) and CDI (2.24 g, 15.87 mmol) in THF (100 mL) was stirred at 55° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 30% to 50%) to give the product (900 mg, 4.18 mmol, 32% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=12.68 (s, 1H), 7.62 (d, 1H), 7.33 (d, 1H).
- To a solution of 5-bromo-3H-oxazolo[4,5-b]pyridin-2-one (200 mg, 0.93 mmol) in THF (10 mL) was added PPh3 (487.98 mg, 1.86 mmol), 2-pyrimidin-2-ylethanol (230.96 mg, 1.86 mmol) and then DIAD (376.2 mg, 1.86 mmol). The resulting mixture was stirred at 25° C. under N2 for 16 hours. The reaction solution was concentrated to give a residue. Water (20 mL) was added to the residue, and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 30% to 50%) to give the product (200 mg, 0.62 mmol, 67% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.63 (d, 2H), 7.25-7.15 (m, 3H), 4.44 (t, 2H), 3.48 (t, 2H).
- A mixture of 5-bromo-3-(2-pyrimidin-2-ylethyl)oxazolo[4,5-b]pyridin-2-one (60 mg, 0.19 mmol), 4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (67.73 mg, 0.22 mmol), K3PO4 (79.33 mg, 0.37 mmol) and Pd(t-Bu3P)2 (14.32 mg, 0.03 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) was stirred at 80° C. under N2 for 16 hours to give a suspension. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (53.55 mg, 0.12 mmol, 68% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.61 (d, 2H), 7.46 (d, 1H), 7.37 (d, 1H), 7.15-7.08 (m, 4H), 4.49 (t, 2H), 3.51 (t, 2H), 2.38 (s, 3H). LCMS Rt=1.18 min in 2.0 min chromatography, MS ESI calcd. for C20H16F3N4O3 [M+H]+ 417.1, found 417.1.
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- A mixture of 5-bromo-3-(2-pyrimidin-2-ylethyl)oxazolo[4,5-b]pyridin-2-one (60 mg, 0.19 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (71.99 mg, 0.22 mmol), K3PO4 (79.33 mg, 0.37 mmol) and Pd(t-Bu3P)2 (14.32 mg, 0.03 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) was stirred at 80° C. under N2 for 16 hours to give a suspension. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (57.98 mg, 0.13 mmol, 71% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.63 (d, 2H), 8.45 (d, 1H), 8.01 (dd, 1H), 7.48-7.40 (m, 2H), 7.12 (t, 1H), 4.90 (q, 2H), 4.52 (t, 2H), 3.54 (t, 2H). LCMS Rt=1.14 min in 2.0 min chromatography, MS ESI calcd. for C19H14F4N5O3 [M+H]+ 436.1, found 436.0.
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- To a mixture of 5[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol), and 2-pyrazin-2-ylethanol (125.73 mg, 1.01 mmol) in THF (10 mL) was added PPh3 (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol). The reaction mixture was stirred at 20° C. under N2 for 16 hours. After cooling to r.t., the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0 to 30%) to give the product (49.1 mg, 0.12 mmol, 36% yield) as a solid.
- 1H NMR (CDCl3, 400 MHz) δH=8.50-8.46 (m, 2H), 8.39 (d, 1H), 7.94 (d, 2H), 7.46 (s, 2H), 7.32 (d, 2H), 4.46 (t, 2H), 3.43 (t, 2H). LCMS Rt=1.37 min in 2.0 min chromatography, MS ESI calcd. for C19H14F3N4O3 [M+H]+ 403.1, found 403.0.
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- To a mixture of 5[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol), 2-pyrimidin-5-ylethanol (125.73 mg, 1.01 mmol) in THF (10 mL) was added PPh3 (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol). The reaction mixture was stirred at 20° C. under N2 for 16 hours. After cooling to r.t., the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0 to 30%) to give the product (23.15 mg, 0.06 mmol, 17% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=9.08 (s, 1H), 8.68 (s, 2H), 7.95-7.90 (d, 2H), 7.48 (s, 2H), 7.34 (d, 2H), 4.30 (t, 2H), 3.26 (t, 2H). LCMS Rt=1.24 min in 2.0 min chromatography, MS ESI calcd. for C19H14F3N4O3 [M+H]+ 403.1, found 402.8.
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- To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (1000 mg, 5.34 mmol) in THF (20 mL) was added NaH (256.36 mg, 6.41 mmol). The reaction mixture was stirred at 20° C. for 0.5 hour. Then iodomethane (1516.13 mg, 10.68 mmol) was added. The reaction mixture was stirred at 20° C. for 2 hours to give a mixture. The reaction mixture was diluted with sat.NH4Cl (30 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give the crude product (1100 mg, 5.47 mmol) as an oil. 1H NMR (CDCl3, 400 MHz) δH=3.97-3.88 (m, 1H), 3.52-3.36 (m, 4H), 3.33 (s, 3H), 2.05-1.85 (m, 2H), 1.46 (s, 9H).
- A mixture of tert-butyl (3S)-3-methoxypyrrolidine-l-carboxylate (1100 mg, 5.47 mmol) in 4M HCl/dioxane (15 mL, 60 mmol) was stirred at 20° C. for 16 hours to give a mixture. The reaction mixture was concentrated to give the crude product (1000 mg, 7.27 mmol) as an oil, which was used directly in next step. 1H NMR (CDCl3, 400 MHz) δH=10.03-9.49 (m, 2H), 4.13-4.06 (m, 1H), 3.53-3.34 (m, 4H), 3.32 (s, 3H), 2.26-2.13 (m, 1H), 2.09-1.93 (m, 1H).
- To the mixture of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol yl]acetic acid (200 mg, 0.57 mmol), (3S)-3-methoxypyrrolidine hydrochloride (155.82 mg, 1.13 mmol) and HATU (645.83 mg, 1.7 mmol) in DMF (3 mL) was added the DIPEA (0.3 mL, 1.7 mmol). The mixture was stirred at 25° C. for 16 hours to give the solution. The mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the impure product. The impure product was further purified by triturating from i-Pr2O (2 mL) to give the product (35.39 mg, 80.5 μmol, 14% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.71 (d, 2H), 7.47-7.36 (m, 5H), 4.81-4.60 (m, 2H), 4.08-3.93 (m, 1H), 3.70-3.40 (m, 3H), 3.34-3.17 (m, 4H), 2.13-1.82 (m, 2H). LCMS Rt=1.23 min in 2.0 min chromatography, MS ESI calcd. for C21H20F3N2O5 [M+H]+ 437.1, found 436.8.
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- To a solution of tert-butyl (3R)-3-hydroxypyrrolidine-l-carboxylate (1000 mg, 5.34 mmol) in THF (20 mL) was added NaH (256.36 mg, 6.41 mmol). The reaction mixture was stirred at 20° C. for 0.5 hour. Then iodomethane (1516.13 mg, 10.68 mmol) was added. The reaction mixture was stirred at 20° C. for 2 hours to give a mixture. The reaction mixture was diluted with sat.NH4Cl (30 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give the crude product (1100 mg, 5.47 mmol) as an oil. 1H NMR (CDCl3, 400 MHz) δH=3.97-3.88 (m, 1H), 3.53-3.36 (m, 4H), 3.33 (s, 3H), 2.06-1.84 (m, 2H), 1.46 (s, 9H).
- A mixture of tert-butyl (3R)-3-methoxypyrrolidine-l-carboxylate (1100 mg, 5.47 mmol) in 4M HCl/dioxane (15 mL, 60 mmol) was stirred at 20° C. for 16 hours to give a mixture. The reaction mixture was concentrated to give the crude (1000 mg, 7.27 mmol) as an oil. 1H NMR CDCl3, 400 MHz δH=10.10-9.39 (m, 2H), 4.13-4.04 (m, 1H), 3.51-3.35 (m, 4H), 3.31 (s, 3H), 2.24-2.12 (m, 1H), 2.08-1.95 (m, 1H).
