CN115843295A - Nampt调节剂 - Google Patents
Nampt调节剂 Download PDFInfo
- Publication number
- CN115843295A CN115843295A CN202180031944.3A CN202180031944A CN115843295A CN 115843295 A CN115843295 A CN 115843295A CN 202180031944 A CN202180031944 A CN 202180031944A CN 115843295 A CN115843295 A CN 115843295A
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- China
- Prior art keywords
- group
- compound
- pharmaceutically acceptable
- alkyl
- acceptable salt
- Prior art date
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- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 title claims description 45
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 title claims description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 452
- 150000003839 salts Chemical class 0.000 claims abstract description 259
- 238000000034 method Methods 0.000 claims abstract description 38
- 125000003118 aryl group Chemical group 0.000 claims description 278
- 125000001072 heteroaryl group Chemical group 0.000 claims description 235
- 229910052739 hydrogen Inorganic materials 0.000 claims description 127
- 125000000217 alkyl group Chemical group 0.000 claims description 125
- 239000001257 hydrogen Substances 0.000 claims description 106
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 105
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 101
- 125000001424 substituent group Chemical group 0.000 claims description 96
- 125000005843 halogen group Chemical group 0.000 claims description 77
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
- 201000010099 disease Diseases 0.000 claims description 69
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 60
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 58
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 45
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 32
- 208000035475 disorder Diseases 0.000 claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims description 29
- 230000000694 effects Effects 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 208000030159 metabolic disease Diseases 0.000 claims description 17
- 208000019622 heart disease Diseases 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 16
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 15
- 230000006378 damage Effects 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 230000005778 DNA damage Effects 0.000 claims description 13
- 231100000277 DNA damage Toxicity 0.000 claims description 13
- 208000017169 kidney disease Diseases 0.000 claims description 13
- 230000001404 mediated effect Effects 0.000 claims description 13
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 238000002512 chemotherapy Methods 0.000 claims description 12
- 210000000130 stem cell Anatomy 0.000 claims description 12
- 230000000451 tissue damage Effects 0.000 claims description 12
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 11
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- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 208000028389 Nerve injury Diseases 0.000 claims description 6
- 230000008764 nerve damage Effects 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 5
- 230000003463 hyperproliferative effect Effects 0.000 claims description 5
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- 206010028289 Muscle atrophy Diseases 0.000 claims description 4
- 208000000474 Poliomyelitis Diseases 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 230000020763 muscle atrophy Effects 0.000 claims description 4
- 201000000585 muscular atrophy Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 201000010374 Down Syndrome Diseases 0.000 claims description 3
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 3
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- 208000003295 carpal tunnel syndrome Diseases 0.000 claims description 3
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- 235000020824 obesity Nutrition 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 69
- -1 alkyl urea compounds Chemical class 0.000 description 270
- 239000000543 intermediate Substances 0.000 description 121
- 238000006243 chemical reaction Methods 0.000 description 98
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 89
- 239000000243 solution Substances 0.000 description 81
- 239000000460 chlorine Substances 0.000 description 73
- 239000007787 solid Substances 0.000 description 71
- 238000002360 preparation method Methods 0.000 description 69
- 125000003003 spiro group Chemical group 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 61
- 238000002390 rotary evaporation Methods 0.000 description 58
- 239000002904 solvent Substances 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- 239000000047 product Substances 0.000 description 46
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 42
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 41
- 238000003786 synthesis reaction Methods 0.000 description 41
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 36
- 229950006238 nadide Drugs 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 28
- 239000003153 chemical reaction reagent Substances 0.000 description 27
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 25
- 238000000746 purification Methods 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- 238000004007 reversed phase HPLC Methods 0.000 description 22
- 239000004202 carbamide Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000012043 crude product Substances 0.000 description 19
- 239000000377 silicon dioxide Substances 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000010791 quenching Methods 0.000 description 15
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 125000003367 polycyclic group Chemical group 0.000 description 13
- 125000006570 (C5-C6) heteroaryl group Chemical class 0.000 description 12
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000012453 solvate Substances 0.000 description 12
- 241000282414 Homo sapiens Species 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- DAYLJWODMCOQEW-TURQNECASA-N NMN zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)([O-])=O)O2)O)=C1 DAYLJWODMCOQEW-TURQNECASA-N 0.000 description 9
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
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- 238000003756 stirring Methods 0.000 description 7
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
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- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 5
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- OAXSVEFCBLZGCA-UHFFFAOYSA-N 1-chloro-4-(isocyanatomethyl)benzene Chemical compound ClC1=CC=C(CN=C=O)C=C1 OAXSVEFCBLZGCA-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 4
- DEOUZFWSQWEPGE-UHFFFAOYSA-N 2-methylheptanamide Chemical compound CCCCCC(C)C(N)=O DEOUZFWSQWEPGE-UHFFFAOYSA-N 0.000 description 4
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- DKHFSVXHPPCSKO-UHFFFAOYSA-N CC(C)(CN(CC1)CCN1C(C(C1)CC1(C1)CC1NC(NCC(C=C1)=CC=C1Cl)=O)=O)O Chemical compound CC(C)(CN(CC1)CCN1C(C(C1)CC1(C1)CC1NC(NCC(C=C1)=CC=C1Cl)=O)=O)O DKHFSVXHPPCSKO-UHFFFAOYSA-N 0.000 description 4
- GVPSRXUXEHUFCE-UHFFFAOYSA-N CC1=CC=C(CC(C2)CC2(C2)CC2NC(NCC(C=C2)=CC=C2OC)=O)C=C1 Chemical compound CC1=CC=C(CC(C2)CC2(C2)CC2NC(NCC(C=C2)=CC=C2OC)=O)C=C1 GVPSRXUXEHUFCE-UHFFFAOYSA-N 0.000 description 4
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
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- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical compound C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- HHOFUZXTBHKGTC-UHFFFAOYSA-N tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCCCN)CC1 HHOFUZXTBHKGTC-UHFFFAOYSA-N 0.000 description 1
- UORHQLNXWYFBIL-UHFFFAOYSA-N tert-butyl carbamate hydrochloride Chemical compound Cl.CC(C)(C)OC(N)=O UORHQLNXWYFBIL-UHFFFAOYSA-N 0.000 description 1
- XBBQALZXPLXYDL-UHFFFAOYSA-N tert-butyl n-(2-hydroxyspiro[3.3]heptan-6-yl)carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC11CC(O)C1 XBBQALZXPLXYDL-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
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- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
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- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- GNXPUXGOQIHJLJ-UHFFFAOYSA-N thiadiazolo[4,5-b]pyridine Chemical compound C1=CN=C2N=NSC2=C1 GNXPUXGOQIHJLJ-UHFFFAOYSA-N 0.000 description 1
- HKMXLNRHGNWKJG-UHFFFAOYSA-N thiadiazolo[4,5-c]pyridine Chemical compound C1=NC=CC2=C1N=NS2 HKMXLNRHGNWKJG-UHFFFAOYSA-N 0.000 description 1
- QKTRRACPJVYJNU-UHFFFAOYSA-N thiadiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SN=NC2=C1 QKTRRACPJVYJNU-UHFFFAOYSA-N 0.000 description 1
- DNWLQCBSEZHTMF-UHFFFAOYSA-N thiadiazolo[5,4-c]pyridine Chemical compound C1=NC=CC2=C1SN=N2 DNWLQCBSEZHTMF-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
- SMZMHUCIDGHERP-UHFFFAOYSA-N thieno[2,3-b]pyridine Chemical compound C1=CN=C2SC=CC2=C1 SMZMHUCIDGHERP-UHFFFAOYSA-N 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical compound N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- CKEPIGUTJLDAEJ-UHFFFAOYSA-M triphenyl(pyrimidin-2-ylmethyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1=NC=CC=N1 CKEPIGUTJLDAEJ-UHFFFAOYSA-M 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- UPCXAARSWVHVLY-UHFFFAOYSA-N tris(2-hydroxyethyl)azanium;acetate Chemical compound CC(O)=O.OCCN(CCO)CCO UPCXAARSWVHVLY-UHFFFAOYSA-N 0.000 description 1
- 230000004906 unfolded protein response Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/18—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
- C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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 to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
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- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C07D209/54—Spiro-condensed
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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Abstract
提供了式(II)的化合物或其药学上可接受的盐,其中R1、n和Y1如本文所定义。还提供了一种药学上可接受的组合物,其包含式(II)的化合物或其药学上可接受的盐。还提供了使用式(II)的化合物或其药学上可接受的盐的方法。
Description
相关申请的交叉引用
本申请要求2020年5月6日提交的美国临时申请号63/020,904的权益和优先权,所述专利的内容特此以引用方式整体并入本文。
技术领域
本文提供了烷基脲化合物、包含此类化合物的药物组合物、以及用此类化合物治疗由烟酰胺磷酸核糖基转移酶(NAMPT)介导的各种疾病和疾患的方法。
背景技术
本公开涉及使用烟酰胺磷酸核糖基转移酶(NAMPT)及其衍生物的调节剂以及NAMPT表达、NAMPT活性或NAMPT介导的信号传导的增强剂或诱导剂来预防或治疗多种病理疾患。
烟酰胺腺嘌呤二核苷酸(NAD+)是一种参与分解代谢和合成代谢的基本生物学过程的必需的辅酶(酶辅因子)。作为辅酶,NAD与许多参与能量代谢的氧化酶(通常是脱氢酶)相关,充当通用的电子载体。NAD以氧化态(NAD+和NADP+)和还原态(NADH和NADPH)存在于细胞中,充当从分解代谢中的氧化过程中捕获和转移自由能的化学方式、或提供小包能量来构建合成代谢中的大分子的化学方式。由碳水化合物、脂质和氨基酸的氧化产生的NADH为线粒体的电子传递链提供还原当量,最终在氧化磷酸化中驱动ATP合成。
超过200种酶使用NAD+或NADP+作为辅酶,并且酶的功能不限于能量代谢。现在理解到,NAD+在调控多种功能(包括线粒体功能、呼吸能力和生物发生、线粒体-核信号传导)方面发挥作用。此外,它控制细胞信号传导、基因表达、DNA修复、造血作用、免疫功能、未折叠蛋白反应和自噬。此外,NAD具有抗炎性,并且是NADPH的前体,NADPH是对抗氧化应激的还原能力的主要来源。大量文献表明,提高NAD水平是预防或改善多种疾病状态的有效策略(等人,Biochem Soc Trans.2019,47(1):119-130;Ralto等人,Nat RevNephrol.2019;Fang等人,Trends Mol Med.2017,23(10):899-916;Yoshino等人,CellMetab.2011,14(4):528-36;Yang和Sauve,Biochim Biophys Acta.2016,1864:1787-1800;Verdin,Science.2015,350(6265):1208-13)。
NAD+和NADP+相关酶的水平在正常生理机能中发挥重要作用,并在各种疾病和应激条件(包括衰老)下发生改变。细胞NAD+水平在衰老、代谢疾病、炎性疾病期间、在缺血/再灌注损伤期间、以及在人(Massudi等人,PLoS ONE.2012,7(7):e42357)和动物(Yang等人,Cell.2007,130(6):1095-107;Braidy等人PLoS One.2011,26;6(4):e19194;Peek等人Science.2013,342(6158):1243417;Ghosh等人,J Neurosci.2012,32(17):5821-32)的其他疾患中降低,这表明细胞NAD+水平的调节影响身体机能衰退和恶化的速度和严重程度。因此,在衰老和与年龄相关的疾病的背景中,细胞NAD+浓度增加可能是有益的。
细胞NAD+池受NAD+合成和消耗酶的活性之间的平衡控制。在哺乳动物中,NAD+由多种饮食来源合成,包括其主要前体中的一种或多种,包括:色氨酸(Trp)、烟酸(NA)、烟酰胺核糖(NR)、烟酰胺单核苷酸(NMN)和烟酰胺(NAM)。基于其前体的生物利用度,在细胞中存在三种合成NAD+的途径:(i)通过从头生物合成途径或犬尿氨酸途径由Trp合成(ii)在Preiss-Handler途径中由NA合成和(iii)在补救途径中由NAM、NR和NMN合成(Verdin等人,Science.2015,350(6265):1208-13)。其中,主要的NAD+生物合成途径涉及使用烟酰胺和5'-磷酸核糖基-焦磷酸通过限速酶烟酰胺磷酸核糖基-转移酶(NAMPT)来合成烟酰胺单核苷酸(NMN)的步骤,NAMPT对于确定寿命和对各种应激的反应至关重要(Fulco等人,DevCell.2008,14(5):661-73;Imai,Curr Pharm Des.2009,15(1):20-8;Revollo等人,J BiolChem.2004,279(49):50754-63;Revollo等人,Cell Metab.2007,Nov;6(5):363-75;vander Veer等人,J Biol Chem.2007,282(15):10841-5;Yang等人,Cell.2007,130(6):1095-107)。因此,通过小分子活化剂增加NAMPT的催化速率将是提高NAD水平的有效策略,并且从而解决广泛的疾病状态。这些包括心脏病、化疗诱导的组织损伤、肾脏疾病、代谢疾病、肌肉疾病、神经系统疾病和损伤、干细胞功能受损引起的疾病、DNA损伤和原发性线粒体病症以及眼部疾病。
发明内容
在一个方面,本文提供了式(II)的化合物:
或其药学上可接受的盐,
其中:
n为0至6;
或者
或者
Y1为-C(O)-N(Rq)-(Rs),其中Rq为H或C1-C6烷基,并且Rs为C3-C8环烷基、任选取代的C6-C14芳基、任选取代的5元至18元杂芳基、或-(C1-C6亚烷基)-(任选取代的C6-C14芳基),并且R1选自由以下组成的组:
或者
或者
或者
R2a和R2b各自独立地为卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d或-N(R2e)C(O)(C1-C6烷基);并且
R2c、R2d和R2e各自独立地为氢或C1-C6烷基;
G1为CH或N;
p1和p2各自独立地为0、1或2;
q1和q2各自独立地为1或2;
r为1、2或3;
R3选自由以下组成的组:
i.未取代的C1-C6烷基;
ii.C6-C14芳基;
iii.任选取代的5元至18元杂芳基;
iv.-NR3aR3b,其中
R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基);
v.-OR3c,其中
R3c为C6-C14芳基、5元至18元杂芳基、或-(C1-C6亚烷基)-(5元至18元杂芳基);
vi.-C(O)R3d,其中
R3d选自由以下组成的组:-NR3fR3g;C3-C8环烷基;被任选取代的C6-C14芳基取代的C3-C8环烷基;C3-C8环烯基;任选取代的C6-C14芳基;任选取代的–(C1-C6亚烷基)-(C6-C14芳基);任选取代的3元至18元杂环烷基;和任选取代的5元至18元杂芳基,
其中
R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选取代的C1-C6烷基,
(c)C6-C14芳基,
(d)任选取代的3元至18元杂环烷基,
(e)任选取代的5元至18元杂芳基,
(f)任选取代的C3-C10环烷基;和
(g)任选取代的C3-C10环烯基;
vii.被一个或多个-OH、-C(O)NR3hR3i、任选取代的C6-C14芳基、任选取代的3元至18元杂环烷基、任选取代的5元至18元杂芳基、-N(R3p)-C(O)R3q、-S(O)2-R3r或-C(O)-R3s取代的C1-C6烷基,
其中
R3h和R3i各自独立地选自C1-C6烷基和-(C1-C6亚烷基)-(C6-C14芳基),
R3p为H或C1-C6烷基,
R3q为C3-C8环烷基、任选取代的3元至18元杂环烷基、或任选取代的5元至18元杂芳基,
R3r为C6-C14芳基或5元至18元杂芳基,并且
R3s为任选取代的3元至18元杂环烷基;
viii.-C(O)OR3j,其中
R3j为氢或C1-C6烷基;
ix.-NHC(O)R3k,其中
R3k为任选取代的C6-C14芳基、任选取代的–(C1-C6亚烷基)-(C6-C14芳基)、或任选取代的5元至18元杂芳基;
x.-NHC(O)OR3l,其中
R3l为氢或C1-C6烷基;
xi.-NHSO2R3m,其中
R3m为任选取代的5元至18元杂芳基、任选取代的C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中每一种都是任选取代的;和
xii.-SO2R3n;其中
R3n为C1-C6烷基、任选取代的C3-C10环烷基、任选取代的C6-C14芳基、或任选取代的–(C1-C6亚烷基)-(C6-C14芳基);
R4为苯基或-C(O)NH-CH2-苯基;
R5a和R5b独立地选自由以下组成的组:氢、甲基、和-NHC(O)O(C1-C6烷基);并且
R6选自由以下组成的组:-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)、-C(O)-(任选取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)、和5元至18元杂芳基,
前提条件是,当R6为-C(O)-(取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)、或5元至18元杂芳基时,那么(1)n为4或5,并且(2)R1选自由以下组成的组:
其中
在一个方面,本文提供了式(I)的化合物:
或其药学上可接受的盐,
其中:
或者
其中
R2a和R2b各自独立地为卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d或-N(R2e)C(O)(C1-C6烷基);并且
R2c、R2d和R2e各自独立地为氢或C1-C6烷基;
G1为CH或N;
p1和p2各自独立地为0、1或2;
q1和q2各自独立地为1或2;
r为1、2或3;
n为0至6;
R3选自由以下组成的组:
i.C1-C6烷基;
ii.C6-C14芳基;
iii.任选取代的5元至18元杂芳基;
iv.-NR3aR3b,其中
R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基);
v.-OR3c,其中
R3c为C6-C14芳基;
vi.-C(O)R3d,其中