- To the mixture of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid (200 mg, 0.57 mmol), (3R)-3-methoxypyrrolidine hydrochloride (116.87 mg, 0.85 mmol) and HATU (645.83 mg, 1.7 mmol) in DMF (3 mL) was added the DIPEA (0.3 mL, 1.7 mmol). And the mixture was stirred at 25° C. for 2 hours to give the solution. The mixture was diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered. The filtrate was concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the impure product. The impure product was further purified by triturating from i-Pr2O (2 mL) to give the product (81.18 mg, 0.18 mmol, 33% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.69 (d, 2H), 7.43-7.35 (m, 5H), 4.77-4.59 (m, 2H), 4.10-3.94 (m, 1H), 3.69-3.41 (m, 3H), 3.34-3.18 (m, 4H), 2.13-1.83 (m, 2H). LCMS Rt=1.26 min in 2.0 min chromatography, MS ESI calcd. for C21H20F3N2O5 [M+H]+ 437.1, found 436.8.
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- A mixture of 3-[[(3S)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (150 mg, 0.40 mmol), Et3N (0.27 mL, 1.98 mmol) and methyl carbonochloridate (74.93 mg, 0.79 mmol) in CH2Cl2 (10 mL) was stirred at 25° C. for 16 hours to give a mixture. The reaction was quenched with sat.NH4Cl (10 mL), and the mixture was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 55-75% B over 6 minutes) to give the product (58.59 mg, 0.13 mmol, 34% yield) as a solid.
- 1H NMR DMSO-d6 400 MHz δH=7.81 (d, 2H), 7.71 (s, 1H), 7.51-7.41 (m, 4H), 3.92 (d, 2H), 3.58-3.49 (m, 3H), 3.48-3.39 (m, 2H), 3.29-3.20 (m, 1H), 3.16-3.09 (m, 1H), 2.82-2.69 (m, 1H), 2.03-1.91 (m, 1H), 1.78-1.62 (m, 1H). LCMS Rt=1.40 min in 2.0 min chromatography, MS ESI calcd. for C21H20F3N2O5 [M+H]+ 437.1, found 437.1.
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- A mixture of 3-[[(3S)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (150 mg, 0.40 mmol), Et3N (0.27 mL, 1.98 mmol) and methanesulfonyl chloride (90.83 mg, 0.79 mmol) in CH2Cl2 (10 mL) was stirred at 25° C. for 16 hours to give a mixture. The reaction was quenched with sat.NH4Cl (10 mL), and the mixture was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 52-69% B over 6 minutes) to give the product (60.97 mg, 0.13 mmol, 34% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.79-7.74 (m, 2H), 7.58 (s, 1H), 7.45-7.37 (m, 4H), 3.96-3.83 (m, 2H), 3.38-3.29 (m, 2H), 3.23-3.14 (m, 1H), 3.06-3.00 (m, 1H), 2.84 (s, 3H), 2.80-2.70 (m, 1H), 2.07-1.94 (m, 1H), 1.78-1.64 (m, 1H). LCMS Rt=1.35 min in 2.0 min chromatograph, MS ESI calcd. for C20H20F3N2O5S [M+H]+ 457.1, found 457.0.
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- A mixture of 3-[[(3R)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (200 mg, 0.48 mmol), Et3N (0.33 mL, 2.41 mmol) and methyl carbonochloridate (91.13 mg, 0.96 mmol) in DCM (25 mL) was stirred at 20° C. for 16 hours. The reaction was diluted with sat.NH4Cl (20 mL), and extracted with DCM (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 55-65% B over 7 minutes) to give the product (53.76 mg, 0.12 mmol, 25% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.78 (d, 2H), 7.61 (s, 1H), 7.50-7.33 (m, 4H), 3.88 (d, 2H), 3.57-3.46 (m, 3H), 3.45-3.34 (m, 2H), 3.28-3.18 (m, 1H), 3.15-3.03 (m, 1H), 2.80-2.68 (m, 1H), 2.03-1.90 (m, 1H), 1.78-1.61 (m, 1H). LCMS Rt=1.41 min in 2 min chromatography, MS ESI calcd. for C21H20F3N2O5 [M+H]+ 437.1, found 437.1.
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- A mixture of 3-[[(3R)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (200 mg, 0.48 mmol), Et3N (0.33 mL, 2.41 mmol) and methanesulfonyl chloride (110.46 mg, 0.96 mmol) in DCM (25 mL) was stirred at 20° C. for 16 hours. The reaction was diluted with sat.NH4Cl (20 mL), and the mixture was extracted with DCM (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 51-71% B over 6 minutes) to give the product (68.23 mg, 0.15 mmol, 31% yield) as a solid. 1H NMR DMSO-d6+D2O 400 MHz δH=7.79 (d, 2H), 7.66-7.60 (m, 1H), 7.47-7.39 (m, 4H), 3.94-3.86 (m, 2H), 3.41-3.30 (m, 2H), 3.24-3.15 (m, 1H), 3.09-3.01 (m, 1H), 2.86 (s, 3H), 2.80-2.70 (m, 1H), 2.07-1.93 (m, 1H), 1.79-1.66 (m, 1H). LCMS Rt=1.28 min in 2 min chromatography, MS ESI calcd. for C20H20F3N2O5S [M+H]+ 457.1, found 456.8.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100 mg, 0.34 mmol), pyrazin-2-ylmethanol (111.9 mg, 1.02 mmol) and PPh3 (177.7 mg, 0.68 mmol) in THF (6 mL) was added the DIAD (136.99 mg, 0.68 mmol) at 0° C. and the mixture was stirred under N2 at 20° C. for 16 hours to give the mixture. The mixture was concentrated to dryness, diluted with H2O (10 mL), and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 35% to 45% to 60%) to give the product (100.9 mg, 260.4 μmol, 77% yield) as an oil. 1H NMR DMSO-d6 400 MHz δH=8.83 (s, 1H), 8.60-8.53 (m, 2H), 7.74 (d, 2H), 7.63 (s, 1H), 7.50-7.42 (m, 4H), 5.35 (s, 2H). LCMS Rt=1.52 min in 2 min chromatography, MS ESI calcd. for C19HDF3N303 [M+H]+ 388.1, found 388.1.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100 mg, 0.34 mmol), pyrimidin-4-ylmethanol (111.9 mg, 1.02 mmol) and PPh3 (177.7 mg, 0.68 mmol) in THF (6 mL) was added the DIAD (136.99 mg, 0.68 mmol) at 0° C. and the mixture was stirred under N2 at 20° C. for 16 hours. The mixture was concentrated to dryness, diluted with H2O (10 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 40% to 55%) to give the product (62.94 mg, 160.4 47% yield) as colorless oil. 1H NMR DMSO-d6 400 MHz δH=9.09 (s, 1H), 8.79 (d, 1H), 7.74 (d, 2H), 7.63-7.59 (m, 2H), 7.51-7.41 (m, 4H), 5.30 (s, 2H). LCMS Rt=1.27 min in 2 min chromatography, MS ESI calcd. for C19H13F3N3O3 [M+H]+ 388.1, found 387.8.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200 mg, 0.68 mmol), tert-butyl 3-hydroxypropanoate (296.11 mg, 2.03 mmol) and PPh3 (354.21 mg, 1.35 mmol) in THF (5 mL) was added the DIAD (273.07 mg, 1.35 mmol) at 0° C. and the mixture was stirred under N2 at 20° C. for 16 hours. The mixture was concentrated to dryness, diluted with H2O (10 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 30% to 45%) to give the product (255 mg, 0.49 mmol, 72% yield) as an oil. LCMS Rt=0.93 min in 1.5 min chromatography, MS ESI calcd. for C20H19F3N2O5Na [M+Na]+ 447.1, found 447.1.
- A mixture of tert-butyl 3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanoate (250 mg, 0.59 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 20° C. for 2 hour. From LCMS, desired MS was observed, and no starting material was remained. The mixture was concentrated to dryness to give the crude product (210 mg, 0.33 mmol) as an oil, which was used directly without any further purification. LCMS Rt=0.94 min in 1.5 min chromatography, MS ESI calcd. for C16H12F3N205 [M+H]+ 369.1, found 369.1.
- To a mixture of 3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin yl]propanoic acid (210.01 mg, 0.57 mmol), HATU (216.83 mg, 0.57 mmol), DIPEA (0.33 mL, 1.9 mmol) in DMF (6 mL) was added N-methylmethanamine hydrochloride (31 mg, 0.38 mmol), and the mixture was stirred at 20° C. for 4 hours. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (DCM) to give the product (25.31 mg, 62.4 μmol, 16% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.18 (d, 2H), 7.84-7.73 (m, 2H), 7.48 (d, 2H), 4.09 (t, 2H), 2.99-2.87 (m, 5H), 2.80 (s, 3H). LCMS Rt=1.27 min in 2 min chromatography, MS ESI calcd. for C18H17F3N3O4 [M+H]+ 396.1, found 396.1.
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- To a solution of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]acetic acid (195 mg, 0.55 mmol) in DMF (5 mL) was added HATU (313.96 mg, 0.83 mmol), DIPEA (0.48 mL, 2.75 mmol) and (2R)-2-methylpyrrolidine (56.25 mg, 0.66 mmol). The resulting mixture was stirred at 25° C. for 16 hours to give a solution. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction mixture and stirred for 5 minutes. After separated, the organic layer was washed with water (20 mL×2) and brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (145.29 mg, 0.34 mmol, 63% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.19-8.11 (m, 2H), 7.91-7.85 (m, 1H), 7.84-7.77 (m, 1H), 7.49 (d, 2H), 4.74 (s, 2H), 4.37-4.29 (m, 0.3H), 4.08-3.96 (m, 0.7H), 3.76-3.55 (m, 1.4H), 3.41-3.35 (m, 0.6H), 2.10-1.79 (m, 3H), 1.76-1.50 (m, 1H), 1.31 (d, 1H), 1.10 (d, 2H). LCMS Rt=1.20 min in 2.0 min chromatography, MS ESI calcd. for C20H19F3N3O4 [M+H]+ 422.1, found 422.1.
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- To a solution of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]acetic acid (195 mg, 0.55 mmol) in DMF (5 mL) was added HATU (313.96 mg, 0.83 mmol), DIPEA (0.48 mL, 2.75 mmol) and (2S)-2-methylpyrrolidine hydrochloride (80.33 mg, 0.66 mmol). The resulting mixture was stirred at 25° C. for 16 hours to give a solution. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction mixture and stirred for 5 minutes. After separated, the organic layer was washed with water (20 mL×2), brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (77.38 mg, 0.18 mmol, 33% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.18-8.12 (m, 2H), 7.91-7.86 (m, 1H), 7.83-7.78 (m, 1H), 7.49 (d, 2H), 4.95-4.65 (m, 2H), 4.37-4.29 (m, 0.3H), 4.08-3.96 (m, 0.7H), 3.75-3.54 (m, 1.4H), 3.40-3.35 (m, 0.6H), 2.11-1.79 (m, 3H), 1.76-1.50 (m, 1H), 1.31 (d, 1H), 1.10 (d, 2H). LCMS Rt=1.20 min in 2.0 min chromatography, MS ESI calcd. for C2oH19F3N3O4 [M+H]+ 422.1, found 422.1.
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- A mixture of 5-bromo-3-(2-pyrimidin-2-ylethyl)oxazolo[4,5-b]pyridin-2-one (40 mg, 0.12 mmol), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (168.21 mg, 0.62 mmol), K3PO4 (52.89 mg, 0.25 mmol) and Pd(t-Bu3P)2 (9.55 mg, 0.02 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) was stirred at 80° C. under N2 for 16 hours to give a suspension. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (14.82 mg, 38.6 μmol, 31% yield) as a solid. 1H NMR CDCl3, 400 MHz δH=8.62 (d, 2H), 7.93 (d, 2H), 7.43 (s, 2H), 7.20 (d, 2H), 7.09 (t, 1H), 6.57 (t, 1H), 4.53 (t, 2H), 3.56 (t, 2H). LCMS Rt=1.22 min in 2.0 min chromatography, MS ESI calcd. for C19H15F2N403 [M+H]+ 385.1, found 385.1.
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- To a solution of 5-bromo-3H-oxazolo[4,5-b]pyridin-2-one (300 mg, 1.4 mmol) in THF (5 mL) was added tert-butyl 2-hydroxyacetate (553.23 mg, 4.19 mmol), PPh3 (731.97 mg, 2.79 mmol) and then DIAD (564.31 mg, 2.79 mmol). The resulting mixture was stirred at 25° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give a residue. Water (20 mL) was added to the residue, and the mixture was extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) to give the product (400 mg, 1.22 mmol, 87% yield) as a solid. 1H NMR CDCl3, 400 MHz δH=7.33-7.29 (m, 1H), 7.27-7.24 (m, 1H), 4.55 (s, 2H), 1.48 (s, 9H).
- A mixture of tert-butyl 2-(5-bromo-2-oxo-oxazolo[4,5-b]pyridin-3-yl)acetate (100 mg, 0.30 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (117.06 mg, 0.36 mmol), K3PO4 (129 mg, 0.61 mmol) and Pd(t-Bu3P)2 (23.29 mg, 0.05 mmol) in 1,4-Dioxane (10 mL) and Water (1 mL) was stirred at 80° C. under N2 for 16 hours to give a suspension. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (120 mg, 0.27 mmol, 89% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.47 (s, 1H), 8.03 (d, 1H), 7.55-7.40 (m, 2H), 4.90 (q, 2H), 4.62 (s, 2H), 1.50 (s, 9H).
- To a solution of tert-butyl 2-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetate (120 mg, 0.27 mmol) in DCM (5 mL) was added TFA (2.78 mL). The resulting mixture was stirred at 25° C. for 2 hours to give a solution. The reaction solution was concentrated to give the crude product (100 mg, 0.25 mmol, 95.40% yield) as a solid. 1H NMR DMSO-d6 400 MHz 6=8.75 (d, 1H), 8.47 (d, 1H), 7.96-7.85 (m, 2H), 5.15 (q, 2H), 4.71 (s, 2H).
- To a solution of 2-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetic acid (100 mg, 0.26 mmol) in DMF (5 mL) was added HATU (147.28 mg, 0.39 mmol), DIPEA (0.14 mL, 0.77 mmol) and pyrrolidine (27.55 mg, 0.39 mmol). The resulting mixture was stirred at 25° C. for 16 hours to give a solution. Saturated NH4Cl aqueous (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (34.11 mg, 75.5 μmol, 29% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=8.44 (d, 1H), 8.03 (dd, 1H), 7.50 (d, 1H), 7.43 (d, 1H), 4.89 (q, 2H), 4.69 (s, 2H), 3.62 (t, 2H), 3.54 (t, 2H), 2.11 (quin, 2H), 1.94 (quin, 2H). LCMS Rt=1.27 min in 2.0 min chromatography, MS ESI calcd. for C19H17F4N4O4 [M+H]+ 441.1, found 441.0.
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- To the mixture of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid (500 mg, 1.42 mmol), DIPEA (0.74 mL, 4.25 mmol) and HATU (1.61 g, 4.25 mmol) in DMF (10 mL) was added the 3-(methoxymethyl)pyrrolidine hydrochloride (321.93 mg, 2.12 mmol), and the mixture was stirred at 25° C. for 2 hours to give the solution. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=20% to 50% to 100%) to give the impure product. The impure product was further purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN; 50-80% B over 8 minutes) to give the product (150 mg).