R3d选自由以下组成的组:-NR3fR3g;C3-C8环烷基;被任选取代的C6-C14芳基取代的C3-C8环烷基;C3-C8环烯基;任选取代的C6-C14芳基;任选取代的–(C1-C6亚烷基)-(C6-C14芳基);任选取代的3元至18元杂环烷基;和任选取代的5元至18元杂芳基,
其中
R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选取代的C1-C6烷基,
(c)C6-C14芳基,
(d)任选取代的3元至18元杂环烷基,
(e)任选取代的5元至18元杂芳基,
(f)任选取代的C3-C10环烷基;和
(g)任选取代的C3-C10环烯基;
vii.被C(O)NR3hR3i、任选取代的3元至18元杂环烷基或任选取代的5元至18元杂芳基取代的C1-C6烷基,
其中R3h和R3i各自独立地选自C1-C6烷基和-(C1-C6亚烷基)-(C6-C14芳基);
viii.-C(O)OR3j,其中
R3j为氢或C1-C6烷基;
ix.-NHC(O)R3k,其中
R3k为任选取代的C6-C14芳基、任选取代的–(C1-C6亚烷基)-(C6-C14芳基)、或任选取代的5元至18元杂芳基;
x.-NHC(O)OR3l,其中
R3l为氢或C1-C6烷基;
xi.-NHSO2R3m,其中
R3m为任选取代的5元至18元杂芳基、任选取代的C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中每一种都是任选取代的;和
xii.-SO2R3n;其中
R3n为任选取代的C3-C10环烷基、任选取代的C6-C14芳基、或任选取代的–(C1-C6亚烷基)-(C6-C14芳基);
R4为苯基或-C(O)NH-CH2-苯基;
R5a和R5b独立地选自由以下组成的组:氢、甲基、和-NHC(O)O(C1-C6烷基);并且
R6选自由-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)和-C(O)-苯基组成的组;并且
其中
在另一个方面,本文提供了式(I-A)的化合物:
或其盐,其中R1、R3、G1、p1、p2、q1、q2和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在另一个方面,本文提供了式(I-B)的化合物:
或其盐,其中R1、R4和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在另一个方面,本文提供了式(I-C)的化合物:
或其盐,其中R1、R5a、R5b和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在另一个方面,本文提供了式(I-D)的化合物:
或其盐,其中R1、R6和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在另一个方面,本文提供了式(I-E)或(I-F)的化合物:
或其盐,其中R1、n和r如对式(II)或式(I)或其任何变型或实施方案所定义。
在另一个方面,本文提供了式(I-G)的化合物:
或其盐,其中R1、Rq、Rs和n如对式(II)或其任何变型或实施方案所定义。
在另一个方面,本文提供了式(I-H)的化合物:
或其盐,其中R1、Rb和n如对式(II)或其任何变型或实施方案所定义。
在一个方面,本文提供了式(I-J)的化合物:
或其盐,其中R1、Rt、Ru和n如本文对式(II)或其任何变型或实施方案所定义。
在一个方面,本文提供了式(I-K)的化合物:
或其盐,其中R1和n如本文对式(II)或其任何变型或实施方案所定义。
在另一方面,本文提供了药物组合物,其包含至少一种式(II)、(I)、(I-A)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物,诸如表1的化合物,或前述化合物中任一种的药学上可接受的盐,任选地还包含药学上可接受的赋形剂。
在另一个方面,本文提供了一种治疗有需要的受试者的NAMPT活性介导的疾病或疾患的方法,其包括向受试者施用有效量的至少一种式(II)、(I)、(I-A)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物(诸如表1的化合物)或其药学上可接受的盐、或包含至少一种式(II)、(I)、(I-A)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物的药物组合物。在一些实施方案中,疾病或疾患选自由以下组成的组:癌症、过度增殖性疾病或疾患、炎性疾病或疾患、代谢障碍、心脏疾病或疾患、化疗诱导的组织损伤、肾脏疾病、代谢疾病、神经系统疾病或损伤、神经退行性病症或疾病、干细胞功能受损引起的疾病、DNA损伤引起的疾病、原发性线粒体病症、或肌肉疾病或肌肉萎缩症。在一些实施方案中,疾病或疾患选自由以下组成的组:肥胖症、动脉粥样硬化、胰岛素抵抗、2型糖尿病、心血管疾病、阿尔茨海默病(Alzheimer’s disease)、亨廷顿病(Huntington’s disease)、帕金森病(Parkinson's disease)、肌萎缩侧索硬化症、抑郁症、唐氏综合症(Downsyndrome)、新生儿神经损伤、衰老、轴索变性、腕管综合征、格林-巴利综合征(Guillain-Barre syndrome)、神经损伤、脊髓灰质炎(polio/poliomyelitis)和脊髓损伤。
本公开的另外的实施方案、特征和优点从以下具体实施方式并通过本公开的实践将显而易见。
为简洁起见,本说明书中引用的出版物的公开内容(包括专利)以引用方式并入本文。
具体实施方式
定义
如在本说明书中所用,以下词语和短语通常旨在具有如下所述的含义,除非使用它们的上下文另有说明。
在整个本申请中,除非上下文另有说明,否则对式(II)或式(I)的化合物的提及包括本文定义的式(II)或式(I)的所有亚组,包括本文定义和/或所述的所有亚结构、亚类、偏好、实施方案、实例和特定化合物。对式(II)或式(I)的化合物及其亚组的提及包括其离子形式、多晶型物、假多晶型物、无定形形式、溶剂合物、共晶体、螯合物、异构体、互变异构体、氧化物(例如,N-氧化物、S-氧化物)、酯、前药、同位素和/或保护形式。在一些实施方案中,对式(II)或式(I)的化合物及其亚组的提及包括其多晶型物、溶剂合物、共晶体、异构体、互变异构体和/或氧化物。在一些实施方案中,对式(II)或式(I)的化合物及其亚组的提及包括其多晶型物、溶剂合物和/或共晶体。在一些实施方案中,对式(II)或式(I)的化合物及其亚组的提及包括其异构体、互变异构体和/或氧化物。在一些实施方案中,对式(II)或式(I)的化合物及其亚组的提及包括其溶剂合物。类似地,术语“盐”包括化合物的盐的溶剂合物。
“烷基”涵盖具有指定数量的碳原子(例如,1个至20个碳原子、或1至8个碳原子、或1个至6个碳原子)的直链和支链碳链。例如,C1-6烷基涵盖1个至6个碳原子的直链和支链烷基。当命名具有特定碳数的烷基残基时,旨在涵盖具有该碳数的所有支链和直链形式;因此,例如,“丙基”包括正丙基和异丙基;并且“丁基”包括正丁基、仲丁基、异丁基和叔丁基。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、己基、2-己基、3-己基和3-甲基戊基。
如本文所用,术语“卤代烷基”是指如上所述的其中烷基部分的氢原子中的一个或多个已经被一个或多个独立选择的卤素原子替换的烷基部分。举例来说,术语“卤代烷基”包括但不限于其中甲基部分的氢原子中的一个或多个已经被一个或多个独立选择的卤素原子(例如,-CH2F、-CHF2、-CH2Cl、-CCl3、-CHClF、-CCl2Br等)替换的甲基部分。
如本文所用,术语“烷氧基”是指-O-烷基部分。
如本文所用,术语“卤代烷氧基”是指如上所述的其中烷氧基部分的氢原子中的一个或多个已经被一个或多个独立选择的卤素原子替换的烷氧基部分。举例来说,术语“卤代烷氧基”包括但不限于其中甲氧基部分的氢原子中的一个或多个已经被一个或多个独立选择的卤素原子(例如,-O-CH2F、-O-CHF2、-O-CH2Cl、-O-CCl3、-O-CHClF、-O-CCl2Br等)替换的甲氧基部分。
如本文所用,术语“亚烷基”是指如上文所定义的具有1个至20个碳原子的二价烷基。除非另有提供,否则亚烷基是指具有1-20个碳原子、1-16个碳原子、1-10个碳原子、1-7个碳原子或1-4个碳原子的部分。亚烷基包括但不限于亚甲基、亚乙基、正亚丙基、异亚丙基、正亚丁基、仲亚丁基、异亚丁基、叔亚丁基、正亚戊基、异亚戊基、新亚戊基、正亚己基、3-甲基亚己基、2,2-二甲基亚戊基、2,3-二甲基亚戊基、正亚庚基、正亚辛基、正亚壬基和正亚癸基。
当给定值的范围(例如,C1-6烷基)时,包括所述范围内的每个值以及所有中间范围。例如,“C1-6烷基”包括C1、C2、C3、C4、C5、C6、C1-6、C2-6、C3-6、C4-6、C5-6、C1-5、C2-5、C3-5、C4-5、C1-4、C2-4、C3-4、C1-3、C2-3和C1-2烷基。
“烯基”是指具有指定数量的碳原子(例如,2个至8个、或2个至6个碳原子)和至少一个碳-碳双键的不饱和支链或直链烷基。所述基团可以是关于一个或多个双键的顺式或反式构型(Z或E构型)。烯基包括但不限于乙烯基、丙烯基(例如,丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、丙-2-烯-2-基)、和丁烯基(例如,丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基)。
“炔基”是指具有指定数量的碳原子(例如,2个至8个、或2个至6个碳原子)和至少一个碳-碳三键的不饱和支链或直链烷基。炔基包括但不限于乙炔基、丙炔基(例如,丙-1-炔-1-基、丙-2-炔-1-基)和丁炔基(例如,丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基)。
“环烷基”表示具有指定数量的碳原子(例如,3个至10个、或3个至8个、或3至6个环碳原子)的非芳族、完全饱和的碳环。环烷基可以是单环或多环(例如,双环、三环)。环烷基的实例包括环丙基、环丁基、环戊基和环己基,以及桥环、笼环和螺环基团(例如,降冰片烷、双环[2.2.2]辛烷、螺[3.3]庚烷)。此外,多环环烷基的一个环可以是芳族的,前体条件是多环环烷基经由非芳族碳与母体结构结合。例如,1,2,3,4-四氢萘-1-基(其中所述部分经由非芳族碳原子与母体结构键合)是环烷基,而1,2,3,4-四氢萘-5-基(其中所述部分经由芳族碳原子与母体结构结合)不被认为是环烷基。下文描述了由稠合至芳环的环烷基组成的多环环烷基的实例。
“环烯基”表示含有指定数量的碳原子(例如,3个至10个、或3个至8个、或3至6个环碳原子)和至少一个碳-碳双键的非芳族碳环。环烯基可以是单环或多环(例如,双环、三环)。环烯基的实例包括环丙烯基、环丁烯基、环戊烯基、环戊二烯基和环己烯基,以及桥环和笼环基团(例如,双环[2.2.2]辛烯)。此外,多环环烯基的一个环可以是芳族的,前体条件是多环烯基经由非芳族碳原子与母体结构键合。例如,茚-1-基(其中所述部分经由非芳族碳原子与母体结构键合)被认为是环烯基,而茚-4-基(其中所述部分经由芳族碳原子与母体结构键合)不被认为是环烯基。下文描述了由稠合至芳环的环烯基组成的多环环烯基的实例。
“芳基”表示具有指定数量的碳原子(例如,6个至12个、或6个至10个碳原子)的芳族碳环。芳基可以是单环或多环(例如,双环、三环)。在一些情况下,多环芳基的两个环都是芳族的(例如,萘基)。在其他情况下,多环芳基可以包括稠合至芳环的非芳环,前提条件是多环芳基经由芳环中的原子与母体结构键合。因此,1,2,3,4-四氢萘-5-基(其中所述部分经由芳族碳原子与母体结构键合)被认为是芳基,而1,2,3,4-四氢萘-1-基(其中所述部分经由非芳族碳原子与母体结构键合)不被认为是芳基。类似地,1,2,3,4-四氢喹啉-8-基(其中所述部分经由芳族碳原子与母体结构键合)被认为是芳基,而1,2,3,4-四氢喹啉-1-基(其中所述部分经由非芳族氮原子与母体结构键合)不被认为是芳基。然而,无论连接点如何,术语“芳基”都不涵盖或与如本文所定义的“杂芳基”重叠(例如,喹啉-5-基和喹啉-2-基都是杂芳基)。在一些情况下,芳基是苯基或萘基。在某些情况下,芳基是苯基。下文描述了包含稠合至非芳环的芳族碳环的芳基的另外的实例。
“杂芳基”表示含有指定数量的原子的芳环(例如,5元至12元、或5元至10元杂芳基),其由选自N、O和S的一个或多个杂原子(例如,1个、2个、3个、4个杂原子)组成,并且剩余的环原子是碳。杂芳基不含有相邻的S和O原子。在一些实施方案中,杂芳基中的S和O原子的总数不超过2。在一些实施方案中,杂芳基中的S和O原子的总数不超过1。除非另有说明,否则杂芳基可以通过碳或氮原子与母体结构键合,只要化合价允许即可。例如,“吡啶基”包括2-吡啶基、3-吡啶基和4-吡啶基,并且“吡咯基”包括1-吡咯基、2-吡咯基和3-吡咯基。
在一些情况下,杂芳基是单环的。实例包括吡咯、吡唑、咪唑、三唑(例如,1,2,3-三唑、1,2,4-三唑、1,2,4-三唑)、四唑、呋喃、异噁唑、噁唑、噁二唑(例如,1,2,3-噁二唑、1,2,4-噁二唑、1,3,4-噁二唑)、噻吩、异噻唑、噻唑、噻二唑(例如,1,2,3-噻二唑、1,2,4-噻二唑、1,3,4-噻二唑)、吡啶、哒嗪、嘧啶、吡嗪、三嗪(例如,1,2,4-三嗪、1,3,5-三嗪)和四嗪。
在一些情况下,多环杂芳基的两个环都是芳族的。实例包括吲哚、异吲哚、吲唑、苯并咪唑、苯并三唑、苯并呋喃、苯并噁唑、苯并异噁唑、苯并噁二唑、苯并噻吩、苯并噻唑、苯并异噻唑、苯并噻二唑、1H-吡咯并[2,3-b]吡啶、1H-吡唑并[3,4-b]吡啶、3H-咪唑并[4,5-b]吡啶、3H-[1,2,3]三唑并[4,5-b]吡啶、1H-吡咯并[3,2-b]吡啶、1H-吡唑并[4,3-b]吡啶、1H-咪唑并[4,5-b]吡啶、1H-[1,2,3]三唑并[4,5-b]吡啶、1H-吡咯并[2,3-c]吡啶、1H-吡唑并[3,4-c]吡啶、3H-咪唑并[4,5-c]吡啶、3H-[1,2,3]三唑并[4,5-c]吡啶、1H-吡咯并[3,2-c]吡啶、1H-吡唑并[4,3-c]吡啶、1H-咪唑并[4,5-c]吡啶、1H-[1,2,3]三唑并[4,5-c]吡啶、呋喃[2,3-b]吡啶、噁唑并[5,4-b]吡啶、异噁唑并[5,4-b]吡啶、[1,2,3]噁二唑并[5,4-b]吡啶、呋喃[3,2-b]吡啶、噁唑并[4,5-b]吡啶、异噁唑并[4,5-b]吡啶、[1,2,3]噁二唑并[4,5-b]吡啶、呋喃[2,3-c]吡啶、噁唑并[5,4-c]吡啶、异噁唑并[5,4-c]吡啶、[1,2,3]噁二唑并[5,4-c]吡啶、呋喃[3,2-c]吡啶、噁唑并[4,5-c]吡啶、异噁唑并[4,5-c]吡啶、[1,2,3]噁二唑并[4,5-c]吡啶、噻吩并[2,3-b]吡啶、噻唑并[5,4-b]吡啶、异噻唑并[5,4-b]吡啶、[1,2,3]噻二唑并[5,4-b]吡啶、噻吩并[3,2-b]吡啶、噻唑并[4,5-b]吡啶、异噻唑并[4,5-b]吡啶、[1,2,3]噻二唑并[4,5-b]吡啶、噻吩并[2,3-c]吡啶、噻唑并[5,4-c]吡啶、异噻唑并[5,4-c]吡啶、[1,2,3]噻二唑并[5,4-c]吡啶、噻吩并[3,2-c]吡啶、噻唑并[4,5-c]吡啶、异噻唑并[4,5-c]吡啶、[1,2,3]噻二唑并[4,5-c]吡啶、喹啉、异喹啉、噌啉、喹唑啉、喹喔啉、酞嗪、萘啶(例如,1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、2,7-萘啶、2,6-萘啶)、咪唑并[1,2-a]吡啶、1H-吡唑并[3,4-d]噻唑、1H-吡唑并[4,3-d]噻唑和咪唑并[2,1-b]噻唑。
在其他情况下,多环杂芳基可以包括稠合至杂芳环的非芳环(例如,环烷基、环烯基、杂环烷基、杂环烯基),前提条件是多环杂芳基经由芳环中的原子与母体结构键合。例如,4,5,6,7-四氢苯并[d]噻唑-2-基(其中所述部分经由芳族碳原子与母体结构键合)被认为是杂芳基,而4,5,6,7-四氢苯并[d]噻唑-5-基(其中所述部分经由非芳族碳原子与母体结构键合)不被认为是杂芳基。下文描述了由稠合至非芳环的杂芳环组成的多环杂芳基的实例。
“杂环烷基”表示具有指定数量的原子的非芳族、完全饱和环(例如,3元至10元、或3元至7元杂环烷基),其由选自N、O和S的一个或多个杂原子(例如,1个、2个、3个、4个杂原子)组成,并且剩余的环原子是碳。杂环烷基可以是单环或多环(例如,双环、三环)。杂环烷基的实例包括环氧乙烷基、氮丙啶基(aziridinyl)、氮杂环丁基(azetidinyl)、吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、哌嗪基、吗啉基和硫代吗啉基。实例包括硫代吗啉S-氧化物和硫代吗啉S,S-二氧化物。螺环杂环烷基的实例包括氮杂螺[3.3]庚烷、二氮杂螺[3.3]庚烷、二氮杂螺[3.4]辛烷和二氮杂螺[3.5]壬烷。此外,多环杂环烷基的一个环可以是芳族的(例如,芳基或杂芳基),前体条件是多环杂环烷基经由非芳族碳原子或氮原子与母体结构键合。例如,1,2,3,4-四氢喹啉-1-基(其中所述部分经由非芳族氮原子与母体结构键合)被认为是杂环烷基,而1,2,3,4-四氢喹啉-8-基(其中所述部分经由芳族碳原子与母体结构键合)不被认为是杂环烷基。下文描述了由稠合至芳环的杂环烷基组成的多环杂环烷基的实例。
“杂环烯基”表示具有指定数量的原子(例如,3元至10元、或3元至7元杂环烷基)的非芳环,其由选自N、O和S的一个或多个杂原子(例如,1个、2个、3个或4个杂原子)和至少一个双键组成,剩余的环原子是碳,并且所述至少一个双键是通过从对应的杂环烷基的相邻碳原子、相邻氮原子、或相邻碳和氮原子上去除一分子的氢而得到的。杂环烯基可以是单环或多环(例如,双环、三环)。杂环烯基的实例包括二氢呋喃基(例如,2,3-二氢呋喃基、2,5-二氢呋喃基)、二氢噻吩基(例如,2,3-二氢噻吩基、2,5-二氢噻吩基)、二氢吡咯基(例如,2,3-二氢-1H-吡咯基、2,5-二氢-1H-吡咯基)、二氢咪唑基(例如,2,3-二氢-1H-咪唑基、4,5-二氢-1H-咪唑基)、吡喃基、二氢吡喃基(例如,3,4-二氢-2H-吡喃基、3,6-二氢-2H-吡喃基)、四氢吡啶基(例如,1,2,3,4-四氢吡啶基、1,2,3,6-四氢吡啶基)和二氢吡啶(例如,1,2-二氢吡啶、1,4-二氢吡啶)。此外,多环杂环烯基的一个环可以是芳族的(例如,芳基或杂芳基),前体条件是多环杂环烷烯基经由非芳族碳原子或氮原子与母体结构键合。例如,1,2-二氢喹啉-1-基(其中所述部分经由非芳族氮原子与母体结构键合)被认为是杂环烯基,而1,2-二氢喹啉-8-基(其中所述部分经由芳族碳原子与母体结构键合)不被认为是杂环烯基。下文描述了由稠合至芳环的杂环烯基组成的多环杂环烯基的实例。
由稠合至非芳环(例如,环烷基、环烯基、杂环烷基、杂环烯基)的芳环(例如,芳基或杂芳基)组成的多环的实例包括茚基、2,3-二氢-1H-茚基、1,2,3,4-四氢萘基、苯并[1,3]二氧杂环戊烯基(dioxolyl)、四氢喹啉基、2,3-二氢苯并[1,4]二氧杂环己烯基(dioxinyl)、吲哚啉基、异吲哚啉基、2,3-二氢-1H-吲唑基、2,3-二氢-1H-苯并[d]咪唑基、2,3-二氢苯并呋喃基、1,3-二氢异苯并呋喃基、1,3-二氢苯并[c]异噁唑基、2,3-二氢苯并[d]异噁唑基、2,3-二氢苯并[d]噁唑基、2,3-二氢苯并[b]噻吩基、1,3-二氢苯并[c]噻吩基、1,3-二氢苯并[c]异噻唑基、2,3-二氢苯并[d]异噻唑基、2,3-二氢苯并[d]噻唑基、5,6-二氢-4H-环戊并[d]噻唑基、4,5,6,7-四氢苯并[d]噻唑基、5,6-二氢-4H-吡咯并[3,4-d]噻唑基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基、吲哚啉(indolin)-2-酮、吲哚啉-3-酮、异吲哚啉-1-酮、1,2-二氢吲唑-3-酮、1H-苯并[d]咪唑-2(3H)-酮、苯并呋喃-2(3H)-酮、苯并呋喃-3(2H)-酮、异苯并呋喃-1(3H)-酮、苯并[c]异噁唑-3(1H)-酮、苯并[d]异噁唑-3(2H)-酮、苯并[d]噁唑-2(3H)-酮、苯并[b]噻吩-2(3H)-酮、苯并[b]噻吩-3(2H)-酮、苯并[c]噻吩-1(3H)-酮、苯并[c]异噻唑-3(1H)-酮、苯并[d]异噻唑-3(2H)-酮、苯并[d]噻唑-2(3H)-酮、4,5-二氢吡咯并[3,4-d]噻唑-6-酮、1,2-二氢吡唑并[3,4-d]噻唑-3-酮、喹啉-4(3H)-酮、喹唑啉-4(3H)-酮、喹唑啉-2,4(1H,3H)-二酮、喹喔啉-2(1H)-酮、喹喔啉-2,3(1H,4H)-二酮、噌啉-4(3H)-酮、吡啶-2(1H)-酮、嘧啶-2(1H)-酮、嘧啶-4(3H)-酮、哒嗪-3(2H)-酮、1H-吡咯并[3,2-b]吡啶-2(3H)-酮、1H-吡咯并[3,2-c]吡啶-2(3H)-酮、1H-吡咯并[2,3-c]吡啶-2(3H)-酮、1H-吡咯并[2,3-b]吡啶-2(3H)-酮、1,2-二氢吡唑并[3,4-d]噻唑-3-酮和4,5-二氢吡咯并[3,4-d]噻唑-6-酮。如本文所讨论的,每个环是否被认为是芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基由所述部分与母体结构键合的原子决定。
“卤素”或“卤基”是指氟、氯、溴或碘。
除非另有说明,否则本文公开和/或描述的化合物包括所有可能的对映异构体、非对映异构体、内消旋异构体和其他立体异构体形式,包括其外消旋混合物、光学纯形式和中间体混合物。对映异构体、非对映异构体、内消旋异构体和其他立体异构形式可以使用手性合成子或手性试剂制备,或使用常规技术拆分。除非另外规定,否则当本文公开和/或描述的化合物含有烯烃双键或其它几何不对称中心时,预期所述化合物包括E和Z异构体两者。当本文所述的化合物含有能够互变异构的部分时,除非另外规定,否则预期所述化合物包括所有可能的互变异构体。
“保护基”具有通常在有机合成中与其相关的含义,即一种基团,其选择性地阻断多功能化合物中的一个或多个反应位点,使得可以选择性地在另一个未受保护的反应位点上进行化学反应,并且使得所述基团在完成所述选择性反应后可以容易地去除。多种保护基在例如T.H.Greene和P.G.M.Wuts,Protective Groups in Organic Synthesis,ThirdEdition,John Wiley&Sons,New York(1999)中公开。例如,“羟基保护形式”含有至少一个受到羟基保护基保护的羟基。同样,胺和其他反应性基团也可以类似地受到保护。
术语“药学上可接受的盐”是指已知无毒的并且通常用于药物文献中的本文的任何化合物的盐。在一些实施方案中,化合物的药学上可接受的盐保留了本文所述的化合物的生物学有效性,并且在生物学或其他方面不是不期望的。药学上可接受的盐的实例可见于Berge等人,Pharmaceutical Salts,J.Pharmaceutical Sciences,January 1977,66(1),1-19。药学上可接受的酸加成盐可以用无机酸和有机酸形成。可以衍生盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸和磷酸。可以衍生盐的有机酸包括例如乙酸、丙酸、乙醇酸、丙酮酸、乳酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、2-羟乙磺酸、对甲苯磺酸、硬脂酸和水杨酸。药学上可接受的碱加成盐可以用无机碱和有机碱形成。可以衍生盐的无机碱包括例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰和铝。可以衍生盐的有机碱包括例如伯胺、仲胺和叔胺;取代胺,包括天然存在的取代胺;环胺;和碱性离子交换树脂。有机碱的实例包括异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。在一些实施方案中,药学上可接受的碱加成盐选自铵盐、钾盐、钠盐、钙盐和镁盐。
如果本文所述的化合物作为酸加成盐获得,则可以通过碱化酸式盐的溶液来获得游离碱。相反,如果化合物是游离碱,则可以根据用于由碱化合物制备酸加成盐的常规程序、通过将游离碱溶解在合适的有机溶剂中并用酸处理溶液来产生加成盐,特别是药学上可接受的加成盐(参见例如,Berge等人,Pharmaceutical Salts,J.PharmaceuticalSciences,January 1977,66(1),1-19)。本领域技术人员将认识到可以用于制备药学上可接受的加成盐的各种合成方法。
“溶剂合物”是由溶剂和化合物的相互作用形成的。合适的溶剂包括例如水和醇类(例如,乙醇)。溶剂合物包括具有任何化合物/水比例的水合物,诸如一水合物、二水合物和半水合物。
术语“取代的”意指指定基团或部分带有一个或多个取代基,包括但不限于诸如以下的取代基:烷氧基、酰基、酰氧基、羰基烷氧基、酰氨基、氨基、氨酰基、氨基羰基氨基、氨基羰氧基、环烷基、环烯基、芳基、杂芳基、芳氧基、氰基、叠氮基、卤基、羟基、硝基、羧基、硫醇、硫代烷基、环烷基、环烯基、烷基、烯基、炔基、杂环烷基、杂环烯基、芳烷基、氨基磺酰基、磺酰基氨基、磺酰基、氧代基、羰基亚烷基烷氧基等。术语“未取代的”意指指定基团不带有取代基。在术语“取代的”用于描述结构系统的情况下,取代意图在系统上任何化合价允许的位置发生。当基团或部分带有多于一个取代基时,应当理解取代基可以彼此相同或不同。在一些实施方案中,取代的基团或部分带有一个至五个取代基。在一些实施方案中,取代的基团或部分带有一个取代基。在一些实施方案中,取代的基团或部分带有两个取代基。在一些实施方案中,取代的基团或部分带有三个取代基。在一些实施方案中,取代的基团或部分带有四个取代基。在一些实施方案中,取代的基团或部分带有五个取代基。
“任选的”或“任选地”意指随后描述的事件或情况可能发生或可能不发生,并且所述描述包括事件或情况发生和不发生的情况的实例。例如,“任选取代的烷基”涵盖如本文所定义的“烷基”和“取代的烷基”两者。本领域技术人员将理解,对于含有一个或多个取代基的任何基团,此类基团不预期引入空间上不切实际、合成不可行和/或内在不稳定的任何取代或取代模式。还应当理解,在基团或部分任选被取代的情况下,本公开包括其中基团或部分被取代的实施方案和其中基团或部分未被取代的实施方案。
本文公开和/或描述的化合物可以是富集的同位素形式,例如,富含2H、3H、11C、13C和/或14C。在一个实施方案中,化合物含有至少一个氘原子。此类氘代形式可以例如通过美国专利号5,846,514和6,334,997中描述的程序来制备。此类氘代化合物可以提高本文公开和/或描述的化合物的功效并增加作用持续时间。可以使用各种方法合成氘取代的化合物,诸如描述于Dean,D.,Recent Advancesi nthe Synthesis and Applications of Radiolabel ed Compounds for Drug Discovery and Development,Curr.Pharm.Des.,2000;6(10);Kabalka,G.等人,The Synthesis of Radiolabeled Compounds viaOrganometallic Intermediates,Tetrahedron,1989,45(21),6601-21;和Evans,E.,Synthesis of radiolabeled compounds,J.Radioanal.Chem.,1981,64(1-2),9-32中的那些。
术语“药学上可接受的载体”或“药学上可接受的赋形剂”包括任何和全部溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。用于药学活性物质的此类介质和剂的用途是本领域众所周知的。除非任何常规介质或剂与活性成分不相容,否则考虑将其用于药物组合物中。补充性活性成分还可以掺入药物组合物中。
术语“患者”、“个体”和“受试者”是指动物,诸如哺乳动物、鸟类或鱼类。在一些实施方案中,患者或受试者是哺乳动物。哺乳动物包括例如小鼠、大鼠、狗、猫、猪、绵羊、马、牛和人。在一些实施方案中,患者或受试者是人,例如已经或将成为治疗对象、观察对象或实验对象的人。本文所述的化合物、组合物和方法可以用于人类疗法和兽医应用两者。
如本文所用,术语“治疗性”是指调节烟酰胺磷酸核糖基转移酶(NAMPT)的能力。如本文所用,“调节”是指相对于如本文所述的化学实体不存在的情况下的活性,作为对所述化学实体的存在的直接或间接响应的活性的变化。变化可能是活性的增加或活性的降低,并且可能是由于化学实体与靶标的直接相互作用或由于化学实体与一种或多种继而影响靶标活性的其他因子的相互作用。例如,化学实体的存在可以例如通过直接与靶标结合、通过(直接或间接地)引起另一种因子以增加或降低靶标活性、或通过(直接或间接地)增加或降低存在于细胞或生物体中的靶标的量来增加或降低靶标活性。
术语“治疗有效量”或“有效量”是指当向需要这种治疗的患者施用时足以影响如本文所定义的治疗的本文公开和/或描述的化合物的量。化合物的治疗有效量可以是足以治疗对烟酰胺磷酸核糖基转移酶(NAMPT)的调节有反应的疾病的量。治疗有效量将根据以下因素而变化:例如受试者和所治疗的疾病状况、受试者的体重和年龄、疾病状况的严重程度、特定化合物、待遵循的给药方案、施用时间、施用方式,所有这些都可以由本领域普通技术人员容易地确定。治疗有效量可以通过实验确定,例如通过测定化学实体的血液浓度,或理论上通过计算生物利用度。
“治疗(Treatment)”(以及相关术语,例如“治疗(treat)”、“治疗(treated)”、“治疗(treating)”)包括以下中的一种或多种:预防疾病或病症(即,引起疾病或病症的临床症状不发展);抑制疾病或病症;减慢或阻止疾病或病症的临床症状的发展;和/或缓解疾病或病症(例如,引起临床症状的缓解或消退)。所述术语涵盖患者已经经历疾病或病症的情况,以及当前未经历疾病或病症但预期会出现的情况。所述术语涵盖疾患或病症的完全和部分减轻或预防以及疾病或病症的临床症状的完全或部分减轻两者。因此,本文描述和/或公开的化合物可以预防现有疾病或病症恶化、帮助管理疾病或病症、或减轻或消除疾病或病症。当以预防方式使用时,本文公开和/或描述的化合物可以预防疾病或病症发展、或减轻可能发展的疾病或病症的程度。
化合物
化合物及其盐(诸如药学上可接受的盐)在本文中详细描述,包括在简要发明内容和所附权利要求中。还提供了本文所述的所有化合物的用途以及制备此类化合物的方法,所述化合物包括任何和所有立体异构体,包括几何异构体(顺式/反式)、E/Z异构体、对映异构体、非对映异构体以及它们以任何比例的混合物,包括外消旋混合物、本文所述的化合物的盐或溶剂合物。本文所述的任何化合物也可以称为药物。
在一个方面,本文提供了式(II)的化合物:
或其药学上可接受的盐,
其中:
n为0至6;
或者
或者
Y1为-C(O)-N(Rq)-(Rs),其中Rq为H或C1-C6烷基,并且Rs为C3-C8环烷基、任选取代的C6-C14芳基、任选取代的5元至18元杂芳基、或-(C1-C6亚烷基)-(任选取代的C6-C14芳基),并且R1选自由以下组成的组:
或者
或者
或者
R2a和R2b各自独立地为卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d或-N(R2e)C(O)(C1-C6烷基);并且
R2c、R2d和R2e各自独立地为氢或C1-C6烷基;
G1为CH或N;
p1和p2各自独立地为0、1或2;
q1和q2各自独立地为1或2;
r为1、2或3;
R3选自由以下组成的组:
i.未取代的C1-C6烷基;
ii.C6-C14芳基;
iii.任选取代的5元至18元杂芳基;
iv.-NR3aR3b,其中
R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基);
v.-OR3c,其中
R3c为C6-C14芳基、5元至18元杂芳基、或-(C1-C6亚烷基)-(5元至18元杂芳基);
vi.-C(O)R3d,其中
R3d选自由以下组成的组:-NR3fR3g;C3-C8环烷基;被任选取代的C6-C14芳基取代的C3-C8环烷基;C3-C8环烯基;任选取代的C6-C14芳基;任选取代的–(C1-C6亚烷基)-(C6-C14芳基);任选取代的3元至18元杂环烷基;和任选取代的5元至18元杂芳基,
其中
R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选取代的C1-C6烷基,
(c)C6-C14芳基,
(d)任选取代的3元至18元杂环烷基,
(e)任选取代的5元至18元杂芳基,
(f)任选取代的C3-C10环烷基;和
(g)任选取代的C3-C10环烯基;
vii.被一个或多个-OH、-C(O)NR3hR3i、任选取代的C6-C14芳基、任选取代的3元至18元杂环烷基、任选取代的5元至18元杂芳基、-N(R3p)-C(O)R3q、-S(O)2-R3r或-C(O)-R3s取代的C1-C6烷基,
其中
R3h和R3i各自独立地选自C1-C6烷基和-(C1-C6亚烷基)-(C6-C14芳基),
R3p为H或C1-C6烷基,
R3q为C3-C8环烷基、任选取代的3元至18元杂环烷基、或任选取代的5元至18元杂芳基,
R3r为C6-C14芳基或5元至18元杂芳基,并且
R3s为任选取代的3元至18元杂环烷基;
viii.-C(O)OR3j,其中
R3j为氢或C1-C6烷基;
ix.-NHC(O)R3k,其中
R3k为任选取代的C6-C14芳基、任选取代的–(C1-C6亚烷基)-(C6-C14芳基)、或任选取代的5元至18元杂芳基;
x.-NHC(O)OR3l,其中
R3l为氢或C1-C6烷基;
xi.-NHSO2R3m,其中
R3m为任选取代的5元至18元杂芳基、任选取代的C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中每一种都是任选取代的;和
xii.-SO2R3n;其中
R3n为C1-C6烷基、任选取代的C3-C10环烷基、任选取代的C6-C14芳基、或任选取代的–(C1-C6亚烷基)-(C6-C14芳基);
R4为苯基或-C(O)NH-CH2-苯基;
R5a和R5b独立地选自由以下组成的组:氢、甲基、和-NHC(O)O(C1-C6烷基);并且
R6选自由以下组成的组:-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)、-C(O)-(任选取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3-至18-元杂环烷基)、-C(O)-(任选取代的5-至18-元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5-至18-元杂芳基)和5-至18-元杂芳基,
前提条件是,当R6为-C(O)-(取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)、或5元至18元杂芳基时,那么(1)n为4或5,并且(2)R1选自由以下组成的组: />
其中
在一个方面,提供了式(I)的化合物:
或其药学上可接受的盐,
其中:
或者
其中
R2a和R2b各自独立地为卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d或-N(R2e)C(O)(C1-C6烷基);并且
R2c、R2d和R2e各自独立地为氢或C1-C6烷基;
G1为CH或N;
p1和p2各自独立地为0、1或2;
q1和q2各自独立地为1或2;
r为1、2或3;
n为0至6;
R3选自由以下组成的组:
i.C1-C6烷基;
ii.C6-C14芳基;
iii.任选取代的5元至18元杂芳基;
iv.-NR3aR3b,其中
R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基);
v.-OR3c,其中
R3c为C6-C14芳基;
vi.-C(O)R3d,其中
R3d选自由以下组成的组:-NR3fR3g;C3-C8环烷基;被任选取代的C6-C14芳基取代的C3-C8环烷基;C3-C8环烯基;任选取代的C6-C14芳基;任选取代的–(C1-C6亚烷基)-(C6-C14芳基);任选取代的3元至18元杂环烷基;和任选取代的5元至18元杂芳基,
其中
R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选取代的C1-C6烷基,
(c)C6-C14芳基,
(d)任选取代的3元至18元杂环烷基,
(e)任选取代的5元至18元杂芳基,
(f)任选取代的C3-C10环烷基;和
(g)任选取代的C3-C10环烯基;
vii.被C(O)NR3hR3i、任选取代的3元至18元杂环烷基或任选取代的5元至18元杂芳基取代的C1-C6烷基,
其中R3h和R3i各自独立地选自C1-C6烷基和-(C1-C6亚烷基)-(C6-C14芳基);
viii.-C(O)OR3j,其中
R3j为氢或C1-C6烷基;
ix.-NHC(O)R3k,其中
R3k为任选取代的C6-C14芳基、任选取代的–(C1-C6亚烷基)-(C6-C14芳基)、或任选取代的5元至18元杂芳基;
x.-NHC(O)OR3l,其中
R3l为氢或C1-C6烷基;
xi.-NHSO2R3m,其中
R3m为任选取代的5元至18元杂芳基、任选取代的C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中每一种都是任选取代的;和
xii.-SO2R3n;其中
R3n为任选取代的C3-C10环烷基、任选取代的C6-C14芳基、或任选取代的–(C1-C6亚烷基)-(C6-C14芳基);
R4为苯基或-C(O)NH-CH2-苯基;
R5a和R5b独立地选自由以下组成的组:氢、甲基、和-NHC(O)O(C1-C6烷基);并且
R6选自由以下组成的组:-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)和-C(O)-苯基。
在式(II)的一些实施方案中,Y1为 -C(O)-N(Rq)-(Rs)、-C(O)-Rb、-N(Rt)-C(O)Ru或/>在式(II)的一些实施方案中,Y1为-C(O)-N(Rq)-(Rs)、-C(O)-Rb、-N(Rt)-C(O)Ru或/>
在另一个方面,式(II)或式(I)的化合物是式(I-A)的化合物:
或其盐,其中R1、R3、G1、p1、p2、q1、q2和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在式(II)、式(I)或式(I-A)的一些实施方案中,R1为在一些实施方案中,R1为/>在一些实施方案中,R1为/>其中R2a选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R2a为卤基或-O(C1-C6烷基)。在一些实施方案中,R2a为卤基。在一些实施方案中,R2a为甲氧基。在一些实施方案中,R1为/>在一些实施方案中,R1为/>在一些实施方案中,R1为其中R2b选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>在一些实施方案中,R1为/>
在一些实施方案中,式(I-A)的化合物是式(I-A1)或(I-A2)的化合物:
或其盐,其中R2a、R2b、R3、G1、p1、p2、q1、q2和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,G1为CH。在一些实施方案中,G1为N。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,p1为0、1或2。在一些实施方案中,p1为0。在一些实施方案中,p1为1。在一些实施方案中,p1为2。在一些实施方案中,p2为0、1或2。在一些实施方案中,p2为0。在一些实施方案中,p2为2。在一些实施方案中,p2为2。在一些实施方案中,q1为1或2。在一些实施方案中,q1为1。在其他实施方案中,q1为2。在一些实施方案中,q2为1或2。在一些实施方案中,q2为1。在其他实施方案中,q2为2。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,p1为1并且q1为1。在一些实施方案中,p1为2并且q1为1。在一些实施方案中,p1为2并且q1为2。在一些实施方案中,p2为1并且q2为1。在一些实施方案中,p2为0并且q2为1。在一些实施方案中,p2为1并且q2为2。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,n为0。在一些实施方案中,n为1。在一些实施方案中,n为2。在一些实施方案中,n为3。在一些实施方案中,n为4。在一些实施方案中,n为5。在其他实施方案中,n为6。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为C1-C6烷基。例如,在一些实施方案中,R3为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基或异丁基。在一些实施方案中,R3为甲基。在一些实施方案中,R3为C6-C14芳基。在一些实施方案中,R3为苯基或萘基。在一些实施方案中,R3为苯基。在一些实施方案中,R3为任选被C1-C6烷基取代的5元至18元杂芳基。在一些实施方案中,R3为任选被C1-C6烷基取代的5元至6元杂芳基。在一些实施方案中,R3为任选被C1-C6烷基取代的吡啶基或嘧啶基。在某些实施方案中,R3为被甲基取代的吡啶基。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-NR3aR3b,其中R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基)。在一些实施方案中,R3为-NR3aR3b,其中R3a为氢并且R3b选自由以下组成的组:C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基)。在一些实施方案中,R3为-NR3aR3b,其中R3a为氢并且R3b选自由以下组成的组:5元至6元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至6元杂芳基)。在一些实施方案中,R3为-NR3aR3b,其中R3a和R3b各自为–(C1-C6亚烷基)-(C6-C14芳基)。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为OR3c,其中R3c为C6-C14芳基。在一些实施方案中,R3c为苯基或萘基。在一些实施方案中,R3为–O-苯基。在一些实施方案中,R3c为C6-C14芳基、5元至18元杂芳基、或-(C1-C6亚烷基)-(5元至18元杂芳基)。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d。在一些实施方案中,R3d为-NR3fR3g并且R3f和R3g各自独立地选自由以下组成的组:(a)氢,(b)任选被选自由-OH、C6-C14芳基和5元至18元杂芳基组成的组的一个或多个取代基取代的C1-C6烷基,其中C6-C14芳基和5元至18元杂芳基各自独立地为未取代的或被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基和CN,(c)C6-C14芳基,(d)3元至18元杂环烷基,(e)任选被甲基或CN取代的5元至18元杂芳基,(f)任选被选自由以下组成的组的一个或多个取代基取代的C3-C10环烷基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基;和(g)任选被选自由以下组成的组的一个或多个取代基取代的C3-C10环烯基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基。在一些实施方案中,R3d为-NR3fR3g,R3f为氢或C1-C6烷基,并且R3g各自独立地选自由以下组成的组:(b)任选被选自由-OH、C6-C14芳基和5元至18元杂芳基组成的组的一个或多个取代基取代的C1-C6烷基,其中C6-C14芳基和5元至18元杂芳基各自独立地为未取代的或被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基和CN,(c)C6-C14芳基,(d)3元至18元杂环烷基,(e)任选被甲基或CN取代的5元至18元杂芳基,(f)任选被选自由以下组成的组的一个或多个取代基取代的C3-C10环烷基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基;和(g)任选被选自由以下组成的组的一个或多个取代基取代的C3-C10环烯基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基取代。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d,R3d为-NR3fR3g,R3f为氢或C1-C6烷基,并且R3g为任选被选自由羟基、C6-C14芳基和5元至18元杂芳基组成的组的一个或多个取代基取代的C1-C6烷基,其中C6-C14芳基和5元至18元杂芳基各自独立地为未取代的或被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基和CN。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为任选被选自由羟基、苯基和5元至6元杂芳基组成的组的一个或多个取代基取代的C1-C6烷基,其中苯基和5元至6元杂芳基各自独立地为未取代的或被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基和CN。在一些实施方案中,R3f为氢并且R3g为被选自由羟基、苯基、吡唑基、吡啶基和嘧啶基组成的组的一个或多个取代基取代的C1-C6烷基,其中苯基、吡唑基、吡啶基和嘧啶基各自独立地为未取代的或被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基和CN。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d,R3d为-NR3fR3g,R3f为氢或C1-C6烷基,并且R3g为C6-C14芳基。在一些实施方案中,R3f为H或C1-C6烷基,并且R3g为苯基偶萘基。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d,R3d为-NR3fR3g,R3f为氢或C1-C6烷基,并且R3g为3元至18元杂环烷基。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为任选被卤基、羟基和–(C1-C6亚烷基)-OH取代的3元至18元杂环烷基。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d,R3d为-NR3fR3g,R3f为氢或C1-C6烷基,并且R3g为任选被甲基或CN取代的5元至10元杂芳基。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为各自任选被甲基或CN取代的吡啶基或嘧啶基。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d,R3d为-NR3fR3g,R3f为氢或C1-C6烷基,并且R3g为被选自由以下组成的组的一个或多个取代基取代的C3-C10环烷基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基。在其他实施方案中,R3f为氢或C1-C6烷基,并且R3g为被选自由以下组成的组的一个或多个取代基取代的C3-C10环烯基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为任选被C6-C14芳基或5元至18元杂芳基取代的C3-C10环烷基。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为任选被C6-C10芳基或5元至6元杂芳基取代的C3-C8环烷基。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为任选被C6-C10芳基或5元至6元杂芳基取代的环丁基。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为任选被苯基或吡啶基取代的C3-C8环烷基。在一些实施方案中,R3f为氢或C1-C6烷基,并且R3g为任选被选自由以下组成的组的一个或多个取代基取代的C3-C10环烯基:卤基、羟基、任选被卤基、羟基和–(C1-C6亚烷基)-OH取代的C1-C6烷基。在一些实施方案中,在一些实施方案中,R3为 在一些实施方案中,R3为/>/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d并且R3d为C3-C8环烷基。在一些实施方案中,R3为-C(O)R3d并且R3d为被C6-C14芳基取代的C3-C8环烷基,其中C6-C14芳基任选被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、C1-C6卤代烷基和C1-C6烷氧基。在一些实施方案中,R3为-C(O)R3d并且R3d为被C6-C10芳基取代的C3-C8环烷基。在一些实施方案中,R3为在一些实施方案中,R3为-C(O)R3d并且R3d为C3-C8环烯基。在一些实施方案中,R3为/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的C6-C14芳基:羟基、卤基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-(C1-C6亚烷基)-OH、-C(O)O(C1-C6烷基)、-NR3e1R3e2、-S(O)2(C1-C6烷基)、5元至18元杂芳基和任选被氧代基取代的3元至18元杂环烷基,其中R3e1和R3e2各自独立地为H或C1-C6烷基。在一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的苯基:羟基、卤基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-(C1-C6亚烷基)-OH、-C(O)O(C1-C6烷基)、-NR3e1R3e2、-S(O)2(C1-C6烷基)、5元至18元杂芳基和任选被氧代基取代的3元至18元杂环烷基,其中R3e1和R3e2各自独立地为H或C1-C6烷基。在一些实施方案中,R3为/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14芳基):卤基、C1-C6烷基、C1-C6卤代烷基和C1-C6烷氧基。在一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-苯基:卤基、C1-C6烷基、C1-C6卤代烷基、和C1-C6烷氧基。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的3元至18元杂环烷基:(a)任选被独立地选自由以下组成的组的一个或多个取代基取代的C1-C6烷基:羟基、卤基、C3-C10环烷基和任选被一个或多个C1-C6烷基取代基取代的5元至18元杂芳基;(b)C6-C14芳基;(c)3元至18元杂环烷基;(d)-C(O)O(C1-C6烷基);(e)-C(O)(C6-C14芳基);(f)卤基;(g)任选被一个或多个卤基取代基取代的C1-C6烷氧基;和(h)氧代基。
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的3元至18元杂环烷基:(a)任选被选自由以下组成的组的一个或多个取代基取代的C1-C6烷基:羟基、卤基、C3-C10环烷基和任选被一个或多个C1-C6烷基取代基取代的5元至18元杂芳基,(b)C6-C14芳基,(c)3元至18元杂环烷基,(d)-C(O)O(C1-C6烷基),(e)-C(O)(C6-C14芳基),(f)卤基,和(g)任选被一个或多个卤基取代基取代的C1-C6烷氧基。在一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的4元至10元杂环烷基:(a)任选被选自由以下组成的组的一个或多个取代基取代的C1-C6烷基:羟基、卤基、C3-C10环烷基和任选被一个或多个C1-C6烷基取代基取代的5元至18元杂芳基,(b)C6-C14芳基,(c)3元至18元杂环烷基,(d)-C(O)O(C1-C6烷基),(e)-C(O)(C6-C14芳基),(f)卤基,和(g)任选被一个或多个卤基取代基取代的C1-C6烷氧基。在一些实施方案中,R3为-C(O)R3d并且R3d为各自任选被选自由以下组成的组的一个或多个取代基取代的氮杂环丁烷基、吡咯烷基、哌嗪基、哌啶基、吲哚啉基、异吲哚基、异吲哚啉基、二氢茚基、四氢喹啉基、二氢苯并噁嗪基或四氢萘啶基:(a)任选被选自由以下组成的组的一个或多个取代基取代的C1-C6烷基:羟基、卤基、C3-C10环烷基和任选被一个或多个C1-C6烷基取代基取代的5元至18元杂芳基,(b)C6-C14芳基,(c)3元至18元杂环烷基,(d)-C(O)O(C1-C6烷基),(e)-C(O)(C6-C14芳基),(f)卤基,和(g)任选被一个或多个卤基取代基取代的C1-C6烷氧基。在一些实施方案中,R3为/>/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的5元至18元杂芳基:C1-C6烷基、羟基、氧代基和3元至18元杂环烷基。在一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的5元至6元杂芳基:C1-C6烷基、羟基、氧代基和3元至18元杂环烷基。在一些实施方案中,R3为-C(O)R3d并且R3d为任选被选自由以下组成的组的一个或多个取代基取代的吡啶基:C1-C6烷基、羟基、氧代基和3元至18元杂环烷基。在一些实施方案中,R3为-C(O)R3d并且R3d为被甲基取代的吡啶基。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为被C(O)NR3hR3i取代的C1-C6烷基,其中R3h和R3i各自独立地选自C1-C6烷基和–(C1-C6亚烷基)-(C6-C14芳基)。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为被3元至18元杂环烷基取代的C1-C6烷基,其中3元至18元杂环烷基任选被独立地选自卤基、氧代基、C1-C6烷基、C6-C14芳基和5元至18元杂芳基的一个或多个取代基取代。在一些实施方案中,R3为被3元至18元杂环烷基取代的C1-C6烷基,其中3元至18元杂环烷基任选被选自卤基和C6-C14芳基的一个或多个取代基取代。在一些实施方案中,R3为被5元至10元杂环烷基取代的C1-C6烷基,其中5元至10元杂环烷基任选被C6-C14芳基取代。
在一些实施方案中,R3为C1-C6烷基,其中R3的C1-C6烷基(i)被5元至18元杂芳基取代,其中5元至18元杂芳基任选被一个或多个C1-C6烷基、C6-C14芳基或氰基取代,并且(ii)任选被一个或多个–OH取代。在一些实施方案中,R3为被5元至18元杂芳基取代的C1-C6烷基。R3为被5元至10元杂芳基取代的C1-C6烷基。在一些实施方案中,R3为在一些实施方案中,R3为/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-NHC(O)R3k。在一些实施方案中,R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的C6-C14芳基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。在一些实施方案中,R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的苯基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。在一些实施方案中,R3为 />在一些实施方案中,R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14芳基):C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。在一些实施方案中,R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-苯基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。在一些实施方案中,R3为/>在一些实施方案中,R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的5元至18元杂芳基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。在一些实施方案中,R3k为任选被一个或多个C1-C6烷基取代基取代的5元至6元杂芳基。在一些实施方案中,R3k为任选被个C1-C6烷基取代的吡啶基。在一些实施方案中,R3为/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-NHSO2R3m,其中R3m为5元至18元杂芳基、C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中5元至18元杂芳基、C6-C14芳基和–(C1-C6亚烷基)-(C6-C14芳基)各自任选被选自卤基和C1-C6烷氧基的一个或多个取代基取代。在一些实施方案中,R3为-NHSO2R3m,其中R3m为任选被选自卤基和C1-C6烷氧基的一个或多个取代基取代的5元至18元杂芳基。在一些实施方案中,R3为-NHSO2R3m,其中R3m为任选被选自卤基和C1-C6烷氧基的一个或多个取代基取代的C6-C14芳基。在一些实施方案中,R3为-NHSO2R3m,其中R3m为任选被选自卤基和C1-C6烷氧基的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14芳基)。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-SO2R3n并且R3n为C1-C6烷基、C3-C10环烷基、C6-C14芳基或–(C1-C6亚烷基)-(C6-C14芳基),其中R3n的C3-C10环烷基、C6-C14芳基和–(C1-C6亚烷基)-(C6-C14芳基)各自独立地任选被独立地选自卤基和-C(O)O(C1-C6烷基)的一个或多个取代基取代。在一些实施方案中,R3为-SO2R3n并且R3n为C1-C6烷基。在一些实施方案中,R3为-SO2R3n并且R3n为甲基。在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为-SO2R3n并且R3n为C3-C10环烷基、C6-C14芳基或–(C1-C6亚烷基)-(C6-C14芳基),其中C3-C10环烷基、C6-C14芳基和–(C1-C6亚烷基)-(C6-C14芳基)各自任选被选自卤基和-C(O)O(C1-C6烷基)的一个或多个取代基取代。在一些实施方案中,R3为-SO2R3n并且R3n为任选被选自卤基和-C(O)O(C1-C6烷基)的一个或多个取代基取代的C3-C10环烷基。在一些实施方案中,R3为-SO2R3n并且R3n为任选被选自卤基和-C(O)O(C1-C6烷基)的一个或多个取代基取代的C6-C14芳基。在一些实施方案中,R3为-SO2R3n并且R3n为任选被选自卤基和-C(O)O(C1-C6烷基)的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14烷基)。在一些实施方案中,R3为 在一些实施方案中,R3为/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为被一个或多个-N(R3p)-C(O)R3q取代的C1-C6烷基,其中R3p为H或C1-C6烷基,并且R3q为C3-C8环烷基、任选取代的3元至18元杂环烷基、或任选取代的5元至18元杂芳基。在一些实施方案中,R3p为H或C1-C6烷基,并且R3q为(i)C3-C8环烷基、(ii)任选被一个或多个独立选择的C1-C6烷基或氧代基取代基取代的3元至18元杂环烷基、或(iii)任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至18元杂芳基。在前述的一些实施方案中,R3p为H或甲基。在一些实施方案中,R3p为H。在一些实施方案中,R3p为甲基。在一些实施方案中,R3q为C3-C8环烷基。在一些实施方案中,R3q为C5-C6环烷基。在一些实施方案中,R3q为环戊基。在一些实施方案中,R3为在一些实施方案中,R3q为任选被一个或多个独立选择的氧代基取代基取代的3元至18元杂环烷基。在一些实施方案中,R3q为任选被一个或多个独立选择的氧代基取代基取代的5元至6元杂环烷基。在一些实施方案中,R3q为任选被一个或多个独立选择的氧代基取代基取代的四氢吡喃基、四氢噻喃基或哌啶基。在一些实施方案中,R3为在一些实施方案中,R3q为任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至18元杂芳基。在一些实施方案中,R3q为任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至6元杂芳基。在一些实施方案中,R3q为任选被一个或多个独立选择的C1-C6烷基取代基取代的吡啶基或吡唑基。在一些实施方案中,R3为/> 在一些实施方案中,R3为/>
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为被一个或多个-S(O)2-R3r取代的C1-C6烷基,其中R3r为C6-C14芳基或5元至18元杂芳基。在一些实施方案中,R3r为C6-C14芳基。在一些实施方案中,R3r为苯基。在一些实施方案中,R3为在一些实施方案中,R3r为5元至18元杂芳基。在一些实施方案中,R3r为5元至6元杂芳基。在一些实施方案中,R3r为吡啶基。在一些实施方案中,R3为/>在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为被一个或多个-C(O)-R3s取代的C1-C6烷基,其中R3s为R3s为任选取代的3元至18元杂环烷基。在一些实施方案中,R3s为任选被一个或多个独立选择的C1-C6烷基取代基取代的3元至18元杂环烷基,其中C1-C6烷基独立地任选被一个或多个-OH取代。在一些实施方案中,R3s为任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至6元杂环烷基,其中C1-C6烷基独立地任选被一个或多个-OH取代。在一些实施方案中,R3s为任选被一个或多个独立选择的C1-C6烷基取代基取代的哌嗪基或吡咯烷基,其中C1-C6烷基独立地任选被一个或多个-OH取代。在一些实施方案中,R3为
在式(II)、(I)、(I-A)、(I-A1)或(I-A2)的一些实施方案中,R3为C1-C6烷基,其中R3的C1-C6烷基被一个或多个独立选择的任选取代的C6-C14芳基取代基取代。在一些实施方案中,R3为C1-C6烷基,其中R3的C1-C6烷基(i)被一个或多个独立选择的C6-C14芳基取代基取代,其中C6-C14芳基任选被一个或多个独立选择的C1-C6烷基取代基取代,并且(ii)任选被一个或多个-OH取代。在一些实施方案中,R3为
在另一个方面,式(II)或式(I)的化合物是式(I-B)的化合物:
或其盐,其中R1、R4和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在式(I-B)的一些实施方案中,R1为在一些实施方案中,R1为在一些实施方案中,R1为/> 在一些实施方案中,R1为其中R2b选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>在一些实施方案中,R1为/>在式(I-B)的一些实施方案中,R1选自由以下组成的组:/> 在式(I-B)的一些实施方案中,R1选自由以下组成的组:
在式(I-B)的一些实施方案中,n为0。在一些实施方案中,n为1。在一些实施方案中,n为2。在一些实施方案中,n为3。在一些实施方案中,n为4。在一些实施方案中,n为5。在其他实施方案中,n为6。
在式(I-B)的一些实施方案中,R4为苯基。在其他实施方案中,R4为-C(O)NH-CH2-苯基。在式(I-B)的一些实施方案中,当R4为苯基并且n为0时,R1选自由以下组成的组: 在式(I-B)的一些实施方案中,当R4为苯基并且n为0时,R1选自由以下组成的组:/>
在另一个方面,式(II)或式(I)的化合物是式(I-C)的化合物:
或其盐,其中R1、R5a、R5b和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在式(I-C)的一些实施方案中,R1为在一些实施方案中,R1为在一些实施方案中,R1为/> 在一些实施方案中,R1为其中R2b选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>在一些实施方案中,R1为/>在式(I-C)的一些实施方案中,R1选自由以下组成的组:/>/> 在式(I-C)的一些实施方案中,R1选自由以下组成的组:
在式(I-C)的一些实施方案中,n为0。在一些实施方案中,n为1。在一些实施方案中,n为2。在一些实施方案中,n为3。在一些实施方案中,n为4。在一些实施方案中,n为5。在其他实施方案中,n为6。
在式(I-C)的一些实施方案中,当R5a和R5b中的一个为H并且R5a和R5b中的另一个为甲基,并且n为0时,R1选自由以下组成的组: 在式(I-C)的一些实施方案中,当R5a和R5b中的一个为H并且R5a和R5b中的另一个为甲基,并且n为0时,R1选自由以下组成的组:/>
在式(I-C)的一些实施方案中,R5a选自由以下组成的组:氢、甲基和-NHC(O)O(C1-C6烷基)。在式(I-C)的一些实施方案中,R5b选自由以下组成的组:氢、甲基和-NHC(O)O(C1-C6烷基)。在式(I-C)的一些实施方案中,R5a为氢,并且R5b选自由以下组成的组:氢、甲基和-NHC(O)O(C1-C6烷基)。在一些实施方案中,R5a和R5b各自为甲基。