- The product was separated by SFC (04250 mm×30 mm,5 μm); A=CO2 and B=EtOH (0.1% NH3H2O); 20° C.; 50 mL/min; 30% B; 7 min run; 14 injections, Rt of peak 1 =4.90 min, Rt of Peak 2=5.82 min) to give the compound 138 (35.08 mg, 77.9 μmol) (Peakl, Rt=2.90 min in SFC) as a solid and compound 139 (42.87 mg, 95.2 μmol) (Peak2, Rt=3.21 min in SFC) as a solid. Note: the enantiomers were randomly assigned.
- Compound 138: 1H NMR DMSO-d6+D2O 400 MHz δH=7.71 (d, 2H), 7.45-7.36 (m, 5H), 4.76-4.59 (m, 2H), 3.72-3.59 (m, 1H), 3.57-3.16 (m, 8H), 3.04-2.98 (m, 0.5H), 2.41-2.36 (m, 0.5H), 2.07-1.86 (m, 1H), 1.73-1.50 (m, 1H). LCMS Rt=1.28 min in 2.0 min chromatography, MS ESI calcd. for C22H22F3N2O5 [M+H]+ 451.1, found 451.0.
- Compound 139: 1H NMR DMSO-d6+D2O 400 MHz δH=7.72 (d, 2H), 7.50-7.36 (m, 5H), 4.79-4.61 (m, 2H), 3.75-3.59 (m, 1H), 3.55-3.12 (m, 8H), 3.06-2.97 (m, 0.5H), 2.41-2.36 (m, 0.5H), 2.09-1.86 (m, 1H), 1.75-1.47 (m, 1H). LCMS Rt=1.27 min in 2.0 min chromatography, MS ESI calcd. for C22H22F3N2O5 [M+H]+ 451.1, found 451.1.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100 mg, 0.34 mmol), chloro(methylsulfanyl)methane (65.43 mg, 0.68 mmol) and Cs2CO3 (220.72 mg, 0.68 mmol) in DMF (2 mL) was stirred at 55° C. for 16 hours to give a mixture. After cooling to r.t., the mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) to give the product 110 mg, 0.31 mmol, 91% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=7.83-7.75 (m, 3H), 7.52-7.44 (m, 4H), 5.11 (s, 2H), 2.17 (s, 3H).
- To a solution of 3-(methylsulfanylmethyl)-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one (110 mg, 0.31 mmol) in DCM (10 mL) was added m-CPBA (160.27 mg, 0.93 mmol). The reaction mixture was stirred at 20° C. for 2 hours to give a solution. The reaction mixture was quenched with sat.NaHCO3 (20 mL), extracted with DCM (10 mL×3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in PE =0% to 15% to 30%) to give the product (69.04 mg, 0.18 mmol, 57% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=7.83-7.75 (m, 3H), 7.54-7.47 (m, 4H), 5.49 (s, 2H), 3.15 (s, 3H). LCMS Rt=1.27 min in 2.0 min chromatography. MS MS ESI calcd. for C16H12F3NO5SNa [M+Na]+ 410.0286, found 410.0282.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol), pyrimidin-4-ylmethanol (74.35 mg, 0.68 mmol), PPh3 (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol) in THF (3 mL) was stirred at 20° C. under N2 for 16 hours. The reaction was quenched with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 45-75% B over 7 minutes) to give the product (68.81 mg, 0.18 mmol, 52% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=9.10 (d, 1H), 8.81 (d, 1H), 8.07 (d, 2H), 7.90 (d, 1H), 7.81 (d, 1H), 7.74-7.70 (m, 1H), 7.44 (d, 2H), 5.27 (s, 2H). LCMS Rt=1.27 min in 2.0 min chromatography, MS ESI calcd. for C18H12F3N4O3 [M+H]+ 389.1, found 389.0.
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- To the mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200 mg, 0.68 mmol), 1-(2-hydroxyethyl)pyrrolidin-2-one (261.63 mg, 2.03 mmol) and PPh3 (354.21 mg, 1.35 mmol) in THF (6 mL) was added DIAD (273.07 mg, 1.35 mmol) at 0° C. and the mixture was stirred under N2 at 20° C. for 16 hours to give the mixture. The mixture was concentrated to dryness, diluted with H2O (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to 40% to 55%) to give the product (127.94 mg, 0.31 mmol, 47% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.21 (d, 2H), 7.84-7.73 (m, 2H), 7.50 (d, 2H), 4.11-4.02 (m, 2H), 3.60 (t, 2H), 3.51 (t, 2H), 1.89-1.79 (m, 2H), 1.75-1.60 (m, 2H). LCMS Rt=1.14 min in 2 min chromatography, MS ESI calcd. for C19H17F3N3O4 [M+H]+ 408.1, found 408.0.
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- A mixture of pyrazin-2-ylmethanol (74.35 mg, 0.68 mmol), 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol), PPh3 (177.10 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol) in THF (3 mL) was stirred at 20° C. for 16 hours. The reaction was diluted with sat.NH4Cl (20 mL), and the mixture was extracted with DCM (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H2O (10 mM NH4HCO3) and B=CH3CN; 42-72% B over 7 minutes) to give the product (64.4 mg, 0.17 mmol, 49% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.91 (s, 1H), 8.64-8.54 (m, 2H), 8.08 (d, 2H), 7.89-7.78 (m, 2H), 7.44 (d, 2H), 5.32 (s, 2H). LCMS Rt=1.17 min in 2 min chromatography, MS ESI calcd. for C18H12F3N4O3 [M+H]+ 389.1, found 389.0.
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- A mixture of tert-butyl 2-(5-bromo-2-oxo-oxazolo[4,5-b]pyridin-3-yl)acetate (100 mg, 0.30 mmol), 4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (110.14 mg, 0.36 mmol), K3PO4 (129 mg, 0.61 mmol) and Pd(t-Bu3P)2 (23.29 mg, 0.05 mmol) in 1,4-Dioxane (5 mL) and water (0.50 mL) was stirred at 80° C. under N2 for 16 hours to give a suspension. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the residue (120 mg). Water (15 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (15 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (110 mg). The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (100 mg, 0.21 mmol, 71% yield) as colorless oil. 1H NMR (CDCl3, 400 MHz) δH=7.51 (d, 1H), 7.38 (d, 1H), 7.18-7.09 (m, 3H), 4.59 (s, 2H), 2.37 (s, 3H), 1.48 (s, 9H).
- To a solution of tert-butyl 2-[5-[2-methyl-4-(trifluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetate (100 mg, 0.24 mmol) in DCM (5 mL) was added TFA (2.5 mL). The resulting solution was stirred at 25° C. for 1 hour to give a solution. The reaction solution was concentrated to give the crude product (86 mg, 0.23 mmol, 99% yield) as a grey solid which was used to next step directly without further purification. LCMS Rt=0.94 min in 1.5 min chromatography, MS ESI calcd. for C16H12F3N2O5 [M+H]+ 369.1, found 369.0.
- To a solution of 2-[5-[2-methyl-4-(trifluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetic acid (86 mg, 0.23 mmol) in DMF (5 mL) was added HATU (133.19 mg, 0.35 mmol), DIPEA (0.12 mL, 0.70 mmol) and pyrrolidine (19.93 mg, 0.28 mmol). The resulting mixture was stirred at 25° C. for 16 hours to give a solution. Water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (30 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (41.09 mg, 95.4 μmol, 41% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.50 (d, 1H), 7.39 (d, 1H), 7.15-7.09 (m, 3H), 4.66 (s, 2H), 3.67-3.45 (m, 4H), 2.35 (s, 3H), 2.04 (quin, 2H), 1.89 (quin, 2H). LCMS Rt=1.35 min in 2.0 min chromatography, MS ESI calcd. for C20H19F3N304 [M+H]+ 422.1, found 422.0.