在另一个方面,式(II)或式(I)的化合物是式(I-D)的化合物:
或其盐,其中R1、R6和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在式(I-D)的一些实施方案中,R1为在一些实施方案中,R1为在一些实施方案中,R1为/> 在一些实施方案中,R1为其中R2b选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>在一些实施方案中,R1为/>在式(I-D)的一些实施方案中,R1选自由以下组成的组:/> 在式(I-D)的一些实施方案中,R1选自由以下组成的组: 在式(I-D)的一些实施方案中,R1选自由以下组成的组:/> 在式(I-D)的一些实施方案中,R1为/>在式(I-D)的一些实施方案中,R1为/>
在式(I-D)的一些实施方案中,n为0。在一些实施方案中,n为1。在一些实施方案中,n为2。在一些实施方案中,n为3。在一些实施方案中,n为4。在一些实施方案中,n为5。在其他实施方案中,n为6。
在式(I-D)的一些实施方案中,R6为-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)、-C(O)-(任选取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)和5元至18元杂芳基。在一些实施方案中,R6为(a)-C(O)OC(CH3)3;(b)-NHC(O)O(C1-C6烷基);(c)-C(O)-(苯基),其中苯基任选被独立地选自C1-C6烷基、C1-C6卤代烷基和5元至18元杂芳基的一个或多个取代基取代;(d)-C(O)-(C1-C6亚烷基)-(苯基),其中苯基任选被一个或多个独立选择的C1-C6烷基取代基取代;(e)-C(O)-(3元至18元杂环烷基),其中3元至18元杂环烷基任选被一个或多个独立选择的氧代基或C1-C6烷基取代基取代;(f)-C(O)-(5元至18元杂芳基),其中5元至18元杂芳基任选被一个或多个独立选择的C1-C6烷基取代基取代;(g)-C(O)-(C1-C6亚烷基)-(5元至18元杂芳基),其中5元至18元杂芳基任选被一个或多个独立选择的C1-C6烷基取代基取代;或(h)5元至18元杂芳基。在一些实施方案中,R6为-C(O)-(任选取代的苯基)。在一些实施方案中,R6为-C(O)-(苯基),其中苯基任选被一个或多个C1-C6烷基、C1-C6卤代烷基或5元至18元杂芳基取代。在一些实施方案中,R6为在式(I-D)的一些实施方案中,R6为-C(O)OC(CH3)3。在一些实施方案中,R6为-NHC(O)O(C1-C6烷基)。在一些实施方案中,R6为-C(O)-(C1-C6亚烷基)-(苯基),其中苯基任选被一个或多个独立选择的C1-C6烷基取代基取代。在一些实施方案中,R6为-C(O)-(3元至18元杂环烷基),其中3元至18元杂环烷基任选被一个或多个独立选择的氧代基或C1-C6烷基取代基取代。在一些实施方案中,R6为-C(O)-(5元至18元杂芳基),其中5元至18元杂芳基任选被一个或多个独立选择的C1-C6烷基取代基取代。在一些实施方案中,R6为-C(O)-(C1-C6亚烷基)-(5元至18元杂芳基),其中5元至18元杂芳基任选被一个或多个独立选择的C1-C6烷基取代基取代。在一些实施方案中,R6为5元至18元杂芳基。
在式(I-D)的一些实施方案中,R6为-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)或-C(O)-(苯基),并且n为0-6。在式(I-D)的一些实施方案中,R6为-C(O)-(取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)或5元至18元杂芳基,并且n为4或5。在一些实施方案中,R6为并且n为4或5。在一些实施方案中,R6为/>并且n为4。在一些实施方案中,R6为/>并且n为5。
在式(I-D)的一些实施方案中,R6为-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)或-C(O)-(苯基);n为0-6;并且R1选自由以下组成的组: 在式(I-D)的一些实施方案中,R6为-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)或-C(O)-(苯基);n为0-6;并且R1选自由以下组成的组:
在式(I-D)的一些实施方案中,R6为-C(O)-(取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)、或5元至18元杂芳基;n为4或5;并且R1选自由以下组成的组: 在式(I-D)的一些实施方案中,R6为-C(O)-(取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)、或5元至18元杂芳基;n为4或5;并且R1选自由以下组成的组:/>
在另一个方面,式(II)或式(I)的化合物是式(I-E)的化合物:
或其盐,其中R1和n如对式(II)或式(I)或其任何变型或实施方案所定义。
在式(I-E)的一些实施方案中,R1为在一些实施方案中,R1为在一些实施方案中,R1为/>其中R2a选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>其中R2b选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>在一些实施方案中,R1为/>
在式(I-E)的一些实施方案中,n为4。在一些实施方案中,n为5。在其他实施方案中,n为6。
在另一个方面,式(II)或式(I)的化合物是式(I-F)的化合物:
或其盐,其中R1、n和r如对式(II)或式(I)或其任何变型或实施方案所定义。
在式(I-F)的一些实施方案中,R1为在一些实施方案中,R1为在一些实施方案中,R1为/>其中R2a选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>其中R2b选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基);并且R2c、R2d和R2e各自独立地为氢或C1-C6烷基。在一些实施方案中,R1为/>在一些实施方案中,R1为/>
在式(I-F)的一些实施方案中,r为1。在一些实施方案中,r为2。在其他实施方案中,r为3。
在式(I-F)的一些实施方案中,n为0。在一些实施方案中,n为1。在一些实施方案中,n为2。在一些实施方案中,n为3。在一些实施方案中,n为4。在一些实施方案中,n为5。在其他实施方案中,n为6。n为4。在一些实施方案中,n为5。在其他实施方案中,n为6。
在式(I-F)的一些实施方案中,r为1并且n为2、3、4、5或6。在一些实施方案中,r为2并且n为0、1、2、3、4、5或6。在其他实施方案中,r为3并且n为0、1、2、3、4、5或6。
在另一个方面,式(II)的化合物是式(I-G)的化合物:
或其盐,其中R1、Rq、Rs和n如对式(II)或其任何变型或实施方案所定义。
在式(I-G)的一些实施方案中,Rq为H或C1-C6烷基,并且Rs为C3-C8环烷基、任选取代的C6-C14芳基、任选取代的5元至18元杂芳基或-(C1-C6亚烷基)-(任选取代的C6-C14芳基)。在一些实施方案中,Rq为H。在一些实施方案中,Rq为C1-C6烷基。在一些实施方案中,Rq为甲基。在一些实施方案中,Rs为C3-C8环烷基。在一些实施方案中,Rs为环戊基或环己基。在式(II)的一些实施方案中,Y1为 在一些实施方案中,Rs为任选取代的C6-C14芳基。在一些实施方案中,Rs为任选被独立地选自卤基、C1-C6烷基和C6-C14芳基的一个或多个取代基取代的C6-C14芳基。在式(II)的一些实施方案中,Y1为 在一些实施方案中,Rs为任选取代的5元至18元杂芳基。在一些实施方案中,Rs为任选被一个或多个C1-C6烷基取代的5元至18元杂芳基。在一些实施方案中,Rs为任选被一个或多个C1-C6烷基取代的吡啶基。在式(II)的一些实施方案中,Y1为/> 在一些实施方案中,Rs为-(C1-C6亚烷基)-(任选取代的C6-C14芳基)。在一些实施方案中,-(C1-C6亚烷基)-(C6-C14芳基),其中-(C1-C6亚烷基)-(C6-C14芳基)的C6-C14芳基任选被一个或多个C1-C6烷基取代。在一些实施方案中,Rs为-(C1-C6亚烷基)-(苯基),其中-(C1-C6亚烷基)-(苯基)的苯基任选被一个或多个C1-C6烷基取代。在式(II)的一些实施方案中,Y1为/> 在式(II)的一些实施方案中,Y1为/>
在式(I-G)的一些实施方案中,n为4或5。在一些实施方案中,n为4。在一些实施方案中,n为5。
在另一个方面,本文提供了式(I-H)的化合物:
或其盐,其中R1、Rb和n如对式(II)或其任何变型或实施方案所定义。
在式(I-H)的一些实施方案中,Rb为任选取代的3元至18元杂环烷基。在一些实施方案中,Rb为任选被一个或多个C1-C6烷基取代的3元至18元杂环烷基,其中C1-C6烷基任选被一个或多个–OH取代。在一些实施方案中,Rb为任选被一个或多个C1-C6烷基取代的6元至10元杂环烷基,其中C1-C6烷基任选被一个或多个–OH取代。在一些实施方案中,Rb为各自独立地任选被一个或多个C1-C6烷基取代的1,2,3,4-四氢喹啉基、吗啉基或哌嗪基,其中C1-C6烷基任选被一个或多个–OH取代。在式(II)的一些实施方案中,Y1为
在式(I-H)的一些实施方案中,n为4或5。在一些实施方案中,n为4。在一些实施方案中,n为5。
在另一个方面,本文提供了式(I-J)的化合物:
或其盐,其中R1、Rt、Ru和n如本文对式(II)或其任何变型或实施方案所定义。
在式(I-J)的一些实施方案中,Rt为H或C1-C6烷基。在一些实施方案中,Rt为H。在一些实施方案中,Rt为C1-C6烷基。在一些实施方案中,Rt为甲基。在一些实施方案中,Ru为任选取代的C6-C14芳基、任选取代的5元至18元杂芳基、或-(C1-C6亚烷基)-(5元至18元杂芳基)。在一些实施方案中,Ru为(a)任选被一个或多个独立选择的C1-C6烷基或卤基取代基取代的C6-C14芳基;(b)任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至18元杂芳基;或(c)-(C1-C6亚烷基)-(5元至18元杂芳基)。在一些实施方案中,Ru为任选被一个或多个独立选择的卤基取代基取代的C6-C14芳基。在一些实施方案中,Ru为任选被一个或多个独立选择的C1-C6烷基或卤基取代基取代的苯基。在式(II)的一些实施方案中,Y1为 在一些实施方案中,Ru为任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至18元杂芳基。在一些实施方案中,Ru为任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至6元杂芳基。在一些实施方案中,Ru为任选被一个或多个独立选择的C1-C6烷基取代基取代的吡啶基。在式(II)的一些实施方案中,Y1为/>在一些实施方案中,Ru为-(C1-C6亚烷基)-(5元至18元杂芳基)。在一些实施方案中,Ru为-(C1-C6亚烷基)-(吡啶基)。在式(II)的一些实施方案中,Y1为/>在式(II)的一些实施方案中,Y1为/>
在式(I-J)的一些实施方案中,n为4或5。在一些实施方案中,n为4。在一些实施方案中,n为5。
在一个方面,本文提供了式(I-K)的化合物:
或其盐,其中R1和n如本文对式(II)或其任何变型或实施方案所定义。
在式(I-K)的一些实施方案中,n为4或5。在一些实施方案中,n为4。在一些实施方案中,n为5。
在一些实施方案中,本文提供的是表1中描述的化合物及其盐。
表1
在一些实施方案中,本文提供了式(II)的化合物或其任何变型,或选自由以下组成的组的前述项中的任一种的药学上可接受的盐:
1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(吡啶-4基甲基)脲;
(6-(3-(4-氨基甲酰基苄基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯;
4-((3-(4,4-二甲基环己基)脲基)甲基)苯甲酰胺;
4-((3-(3-苯基环丁基)脲基)甲基)苯甲酰胺;
4-(3-(4-氨基甲酰基苄基)脲基)哌啶-1-甲酸叔丁酯;
(6-(3-(吡啶-4-基甲基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯;
(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯;
(6-(3-(4-(羟甲基)苄基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯;
(6-(3-((1H-吡唑-4-基)甲基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯;
(6-(3-(噁唑-5-基甲基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯;
(4-(3-(4-氨基甲酰基苄基)脲基)环己基)氨基甲酸叔丁酯;
4-((3-(1-苯甲酰基哌啶-4-基)脲基)甲基)苯甲酰胺;
N-(6-(3-(4-氨基甲酰基苄基)脲基)螺[3.3]庚-2-基)苯甲酰胺;
N-(6-(3-(吡啶-4-基甲基)脲基)螺[3.3]庚-2-基)苯甲酰胺;
1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(4-氯苄基)脲;
N-(6-(3-((1H-吡唑-4-基)甲基)脲基)螺[3.3]庚-2-基)苯甲酰胺;
N-(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)苯甲酰胺;
4-((3-(4-(1-苯甲酰基哌啶-4-基)丁基)脲基)甲基)苯甲酰胺;
1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(4-甲氧基苄基)脲;
4-((3-(3-(苄基氨基甲酰基)环丁基)脲基)甲基)苯甲酰胺;
1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(4-(羟甲基)苄基)脲;
1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(噁唑-5-基甲基)脲;
4-((3-(6-(苄基氨基)螺[3.3]庚-2-基)脲基)甲基)苯甲酰胺;
1-((3-(吡啶-4-基甲基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
4-((3-(6-(吡啶-2-基氨基)螺[3.3]庚-2-基)脲基)甲基)苯甲酰胺;
1-((3-(4-氯苄基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
1-((3-(4-甲氧基苄基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
1-((3-(4-(羟甲基)苄基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
1-((3-(噁唑-5-基甲基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
1-((3-((1H-吡唑-4-基)甲基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
1-((3-(4-乙酰氨基苄基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
1-((3-(4-氨基甲酰基苄基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯;
4-((3-(6-((吡啶-2-基甲基)氨基)螺[3.3]庚-2-基)脲基)甲基)苯甲酰胺;
6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酸甲酯;
(5-(3-(4-甲氧基苄基)脲基)戊基)氨基甲酸叔丁酯;
6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯;
1-(2-(2-(2-氟苯基)乙酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(2-(2-氯苯基)乙酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(2-(2-(2-甲氧基苯基)乙酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(2-(2-(三氟甲基)苯基)乙酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(2-(邻甲苯基)乙酰基)-2-氮杂螺[3.3]庚-6-基)脲;
6-(3-(4-甲氧基苄基)脲基)-N-(1-苯基环丙基)螺[3.3]庚烷-2-甲酰胺;
1-(4-甲氧基苄基)-3-(6-(2-苯基吡咯烷-1-羰基)螺[3.3]庚-2-基)脲;
6-(3-(4-甲氧基苄基)脲基)-N-(1-苯基乙基)螺[3.3]庚烷-2-甲酰胺;
N-(2-羟基-1-苯基乙基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
1-(4-甲氧基苄基)-3-(6-(2-苯基氮杂环丁烷-1-羰基)螺[3.3]庚-2-基)脲;
6-(3-(4-甲氧基苄基)脲基)-N-(吡啶-3基甲基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(吡啶-4基甲基)螺[3.3]庚烷-2-甲酰胺;
N-苄基-6-(3-(4-甲氧基苄基)脲基)-N-甲基螺[3.3]庚烷-2-甲酰胺;
1-(4-甲氧基苄基)-3-(6-((2-苯基吡咯烷-1-基)甲基)螺[3.3]庚-2-基)脲;
N-(1-(2-氟苯基)乙基)-6-(3-(4-甲氧基苄基)脲基)-N-甲基螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(2-甲基-2-(邻甲苯基)丙基)螺[3.3]庚烷-2-甲酰胺;
N-(2-(2-氟苯基)-2-甲基丙基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(吡啶-2基甲基)螺[3.3]庚烷-2-甲酰胺;
1-(4-甲氧基苄基)-3-(6-(3-苯基吡咯烷-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(2-(吡啶-4-基)吡咯烷-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(2-(吡啶-3-基)吡咯烷-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(3-苯基氮杂环丁烷-1-羰基)螺[3.3]庚-2-基)脲;
1-(6-(4-苯甲酰基哌嗪-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
6-(3-(4-甲氧基苄基)脲基)-N-(3-苯基环丁基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(2-(2-甲氧基苯基)-2-甲基丙基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(2-甲基-2-(吡啶-2-基)丙基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(2-甲基-2-(吡啶-3-基)丙基)螺[3.3]庚烷-2-甲酰胺;
N-苄基-2-(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)-N-甲基乙酰胺;
N-苄基-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-苯乙基螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(2-苯基丙-2-基)螺[3.3]庚烷-2-甲酰胺;
1-(4-甲氧基苄基)-3-(6-(1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(7-(三氟甲基)-1,2,3,4-四氢异喹啉-2-羰基)螺[3.3]庚-2-基)脲;
1-(6-(异吲哚啉-2-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-(吲哚啉-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
N-(2-(1H-吡唑-4-基)乙基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
1-(6-(4-(2-羟基-2-甲基丙基)哌嗪-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
N-(4-氰基-2-氟苄基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(3-(吡啶-4-基)环丁基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-甲基-N-(四氢呋喃-3-基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(2-甲基-2-(吡啶-4-基)丙基)螺[3.3]庚烷-2-甲酰胺;
2-(3-(4-甲氧基苄基)脲基)-6-氮杂螺[3.4]辛烷-6--甲酸叔丁酯;
6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.4]辛烷-2--甲酸叔丁酯;
1-(4-甲氧基苄基)-3-(6-(6-甲基-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)脲;
1-(6-(3,4-二氢-2H-苯并[b][1,4]噁嗪-4-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
6-(3-(4-甲氧基苄基)脲基)-N-苯基螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-甲基-N-苯基螺[3.3]庚烷-2-甲酰胺;
N-((2-(二氟甲氧基)吡啶-4-基)甲基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
N-([1,2,4]三唑[4,3-a]吡啶-6-基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
1-(4-甲氧基苄基)-3-(6-(1,2,3,4-四氢-1,6-萘啶-1-羰基)螺[3.3]庚-2-基)脲;
N-(2,3-二氢-1H-茚-1-基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
N-(3-(羟甲基)-2,3-二氢-1H-茚-1-基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
N-(1-羟基-2,3-二氢-1H-茚-2-基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
N-(2,3-二氢-2H-茚-1-基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(1,2,3,4-四氢萘-2-基)螺[3.3]庚烷-2-甲酰胺;
N-(7-氟-1,2,3,4-四氢萘-1-基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
N-(6-氟-1,2,3,4-四氢萘-1-基)-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(1,2,3,4-四氢萘-1-基)螺[3.3]庚烷-2-甲酰胺;
1-(6-(6-氟-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-(7,8-二氟-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-(6-(二氟甲氧基)-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(6-(6-(三氟甲基)-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)脲;
1-(6-(5-氟-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-(7-氟-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(6-(6-(三氟甲氧基)-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(7-甲基-1,2,3,4-四氢喹啉-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-氟苄基)-3-(6-(4-(2-羟基-2-甲基丙基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(4-(氧杂环丁烷-3-基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲;
1-(6-(4-(环丙基甲基)哌嗪-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-(2-(羟甲基)-4-甲基哌嗪-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)苯甲酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-2-苯基乙酰胺;
1-(2-((2-氯苯基)磺酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-((2-氯苄基)磺酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-((2-氯苯乙基)磺酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(4-氯苄基)-3-(6-(二苄基氨基)螺[3.3]庚-2-基)脲;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-1-(2-氯苯基)甲磺酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)苯磺酰胺;
1-(6-(4-异丙基哌嗪-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(6-(4-((1-甲基-1H-吡唑-4-基)甲基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(4-(吡啶-4基甲基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(4-(吡啶-2基甲基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲;
1-(6-(3-(羟甲基)-4-甲基哌嗪-1-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-((5,7-二氟-3,4-二氢喹啉-1(2H)-基)甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-(吲哚啉-1基甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(6-(异吲哚啉-2基甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(2-(双环[2.2.1]庚-2-基磺酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
4-((6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.3]庚-2-基)磺酰基)环己烷-1-甲酸甲酯;
N-(6-氰基吡啶-2-基)-6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.3]庚烷-2-甲酰胺;
6-(3-(4-甲氧基苄基)脲基)-N-(2-甲基嘧啶-5-基)-2-氮杂螺[3.3]庚烷-2-甲酰胺;
1-(6-((1H-吲唑-1-基)甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(2-(3-(2-氯苯基)丙酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
3-(6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.3]庚烷-2-羰基)哌啶-1-甲酸叔丁酯;
1-(4-甲氧基苄基)-3-(2-(1,2,3,4-四氢萘-1-羰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(6-甲基烟酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(2-异烟酰基-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(2-(2-甲基异烟酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(2-苯甲酰基-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(2-(2-甲基-2-苯基丙酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(1-苯基环丙烷-1-羰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(1-甲基-6-氧代-1,6-二氢吡啶-3-羰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(3-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(4-(三氟甲基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(2-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(5-苯氧基戊基)脲;
1-(4-甲氧基苄基)-3-(6-苯氧基己基)脲;
2-(3-(4-氯苄基)脲基)-6-氮杂螺[3.4]辛烷-6--甲酸叔丁酯;
1-(4-甲氧基苄基)-3-(2-(2-甲基-2-(对甲苯基)丙酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(2-甲基-2-(间甲苯基)丙酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(2-(4-甲氧基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(4-氰基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(4-(2-羟基丙-2-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(4-氯苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(4-氯苄基)-3-(6-(4-甲基苯甲酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(2-甲基异烟酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(3-甲基苯甲酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(2-甲基苯甲酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(4-甲氧基苯甲酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(3-甲基异烟酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(4-氟苯甲酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(3-异丙基苯甲酰基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(嘧啶-2-基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(4-氯苄基)-3-(6-(2-甲基吡啶-4-基)-6-氮杂螺[3.4]辛-2-基)脲;
1-(2-(3-乙基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(3-异丙基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(3-(叔丁基)苯甲酰基)-2-氮杂螺[3.3]己-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(3-(2-羟基丙-2-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(3-甲氧基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(3-羟基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(2-(3-(二甲基氨基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(2-(3-(吡咯烷-1-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(3-(甲基磺酰基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
3-(6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.3]庚烷-2-羰基)苯甲酸甲酯;
1-(4-氯苄基)-3-(6-(4-(2-羟基-2-甲基丙基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)烟酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)异烟酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-2-甲基异烟酰胺;
1-(4-甲氧基苄基)-3-(2-(3-(2-氧代吡咯烷-1-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(2-(3-(1H-吡咯-1-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲;
1-(4-甲氧基苄基)-3-(2-(3-(哌啶-1-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-甲氧基苄基)-3-(2-(3-吗啉代苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-6-甲基烟酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-2-甲基苯甲酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-3-甲氧基苯甲酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-3-(甲基磺酰基)苯甲酰胺;
1-(4-氯苄基)-3-(2-(2-苯氧基乙氧基)乙基)脲;
6-(3-(4-氯苄基)脲基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯;
(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯;
1-(4-氯苄基)-3-(6-(6-甲基吡啶-2-基)-6-氮杂螺[3.4]辛-2-基)脲;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-3-羟基苯甲酰胺;
6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-甲酸甲酯;
6-(3-(4-氯苄基)脲基)-N-甲基-N-(四氢呋喃-3-基)螺[3.3]庚烷-2-甲酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-2-甲基烟酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-3-甲基异烟酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-4-甲基烟酰胺;
1-(4-氯苄基)-3-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-氟苄基)-3-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-2-羟基苯甲酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-2-(二甲基氨基)苯甲酰胺;
1-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(吡啶-4基甲基)脲;
4-((3-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲基)甲基)苯甲酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-2-氰基苯甲酰胺;
N-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)吡啶-3-磺酰胺;
1-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-((6-氧代-1,6-二氢吡啶-3-基)甲基)脲;
5-((3-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲基)甲基)吡啶酰胺;
1-(4-氯苄基)-3-(2-((2-氯苯基)磺酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-氯苄基)-3-(2-((3-氯苯基)磺酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-氯苄基)-3-(2-((2-甲氧基苯基)磺酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(2-(3-(1H-吡咯-1-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-氯苄基)脲;
1-(4-氯苄基)-3-(2-(3-异丙基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(4-氯苄基)-3-(2-(2-甲基-2-苯基丙酰基)-2-氮杂螺[3.3]庚-6-基)脲;
4-((3-(2-(3-(吡咯烷-1-基)苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲基)甲基)苯甲酰胺;
4-((3-(2-(5-(吡咯烷-1-基)烟酰基)-2-氮杂螺[3.3]庚-6-基)脲基)甲基)苯甲酰胺;
4-((3-(2-(4-氯苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲基)甲基)苯甲酰胺;
4-((3-(2-(6-甲基烟酰基)-2-氮杂螺[3.3]庚-6-基)脲基)甲基)苯甲酰胺;
4-((3-(2-(2-甲基异烟酰基)-2-氮杂螺[3.3]庚-6-基)脲基)甲基)苯甲酰胺;
1-((1H-吡唑-4-基)甲基)-3-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)脲;
1-(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)-3-(噁唑-4基甲基)脲;
1-(4-甲氧基苄基)-3-(6-(4-甲基哌嗪-1-羰基)螺[3.3]庚-2-基)脲;
4-(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-羰基)哌嗪-1-甲酸甲酯;
1-(6-(1,1-二氧化硫吗啉-4-羰基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
4-(6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-羰基)哌嗪-1-甲酸甲酯;
1-(4-氯苄基)-3-(6-(2-(4-(2-羟基-2-甲基丙基)哌嗪-1-基)-2-氧代乙基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(2-(2-(羟甲基)吡咯烷-1-基)-2-氧代乙基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(2-氧代-2-(吡咯烷-1-基)乙基)螺[3.3]庚-2-基)脲;
N-苄基-2-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)-N-甲基丙酰胺;
1-(4-氯苄基)-3-(6-((4-甲基-3-氧代哌嗪-1-基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((2-(吡啶-3-基)吡咯烷-1-基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((2-甲基-5-氧代吡咯烷-1-基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((5-苯基-1H-1,2,3-三唑-1-基)甲基)螺[3.3]庚-2-基)脲;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)四氢-2H-噻喃-4-甲酰胺1,1-二氧化物;
1-(4-氯苄基)-3-(6-((3-甲基-2-氧代吡咯烷-1-基)甲基)螺[3.3]庚-2-基)脲;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)-6-甲基吡啶酰胺;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)-2-甲基异烟酰胺;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)-1H-吡唑-4-甲酰胺;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)-N,6-二甲基烟酰胺;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)-6-甲基烟酰胺;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)四氢-2H-吡喃-4-甲酰胺;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)环戊烷甲酰胺;
N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)-2-氧代哌啶-4-甲酰胺;
1-(4-氯苄基)-3-(6-(1-(4-甲基-3-氧代哌嗪-1-基)乙基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((4-甲基-2-苯基哌嗪-1-基)甲基)螺[3.3]庚-2-基)脲;
N-(1-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)乙基)-6-甲基烟酰胺;
1-(4-氯苄基)-3-(5-(3,4-二氢喹啉-1(2H)-基)-5-氧代戊基)脲;
6-(3-(4-氯苄基)脲基)-N-环己基己酰胺;
6-(3-(4-氯苄基)脲基)-N-环戊基己酰胺;
1-(4-氯苄基)-3-(6-吗啉代-6-氧代己基)脲;
1-(4-氯苄基)-3-(6-(4-新戊基哌嗪-1-基)-6-氧代己基)脲;
1-(4-氯苄基)-3-(6-(4-(2-羟基-2-甲基丙基)哌嗪-1-基)-6-氧代己基)脲;
6-(3-(4-氯苄基)脲基)-N-(邻甲苯基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-(吡啶-4-基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-甲基-N-(间甲苯基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-甲基-N-(吡啶-4-基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-甲基-N-(邻甲苯基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-甲基-N-(3-甲基苄基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-甲基-N-苯基己酰胺;
N-苄基-6-(3-(4-氯苄基)脲基)-N-甲基己酰胺;
6-(3-(4-氯苄基)脲基)-N-甲基-N-(吡啶-3-基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-甲基-N-(吡啶-2-基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-(2-氟苯基)己酰胺;
N-([1,1'-双苯基]-2-基)-6-(3-(4-氯苄基)脲基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-(2-氟苯基)-N-甲基己酰胺;
N-(5-(3-(4-氯苄基)脲基)戊基)-2-甲基苯甲酰胺;
N-(5-(3-(4-氯苄基)脲基)戊基)-3-甲基苯甲酰胺;
N-(5-(3-(4-氯苄基)脲基)戊基)烟酰胺;
6-(3-(4-氯苄基)脲基)-N-(6-甲基吡啶-3-基)己酰胺;
N-(5-(3-(4-氯苄基)脲基)戊基)吡啶酰胺;
N-(5-(3-(4-氯苄基)脲基)戊基)-2-氟苯甲酰胺;
N-(5-(3-(4-氯苄基)脲基)戊基)-6-甲基烟酰胺;
N-(2-氟苯基)-6-(3-(4-甲氧基苄基)脲基)-N-甲基己酰胺;
N-(5-(3-(4-氯苄基)脲基)戊基)-2-(吡啶-3-基)乙酰胺;
6-(3-(4-氯苄基)脲基)-N-(4-氟苯基)己酰胺;
6-(3-(4-氯苄基)脲基)-N-(3-氟苯基)己酰胺;
N-(2-氟苯基)-N-甲基-6-(3-(吡啶-4基甲基)脲基)己酰胺;
6-(3-((1H-吡唑-4-基)甲基)脲基)-N-(2-氟苯基)-N-甲基己酰胺;
N-(2-氟苯基)-N-甲基-6-(3-(噁唑-5基甲基)脲基)己酰胺;
1-(4-氯苄基)-3-(4-(1-烟酰基哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-异烟酰基哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-苯基乙酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-吡啶甲酰基哌啶-4-基)丁基)脲;
1-(4-(1-苯甲酰基哌啶-4-基)丁基-1,1-d2)-3-(噁唑-5基甲基)脲;
1-(4-氯苄基)-3-(4-(1-(2-(吡啶-3-基)乙酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-(吡啶-4-基)乙酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(3-甲基苯甲酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-甲基苯甲酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(6-甲基吡啶甲酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-(6-甲基吡啶-2-基)乙酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(四氢-2H-吡喃-4-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-氧代哌啶-4-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(1-甲基-2-氧代哌啶-4-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(5-氧代吡咯烷-3-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(1-甲基-5-氧代吡咯烷-3-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(噁唑-2-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(异噁唑-5-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(吡啶-2-基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(吡啶-4-基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(6-甲基烟酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-(2-甲基吡啶-3-基)乙酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-(6-甲基吡啶-3-基)乙酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(1-甲基-1H-1,2,3-三唑-4-羰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-(邻甲苯基)乙酰基)哌啶-4-基)丁基)脲;
1-(4-氯苄基)-3-(4-(1-(2-(二氟甲基)苯甲酰基)哌啶-4-基)丁基)脲;
1-(4-(1-(2-(1H-四唑-5-基)苯甲酰基)哌啶-4-基)丁基)-3-(4-氯苄基)脲;
1-(4-(1-(2-(1H-吡唑-4-基)乙酰基)哌啶-4-基)丁基)-3-(4-氯苄基)脲;
1-(4-(4-苯甲酰基哌嗪-1-基)丁基)-3-(4-氯苄基)脲;
1-(4-(1-(2H-四唑-5-基)哌啶-4-基)丁基)-3-(4-氯苄基)脲;
1-(4-氯苄基)-3-(4-(1-(2,6-二甲基苯甲酰基)哌啶-4-基)丁基)脲;
1-(4-(1-(2-甲基苯甲酰基)哌啶-4-基)丁基)-3-(噁唑-5基甲基)脲;
4-((3-(4-(1-(2-甲基苯甲酰基)哌啶-4-基)丁基)脲基)甲基)苯甲酰胺;
1-(4-甲氧基苄基)-3-(4-(1-(2-甲基苯甲酰基)哌啶-4-基)丁基)脲;
1-(4-(1-(2-甲基苯甲酰基)哌啶-4-基)丁基)-3-(吡啶-4基甲基)脲;
1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(噁唑-5基甲基-d2)脲;
1-(4-甲氧基苄基)-3-(6-(5-苯基-1,3,4-噁二唑-2-基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(4-苯基噁唑-2-基)螺[3.3]庚-2-基)脲;
1-(6-(苯并[d]噁唑-2-基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲;
1-(4-氯苄基)-3-(6-(羟基(苯基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(吡啶-4基甲基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(吡啶-4基甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(吡嗪-2基甲基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(5-(6-甲基吡啶-3-基)-1,3,4-噁二唑-2-基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((4-氰基-1H-吡唑-1-基)甲基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(4-甲基苄基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(3-甲基苄基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(2-甲基苄基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-((6-甲基吡啶-3-基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(1-羟基-1-(6-甲基吡啶-3-基)乙基)螺[3.3]庚-2-基)脲;
1-(6-((1H-1,2,4-三唑-1-基)甲基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲;
1-(4-氯苄基)-3-(6-(嘧啶-2基甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(吡啶-4-基氧基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(甲基磺酰基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(吡啶-3-基氧基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(吡啶-3-基氧基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(吡啶-3基甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((2-甲基吡啶-3-基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((6-甲基吡啶-3-基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(吡啶-4-基甲氧基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(吡啶-4-基甲氧基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-(吡啶-3-基甲氧基)螺[3.3]庚-2-基)脲;
1-(4-甲氧基苄基)-3-(6-(吡啶-3-基甲氧基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((苯基磺酰基)甲基)螺[3.3]庚-2-基)脲;
1-(4-氯苄基)-3-(6-((吡啶-3-基磺酰基)甲基)螺[3.3]庚-2-基)脲;和
1-(6-([1,4'-双哌啶]-1'-羰基)-6-氮杂螺[3.4]辛-2-基)-3-(4-氯苄基)脲,
或前述项中任一种的药学上可接受的盐。
在一些变型中,本文所述的化合物中的任一种(诸如式(I)或式(II)的化合物或其任何变型)或表1的化合物可以是氘化的(例如,氢原子被氘原子替换)。在这些变型的一些中,化合物在单个位点是氘化的。在其他变型中,化合物在多个位点是氘化的。氘代化合物可以由氘代原料以类似于制备对应的非氘代化合物的方式制备。还可以使用本领域已知的其他方法用氘原子替代氢原子。
本文给定的任何式,诸如式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)旨在表示具有由结构式描述的结构以及某些变型或形式的化合物。具体来说,本文给定的任何式的化合物可以具有不对称中心,并且因此以不同的对映异构体或非对映异构体形式存在。通式的化合物的所有旋光异构体和立体异构体以及它们以任何比例的混合物都被认为在所述式的范围内。因此,本文给定的任何式旨在表示外消旋体、一种或多种对映异构体形式、一种或多种非对映异构体形式、一种或多种阻转异构体形式以及它们以任何比例的混合物。当表1的化合物被描述为具有特定立体化学构型时,本文还提供了所述化合物的任何替代立体化学构型,以及所述化合物的立体异构体以任何比例的混合物。例如,在表1的化合物具有位于“S”立体化学构型中的立体中心的情况下,本文还提供了其中该立体中心位于“R”立体化学构型中的所述化合物的对映异构体。同样,当表1的化合物具有位于“R”构型中的立体中心时,本文还提供了“S”立体化学构型中的所述化合物的对映异构体。还提供了具有“S”和“R”立体化学构型两者的化合物的混合物。此外,如果表1的化合物具有两个或更多个立体中心,则还提供了所述化合物的任何对映异构体或非对映异构体。例如,如果表1的化合物含有分别带有“R”和“R”立体化学构型的第一立体中心和第二立体中心,则还提供了化合物的立体异构体,其具有分别带有“S”和“S”立体化学构型、分别带有“S”和“R”立体化学构型、以及分别带有“R”和“S”立体化学构型的第一和第二立体中心。如果表1的化合物含有分别带有“S”和“S”立体化学构型的第一立体中心和第二立体中心,则还提供了化合物的立体异构体,其具有分别带有“R”和“R”立体化学构型、分别带有“S”和“R”立体化学构型、以及分别带有“R”和“S”立体化学构型的第一和第二立体中心。如果表1的化合物含有分别带有“S”和“R”立体化学构型的第一立体中心和第二立体中心,则还提供了化合物的立体异构体,其具有分别带有“R”和“S”立体化学构型、分别带有“R”和“R”立体化学构型、以及分别带有“S”和“S”立体化学构型的第一和第二立体中心。类似地,如果表1的化合物含有分别带有“R”和“S”立体化学构型的第一立体中心和第二立体中心,则还提供了化合物的立体异构体,其具有分别带有“S”和“R”立体化学构型、分别带有“R”和“R”立体化学构型、以及分别带有“S”和“S”立体化学构型的第一和第二立体中心。此外,某些结构可以作为几何异构体(即,顺式和反式异构体)、互变异构体或阻转异构体存在。此外,本文给定的任何式旨在指代此类化合物的水合物、溶剂合物、以及无定形和多晶型形式的任一种,及其混合物,即使此类形式未明确列出。在一些实施方案中,溶剂是水并且溶剂合物是水合物。
本文详述的化合物的代表性实例(包括中间体和最终化合物)在表格和本文的别处描绘。应当理解,在一个方面,化合物中的任一种都可以用于本文详述的方法中,包括,在适当的情况下,可以分离并且向个体或受试者施用的中间体化合物。
如本领域技术人员充分理解的,即使未描绘盐,本文描绘的化合物也可以作为盐存在,并且应当理解,本文提供的组合物和方法包括此处描绘的化合物的所有盐和溶剂合物,以及所述化合物的非盐和非溶剂合物形式。在一些实施方案中,本文提供的化合物的盐是药学上可接受的盐。
在一个变型中,本文的化合物是制备用于向个体或受试者施用的合成化合物。在另一个变型中,提供了含有基本上纯形式的化合物的组合物。在另一个变型中,提供了药物组合物,其包含本文详述的化合物和药学上可接受的载体。在另一个变型中,提供了施用化合物的方法。纯化的形式、药物组合物和施用化合物的方法适用于本文详述的任何化合物或其形式。
本文提供的Ra、Rb、Rq、Rs、Rt、Ru、R1、n、Y1、R2a、R2b、R2c、R2d、R2e、G1、p1、p2、q1、q2、r、R3、R3a、R3b、R3c、R3d、R3f、R3g、R3h、R3i、R3j、R3k、R3l、R3m、R3n、R3p、R3q、R3r、R3s、R4、R5和R6的任何变型或实施方案可以与Ra、Rb、Rq、Rs、Rt、Ru、R1、n、Y1、R2a、R2b、R2c、R2d、R2e、G1、p1、p2、q1、q2、r、R3、R3a、R3b、R3c、R3d、R3f、R3g、R3h、R3i、R3j、R3k、R3l、R3m、R3n、R3p、R3q、R3r、R3s、R4、R5和R6的每种其他的变型或实施方案组合,其程度如同每个组合已经单独地并且明确地描述。
根据以下具体实施方式,其他实施方案对于本领域技术人员将是显而易见的。
如本文所用,当任何变量在化学式中出现超过一次时,其在每次出现时的定义与其在所有其他出现时的定义无关。
式(II)和/或式(I)包括其所有子式。
本文提供的化合物名称(包括表1)由ChemBioDrawProfessional15.0提供。本领域技术人员将理解,可以使用各种普遍认可的命名系统和符号来命名或鉴定化合物。例如,可以用常见名称、系统名称或非系统名称来命名或鉴定化合物。化学领域中普遍认可的命名系统和符号包括例如化学文摘社(Chemical Abstract Service,CAS)、ChemBioDraw Ultra和国际纯化学和应用化学联合会(International Union of Pure and AppliedChemistry,IUPAC)。
组合物
还提供了组合物,诸如药物组合物,其包括本文公开和/或描述的化合物和一种或多种另外的剂、药剂、佐剂、载体、赋形剂等。合适的药物和药剂包括本文所述的那些。在一些实施方案中,药物组合物包括药学上可接受的赋形剂或佐剂和至少一种如本文所述的化学实体。药学上可接受的赋形剂的实例包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、交联羧甲基纤维素钠、葡萄糖、明胶、蔗糖和碳酸镁。在一些实施方案中,提供了组合物,诸如含有本文所述的一种或多种化合物或其药学上可接受的盐的药物组合物。
在一些实施方案中,提供了一种药学上可接受的组合物,其包含式(II)或式(I)的化合物(诸如式(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物)、或表1的化合物、或其药学上可接受的盐。在一些方面,组合物可以含有可以用于制备本文所述化合物的合成中间体。本文所述的组合物可包含任何其他合适的活性剂或非活性剂。
本文所述的组合物中的任一种可以是无菌的或含有无菌的组分。可以通过本领域已知的方法实现灭菌。本文所述的组合物中的任一种可以含有一种或多种基本上纯的化合物或缀合物。
还提供了包装的药物组合物,其包含如本文所述的药物组合物和使用所述组合物治疗罹患本文所述的疾病或疾患的患者的说明书。
使用方法
本文详述的化合物和组合物,诸如包含本文提供的任何式的化合物或其药学上可接受的盐和药学上可接受的载体或赋形剂的药物组合物,可以用于本文提供的施用和治疗方法中。
不受理论束缚,据信本文公开的化合物和药物组合物通过调节烟酰胺磷酸核糖基转移酶(NAMPT)而发挥作用。在一些实施方案中,本文公开的化合物和药物组合物是NAMPT的活化剂。在一些实施方案中,提供了治疗个体或受试者的由NAMPT活性介导的疾病或疾患的方法,其包括向有需要的个体或受试者施用式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物或表1的化合物或其药学上可接受的盐。在一些实施方案中,提供了治疗个体或受试者的癌症、过度增殖性疾病或疾患、炎性疾病或疾患、代谢障碍、心脏疾病或疾患、化疗诱导的组织损伤、肾脏疾病、代谢疾病、神经系统疾病或损伤、神经退行性病症或疾病、干细胞功能受损引起的疾病、DNA损伤引起的疾病、原发性线粒体病症或肌肉疾病或肌肉萎缩症的方法,其包括向有需要的个体或受试者施用式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物或表1的化合物或其药学上可接受的盐。