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- A mixture of tert-butyl 2-5-bromo-2-oxo-oxazolo[4, 5]pyridin-3-yl)acetate (100 mg, 0.30 mmol), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane (98.46 mg, 0.36 mmol), K3PO4 (129 mg, 0.61 mmol) and Pd(t-Bu3P)2 (23.29 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at 80° C. under N2 for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the residue (90 mg). Water (15 mL) was added to the residue, and the resulting mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (15 mL×2), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (90 mg, 0.22 mmol, 73% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.95 (d, 2H), 7.48 (s, 2H), 7.21 (d, 2H), 6.81-6.34 (m, 1H), 4.63 (s, 2H), 1.49 (s, 9H).
- To a solution of tert-butyl 2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetate (90 mg, 0.23 mmol) in DCM (5 mL) was added TFA (2.5 mL). The resulting solution was stirred at 25° C. for 2 hours. The reaction solution was concentrated to give the crude product (75 mg, 0.22 mmol, 99% yield) as a grey solid, which was used to the next step directly without further purification. LCMS Rt=0.76 min in 1.5 min chromatography, MS ESI calcd. for C15H11F2N2O5 [M+H]+ 337.1, found 336.9.
- To a solution of 2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin yl]acetic acid (75 mg, 0.22 mmol) in DMF (3 mL) was added HATU (127.21 mg, 0.33 mmol), DIPEA (0.12 mL, 0.67 mmol) and pyrrolidine (31.73 mg, 0.45 mmol). The resulting mixture was stirred at 25° C. for 16 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 30% to 50%) to give the product (24.63 mg, 0.06 mmol, 27% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.92 (d, 2H), 7.50-7.42 (m, 2H), 7.20 (d, 2H), 6.56 (t, 1H), 4.70 (s, 2H), 3.61 (t, 2H), 3.54 (t, 2H), 2.09 (quin, 2H), 1.92 (quin, 2H). LCMS Rt=1.17 min in 2.0 min chromatography, MS ESI calcd. for C19H18F2N3O4 [M+H]+ 390.1, found 390.0.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol), 2-pyrimidin-4-ylethanol (83.82 mg, 0.68 mmol), PPh3 (177.10 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol) in THF (3 mL) was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=40% to 70%) to give the product (53.90 mg, 0.13 mmol, 39% yield) as solid. 1H NMR (DMSO-d6+D2O 400 MHz) δH=8.94 (s, 1H), 8.59 (d, 1H), 8.03 (d, 2H), 7.76-7.63 (m, 2H), 7.52-7.40 (m, 3H), 4.28 (t, 2H), 3.26 (t, 2H). LCMS Rt=1.28 min in 2 min chromatography, MS ESI calcd. for C19H14F3N4O3 [M+H]+ 403.1, found 403.1.
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- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100 mg, 0.34 mmol), 2-pyrimidin-4-ylethanol (83.82 mg, 0.68 mmol), PPh3 (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol) in THF (3 mL) was stirred at 20° C. under N2 for 16 hours.
- The reaction was quenched with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=40% to 80%) to give the impure product. The impure product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 43-73% B over 6 minutes) to give the product (17.19 mg, 42.8 μmol, 13% yield) as a solid,. 1H NMR (DMSO-d6400 MHz) δH=9.06 (d, 1H), 8.68 (d, 1H), 7.78 (d, 2H), 7.59 (s, 1H), 7.52 (dd, 1H), 7.47 (d, 2H), 7.42 (d, 2H), 4.30 (t, 2H), 3.23 (t, 2H). LCMS Rt=1.18 min in 2.0 min chromatography, MS ESI calcd. for C20H15F3N303 [M+H]+ 402.1, found 402.1.
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- To a mixture of 5-bromo-3H-1,3-benzoxazol-2-one (500 mg, 2.34 mmol) and Cs2CO3 (1.52 g, 4.67 mmol) in DMF (10 mL) was added tert-butyl 2-bromoacetate (911.36 mg, 4.67 mmol). The reaction mixture was stirred at 55° C. for 16 hours to give a mixture. After cooling to r.t., the mixture was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was triturated from PE (5 mL) to give the product (660 mg, 2.01 mmol, 86% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.66 (d, 1H), 7.41-7.27 (m, 2H), 4.65 (s, 2H), 1.42 (s, 9H).
- To a mixture of tert-butyl 2-(5-bromo-2-oxo-1,3-benzoxazol-3-yl)acetate (200 mg, 0.61 mmol), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (197.52 mg, 0.73 mmol), K3PO4 (258.78 mg, 1.22 mmol) and Pd(t-Bu3P)2 (62.29 mg, 0.12 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was stirred at 80° C. for 16 hours under N2. After cooling to r.t., the mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 4% to 8% to 15%) to give the product (180 mg, 0.46 mmol, 75% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.83-7.61 (m, 3H), 7.55-7.04 (m, 5H), 4.72 (s, 2H), 1.43 (s, 9H).
- A mixture of tert-butyl 2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-1,3-benzoxazol-3-yl]acetate (180 mg, 0.46 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 15° C. for 4 hours. The mixture was concentrated to dryness to give the product (150 mg, 0.45 mmol, 97% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=7.80-7.66 (m, 3H), 7.55-7.04 (m, 5H), 4.71 (s, 2H).
- A mixture of 2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-1,3-benzoxazol-3-yl]acetic acid (130 mg, 0.39 mmol), HATU (294.88 mg, 0.78 mmol), and DIPEA (0.27 mL, 1.55 mmol) in DMF (6 mL) was stirred at 25° C. for 10 min. Then to the mixture was added pyrrolidine (41.37 mg, 0.58 mmol), and the mixture was stirred at 25° C. for 8 hours. The mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Kromasil (150 mm×25 mm, 5 μm), A=H2O (0.05% NH4OH) and B=CH3CN; 40-70% B over 7 minutes) to give the product (23.5 mg, 60.5 μmol, 16% yield) as a solid. 1H NMR (DMSO-dδ400 MHz) δH=7.69 (d, 2H), 7.53 (s, 1H), 7.47-6.97 (m, 5H), 4.73 (s, 2H), 3.56 (t, 2H), 3.30 (t, 2H), 2.00-1.87 (m, 2H), 1.86-1.70 (m, 2H). LCMS Rt=1.11 min in 2 min chromatography, MS ESI calcd. for C20oH19F2N2O4 [M+H]+ 389.1, found 389.1.
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- To a mixture of ethyl 2-pyrimidin-2-ylacetate (900 mg, 5.42 mmol) in THF (20 mL) was added LDA (3.25 mL, 6.5 mmol) at −78° C., then the mixture was stirred at −78° C. for 2 hours. To the mixture was added iodomethane (922.46 mg, 6.5 mmol), then the mixture was stirred at −78° C. to 20° C. for 3 hours. The mixture was quenched with sat. NH4Cl (30 mL), then the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 45%) to give the product (730 mg, 4.05 mmol, 75% yield) as oil. 1H NMR (CDCl3, 400 MHz) δH=8.72 (d, 2H), 7.19 (t, 1H), 4.19 (q, 2H), 4.14-4.07 (m, 1H), 1.62 (d, 3H), 1.22 (t, 3H).
- To a mixture of ethyl 2-pyrimidin-2-ylpropanoate (650 mg, 3.61 mmol) in THF (20 mL) was added DIBAL-H (10.82 mL, 10.82 mmol) at 0° C., then the mixture was stirred at 0° C. for 5 hours. The mixture was quenched with Na2SO4.10 H2O (20 g). The mixture was filtered through Celite, eluted with THF (30 mL×2), the filtrate was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 50% to 100%) to give the product (150 mg, 1.06 mmol, 29% yield) as an oil. 1H NMR (CDCl3, 400 MHz) δH=8.70 (d, 2H), 7.20 (t, 1H), 4.03-3.96 (m, 1H), 3.95-3.86 (m, 1H), 3.33-3.21 (m, 1H), 1.39 (d, 3H). LCMS Rt=0.12 min in 1.5 min chromatography, MS ESI calcd. for C7H11N2O [M+H]+ 139.1, found 138.9.
- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol) in THF (5 mL) was added PPh3 (177.1 mg, 0.68 mmol), 2-pyrimidin-2-ylpropan-1-ol (139.94 mg, 1.01 mmol) and DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 25° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give a residue. To the residue was added water (20 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with water (15 mL×2) and brine (15 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (130 mg) as a solid. LCMS Rt=1.38 min in 2.0 min chromatography, MS ESI calcd. for C20H16F3N4O3 [M+H]+ 417.1, found 417.1.
- The product was separated by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm); A=CO2 and B=Neu-ETOH; 40° C.; 60 mL/min; 15% B; 11 min run; 17 injections, Rt of peak 1=8.43 min, Rt of Peak 2=9.53 min) to give the Compound 149 (37.47 mg, 0.09 mmol, 27% yield, Peak 1) as a solid and Compound 150 (52.19 mg, 0.13 mmol, 37% yield, Peak 2) as a solid.
- Compound 149 1H NMR (CDCl3, 400 MHz) δH=8.61 (d, 2H), 7.94 (d, 2H), 7.42 (s, 2H), 7.30 (d, 2H), 7.04 (t, 1H), 4.45-4.28 (m, 2H), 3.90-3.78 (m, 1H), 1.52 (d, 3H). LCMS Rt=1.25 min in 2.0 min chromatography, MS ESI calcd. for C20H16F3N4O3 [M+H]+ 417.1, found 417.0.
- Compound 150 1H NMR (CDCl3, 400 MHz) δH=8.61 (d, 2H), 7.94 (d, 2H), 7.42 (s, 2H), 7.30 (d, 2H), 7.04 (t, 1H), 4.46-4.26 (m, 2H), 3.91-3.77 (m, 1H), 1.52 (d, 3H). LCMS Rt=1.25 min in 2.0 min chromatography, MS ESI calcd. for C20H16F3N4O3 [M+H]+ 417.1, found 417.1.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), (1-methylpyrazol-4-yl)methanol (68.14 mg, 0.61 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (3 mL) was added DIAD (81.92 mg, 0.41 mmol). The resulting mixture was stirred at 20° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give a residue. The residue was diluted with water (5 mL), extracted with EtOAc (10 mL×2). The combined organic layer was washed with water (5 mL×2), brine (5 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product.
- The crude product was purified by flash chromatography on silica gel (EtOAc in PE =0% to 20% to 30%) to give the product (31.82 mg, 81.5 μmol, 40% yield) as a solid. 1H NMR (400 Mz, CDCl3) δH=8.03 (d, 2H), 7.67 (s, 1H), 7.57 (s, 1H), 7.50-7.42 (m, 2H), 7.35 (d, 2H), 5.03 (s, 2H), 3.87 (s, 3H). LCMS Rt=1.26 min in 2.0 min chromatography, MS ESI calcd. for C18H14F3N4O3 [M+H]+ 391.1, found 390.9.
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- To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), (3,5-dimethylisoxazol-4-yl)methanol (77.26 mg, 0.61 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (3 mL) was added DIAD (81.92 mg, 0.41 mmol). The resulting mixture was stirred at 20° C. under N2 for 16 hours to give a solution. The reaction solution was concentrated to give a residue. The residue was diluted with water (5 mL), extracted with EtOAc (10 mL×2). The combined organic layer was washed with water (5 mL×2), brine (5 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to 30%) to give the product (51.04 mg, 125.9 μmol, 62% yield) as a solid. NMR (400 MHz, CDCl3) δH=7.95 (d, 2H), 7.49 (s, 2H), 7.34 (d, 2H), 4.90 (s, 2H), 2.61 (s, 3H), 2.43 (s, 3H). LCMS Rt=1.35 min in 2.0 min chromatography, MS ESI calcd. for C19H15F3N304 [M+H]+ 406.1, found 405.9.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), PPh3 (106.26 mg, 0.41 mmol) and (5-methyl-1,3,4-oxadiazol-2-yl)methanol (46.23 mg, 0.41 mmol) in THF (1 mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (15 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 47-67% B over 6 minutes) to give the product (23.49 mg, 58.60 μmol, 29% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.96 (d, 2H), 7.54 (s, 2H), 7.32-7.28 (m, 2H), 5.37 (s, 2H), 2.54 (s, 3H). LCMS Rt=1.12 min in 2 min chromatography, MS ESI calcd. for C17H12F3N4O4 [M+H]+ 393.1, found 393.0.
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- To a mixture of (5-methylisoxazol-4-yl)methanol (45.82 mg, 0.41 mmol), 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (1 mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30%) to give the product (48.92 mg, 0.12 mmol, 62% yield) as a solid. 1H NMR (CDCl3, 400 MHz,) δH=8.43 (s, 1H), 7.99 (d, 2H), 7.49 (d, 2H), 7.35 (d, 2H), 4.96 (s, 2H), 2.63 (s, 3H). LCMS Rt=1.25 min in 2.0 min chromatography, MS ESI calcd. for C18H13F3N3O4 [M+H]+ 392.1, found 392.1.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), PPh3 (106.26 mg, 0.41 mmol) and (5-methyl-1,3,4-thiadiazol-2-yl)methanol (52.74 mg, 0.41 mmol) in THF (1 mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (15 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 49-69% B over 6 minutes) to give the product (36.17 mg, 87.40 mmol, 43% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.17 (d, 2H), 7.92-7.80 (m, 2H), 7.49 (d, 2H), 5.52 (s, 2H), 2.69 (s, 3H). LCMS Rt=1.15 min in 2 min chromatography, MS ESI calcd. for C17H12F3N4O3S [M+H]+ 409.1, found 409.0.
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- To a mixture of (5-methylisoxazol-3-yl)methanol (45.82 mg, 0.41 mmol), 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (3 mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30%) to give the product (52.56 mg, 0.13 mmol, 66% yield) as a solid. 1H NMR (CDCl3, 400 MHz,) δH=8.01 (d, 2H), 7.46-7.54 (m, 2H), 7.31 (d, 2H), 6.12 (s, 1H), 5.22 (s, 2H), 2.40 (s, 3H). LCMS Rt=1.22 min in 2.0 min chromatography, MS ESI calcd. for C18H13F3N304 [M+H]+ 392.1, found 392.0.
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- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.2 mmol), (1-methyl-1,2,4-triazol-3-yl)methanol (45.83 mg, 0.41 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (1 mL) was added the DIAD (81.92 mg, 0.41 mmol) , and the mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by purified by prep-HPLC [Kromasil (150 mm×25 mm, 5 μm) A=H2O (0.05% NH4OH) and B=CH3CN; 47-87% B over 7 minutes] to give the product (21.81 mg, 0.06 mmol, 28% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.40 (s, 1H), 8.12 (d, 2H), 7.87 (d, 1H), 7.80 (d, 1H), 7.47 (d, 2H), 5.13 (s, 2H), 3.80 (s, 3H). LCMS Rt=1.12 min in 2 min chromatography, MS ESI calcd. for C17H13F3N5O3 [M+H]+ 392.1, found 392.0.
-
- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.2 mmol), (2-methylpyrazol-3-yl)methanol (45.43 mg, 0.41 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (1 mL) was added the DIAD (81.92 mg, 0.41 mmol), and the mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=20% to 70%) to give the product (9.03 mg, 23.1 mol, 11% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.18 (d, 2H), 7.88-7.77 (m, 2H), 7.50 (d, 2H), 7.35 (d, 1H), 6.38 (d, 1H), 5.18 (s, 2H), 3.97 (s, 3H). LCMS Rt=1.20 min in 2.0 min chromatography, MS ESI calcd. for C18H14F3N403 [M+H]+ 391.1, found 391.1.