本文还提供了式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物或表1的化合物或其药学上可接受的盐在制造用于治疗受试者的由NAMPT活性介导的疾病或疾患的药物中的用途。在一些方面,提供了如本文所述用于通过疗法治疗人体或动物体的方法中的化合物或组合物。在一些实施方案中,本文提供了用于通过疗法治疗人体或动物体的方法中的式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物或表1的化合物或其药学上可接受的盐。在一些实施方案中,本文提供了用于治疗由NAMPT活性介导的疾病或疾患的式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物或表1的化合物或其药学上可接受的盐。在一些实施方案中,疾病或疾患选自由以下组成的组:癌症、过度增殖性疾病或疾患、炎性疾病或疾患、代谢障碍、心脏疾病或疾患、化疗诱导的组织损伤、肾脏疾病、代谢疾病、神经系统疾病或损伤、神经退行性病症或疾病、干细胞功能受损引起的疾病、DNA损伤引起的疾病、原发性线粒体病症、或肌肉疾病或肌肉萎缩症。
本文还提供了如本文所述用于治疗、预防和/或延缓本文所述的疾病的发作和/或发展的组合物(包括药物组合物)以及本文所述的其他方法。在某些实施方案中,组合物包含以单位剂型存在的药物制剂。
在一些实施方案中,受试者是哺乳动物。在一些实施方案中,受试者是小鼠、大鼠、狗、猫、兔、猪、绵羊、马、牛或人。在一些实施方案中,受试者是人。
在许多疾患中,小分子介导的NAMPT活性刺激提高NAD+水平可能将具有临床益处(等人,Biochem Soc Trans.2019,47(1):119-130;Ralto等人,Nat RevNephrol.2019;Fang等人,Trends Mol Med.2017,23(10):899-916;Yoshino等人,CellMetab.2011,14(4):528-36;Yang和Sauve,Biochim Biophys Acta.2016,1864:1787-1800;Verdin,Science.2015,350(6265):1208-13)。这些疾患包括但不限于心脏病、化疗诱导的组织损伤、肾脏疾病、代谢疾病、肌肉疾病、神经系统疾病和损伤、干细胞功能受损引起的疾病、以及DNA损伤和原发性线粒体病症。在一些实施方案中,由NAMPT活性介导的疾病或疾患是心脏病、化疗诱导的组织损伤、肾脏疾病、代谢疾病、肌肉疾病、神经系统疾病或损伤、干细胞功能受损引起的疾病、或DNA损伤和原发性线粒体病症。
心脏疾病。在心力衰竭的各种临床前模型中,NAD以及NAMPT水平降低。在这些模型中,可以通过经由口服补充来恢复NAD或过表达NAMPT来挽救心脏功能(Diguet等人,Circulation.2018,137:2256–2273;Zheng等人,Clin Sci(Lond).2019,133(13):1505-1521;Smyrnias等人,J Am Coll Cardiol.2019,73(14):1795-1806)。因此,用小分子活化剂增加NAMPT的催化效率以补偿降低的蛋白质水平是治疗各种形式的心力衰竭的有前景的策略。
化疗诱导的组织损伤。化疗方案的使用频繁受到对健康组织的毒性的限制,并且严重的氧化应激被认为发挥主要作用。NAD提高已经显示触发强抗氧化反应。因此,NAMPT活化剂被认为可以在各种化疗环境中广泛用于预防可逆和不可逆的继发性病变。实例是蒽环类和曲妥珠单抗(trastuzumab)心脏毒性;顺铂诱导的肾脏损伤;顺铂、紫杉醇、长春新碱和其他剂诱导的周围神经病变。由NAMPT激活引起的神经保护也可用于治疗/预防化疗相关的认知功能障碍(“化疗脑”),这是在积极治疗期间和在治疗停止长时间后由健康神经组织的破坏引起的。例如,参见Zheng等人,Clin Sci(Lond).2019,133(13):1505-1521。
肾脏疾病。肾脏疾病非常普遍,并且是一个紧急未满足的医疗需求领域。大约3%的住院患者被诊断为急性肾损伤(AKI)。一部分患者将发展为可能需要长期透析或肾移植的慢性肾病。肾功能障碍的一个关键特征是SIRT1和SIRT3的活性降低,其特征是主要是由从头NAD+合成受损引起的去乙酰化酶底物NAD减少。NAMPT在肾损伤期间强烈表达,因此使用NAMPT激活小分子被认为是预防AKI的有效措施。同样,肾系膜细胞肥大表现出NAD+的耗竭,并且细胞内NAD+水平的恢复被认为是有效的。例如,参见Poyan Mehr等人,NatMed.2018,Sep;24(9):1351–9。
代谢疾病。NAD+提高改善代谢疾病中的胰岛素敏感性、血脂异常、线粒体功能,并在临床前模型中防止/改善非酒精性和酒精性脂肪性肝炎。仅在美国,每年有超过300万人被诊断出患有非酒精性脂肪性肝炎,并且它是肝移植的主要原因之一。参见Guarino和Dufour,Metabolites.2019,Sep 10;9(9),pii:E180;Yoshino等人,Cell Metab.2011,14(4):528-36。
肌肉疾病。临床前数据已经表明,NAD+提高策略可以缓解多种疾患(包括杜氏肌营养不良症(Duchenne’s muscular dystrophy)和与年龄相关的肌肉减少症)中的骨骼肌功能障碍。参见Zhang等人,Clin Sci(Lond).2019,133(13):1505-1521;Mohamed等人,Aging(Albany NY).2014,6(10):820-34;Ryu等人,Sci Transl Med.2016,8(361):361ra139。
神经系统疾病和损伤。通过NAMPT激活方式补充NAD具有神经保护作用,并且在多种神经系统疾病和损伤(包括与年龄相关的认知衰退、青光眼、缺血性中风和ALS)的临床前模型中具有治疗益处。参见Johnson等人,NPJ Aging Mech Dis.2018,4:10;Harlan等人,JBiol Chem.2016,291(20):10836-46;Zhao等人,Stroke.2015年7月;46(7):1966-74;Williams等人,Front Neurosci.2017年4月25日;11:232。
干细胞功能受损引起的疾病。NAD提高促进干细胞活化和造血作用,并且可用于在干细胞移植后加速干细胞群的扩增。参见Pi等人,Aging(Albany NY).2019,11(11):3505-3522。
DNA损伤病症和原发性线粒体病症。NAMPT活化剂还将可用于治疗与加速衰老表型相关的DNA损伤病症,诸如色素性干皮病、Cockayne综合征和共济失调毛细血管扩张症(Ataxia telangiectasia)。类似地,存在若干种具有共同症状和表现的原发性线粒体病症,对于所述病症,经由NAMPT激活提高NAD可能是一种合适的治疗干预措施。参见Fang等人,Cell.2014,157(4):882-896;Khan等人,EMBO Mol Med.2014,Jun;6(6):721-31;Cerutti等人,Cell Metab.2014,19(6):1042-9。
在一些实施方案中提供了治疗有需要的受试者的由NAMPT活性介导的疾病或疾患的方法,其包括向有需要的个体或受试者施用式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物或表1的化合物或其药学上可接受的盐,其中所述疾病或疾患选自由以下组成的组:心脏疾病、化疗诱导的组织损伤、肾脏疾病、代谢疾病、肌肉疾病、神经系统疾病或损伤、干细胞功能受损引起的疾病、以及DNA损伤和原发性线粒体病症。
小分子NAMPT活化剂的另外的应用在表2中提供。
表2
在一些实施方案中,由NAMPT活性介导的疾病或疾患是癌症和化学疗法诱导的组织损伤、心血管疾病、肾脏疾病、慢性炎性和纤维化疾病、血管疾病、代谢功能障碍、肌肉疾病、神经系统疾病或损伤、或DNA损伤病症或原发性线粒体病症。在一些实施方案中提供了治疗有需要的受试者的由NAMPT活性介导的疾病或疾患的方法,其包括向有需要的个体或受试者施用式(II)、(I)、(I-A)、(I-A1)、(I-A2)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-J)或(I-K)的化合物或表1的化合物或其药学上可接受的盐。在一些实施方案中,所述疾病或疾患是癌症或化学疗法诱导的组织损伤、心血管疾病、肾脏疾病、慢性炎性或纤维化疾病、血管疾病、代谢功能障碍、肌肉疾病、神经系统疾病或损伤、DNA损伤病症或原发性线粒体病症,包括表2中列出的疾病中的任一种。
剂量
本文公开和/或描述的化合物和组合物以治疗有效剂量(例如,足以为疾病状态提供治疗的剂量)施用。虽然人剂量水平尚未针对本文所述的化学实体进行优化,但日剂量范围通常为约0.01至100mg/kg体重;在一些实施方案中,约0.05至10.0mg/kg体重,并且在一些实施方案中,约0.10至1.4mg/kg体重。因此,对于向70kg的人施用,在一些实施方案中,剂量范围将为每天约0.7至7000mg;在一些实施方案中,每天约3.5至700.0mg,并且在一些实施方案中,每天约7至100.0mg。施用的化学实体的量将取决于例如治疗的受试者和疾病状态、病痛的严重程度、施用的方式和时间表以及处方医生的判断。例如,用于口服施用的示例性剂量范围为每天约5mg至约500mg,并且示例性静脉内施用剂量为每天约5mg至约500mg,各自取决于化合物的药代动力学。
日剂量是一天中施用的总量。日剂量可以但不限于每天、每隔一天、每周、每2周、每月或以不同的间隔施用。在一些实施方案中,施用日剂量的时间段的范围为一天至受试者的一生。在一些实施方案中,日剂量每天施用一次。在一些实施方案中,日剂量以多个分开的剂量施用,诸如以2个、3个或4个分开的剂量。在一些实施方案中,日剂量以2个分开的剂量施用。
本文公开和/或描述的化合物和组合物的施用可以经由任何可接受的治疗剂施用模式,包括但不限于口服、舌下、皮下、胃肠外、静脉内、鼻内、局部、透皮、腹膜内、肌内、肺内、阴道、直肠或眼内施用。在一些实施方案中,化合物或组合物是口服或静脉内施用的。在一些实施方案中,本文公开和/或描述的化合物或组合物是口服施用的。
药学上可接受的组合物包括固体、半固体、液体和气雾剂剂型,诸如片剂、胶囊、粉剂、液体、悬浮液、栓剂和气雾剂形式。本文公开和/或描述的化合物还可以以缓释或控释剂型(例如,控释/缓释丸剂、长效仓库注射剂、渗透泵或透皮(包括电转运)贴剂形式)长期施用和/或以预定速率脉冲式施用。在一些实施方案中,组合物以适合单次施用精确剂量的单位剂型提供。
本文公开和/或描述的化合物可以单独施用或与一种或多种常规药用载体或赋形剂(例如,甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、交联羧甲基纤维素钠、葡萄糖、明胶、蔗糖、碳酸镁)组合施用。如果期望,药物组合物还可以含有少量无毒辅助物质,诸如润湿剂、乳化剂、增溶剂、pH缓冲剂等(例如,乙酸钠、柠檬酸钠、环糊精衍生物、山梨醇单月桂酸酯、乙酸三乙醇胺、油酸三乙醇胺)。一般来讲,取决于预期的施用模式,药物组合物将含有按重量计约0.005%至95%、或约0.5%至50%的本文公开和/或描述的化合物。制备此类剂型的实际方法是本领域技术人员已知的或将对他们显而易见;例如参见Remington's Pharmaceutical Sciences,Mack Publishing Company,Easton,Pennsylvania。
在一些实施方案中,组合物将采取丸剂或片剂的形式,并且因此组合物可以与本文公开和/或描述的化合物一起含有一种或多种稀释剂(例如,乳糖、蔗糖、磷酸二钙)、润滑剂(例如,硬脂酸镁)和/或粘合剂(例如,淀粉、阿拉伯树胶、聚乙烯吡咯烷、明胶、纤维素、纤维素衍生物)。其他固体剂型包括封装在明胶胶囊中的粉末、丸粒(marume)、溶液或悬浮液(例如,碳酸亚丙酯、植物油或甘油三酯中的)。
液体可药用组合物可以例如通过以下方式制备:将本文公开和/或描述的化合物和任选的药物添加剂溶解、分散或悬浮等在载体(例如,水、盐水、葡萄糖水溶液、甘油、乙二醇、乙醇等)中以形成溶液或悬浮液。可以将注射剂制备成常规形式,或者作为液体溶液或悬浮液、作为乳液,或者制备成适合在注射前溶解或悬浮在液体中的固体形式。包含在此类胃肠外组合物中的化合物的百分比取决于例如化合物的物理性质、化合物的活性和受试者的需要。然而,在溶液中0.01%至10%的活性成分的百分比是可以采用的,并且如果组合物是随后将被稀释至另一浓度的固体,则可以更高。在一些实施方案中,组合物将包含溶液中约0.2%至2%的本文公开和/或描述的化合物。
本文公开和/或描述的化合物的药物组合物还可以作为用于喷雾器的气雾剂或溶液或作为用于吹入的微细粉末,单独或与惰性载体(诸如乳糖)组合向呼吸道施用。在这种情况下,药物组合物的颗粒可以具有小于50微米的直径,或者在一些实施方案中,小于10微米。
此外,药物组合物可以包括本文公开和/或描述的化合物和一种或多种另外的要用剂、药剂、佐剂等。合适的药物和药剂包括本文所述的那些。
试剂盒
还提供了含有本文提供的化合物或药物组合物中的任一种的制品和试剂盒。制品可以包括带有标签的容器。合适的容器包括例如瓶、小瓶、注射器和试管。容器可以由多种材料(诸如玻璃或塑料)形成。容器可以容纳本文提供的药物组合物。容器上的标签可以指示药物组合物用于预防、治疗或抑制本文所述的疾患,并且还可以指示体内或体外使用的说明。
在一个方面,本文提供了含有本文所述的化合物或组合物和使用说明书的试剂盒。试剂盒可以含有用于治疗有需要的个体或受试者的心脏疾病的说明书。试剂盒可以另外含有可以用于施用化合物或组合物的任何材料或设备,诸如小瓶、注射器或IV袋。试剂盒还可以含有无菌包装。
组合
本文描述和/或公开的化合物和组合物可以单独施用或与可用于治疗上文提及的病症、疾病或疾患的其他疗法和/或治疗剂组合施用。
列举的实施方案
以下列举的实施方案代表本发明的一些方面。
1.一种式(I)的化合物:
或其药学上可接受的盐,
其中:
或者
其中
R2a和R2b各自独立地为卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d或-N(R2e)C(O)(C1-C6烷基);并且
R2c、R2d和R2e各自独立地为氢或C1-C6烷基;
G1为CH或N;
p1和p2各自独立地为0、1或2;
q1和q2各自独立地为1或2;
r为1、2或3;
n为0至6;
R3选自由以下组成的组:
i.C1-C6烷基;
ii.C6-C14芳基;
iii.任选取代的5元至18元杂芳基;
iv.-NR3aR3b,其中
R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基);
v.-OR3c,其中
R3c为C6-C14芳基;
vi.-C(O)R3d,其中
R3d选自由以下组成的组:-NR3fR3g;C3-C8环烷基;被任选取代的C6-C14芳基取代的C3-C8环烷基;C3-C8环烯基;任选取代的C6-C14芳基;任选取代的–(C1-C6亚烷基)-(C6-C14芳基);任选取代的3元至18元杂环烷基;和任选取代的5元至18元杂芳基,
其中
R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选取代的C1-C6烷基,
(c)C6-C14芳基,
(d)任选取代的3元至18元杂环烷基,
(e)任选取代的5元至18元杂芳基,
(f)任选取代的C3-C10环烷基;和
(g)任选取代的C3-C10环烯基;
vii.被C(O)NR3hR3i、任选取代的3元至18元杂环烷基或任选取代的5元至18元杂芳基取代的C1-C6烷基,
其中R3h和R3i各自独立地选自C1-C6烷基和-(C1-C6亚烷基)-(C6-C14芳基);
viii.-C(O)OR3j,其中
R3j为氢或C1-C6烷基;
ix.-NHC(O)R3k,其中
R3k为任选取代的C6-C14芳基、任选取代的–(C1-C6亚烷基)-(C6-C14芳基)、或任选取代的5元至18元杂芳基;
x.-NHC(O)OR3l,其中
R3l为氢或C1-C6烷基;
xi.-NHSO2R3m,其中
R3m为任选取代的5元至18元杂芳基、任选取代的C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中每一种都是任选取代的;和
xii.-SO2R3n;其中
R3n为任选取代的C3-C10环烷基、任选取代的C6-C14芳基、或任选取代的–(C1-C6亚烷基)-(C6-C14芳基);
R4为苯基或-C(O)NH-CH2-苯基;
R5a和R5b独立地选自由以下组成的组:氢、甲基、和-NHC(O)O(C1-C6烷基);并且
R6选自由-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)和-C(O)-苯基组成的组;并且
其中
3.如实施方案1或实施方案2所述的化合物或其药学上可接受的盐,其中p1为1并且q1为1。
4.如实施方案1或实施方案2所述的化合物或其药学上可接受的盐,其中p1为2并且q1为1。
5.如实施方案1或实施方案2所述的化合物或其药学上可接受的盐,其中p1为2并且q1为2。
6.如实施方案1-5中任一项所述的化合物或其药学上可接受的盐,其中p2为1并且q2为1。
7.如实施方案1-5中任一项所述的化合物或其药学上可接受的盐,其中p2为0并且q2为1。
8.如实施方案1-5中任一项所述的化合物或其药学上可接受的盐,其中p2为1并且q2为2。
9.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为C1-C6烷基。
10.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为C6-C14芳基。
11.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为任选被C1-C6烷基取代的5元至18元杂芳基。
12.如实施方案11所述的化合物或其药学上可接受的盐,其中R3为任选被C1-C6烷基取代的吡啶基或嘧啶基。
14.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-NR3aR3b,其中R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基)。
16.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为OR3c,其中R3c为C6-C14芳基。
17.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-C(O)R3d。
18.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为-NR3fR3g,并且R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选被选自由-OH、C6-C14芳基和5元至18元杂芳基组成的组的一个或多个取代基取代的C1-C6烷基,其中C6-C14芳基和5元至18元杂芳基各自独立地为未取代的或被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基和CN。
(c)C6-C14芳基,
(d)3元至18元杂环烷基,
(e)任选被甲基或CN取代的5元至18元杂芳基,
(f)任选被选自由以下组成的组的一个或多个取代基取代的C3-C10环烷基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基;和
(g)任选被选自由以下组成的组的一个或多个取代基取代的C3-C10环烯基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基。
20.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为C3-C8环烷基。
21.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为被C6-C14芳基取代的C3-C8环烷基,其中C6-C14芳基任选被选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、C1-C6卤代烷基和C1-C6烷氧基。
23.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为C3-C8环烯基。
24.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为任选被选自由以下组成的组的一个或多个取代基取代的C6-C14芳基:羟基、卤基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-(C1-C6亚烷基)-OH、-C(O)O(C1-C6烷基)、-NR3e1R3e2、-S(O)2(C1-C6烷基)、5元至18元杂芳基和任选被氧代基取代的3元至18元杂环烷基,其中R3e1和R3e2各自独立地为H或C1-C6烷基。
26.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为任选被选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14芳基):卤基、C1-C6烷基、C1-C6卤代烷基、和C1-C6烷氧基。
28.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为任选被选自由以下组成的组的一个或多个取代基取代的3元至18元杂环烷基
(a)任选被选自由以下组成的组的一个或多个取代基取代的C1-C6烷基:羟基、卤基、C3-C10环烷基和任选被一个或多个C1-C6烷基取代基取代的5元至18元杂芳基,
(b)C6-C14芳基,
(c)3元至18元杂环烷基,
(d)-C(O)O(C1-C6烷基),
(e)-C(O)(C6-C14烷基),
(f)卤基,和
(g)任选被一个或多个卤基取代基取代的C1-C6烷氧基。
30.如实施方案17所述的化合物或其药学上可接受的盐,其中R3d为任选被选自由以下组成的组的一个或多个取代基取代的5元至18元杂芳基:C1-C6烷基、羟基、氧代基和3元至18元杂环烷基。
32.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被C(O)NR3hR3i取代的C1-C6烷基,其中R3h和R3i各自独立地选自C1-C6烷基和–(C1-C6亚烷基)-(C6-C14芳基)。
34.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被3元至18元杂环烷基取代的C1-C6烷基,其中3元至18元杂环烷基任选被选自卤基和C6-C14芳基的一个或多个取代基取代。
36.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被5元至18元杂芳基取代的C1-C6烷基。
38.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-C(O)OR3j,其中R3j为氢或C1-C6烷基。
40.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-NHC(O)R3k。
41.如实施方案40所述的化合物或其药学上可接受的盐,其中R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的C6-C14芳基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基、和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。
43.如实施方案40所述的化合物或其药学上可接受的盐,其中R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14芳基):C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基、和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。
45.如实施方案40所述的化合物或其药学上可接受的盐,其中R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的5元至18元杂芳基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基、和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。
47.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-NHC(O)OR3l,其中R3l为氢或C1-C6烷基。
49.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-NHSO2R3m,其中R3m为5元至18元杂芳基、C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中5元至18元杂芳基、C6-C14芳基和–(C1-C6亚烷基)-(C6-C14芳基)各自任选被选自卤基和C1-C6烷氧基的一个或多个取代基取代。
51.如实施方案1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-SO2R3n并且R3n为C3-C10环烷基、C6-C14芳基或–(C1-C6亚烷基)-(C6-C14芳基),其中C3-C10环烷基、C6-C14芳基和–(C1-C6亚烷基)-(C6-C14芳基)各自任选被选自卤基和-C(O)O(C1-C6烷基)的一个或多个取代基取代。
53.如实施方案1-52中任一项所述的化合物或其药学上可接受的盐,其中G1为CH。
54.如实施方案1-52中任一项所述的化合物或其药学上可接受的盐,其中G1为N。
57.如实施方案56所述的化合物或其药学上可接受的盐,其中r为1。
58.如实施方案56所述的化合物或其药学上可接受的盐,其中r为2。
60.如实施方案59所述的化合物或其药学上可接受的盐,其中R4为苯基。
61.如实施方案59所述的化合物或其药学上可接受的盐,其中R4为-C(O)NH-CH2-苯基。
63.如实施方案62所述的化合物,或其药学上可接受的盐,其中R5a选自由以下组成的组:氢、甲基和-NHC(O)O(C1-C6烷基)。
64.如实施方案62或实施方案63所述的化合物,或其药学上可接受的盐,其中R5b选自由以下组成的组:氢、甲基和-NHC(O)O(C1-C6烷基)。
66.如实施方案65所述的化合物或其药学上可接受的盐,其中R6选自由-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)和-C(O)-苯基组成的组。
67.如实施方案1-54、56和58-66中任一项所述的化合物或其药学上可接受的盐,n为0。
68.如实施方案1-54、56和58-66中任一项所述的化合物或其药学上可接受的盐,其中n为1。
69.如实施方案1-54和58-66中任一项所述的化合物或其药学上可接受的盐,其中n为2。
70.如实施方案1-54和56-66中任一项所述的化合物或其药学上可接受的盐,其中n为3。
71.如实施方案1-66中任一项所述的化合物或其药学上可接受的盐,其中n为4。
72.如实施方案1-66中任一项所述的化合物或其药学上可接受的盐,其中n为5。
73.如实施方案1-66中任一项所述的化合物或其药学上可接受的盐,其中n为6。
76.如实施方案1-58和67-73中任一项所述的化合物或其药学上可接受的盐,其中R1为并且R2a选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基),其中R2c、R2d和R2e各自独立地为氢或C1-C6烷基。
78.如实施方案1-73中任一项所述的化合物或其药学上可接受的盐,其中R1为并且R2b选自由以下组成的组:卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d和-N(R2e)C(O)(C1-C6烷基),其中R2c、R2d和R2e各自独立地为氢或C1-C6烷基。
81.一种化合物,其选自由表1的化合物或其药学上可接受的盐组成的组。
82.一种药物组合物,其包含根据实施方案1-81中任一项所述的化合物或其药学上可接受的盐和药学上可接受的赋形剂。
83.一种治疗有需要的受试者的由NAMPT活性介导的疾病或疾患的方法,其包括向受试者施用如实施方案1-81中任一项所述的化合物或其药学上可接受的盐、或如实施方案82所述的药物组合物。
84.如实施方案83所述的方法,其中疾病或疾患选自由以下组成的组:癌症、过度增殖性疾病或疾患、炎性疾病或疾患、代谢障碍、心脏疾病或疾患、化疗诱导的组织损伤、肾脏疾病、代谢疾病、神经系统疾病或损伤、神经退行性病症或疾病、干细胞功能受损引起的疾病、DNA损伤引起的疾病、原发性线粒体病症、或肌肉疾病或肌肉萎缩症。
85.如实施方案83所述的方法,其中疾病或疾患选自由以下组成的组:肥胖症、动脉粥样硬化、胰岛素抵抗、2型糖尿病、心血管疾病、阿尔茨海默病、亨廷顿病、帕金森病、肌萎缩侧索硬化症、抑郁症、唐氏综合症、新生儿神经损伤、衰老、轴索变性、腕管综合征、格林-巴利综合征、神经损伤、脊髓灰质炎和脊髓损伤。
一般合成方法
式(II)或式(I)的化合物、或其任何变型或实施方案、或前述项中的任一种的盐,现在将通过参考下文的用于其一般性制备的例示性合成方案和以下具体实例来描述。技术人员将认识到,为了获得本文中的各种化合物,可以适当地选择原料,使得最终期望的取代基将在有或没有适当保护的情况下通过反应方案来携带以产生期望的产物。或者,可能有必要或期望采用可以通过反应方案来携带并且适当地被期望的取代基替换的合适的基团来代替最终期望的取代基。此外,本领域技术人员将认识到,保护基可以用于保护某些官能团(氨基、羧基或侧链基团)免受反应条件的影响,并且在适当时在标准条件下将此类基团去除。除非另有说明,否则变量如上文参考式(II)或式(I)所定义。
在期望获得化合物的特定对映异构体的情况下,这可以使用任何合适的用于分离或拆分对映异构体的常规程序从对应的对映异构体混合物中完成。因此,例如,非对映异构体衍生物可以通过对映异构体(例如,外消旋体和适当手性化合物)的混合物的反应来产生。然后可以通过任何方便的方式分离非对映异构体,例如通过结晶和回收期望的对映异构体。在另一个拆分过程中,可以使用手性高效液相色谱法来分离外消旋体。或者,如果期望,可以通过在所述过程之一中使用合适的手性中间体来获得特定的对映异构体。
色谱法、重结晶和其他常规分离程序也可以用于中间体或最终产物,其中期望获得化合物的特定异构体或期望以其他方式纯化反应产物。
在下文的实施例部分中提供了特定的非限制性实例。
实施例
提供以下实例以说明但不限制本文提供的组合物、用途和方法。使用上述一般方法制备化合物。
在整个实施例中使用以下缩写:TEA(三乙胺)、DCM(二氯甲烷)、(Boc)2O(二碳酸二叔丁酯)、EA(乙酸乙酯)、PE(石油醚)、DMF(N,N-二甲基甲酰胺)、DIEA(N-乙基-N-异丙基丙-2-胺)、HATU(1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化六氟磷酸酯)、HOAt(1-羟基-7-氮杂苯并三唑)、HOBt(羟基苯并三唑)、EDCI(1-乙基-3-(3-二甲氨基丙基)碳二亚胺)、MeOH(甲醇)、EtOH(乙醇)、iPrOH(丙-2-醇)、ACN(乙腈)、TFA(三氟乙酸)、DPPA(叠氮磷酸二苯酯)、DBU(1,8-二氮杂双环(5.4.0)十一-7-烯)、THF(四氢呋喃)、PPh3(三苯基膦)、SM(原料)、Hex(己烷)、NCS(N-氯代琥珀酰亚胺)、r.t.(室温)、DCE(二氯乙烷)、FA(甲酸)、CHCl3(氯仿)、BnBr(苄基溴)、HCl(氯化氢)、equiv(当量)、和DSC(双(2,5-二氧代吡咯烷-1-基)碳酸酯)、HBTU(O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯)。
实施例A
化合物168、化合物201和中间体1.15的合成
6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-甲酸甲酯(化合物168)的制备。在室温下,将1-氯-4-(异氰酸甲基)苯(6.8g,40.8mmol,1当量)添加到6-氨基螺[3.3]庚烷-2-甲酸甲酯(8.4g,40.8mmol,1当量)在CH2Cl2(100mL)中的搅拌溶液中。12小时后,通过旋转蒸发去除溶剂,将粗制的物质在EtOH(100mL)中研磨10分钟,过滤,用EtOH(2x25mL)洗涤,并且在高真空下干燥,得到为白色固体的化合物168(12g,87%)。LRMS(APCI)m/z 337.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.31(d,J=8.6Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2H),4.02(p,J=8.0Hz,1H),3.66(s,3H),3.37(s,3H),3.06(p,J=8.6Hz,1H),2.49(ddd,J=11.8,7.4,5.2Hz,1H),2.33(tq,J=8.5,3.2,2.5Hz,3H),2.28–2.07(m,2H),1.87(ddd,J=25.8,11.2,8.6Hz,2H).