-
- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.2 mmol), (2-methyloxazol-4-yl)methanol (45.82 mg, 0.41 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (2 mL) was added the DIAD (81.92 mg, 0.41 mmol), and the mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0 to 40% to 70%) to give the product (36.56 mg, 0.09 mmol, 46% yield) as a solid.
- 1H NMR (CDCl3, 400 MHz) δH=8.00 (d, 2H), 7.66 (s, 1H), 7.50-7.45 (m, 2H), 7.32 (d, 2H), 5.07 (s, 2H), 2.43 (s, 3H). LCMS Rt=1.18 min in 2 min chromatography, MS ESI calcd. for C18H13F3N304 [M+H]+ 392.1, found 392.0.
-
- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.2 mmol), (3-methylisoxazol-5-yl)methanol (45.82 mg, 0.41 mmol) and PPh3 (106.26 mg, 0.41 mmol) in THF (1 mL) was added the DIAD (81.92 mg, 0.41 mmol), and the mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=20% to 70%) to give the product (43.59 mg, 0.11 mmol, 55% yield) as solid. 1H NMR (DMSO-d6 400 MHz) δH=8.17 (d, 2H), 7.89-7.81 (m, 2H), 7.48 (d, 2H), 6.50 (s, 1H), 5.23 (s, 2H), 2.20 (s, 3H). LCMS Rt=1.21 min in 2.0 min chromatography, MS ESI calcd. for C18H13F3N3O4 [M+H]+ 392.1, found 392.0.
-
- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), PPh3 (106.26 mg, 0.41 mmol) and (3-methyl-1,2,4-oxadiazol-5-yl)methanol (46.23 mg, 0.41 mmol) in THF (1 mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N2 for 16 hours. The mixture was diluted with NH4Cl (20 mL), and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 52-72% B over 7 minutes) to give the product (34.48 mg, 85.80 μmol, 42% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.13 (d, 2H), 7.95-7.81 (m, 2H), 7.48 (d, 2H), 5.49 (s, 2H), 2.32 (s, 3H). LCMS Rt=1.17 min in 2 min chromatography, MS ESI calcd. for C17H12F3N4O4 [M+H]+ 393.1, found 393.0.
-
- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), PPh3 (106.26 mg, 0.41 mmol) and (5-methyl-1,2,4-oxadiazol-3-yl)methanol (46.23 mg, 0.41 mmol) in THF (1 mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (20 mL), and the mixture was extracted with EtOAc (15 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 52-72% B over 6 minutes) to give the product (18.43 mg, 46.80 mmol, 23% yield) as a solid. 1H NMR DMSO-d6 400 MHz δH=8.14 (d, 2H), 7.95-7.80 (m, 2H), 7.48 (d, 2H), 5.26 (s, 2H), 2.56 (s, 3H). LCMS Rt=1.16 min in 2 min chromatography, MS ESI calcd. for C17H12F3N4O4 [M+H]+ 393.1, found 393.0.
-
- A mixture of (4-methyl-1,2,4-triazol-3-yl)methanol (45.83 mg, 0.41 mmol), 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), PPh3 (106.26 mg, 0.41 mmol) and DIAD (81.92 mg, 0.41 mmol) in THF (3 mL) was stirred at 20 ° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 32-47% B over 8 minutes) to give the impure product. The impure product was triturated from i-Pr2O (10 mL) and purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 33-63% B over 6 minutes) to give the product (16.59 mg, 41.1 μmol, 20% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.48 (s, 1H), 8.14 (d, 2H), 7.88 (d, 1H), 7.81 (d, 1H), 7.48 (d, 2H), 5.30 (s, 2H), 3.79 (s, 3H). LCMS Rt=1.10 min in 2.0 min chromatography, MS ESI calcd. for C17H13F3N503 [M+H]+ 392.1, found 391.9.
-
- A mixture of (2-methyl-1,2,4-triazol-3-yl)methanol (45.83 mg, 0.41 mmol), 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), PPh3 (106.26 mg, 0.41 mmol) and DIAD (81.92 mg, 0.41 mmol) in THF (3 mL) was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=10% to 40%) to give impure product. The impure product was purified by Prep-HPLC (Xbridge BEH C18 (250 mm×50 mm, 10 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 38-68% B over 9 minutes) to give the product (20.82 mg, 52.6 μmol, 26% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=8.12 (d, 2H), 7.90-7.86 (m, 1H), 7.84-7.79 (m, 2H), 7.48 (d, 2H), 5.34 (s, 2H), 4.01 (s, 3H). LCMS Rt=1.09 min in 2.0 min chromatography, MS ESI calcd. for C17H13F3N503 [M+H]+ 392.1, found 392.0.
-
- A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg, 0.20 mmol), 1H-pyrazol-4-ylmethanol (39.74 mg, 0.41 mmol), PPh3 (106.26 mg, 0.41 mmol) and DIAD (81.92 mg, 0.41 mmol) in THF (3 mL) was stirred at 20° C. under N2 for 16 hours. The reaction was diluted with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H2O (10 mM NH4HCO3) and B=CH3CN; 46-66% B over 6 minutes) to give the product (23.1 mg, 61.4 μmol, 30% yield) as a solid. 1H NMR (DMSO-d6 400 MHz) δH=12.83 (br s, 1H), 8.22 (d, 2H), 7.87-7.77 (m, 3H), 7.59 (s, 1H), 7.50 (d, 2H), 4.97 (s, 2H). LCMS Rt=1.13 min in 2.0 min chromatography, MS ESI calcd. for C17H12F3N4O3 [M+H]+ 377.1, found 377.1.
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- A mixture of 5[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (150 mg, 0.51 mmol), chloro(methylsulfanyl)methane (244.55 mg, 2.53 mmol) and DIPEA (0.44 mL, 2.53 mmol) in MeCN (10 mL) was stirred at 50° C. for 12 hours. After cooling to r.t., the mixture was diluted with H2O (30 mL), and the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 15% to 30%) to give the product (110 mg, 0.31 mmol, 61% yield) as a solid. LCMS Rt=0.97 min in 1.5 min chromatography, MS ESI calcd. for C15H12F3N2O3S [M+H]+ 357.0, found 357.0. To a mixture of 3-(methylsulfanylmethyl)-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin one (60 mg, 0.17 mmol) in THF (10 mL) was added m-CPBA (102.56 mg, 0.51 mmol) at 0° C., then the mixture was stirred at 0° C. for 3 hours. The mixture was quenched with sat. Na2CO3 (10 mL), then the mixture was extracted with EtOAc (30 mL×2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC (silica gel, PE : EtOAc=1:1) to give the product (52.19 mg, 134.4 μmol, 80% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=7.99 (d, 2H), 7.62-7.55 (m, 2H), 7.33 (d, 2H), 5.23 (s, 2H), 3.17 (s, 3H). LCMS Rt=1.11 min in 2.0 min chromatography, MS ESI calcd. for C15H12F3N2O5S [M+H]+ 389.0, found 388.9.
-
- To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg, 0.34 mmol), (3-methyl-1H-pyrazol-4-yl)methanol (75.71 mg, 0.68 mmol) and PPh3 (265.65 mg, 1.01 mmol) in THF (3 mL) was added DIAD (204.8 mg, 1.01 mmol). The mixture was stirred at 20° C. for 16 hours. The reaction was quenched with sat.NH4Cl (10 mL), and the mixture was extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by prep-HPLC (Xbridge (150 mm×30 mm, 10 μm) A=H2O (0.05% NH4OH) and B=CH3CN; 48-78% B over 7 minutes) to give the product (33.96 mg, 87.00 μmol, 26% yield) as a solid. 1H NMR (CDCl3, 400 MHz) δH=10.00-9.24 (m, 1H), 8.02 (d, 2H), 7.79 (s, 1H), 7.50-7.41 (m, 2H), 7.34 (d, 2H), 5.02 (s, 2H), 2.49 (s, 3H). LCMS Rt=1.12 min in 2.0 min chromatography, MS ESI calcd. for C18H14F3N4O3 [M+H]+ 391.1, found 391.0.
- Functional characterization of exemplary compounds to modulate INaL expressed by the Nav1.6 voltage-gated sodium channel was accomplished using the PatchXpress™ high throughput electrophysiology platform (Molecular Devices, Sunnyvale, Calif.). HEK-293 cells expressing recombinant, human Nav1.6 (hNav1.6)were grown in DMEM/high-glucose Dulbecco's modified, 10% FBS, 2 mM sodium pyruvate, 10 mM HEPES and 400 μg/mL G418. Cells were grown to 50%-80% confluency prior to harvesting. Trypsinized cells were washed, allowed to recover for 1 hour and then resuspended in extracellular recording solution at a concentration of 1×106 cells/ml. The onboard liquid handling facility of the
- PatchXpress was used for dispensing cells and applying test compounds. Nav late currents were evoked by the application of 300 nM ATX-II. INaL was evoked by depolarizing pulses to 0 mV for 200 ms from a non-inactivating holding potential (e.g., −120 mV) at a frequency of 0.1 Hz. INaL amplitude and stability were determined by analyzing the mean current amplitude over the final 20 ms of thetest pulse. Following steady state block with exemplary compounds (e.g., as described herein), a Na+ free solution containing an impermeant cation (e.g., Choline or NDMG) was added to confirm the identify of the sodium current. Percent steady-state inhibition of INaL was calculated as: [(INaL_compound)/(INaL_control)]*100, where INaL_compound and INaL_control represent INaL recorded in the presence or absence of compound, respectively.
- Results from this assay relating to percent inhibition of INaL at hNav1.5 (measured using procedure similar to described above but using HEK-293 cells expressing recombinant, human Nav1.5 (hNav1.5) at 1 μM are summarized in Table 1 below. In this table, “A” indicates inhibition of less than 30%; “B” indicates inhibition of between about 30% to about 70%; and “C” indicates inhibition of greater than 70%.
-
TABLE 1 INaL v1.6 Compound (1 μM, % Inhibition) 1 C 2 B 3 C 4 C 5 C 6 B 7 C 8 A 9 A 10 C 11 C 12 C 13 C 14 B 15 A 16 A 17 B 18 A 19 C 20 B 21 B 22 A 23 A 24 A 25 C 26 C 27 B 28 C 29 A 30 B 31 B 32 B 33 C 34 B 35 C 36 A 37 B 38 B 39 C 40 B 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 B 49 A 50 B 51 B 52 B 53 C 54 B 55 B 56 C 57 C 58 C 59 B 61 C 62 C 64 C 65 B 66 C 67 C 68 C 69 C 70 B 71 A 72 C 73 C 75 C 76 C 77 B 78 C 79 B 80 B 81 C 84 C 85 B 86 C 87 B 88 A 89 C 90 B 91 B 92 A 93 C 96 B 97 C 98 B 99 C 100 C 101 C 102 C 103 C 104 C 105 C 106 C 107 B 108 B 109 C 110 B 111 B 112 C 113 B 114 A 115 A 116 C 117 C 118 A 119 C 120 C 121 B 122 A 123 C 124 C 125 A 126 B 127 C 128 B 129 C 130 A 131 C 132 C 133 C 134 C 135 B 136 A 137 A 138 B 139 B 140 B 141 B 142 A 143 C 144 A 145 A 146 C 147 C 148 A 149 C 150 B 151 C 152 A 153 B 154 C 155 C 156 C 157 B 158 B 159 C 160 C 161 C 162 C 163 A 164 B 165 B 166 B 167 A - Equivalents and Scope
- In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
- Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub—range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
- This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
- Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein.
- The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.
Claims (26)
1. A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O, C(R2a)(R2b), or N(R2c);
A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3;
R′ is hydrogen, alkyl, —ORc, or halogen;
R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6;
or two Rd, taken together with the atoms to which they are attached, form a ring;
each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and
each R7 is independently alkyl, halo, or oxo.
2. A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I-1):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O, C(R2a)(R2b), or N(R2c);
A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3;
R′ is hydrogen, alkyl, —ORc, or halogen;
R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by one or more R6;
each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6;
or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
each Re is alkyl;
each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and
each R7 is independently alkyl, halo, oxo, —C(O)Rc, or —C(O)ORc;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
3-24. (canceled)
25. The method of claim 2 , wherein the compound of Formula (I-1) is a compound of Formula (I-2):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O or C(R2a)(R2b);
R′ is hydrogen, alkyl, —ORc, or halogen;
R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
each of R2a and R2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with-OH, alkoxy, or alkyl optionally substituted with alkoxy;
each Re is alkyl;
each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; n is 0, 1, 2, 3, or 4.
30-35. (canceled)
36. The method of claim 25 , wherein the compound of Formula (I-1) is a compound of Formula (I-7):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is N(R2c);
R′ is hydrogen, alkyl, —ORc, or halogen;
R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
each of R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
each Re is alkyl;
each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; n is 0, 1, 2, 3, or 4;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
37-41. (canceled)
42. A compound of Formula (I-1):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O, C(R2a)(R2b), or N(R2c); A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl and heteroaryl are substituted by one or more R3;
R′ is hydrogen, alkyl, —ORc, or halogen;
R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
each of R2a, R2b, and R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
each R3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —ORc, —N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Re, —S(O)2N(Rd)2, or —C(O)N(Rd)2, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
each Rd is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R6; or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with -OH, alkoxy, or alkyl optionally substituted with alkoxy;
each Re is alkyl;
each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and
each R7 is independently alkyl, halo, oxo, —C(O)Rc, or —C(O)ORc;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
43-59. (canceled)
60. The compound of claim 42 , wherein the compound of Formula (I-1) is a compound of Formula (I-2):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is O or C(R2a)(R2b);
R′ is hydrogen, alkyl, —ORc, or halogen;
R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
each of R2a and R2b is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Rc, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyl optionally substituted with alkoxy;
each Re is alkyl;
each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; n is 0, 1, 2, 3, or 4, wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof.
65-72. (canceled)
73. The compound of claim 42 , wherein the compound of Formula (I-1) is a compound of Formula (I-7):
or a pharmaceutically acceptable salt thereof, wherein:
each of X, Y, and Z is independently N or CR′;
M is N(R2c);
R′ is hydrogen, alkyl, —ORc, or halogen;
R1 is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R4;
each of R2c is independently hydrogen or alkyl, wherein alkyl is optionally substituted by one or more R4;
each R3a is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —ORc, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R5;
each of R4 and R5 is independently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(Rd)2, —C(O)Rc, —C(O)ORc, —S(O)2—Rc, —S(O)2N(Rd)2, or —ORc, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R7;
each Rc is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R6;
each Rd is independently hydrogen or alkyl optionally substituted with one or more halogen;
or two Rd, taken together with the atoms to which they are attached, form a heterocyclyl optionally substituted with-OH, alkoxy, or alkyl optionally substituted with alkoxy;
each Re is alkyl;
each R6 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH;
each R7 is independently alkyl, oxo, halo, —C(O)Rc, or —C(O)ORc; n is 0, 1, 2, 3, or 4;
wherein the compound is not one of the following:
and a pharmaceutically acceptable salt thereof
74-78. (canceled)
80. A pharmaceutical composition comprising a compound of claim 42 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
81. The method of claim 1 , wherein the method comprises administering the pharmaceutical composition of claim 80 .
82. A method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof the compound of claim 42 .
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