6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-羧酸甲酯的手性分离。将五克的6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-甲酸甲酯通过手性SFC(Chiralpak AD-H,30%共溶剂(含有0.25%异丙胺的EtOH),速率为70克/分钟)进行拆分,得到为白色固体的两种手性片段:化合物201(2.4g,48%)和中间体1.15(2.4g,48%)。未确认每种片段的绝对立体化学。首先使用规定的条件将化合物201从SFC中洗脱,然后是中间体1.15。
化合物201:LRMS(APCI)m/z 337.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.32(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2H),4.02(p,J=8.0Hz,1H),3.66(s,3H),3.06(p,J=8.5Hz,1H),2.49(ddd,J=11.7,7.3,5.5Hz,1H),2.39–2.28(m,3H),2.28–2.10(m,2H),1.87(ddd,J=25.9,11.1,8.7Hz,2H).
中间体1.15:LRMS(APCI)m/z 337.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.32(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2H),4.02(p,J=8.0Hz,1H),3.66(s,3H),3.06(p,J=8.5Hz,1H),2.49(ddd,J=11.6,7.2,5.3Hz,1H),2.39–2.28(m,3H),2.28–2.11(m,2H),1.87(ddd,J=25.8,11.0,8.7Hz,2H).
化合物35、8、197、37、151、152、83、81、82和36以及中间体1.3和1.7以与化合物168类似的方式制备,使用下表中提供的试剂代替6-氨基螺[3.3]庚烷-2-甲酸甲酯和1-氯-4-(异氰酸甲基)苯。
实施例B
中间体2.1、2.4和2.5的合成
6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-羧酸(中间体2.1)的制备。将LiOH(622mg,25.98mmol,1.25当量)和6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-甲酸甲酯(化合物168)(7g,20.78mmol,1当量)悬浮在MeOH/H2O(50mL/5mL)中并加热至60℃。1小时后,将反应冷却至室温,并且通过旋转蒸发去除溶剂。将粗制的物质溶解在H2O/MeOH(90mL/10mL)中,然后用3M HCl沉淀,过滤,用水(3x20mL)洗涤,并在高真空下干燥,得到为白色固体的期望产物2.1(5.2g,78%)。LRMS(APCI)m/z 323.0(M+H).1H NMR(400MHz,甲醇-d4)δ7.31(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2H),4.02(p,J=8.1Hz,1H),3.02(p,J=8.4Hz,1H),2.56–2.43(m,1H),2.33(td,J=9.8,8.4,6.0Hz,3H),2.29–2.11(m,2H),1.87(ddd,J=24.6,11.0,8.7Hz,2H).
6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-羧酸的手性分离。将五克的6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-羧酸通过手性SFC(Chiralpak AD-H,30%共溶剂(含有0.25%异丙胺的EtOH),速率为70克/分钟)进行拆分,得到为白色固体的两种手性片段:2.4(2.3g,46%)和2.5(2.1g,42%)。未确认每种片段的绝对立体化学。首先使用规定的条件将中间体2.4从SFC中洗脱,然后是中间体2.5。
中间体2.4:LRMS(APCI)m/z 323.1(M+H).1H NMR(400MHz,DMSO-d6)δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),6.40(t,J=6.1Hz,1H),6.29(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.89(h,J=8.1Hz,1H),3.09(p,J=6.4Hz,1H),2.75(p,J=8.5Hz,1H),2.31(ddd,J=10.7,7.3,5.2Hz,1H),2.20–2.01(m,4H),2.01–1.90(m,1H),1.82–1.63(m,2H),1.06(d,J=6.3Hz,5H).(发现复合异丙醇)
中间体2.5:LRMS(APCI)m/z 323.1(M+H).1H NMR(400MHz,DMSO-d6)δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.2Hz,2H),6.36(t,J=6.1Hz,1H),6.25(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.89(h,J=8.0Hz,1H),3.07(p,J=6.4Hz,1H),2.78(p,J=8.5Hz,1H),2.36–2.25(m,1H),2.11(tdd,J=19.6,9.3,6.7Hz,4H),1.97(ddd,J=11.2,8.6,2.4Hz,1H),1.74(ddd,J=29.1,10.8,8.7Hz,2H),1.04(d,J=6.3Hz,5H).
中间体2.2和2.3以与中间体2.1类似的方式制备,使用下表中提供的试剂代替6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-甲酸甲酯(化合物168)。
实施例C
中间体3.1的合成
1-(4-氯苄基)-3-(2-氮杂螺[3.3]庚-6-基)脲的制备(中间体3.1)。在室温下,将TFA(100mL)添加到6-(3-(4-氯苄基)脲基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯(中间体1.5)(17.8g,46.9mmol,1当量)在CH2Cl2(200mL)中的搅拌溶液中。1小时后,通过旋转蒸发去除溶剂,将粗制的油状物与甲苯(3x100mL)共沸,并且在高真空下干燥。将粗制的油状物悬浮在MeOH(250mL)中,添加IONACNa-38OH-树脂(50g),并将反应温和搅拌1小时。然后通过硅藻土垫过滤反应,并且通过旋转蒸发去除溶剂,得到为白色固体的产物(12.5g,95%)。LRMS(APCI)m/z 280.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.32(d,J=8.4Hz,2H),7.26(d,J=8.5Hz,2H),4.75(s,1H),4.64(s,1H),4.29(d,J=4.3Hz,2H),4.14(s,1H),4.03(d,J=4.8Hz,2H),2.68(dddd,J=17.8,10.3,7.7,3.0Hz,2H),2.32–2.24(m,2H),2.22–2.13(m,1H).
中间体3.2、3.3、3.4、3.5和3.6以与中间体3.1类似的方式制备,使用下表中提供的试剂代替6-(3-(4-氯苄基)脲基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯(化合物197)。
实施例D
中间体4.1的合成(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)甲磺酸甲酯(中间体4.1)的制备
步骤1:3-[6-(羟甲基)螺[3.3]庚-2-基]-1-[(4-甲氧基苯基)甲基]脲的制备。在0℃下,向6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-羧酸(2.0g,6.28mmol,1.0当量)在DCM(20mL)中的溶液中添加三乙胺(2当量),然后滴加氯甲酸异丁酯。将溶液在室温搅拌并通过LCMS监测。1小时后,将溶液冷却至0℃,并且过滤沉淀物并用DCM冲洗。将粗制的(碳酸异丁酯)6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-羧酸酐直接用于下一步(99%产率)。
将上文的粗制的酸酐溶解在THF(20mL)中,并且在室温下分批添加硼氢化钠(0.475g,12.6mmol,2.0当量)。通过LCMS分析监测溶液。将溶液冷却至0℃,并且添加饱和碳酸钠水溶液(20mL),并将溶液剧烈搅拌10分钟。分离有机层,并且用30mL DCM萃取水层。将组合的有机层用盐水洗涤,干燥,过滤并浓缩,得到为白色泡沫状物的产物(1.82g,92%产率)。LCMS-APCI(POS.)m/z:315.0(M+H)+.1H NMR(400MHz,DMSO-d6)δ7.15(dd,J=8.5,1.7Hz,2H),6.87(dt,J=8.6,2.3Hz,2H),6.18–5.95(m,2H),4.40(td,J=5.4,1.3Hz,1H),4.09(d,J=5.9Hz,2H),3.91(q,J=8.1Hz,1H),3.82(td,J=9.3,7.3,2.9Hz,1H),3.31(t,J=5.8Hz,3H),2.83(q,J=6.9,4.7Hz,1H),2.79–2.71(m,1H),2.24–2.08(m,2H),2.02(t,J=9.1Hz,1H),1.87(t,J=9.9Hz,1H),1.81–1.57(m,4H).
步骤2:(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)甲磺酸甲酯的制备。将NEt3(2.0当量)添加到3-[6-(羟甲基)螺[3.3]庚-2-基]-1-[(4-甲氧基苯基)甲基]脲(1.8g,5.71mmol,1.0当量)在CH2Cl2(0.33M)中的溶液中。将反应冷却至0℃,并且滴加甲磺酰氯(0.72g,0.31mmol,1.1当量)并搅拌30分钟。将溶液冷却至0℃,并且添加饱和氯化铵水溶液,并且将溶液剧烈搅拌10分钟。分离有机层,并且用10mL DCM萃取水层。将组合的有机层用盐水洗涤,干燥,过滤并浓缩,得到为白色泡沫状物的产物(1.96g,84%产率)。LCMS-APCI(POS.)m/z:384.0(M+H).1H NMR(400MHz,DMSO-d6)δ7.21(dd,J=8.2,1.6Hz,2H),6.94(dt,J=8.2,1.6Hz,2H),6.24–6.00(m,2H),5.44(td,J=5.4Hz,1.3Hz,2H),4.59(td,J=5.2,1.3Hz,1H),3.91(q,J=8.1Hz,1H),3.31(t,J=5.8Hz,3H),2.83(q,J=6.9,4.7Hz,1H),2.65(s,3H),2.79–2.71(m,1H),2.24–2.08(m,2H),2.02(t,J=9.1Hz,1H),1.87(t,J=9.9Hz,1H),1.81–1.57(m,4H).
实施例E
中间体5.1的合成
N-(6-氨基螺[3.3]庚-2-基)苯甲酰胺盐酸盐(中间体5.1)的制备
步骤1:(6-苯甲酰胺螺[3.3]庚-2-基)氨基甲酸叔丁酯的制备。在0℃下,将NEt3(670mg,6.628mmol,3当量)和苯甲酰氯(341.61mg,2.430mmol,1.1当量)添加到N-(6-氨基螺[3.3]庚-2-基)氨基甲酸叔丁酯(500.00mg,2.209mmol,1.0当量)在CH2Cl2(5mL)中的搅拌溶液中,然后允许反应回到室温。2小时后,然后用H2O(20mL)淬灭反应,用CH2Cl2(2x20mL)萃取。将有机物组合,用饱和氯化钠(20mL)洗涤,在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂,得到粗制的产物(850mg),其不经过进一步纯化用于下一步。LRMS(APCI)m/z 275(M+H-56).
步骤2:N-(6-氨基螺[3.3]庚-2-基)苯甲酰胺盐酸盐的制备。在室温下,将HCl(二噁烷中的2.5mL,4M)添加到N-[6-苯甲酰胺螺[3.3]庚-2-基]氨基甲酸叔丁酯(830mg,2.5mmol,1.0当量)在CH2Cl2(10mL)中的搅拌溶液中。1小时后,通过旋转蒸发浓缩反应,得到为白色固体的粗制的产物(620mg),其不经过进一步纯化使用。LRMS(APCI)m/z 231(M+H).
实施例F
中间体6.1的合成
N2-(吡啶-2-基)螺[3.3]庚烷-2,6-二胺盐酸盐(中间体6.1)的制备
步骤1:(6-(吡啶-2-基氨基)螺[3.3]庚-2-基)氨基甲酸叔丁酯的制备。在室温下,将2-氨基吡啶(200mg,2.1mmol,2.0当量)和TFA(243mg,2.1mmol,2当量)添加到N-[6-氧代螺[3.3]庚-2-基]氨基甲酸叔丁酯(240mg,1.1mmol,1.0当量)在DCE(10mL)中的搅拌溶液中。30分钟后,添加NaHB(OAc)3(677mg,3.2mmol,3.0当量),并且将反应搅拌12小时。用H2O(20mL)淬灭反应,用CH2Cl2(2x20mL)萃取。将有机物组合,用饱和氯化钠(20mL)洗涤,在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂,得到为黄色固体的粗制的产物(380mg),其不经过进一步纯化用于下一步。LRMS(APCI)m/z 248(M+H-56).
步骤2:N2-(吡啶-2-基)螺[3.3]庚烷-2,6-二胺盐酸盐的制备。在室温下,将HCl(二噁烷中的2.5mL,4M)添加到N-[6-(吡啶-2-基氨基)螺[3.3]庚-2-基]氨基甲酸叔丁酯(360mg,1.187mmol,1.0当量)在CH2Cl2(5mL)中的搅拌溶液中。2小时后,通过旋转蒸发浓缩反应,得到为白色固体的粗制的产物(280mg),其不经过进一步纯化使用。LRMS(APCI)m/z204(M+H).
实施例G
中间体7.1的合成((1r,3r)-3-(苄基氨基甲酰基)环丁基)氨基甲酸叔丁酯(中间体7.1)的制备
步骤1:((1r,3r)-3-(苄基氨基甲酰基)环丁基)氨基甲酸叔丁酯的制备。在室温下,将EDCI(670mg,3.49mmol,1.5当量)添加到(1r,3r)-3-[(叔丁氧基羰基)氨基]环丁烷-1-羧酸(500.00mg,2.323mmol,1.00当量)在吡啶(5mL)中的搅拌溶液中。5分钟后,添加苄胺(298.50mg,2.786mmol,1.20当量),并且在室温下将反应搅拌1小时。然后用H2O(20mL)淬灭反应,用EtOAc(2x20mL)萃取。然后用H2O(20mL)淬灭反应,并且用EtOAc(2x20mL)萃取。将有机层组合,用饱和氯化钠(20mL)洗涤,在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂,得到粗制的产物(640mg),其不经过进一步纯化用于下一步。LRMS(APCI)m/z 249(M+H-56).
步骤2:(1r,3r)-3-氨基-N-苄基环丁烷-1-甲酰胺盐酸盐的制备。在室温下,将HCl(二噁烷中的2mL,4M)添加到N-[(1r,3r)-3-(苄基氨基甲酰基)环丁基]氨基甲酸叔丁酯(827mg,1.00当量)在CH2Cl2(10mL)中的搅拌溶液中。1小时后,通过旋转蒸发浓缩反应,得到为棕色固体的粗制的产物(640mg),其不经过进一步纯化用于下一步。LRMS(APCI)m/z 241(M+H).
实施例H
中间体8.1的合成(6-氨基-2-氮杂螺[3.3]庚-2-基)(对甲苯基)甲酮(中间体8.1)的制备
步骤1:(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)氨基甲酸叔丁酯的制备。在室温下,将HATU(6.88g,18.1mmol,1.5当量)添加到(2-氮杂螺[3.3]庚-6-基)氨基甲酸叔丁酯盐酸盐(3g,12.1mmol,1当量)、4-甲基苯甲酸(2.46g,18.1mmol,1.5当量)和NEt3(4.9mL,36.2mmol,3当量)在DMF(100mL)中的搅拌溶液中。12小时后,将反应倒入EtOAc(500mL)中,用饱和碳酸氢钠(3x250mL)、盐水(2x250mL)洗涤,在硫酸钠上干燥,通过硅胶垫过滤,并通过旋转蒸发去除溶剂,得到为白色固体的粗制的产物(3.6g)。
步骤2:(6-氨基-2-氮杂螺[3.3]庚-2-基)(对甲苯基)甲酮。在室温下,将TFA(25mL)添加到(2-(4-甲基苯甲酰基)-2-氮杂螺[3.3]庚-6-基)氨基甲酸叔丁酯(1g,3.03mmol,1当量)在CH2Cl2(50mL)中的搅拌溶液中。1小时后,通过旋转蒸发去除溶剂,与甲苯(3x50mL)共沸,并且在高真空下干燥,得到为黄色油状物的粗制的产物,其不经过进一步纯化用于下一步。LRMS(APCI)m/z 231.1(M+H).
实施例I
化合物198和中间体9.2的合成
(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(化合物8)的手性拆分。将外消旋(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(25g)化合物8通过手性SFC(Chiralpak AD-H,20%共溶剂(含有0.25%异丙胺的EtOH),速率为80克/分钟)进行拆分,得到为白色固体的两种手性片段:化合物198(9.4g,38%)和中间体9.2(12g,48%)。未确认每种片段的绝对立体化学。首先使用规定的条件将化合物198从SFC中洗脱,然后是中间体9.2。未确定绝对立体化学。首先使用规定的条件将化合物8从SFC中洗脱,然后是中间体9.2。
化合物198:LRMS(APCI)m/z 294.1(M+H-Boc).1H NMR(400MHz,DMSO-d6)δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.04(d,J=8.0Hz,1H),6.25(t,J=6.1Hz,1H),6.17(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.92(h,J=8.2Hz,1H),3.79(q,J=8.3Hz,1H),2.27(dp,J=18.8,6.3Hz,2H),2.19–2.00(m,2H),1.93–1.69(m,4H),1.36(s,9H).
中间体9.2LRMS(APCI)m/z 294.1(M+H-Boc).1H NMR(400MHz,DMSO-d6)δ7.36(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.04(d,J=7.8Hz,1H),6.25(t,J=6.1Hz,1H),6.17(d,J=8.1Hz,1H),4.15(d,J=6.0Hz,2H),3.92(h,J=7.9Hz,1H),3.79(q,J=8.2Hz,1H),2.27(dp,J=18.9,7.5,6.2Hz,2H),2.09(tq,J=13.3,6.1Hz,2H),1.93–1.68(m,4H),1.36(s,9H).
实施例J
中间体10.1的合成
1-(6-(羟甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲(中间体10.1)的制备。在室温下,将二异丁基氢化铝(甲苯中的25%,10.1g,17.8mmol,3当量)添加到6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-甲酸甲酯(2.0g,17.8mmol,1当量)在THF(100mL)中的搅拌溶液中。2小时后,通过添加MeOH(50mL)和二氧化硅淬灭反应,然后通过旋转蒸发去除溶剂。通过二氧化硅色谱法(0->10% MeOH/CH2Cl2)纯化为白色固体(1.5g,81%)。LRMS(APCI)m/z309.1(M+H).1H NMR(400MHz,DMSO-d6)δ7.14(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H),6.09(t,J=5.9Hz,1H),6.06(d,J=8.1Hz,1H),4.40(t,J=5.2Hz,1H),4.09(d,J=5.9Hz,2H),3.91(h,J=8.2Hz,1H),3.30(dd,J=6.5,5.3Hz,2H),2.29(ddd,J=10.6,7.4,5.3Hz,1H),2.21(dt,J=16.6,8.2Hz,1H),2.16–2.08(m,1H),2.01(td,J=9.6,8.3,3.0Hz,1H),1.87(ddd,J=11.2,8.2,3.0Hz,1H),1.79–1.60(m,4H).
中间体10.2以与中间体10.1类似的方式制备,使用下表中提供的试剂。
实施例K
中间体11.1的合成
1-(4-氯苄基)-3-(6-甲酰基螺[3.3]庚-2-基)脲(中间体11.1)的制备。在室温下,将戴斯-马丁氧化剂(Dess-MartinPeriodinane)(4.1g,9.72mmol,1当量)添加到1-(4-氯苄基)-3-(6-(羟甲基)螺[3.3]庚-2-基)脲(3.0g,9.72mmol,1当量)在CH2Cl2(100mL)和乙腈(100mL)中的搅拌溶液中。2小时后,用饱和硫代硫酸钠(100mL)淬灭反应,并且用饱和碳酸氢钠稀释至700mL,并且剧烈搅拌10分钟。然后用CH2Cl2(3x500mL)萃取反应,将有机层组合,在硫酸钠上干燥,并且通过旋转蒸发去除溶剂,得到为棕褐色固体的粗制的产物(2.5g,84%)。LRMS(APCI)m/z 307.1(M+H).
实施例L
中间体12.1和12.2的合成
1-(6-(氨基甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲(中间体12.2)的制备。
步骤1:1-(6-(叠氮甲基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲的制备。在室温下,将甲磺酰氯(857mg,7.5mmol,1.1当量)添加到1-(6-(羟甲基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲(2.1g,6.8mmol,1当量)和NEt3(2.1g,20.4mmol,3当量)在CH2Cl2(50mL)中的搅拌溶液中。2小时后,用饱和碳酸氢钠(250mL)淬灭反应,用CH2Cl2(3x250mL)萃取,将有机物组合,在硫酸钠上干燥,过滤,并通过旋转蒸发去除溶剂。将粗制的物质悬浮在DMF(8mL)中,然后添加NaN3(0.66g,10.2mmol,1.5当量),并且将反应加热至70℃,持续12小时。将反应冷却至室温,倒入EtOAc(500mL)中,用饱和碳酸氢钠(3x400mL)洗涤,使有机层在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂,得到为白色固体的期望产物(1.98g,87%)。LRMS(APCI)m/z 334.1(M+H).
步骤2:1-(6-(氨基甲基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲的制备。在室温下,将PtO2(0.1g,0.449mmol,0.1当量)和1-(6-(叠氮甲基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲(1.5g,4.5mmol,1当量)悬浮在MeOH(50mL)中,然后在H2(80psi)下搅拌1小时。然后通过硅藻土垫过滤反应,并且通过旋转蒸发去除溶剂,得到为白色半固体的期望产物(1.3g,98%)。LRMS(APCI)m/z 308.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.31(d,J=7.8Hz,2H),7.26(d,J=7.9Hz,2H),4.29(d,J=8.7Hz,2H),4.02(t,J=8.1Hz,1H),2.64(d,J=7.0Hz,2H),2.46(t,J=7.8Hz,1H),2.25(ddd,J=24.0,11.5,6.4Hz,3H),2.11–1.99(m,1H),1.92–1.73(m,3H),1.69(dd,J=11.1,7.4Hz,1H).
实施例M
中间体13.1的合成2-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)乙酸的制备(实施例13.1)。
步骤1:2-(6-((叔丁氧基羰基)氨基)螺[3.3]庚-2-亚烷基)乙酸乙酯的制备。在室温下,将2-(二乙氧基磷酰基)乙酸乙酯(4.9g,22.2mmol,1当量)添加到LiCl(2.26g,53.3mmol,2.4当量)在THF(25mL)中的搅拌溶液中。10分钟后,添加DBU(7.43g,48.8mmol,2.2当量)并将反应再搅拌10分钟。然后添加THF(20mL)中的(6-氧代螺[3.3]庚-2-基)氨基甲酸叔丁酯(5.0g,22.2mmol,1当量)并且将反应搅拌14小时。通过旋转蒸发浓缩反应,并且通过二氧化硅色谱法(0->50%EtOAc/Hex)分离出为白色固体的产物(5.05g,77%)。LRMS(APCI)m/z 296.1(M+H).1H NMR(400MHz,氯仿-d)δ5.62(d,J=6.8Hz,1H),4.66(s,1H),4.22–4.10(m,2H),4.05(s,1H),3.13(d,J=38.8Hz,2H),2.84(d,J=38.1Hz,2H),2.57–2.37(m,2H),1.94(td,J=8.8,4.2Hz,2H),1.45(s,9H),1.28(t,J=6.9Hz,3H).
步骤2:2-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)乙酸乙酯的制备。将2-(6-((叔丁氧基羰基)氨基)螺[3.3]庚-2-亚烷基)乙酸乙酯(5.05g,17.1mmol,1当量)和PtO2(308mg,0.17mmol,1当量)悬浮在MeOH(150mL)中并在H2(80psi)下搅拌1小时。然后通过硅藻土垫过滤反应,并且通过旋转蒸发去除溶剂。将粗制的物质悬浮在CH2Cl2(20mL)中,然后添加HCl(二噁烷中的4M,42mL,170.9mmol,10当量),并且在室温下搅拌反应2小时。溶剂通过旋转蒸发去除并且在高真空下干燥,然后悬浮在CH2Cl2(100mL)中,添加NEt3(3.46g,34.2mmol,2当量)和1-氯-4-(异氰酸甲基)苯(3g,18.0mmol,1.05当量)并且在室温搅拌反应。12小时后,通过旋转蒸发浓缩反应,并且通过二氧化硅色谱法(0->10% MeOH/CH2Cl2)分离出为白色固体的产物(6.3g,98%)。LRMS(APCI)m/z 365.1(M+H).1H NMR(400MHz,氯仿-d)δ7.31(s,2H),7.22(d,J=8.0Hz,2H),4.67(t,J=6.0Hz,1H),4.54(d,J=7.3Hz,1H),4.33(d,J=5.9Hz,2H),4.11(q,J=7.1Hz,2H),4.01(q,J=7.8Hz,1H),3.51(d,J=5.1Hz,3H),2.62–2.45(m,2H),2.37(d,J=7.9Hz,2H),2.35–2.21(m,2H),2.10(ddd,J=11.9,7.7,4.1Hz,1H),1.77(dq,J=19.7,10.6,10.1Hz,4H),1.67(s,2H),1.30–1.20(m,3H),1.09(q,J=5.6Hz,1H).
步骤3:2-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)乙酸的制备。在室温下,将2-(6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)乙酸乙酯(6.3g,17.3mmol,1当量)和LiOH(827mg,34.5mmol,2当量)悬浮在MeOH/水(19mL/1mL)中。4小时后,通过旋转蒸发去除MeOH并且用水(约25mL)稀释粗制的产物,然后通过添加1M HCl(约20mL)来沉淀产物。通过过滤收集所得沉淀,用水洗涤,并且在高真空下干燥,得到为白色固体的期望产物(4.5g,77%)。LRMS(APCI)m/z337.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.39–7.15(m,4H),4.37–4.18(m,2H),4.01(d,J=8.9Hz,1H),2.49(pd,J=11.3,7.6,5.9Hz,2H),2.31(dq,J=36.6,6.3Hz,4H),2.10(d,J=10.4Hz,1H),1.77(ddt,J=36.3,19.2,10.0Hz,4H).
中间体13.2以与中间体13.1类似的方式制备,使用下表中提供的试剂。
实施例N
中间体14.1的合成1-(6-乙酰螺[3.3]庚-2-基)-3-(4-氯苄基)脲(中间体14.1)的制备。
步骤1:6-(3-(4-氯苄基)脲基)-N-甲氧基-N-甲基螺[3.3]庚烷-2-甲酰胺的制备。在室温下,将HATU(6.48g,17.0mmol,1.1当量)添加到6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-羧酸(5.0g,15.5mmol,1当量)、N,O-二甲基羟胺(3g,31.0mmol,2当量)和NEt3(6.3g,61.96mmol,4当量)在EtOAc(30mL)和iPOH(10mL)中的搅拌溶液中。12小时后,添加二氧化硅并通过旋转蒸发去除溶剂,然后通过二氧化硅色谱法(0->10% MeOH/CH2Cl2)分离出为玻璃状固体的产物(5.6g,98%)。LRMS(APCI)m/z 366.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.32(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2H),4.03(p,J=8.0Hz,1H),3.69(s,3H),3.44(d,J=14.8Hz,1H),3.18(s,3H),2.54(ddd,J=11.7,7.2,5.2Hz,1H),2.35–2.27(m,3H),2.27–2.20(m,1H),2.11(t,J=9.8Hz,1H),1.93(dd,J=11.0,8.5Hz,1H),1.83(dd,J=11.4,8.7Hz,1H).
步骤2:1-(6-乙酰螺[3.3]庚-2-基)-3-(4-氯苄基)脲的制备。在0℃下,将MeMgBr(THF中的3M,15.4mL,46.4mmol,3当量)滴加到6-(3-(4-氯苄基)脲基)-N-甲氧基-N-甲基螺[3.3]庚烷-2-甲酰胺(5.6g,15.5mmol,1当量)在THF(150mL)中的搅拌溶液中。1小时后,用饱和碳酸氢钠(500mL)淬灭反应,用CH2Cl2(3x250mL)萃取,将有机物组合,在硫酸钠上干燥,过滤,并通过旋转蒸发去除溶剂,得到为白色固体的期望化合物。LRMS(APCI)m/z 321.(M+H).1H NMR(400MHz,DMSO-d6)δ7.36(d,J=8.3Hz,2H),7.24(d,J=8.2Hz,2H),6.26(t,J=6.1Hz,1H),6.18(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.90(q,J=8.1Hz,1H),3.15(p,J=8.6Hz,1H),2.34(ddd,J=10.6,7.3,5.3Hz,1H),2.23–1.96(m,8H),1.86–1.64(m,2H).
实施例O
中间体15.1的合成
1-(6-(1-氨基乙基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲(中间体15.1)的制备
步骤1:1-(4-氯苄基)-3-(6-(1-羟乙基)螺[3.3]庚-2-基)脲的制备。在室温下,将LiBH4(THF中的1M,468μL,0.468mmol,0.5当量)添加到1-(6-乙酰螺[3.3]庚-2-基)-3-(4-氯苄基)脲(300mg,0.935mmol,1当量)在THF(10mL)中的搅拌溶液中。1小时后,用MeOH(10mL)和二氧化硅淬灭反应,然后通过旋转蒸发去除溶剂。然后通过二氧化硅色谱法(0->15% MeOH/CH2Cl2)分离出为白色固体的产物(300mg,99%)。LRMS(APCI)m/z 323.1(M+H).1H NMR(400MHz,氯仿-d)δ7.31(d,J=8.4Hz,2H),7.23(d,J=8.3Hz,2H),4.61(s,1H),4.50(t,J=6.4Hz,1H),4.34(d,J=5.8Hz,2H),4.02(q,J=7.9,7.3Hz,1H),3.65(d,J=5.8Hz,1H),3.51(d,J=5.1Hz,2H),2.56–2.43(m,1H),2.31(td,J=11.6,4.8Hz,1H),2.21–2.03(m,2H),1.90–1.69(m,4H),1.08(dd,J=6.2,3.0Hz,3H).
步骤2:1-(6-(1-叠氮乙基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲的制备。在0℃下,将DIAD(376mg,1.86mmol,1.5当量)添加到三苯膦(1.2g,1.86mmol,1.5当量)在THF中的搅拌溶液中。10分钟后,添加DPPA(682mg,2.48mmol,2当量)和1-(4-氯苄基)-3-(6-(1-羟乙基)螺[3.3]庚-2-基)脲(400mg,1.24mmol,1当量),并且将反应搅拌14小时同时返回至室温。通过旋转蒸发去除溶剂,并且通过二氧化硅色谱法(0->100% EtOAc/己烷)分离出为白色固体的产物(350mg,81%)。LRMS(APCI)m/z 348.1(M+H).
步骤3:1-(6-(1-氨基乙基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲的制备。将1-(6-(1-叠氮乙基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲(800mg,2.3mmol,1当量)和PtO2(52mg,0.23mmol,0.1当量)悬浮在MeOH(25mL)中,然后在H2(80psi)搅拌1小时。通过硅藻土垫过滤反应,并且通过旋转蒸发去除溶剂,得到为粘性半固体的产物(740mg,99%)。LRMS(APCI)m/z 322.1(M+H).
实施例P
中间体16.1的合成
1-(4-氯苄基)-3-(6-((甲基氨基)甲基)螺[3.3]庚-2-基)脲(中间体16.1)的制备
步骤1:N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)甲酰胺的制备。将甲酸(61mg,1.34mmol,2.3当量)和乙酸酐(77mg,0.755mmol,1.3当量)加热至60℃,持续2小时。然后将反应冷却至室温,然后添加1-(6-(氨基甲基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲(200mg,0.581mmol,1当量)和DIPEA(300mg,2.32mmol,4当量)。2小时后,用MeOH淬灭反应,通过旋转蒸发浓缩,并且在高真空下干燥。LRMS(APCI)m/z 336.2(M+H).
步骤2:1-(4-氯苄基)-3-(6-((甲基氨基)甲基)螺[3.3]庚-2-基)脲的制备。在0℃下,将THF(500μL)中的N-((6-(3-(4-氯苄基)脲基)螺[3.3]庚-2-基)甲基)甲酰胺(138mg,0.412mmol,1当量)滴加到BH3(二甲基硫醚复合物,THF中的2M,0.791mL,1.58mmol,4当量)的搅拌溶液中,然后允许返回至室温。2小时后,用MeOH淬灭反应,并且通过旋转蒸发浓缩。将所得油状物悬浮在HCl(二噁烷中的4M,5mL)中,通过旋转蒸发浓缩。将残余物与EtOAc一起研磨,并且将所得固体在高真空下干燥,得到为白色固体的产物(163mg,115%)。LRMS(APCI)m/z 322.2(M+H).
实施例Q
中间体17.1的合成
6-((2-氟苯基)(甲基)氨基)-6-氧代己-1-氯化铵(中间体17.1)的制备
步骤1:(6-((2-氟苯基)(甲基)氨基)-6-氧代己基)氨基甲酸叔丁酯。在室温下,将HATU(6.56g,17.2mmol,2当量)添加到6-((叔丁氧基羰基)氨基)己酸(2g,8.6mmol,1当量)、2-氟-N-甲基苯胺(1.62g,12.9mmol,1.5当量)和DIPEA(3.34g,25.9mmol,3当量)在DMF(15mL)中的搅拌溶液中。72小时后,将反应倒入水(200mL)中,用EtOAc(3x75mL)萃取,将有机物合并,用氯化铵(3x50mL)洗涤,在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂。将所得油状物通过二氧化硅塞过滤,得到为琥珀色油状物的产物(2.5g,85%)。LRMS(APCI)m/z 339.1(M+H).
步骤2:6-((2-氟苯基)(甲基)氨基)-6-氧代己-1-氯化铵。在室温下,将HCl(二噁烷中的4M,15mL,60mmol,10当量)添加到(6-((2-氟苯基)(甲基)氨基)-6-氧代己基)氨基甲酸叔丁酯(2.1g,6.2mmol,1当量)在MeOH(100mL)中的搅拌溶液中。4小时后,通过旋转蒸发去除溶剂并且在高真空下干燥,得到为白色固体的产物(1.5g,101%)。LRMS(APCI)m/z239.1(M+H).
实施例R
中间体18.1的合成
6-((2-氟苯基)(甲基)氨基)-6-氧代己-1-氯化铵(中间体18.1)的制备
步骤1:4-(4-异氰酸丁基)哌啶-1-甲酸叔丁酯。在0℃下,将三光气(926mg,3.12mmol,0.4当量)添加到4-(4-氨基丁基)哌啶-1-甲酸叔丁酯(2g,7.8mmol,1当量)在饱和碳酸氢钠(30mL)和CH2Cl2(30mL)中的剧烈搅拌溶液中。15分钟后,去除有机层,用CH2Cl2(3x30mL)萃取水层,将有机层组合,在硫酸钠上干燥,并过滤。将异氰酸酯溶液分开,并且不经过进一步纯化用于后续步骤。
步骤2:4-(4-(3-(噁唑-5-基甲基)脲基)丁基)哌啶-1-甲酸叔丁酯。在室温下,将噁唑-5-基甲胺(152mg,1.56mmol,1当量)添加到4-(4-异氰酸丁基)哌啶-1-甲酸叔丁酯(441mg,1.56mmol,1当量)在CH2Cl2(5mL)和饱和碳酸氢钠(3mL)中的搅拌溶液中。4小时后,分离有机层并通过二氧化硅垫过滤,用5% MeOH/CH2Cl2(20mL)洗涤,并且通过旋转蒸发去除溶剂,得到粗制的产物(459mg,44%),其不经过进一步纯化使用。LRMS(APCI)m/z 381.2(M+H).
中间体18.2-18.5以与中间体18.1类似的方式制备,使用下表中提供的试剂。
实施例S
中间体19.1的合成
(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)4-甲基苯磺酸甲酯(中间体19.1)的制备。在室温下,将4-甲基苯磺酰氯(532mg,2.79mmol,1.25当量)添加到1-(6-(羟甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲(中间体10.1,680mg,2.23mmol,1当量)和三乙胺(452mg,4.47mmol,2当量)在CH2Cl2(25mL)中的搅拌溶液中。12小时后,用饱和碳酸氢钠(100mL)淬灭反应,用CH2Cl2(3x100mL)萃取,将有机物组合,在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂。LRMS(APCI)m/z 459.1(M+H).1H NMR(400MHz,氯仿-d)δ7.79(d,J=8.2Hz,2H),7.36(d,J=7.8Hz,2H),7.22(d,J=8.2Hz,2H),6.91–6.81(m,2H),4.57(t,J=5.6Hz,1H),4.47(d,J=7.4Hz,1H),4.28(d,J=5.5Hz,2H),4.00(d,J=7.0Hz,2H),3.94(d,J=6.6Hz,2H),3.81(s,3H),2.47(s,3H),2.47–2.40(m,1H),2.27(dt,J=12.1,6.3Hz,1H),2.11(ddd,J=11.7,8.4,3.4Hz,1H),1.98(td,J=10.0,8.3,2.8Hz,1H),1.80–1.71(m,4H).
中间体19.2以与中间体19.1类似的方式制备,使用下表中提供的试剂。
实施例T
中间体20.1的合成
4-(4-氨基丁基-4,4-d2)哌啶-1-甲酸叔丁酯(中间体20.1)的制备
步骤1:4-(4-羟基丁基-4,4-d2)哌啶-1-甲酸叔丁酯。在0℃下,在氮气气氛下,将LiAlD4(4.4mL,1mol/L,1.20当量)滴加到4-[1-(叔丁氧基羰基)吡啶-4-基]丁酸(1g,3.685mmol,1当量)在THF(15mL)中的溶液中。在0℃下在氮气气氛下搅拌2小时后,通过LCMS测定反应。用KOH(水溶液)将混合物调节至pH 8并且过滤以去除固体。将滤液在无水Na2SO4上干燥并且在减压下浓缩,得到为白色油状物的产物(860mg)。LRMS(APCI)m/z 204[M+H-56].
步骤2:4-(4-((甲基磺酰基)氧基)丁基-4,4-d2)哌啶-1-甲酸叔丁酯。在0℃下,将甲磺酰氯(526mg,4.59mmol,1.5当量)和三乙胺(621mg,6.14mmol,1.99当量)添加到4-[4-羟基(4,4-2H2)丁基]哌啶-1-甲酸叔丁酯(800mg,3.084mmol,1当量)在DCM(10mL)中的溶液中。在室温下搅拌2小时后,向所得混合物中添加水(20mL),用CH2Cl2(3x30mL)萃取。将组合的有机层用盐水(2x30mL)洗涤,在无水Na2SO4上干燥,在减压下浓缩,得到为黄色油状物的产物(1g)。LRMS(APCI)m/z 282[M+H-56].
步骤3:4-(4-(1,3-二氧代异吲哚啉-2-基)丁基-4,4-d2)哌啶-1-甲酸叔丁酯。在室温下,将2-钾异吲哚-1,3-二酮(0.83g,4.48mmol,1.5当量)添加到4-[4-(甲磺酰氧基)(4,4-2H2)丁基]哌啶-1-甲酸叔丁酯(1.0g,2.96mmol,1当量)在MeCN(15mL)中的溶液中。在80℃下搅拌过夜后,将所得混合物冷却至室温,添加水(30mL),用CH2Cl2(3x30mL)萃取。将组合的有机层用盐水(2x30mL)洗涤,在无水Na2SO4上干燥。过滤后,将滤液在减压下浓缩,得到为黄色油状物的产物(1g)。LRMS(APCI)m/z 333[M+H-56].
步骤4:4-(4-氨基丁基-4,4-d2)哌啶-1-甲酸叔丁酯。在室温下,将一水合肼(642mg,13.1mmol,5.1当量)添加到4-[4-(1,3-二氧代异吲哚-2-基)(4,4-2H2)丁基]哌啶-1-甲酸叔丁酯(1.0g,2.57mmol,1当量)在乙醇(10mL)中的溶液中。在80℃下搅拌过夜后,将混合物冷却至室温并且过滤以去除固体。将滤液在减压下浓缩,得到为黄色半固体的产物(630mg)。LRMS(ES)m/z 203[M+H-56].
实施例U
中间体21.1的合成
噁唑-5-基甲-d2-胺(中间体21.1)的制备。将固体LiAlD4(84mg,2.00mmol,1.0当量)添加到噁唑-5-甲腈(188mg,2.00mmol,1.0当量)在THF(6mL)中的溶液中。在23℃下,将混合物剧烈搅拌3小时。完成后,小心地添加Na2SO4·10H2O以淬灭反应,直到气体逸出停止。滤出固体并且将滤液浓缩,得到粗制的噁唑-5-基甲-d2-胺(90mg,45%),其不经进一步纯化直接使用。LRMS(APCI+)m/z 101.2(M+H).
实施例V
中间体22.1的合成
6-(吡啶-4-基甲基)螺[3.3]庚-2-胺(中间体22.1)的制备。
步骤1:(6-羟基-6-(吡啶-4-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。在-30℃下,将正BuLi(己烷中的2.5M,1.17mL,2.93mmol,2.2当量)添加到二异丙胺(303mg,3.00mmol,2.25当量)在THF(5mL)中的溶液中。在20分钟内将溶液稍微温热至-10℃。然后将新鲜制备的LDA溶液冷却至-78℃,然后滴加4-甲基吡啶(273mg,2.93mmol,2.2当量)的THF溶液(1mL)。在此温度下,将去质子化作用保持1小时。然后在-78℃下,在1分钟内添加(6-氧代螺[3.3]庚-2-基)氨基甲酸叔丁酯(300mg,1.33mmol,1.0当量)在THF(2mL)中的溶液。然后允许反应在2小时内温热至23℃,并且反应在此温度下进一步搅拌1小时。完成后,添加半饱和NH4Cl溶液以淬灭反应。用EtOAc(5mL×2)萃取水相。用盐水洗涤合并的有机相,干燥(MgSO4),过滤并浓缩,得到粗制的(6-羟基-6-(吡啶-4-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。LRMS(APCI+)m/z 319.1(M+H).
步骤2:(6-(吡啶-4-基亚甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。将Et3N(269mg,2.66mmol,2.0当量)和MsCl(183mg,1.60mmol,1.2当量)添加到粗制的(6-羟基-6-(吡啶-4-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(至多1.33mmol,1.0当量)在CH2Cl2(2mL)中的溶液中。在23℃下,将反应搅拌2小时。完成后,真空去除挥发物并且添加PhMe(1.5mL),然后添加DBU(1.01g,6.65mmol,5.0当量)。将混合物在60℃下加热14小时。完成后,然后将反应倒入半饱和盐水(10mL)和EtOAc(10mL)的混合物中。用EtOAc(5mL×2)萃取水相。用盐水洗涤合并的有机相,干燥(MgSO4),过滤,浓缩,并且通过快速柱色谱法(二氧化硅、己烷/EtOAc)纯化,得到为无色油状物的(6-(吡啶-4-基亚甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(241mg,2步骤中60%产率)。LRMS(APCI+)m/z 301.1(M+H).
步骤3:(6-(吡啶-4-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。将Pd/C(10%重量负载,30%质量当量)添加到(6-(吡啶-4-基亚甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(240mg,0.80mmol,1.0当量)在THF/MeOH(6mL,2:1)中的溶液中。将混合物通过H2气体鼓泡3分钟,然后在1at m H2气氛下在23℃下搅拌14小时。完成后,滤出固体并且浓缩滤液,得到粗制的(6-(吡啶-4-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯,其直接用于下一步。LRMS(APCI+)m/z 303.1(M+H).
步骤4:6-(吡啶-4-基甲基)螺[3.3]庚-2-胺。在23℃下,将TFA(0.5mL)添加到粗制的(6-(吡啶-4-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(至多0.80mmol)在CH2Cl2(3mL)中的溶液中。在此温度下,将混合物搅拌3小时。完成后,真空去除挥发物,得到粗制的6-(吡啶-4-基甲基)螺[3.3]庚-2-胺(中间体22.1,150mg,93%),其不经进一步纯化直接使用。LRMS(APCI+)m/z 203.1(M+H).
实施例W
中间体23.1的合成
6-(5-(6-甲基吡啶-3-基)-1,3,4-噁二唑-2-基)螺[3.3]庚-2-胺(中间体23.1)的制备。
步骤1:(6-(2-(6-甲基烟酰基)肼-1-羰基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。将6-甲基烟酰肼(107mg,0.71mmol,1.0当量)和HATU(280mg,0.78mmol,1.1当量)添加到6-((叔丁氧基羰基)氨基)螺[3.3]庚烷-2-羧酸(180mg,0.71mmol,1.0当量)在DMF(2mL)中的溶液中,然后添加DIPEA(215mg,2.12mol,3.0当量)。在23℃下,将反应搅拌14小时。完成后,添加EtOAc(5mL)。用盐水洗涤有机相,干燥(MgSO4),过滤,并且浓缩,得到粗制的(6-(2-(6-甲基烟酰基)肼-1-羰基)螺[3.3]庚-2-基)氨基甲酸叔丁酯,其不经过进一步纯化直接用于下一步。LRMS(APCI+)m/z 389.1(M+H).
步骤2:(6-(5-(6-甲基吡啶-3-基)-1,3,4-噁二唑-2-基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。将三苯基膦(223mg,0.85mmol,1.2当量)、咪唑(145mg,2.12mmol,3.0当量)、四溴甲烷(259mg,0.78mmol,1.1当量)依次添加到粗制的(6-(2-(6-甲基烟酰基)肼-1-羰基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(0.71mmol,1.0当量)在THF(2mL)中的溶液中。在23℃下,将反应搅拌16小时。完成后,添加NaHCO3和Na2S2O3的混合溶液以淬灭反应。用CH2Cl2(5mL×3)萃取水相。用盐水洗涤合并的有机相,干燥(MgSO4),过滤,浓缩,并通过快速柱色谱法(二氧化硅、CH2Cl2/MeOH)纯化,得到为白色固体的(6-(5-(6-甲基吡啶-3-基)-1,3,4-噁二唑-2-基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(148mg,2步中57%)。LRMS(APCI+)m/z 371.1(M+H).
步骤3:6-(5-(6-甲基吡啶-3-基)-1,3,4-噁二唑-2-基)螺[3.3]庚-2-胺。将HCl(1,4-二噁烷中的4M,0.40mL,1.60mmol,8.0当量)添加到(6-(5-(6-甲基吡啶-3-基)-1,3,4-噁二唑-2-基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(74mg,0.20mmol,1.0当量)在CH2Cl2(1mL)中的溶液中。在23℃下,将混合物搅拌20小时。完成后,真空去除挥发物,得到为白色蜡状固体的粗制的6-(5-(6-甲基吡啶-3-基)-1,3,4-噁二唑-2-基)螺[3.3]庚-2-胺(中间体23.1,52mg,96%),其不经过进一步纯化直接使用。LRMS(APCI+)m/z 271.1(M+H).
实施例X
中间体24.1的合成
6-(嘧啶-2-基甲基)螺[3.3]庚-2-胺(中间体24.1)的制备
步骤1:(6-(嘧啶-2-基亚甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。将三苯基膦(787mg,3.00mmol,1.0当量)和甲苯(2mL)添加到装有2-(氯甲基)嘧啶盐酸盐(495mg,3.00mmol,1.0当量)的小瓶中。在100℃下,将混合物搅拌16小时。然后倒出溶剂并将残余物干燥,得到粗制的三苯基(嘧啶-2-基-甲基)氯化鏻。在23℃下,将DMSO(2mL)添加到粗制的叶立德(ylide)中,然后添加叔丁醇钠(577mg,6.00mmol,2.0当量)。在此温度下,将反应搅拌1小时,然后添加(6-氧代螺[3.3]庚-2-基)氨基甲酸叔丁酯(676mg,3.00mmol,1.0当量)。在23℃下,将深褐色混合物搅拌18小时,然后将其倒入半饱和NH4Cl溶液(10mL)和CH2Cl2(10mL)的混合物中。将层分离,并且用CH2Cl2(5mL×2)萃取水相。用盐水洗涤合并的有机相,干燥(MgSO4),过滤,浓缩,并且通过快速柱色谱法(二氧化硅、CH2Cl2/MeOH)纯化,得到为淡黄色胶状物的(6-(嘧啶-2-基亚甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(250mg,28%产率)。LRMS(APCI+)m/z 302.1(M+H).
步骤2:(6-(嘧啶-2-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。向装有产率(6-(嘧啶-2-基亚甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(250mg,0.83mmol,1.0当量)、哌啶(74mg,0.87mmol,1.05当量)、甲酸(40mg,0.87mmol,1.05当量)、Pd/C(10%重量负载,20%质量当量)和EtOH(3mL)的小瓶中。在75℃下,将混合物搅拌6小时。完成后,滤出固体并且将滤液浓缩,并且通过快速柱色谱法(二氧化硅、CH2Cl2/MeOH)纯化,得到为微淡黄色胶状物的(6-(嘧啶-2-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(142mg,56%产率)。LRMS(APCI+)m/z 304.2(M+H).
步骤3:6-(嘧啶-2-基甲基)螺[3.3]庚-2-胺。将HCl(1,4-二噁烷中的4M,0.93mL,3.74mmol,8.0当量)添加到(6-(嘧啶-2-基甲基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(142mg,0.47mmol,1.0当量)在CH2Cl2(1mL)中的溶液中。在23℃下,将混合物搅拌20小时。完成后,真空去除挥发物,得到为微淡黄色胶状物的粗制的6-(嘧啶-2-基甲基)螺[3.3]庚-2-胺(中间体24.1,95mg,99%),其不经过进一步纯化直接使用。LRMS(APCI+)m/z 204.1(M+H).
实施例Y
中间体25.1的合成
6-(吡啶-4-基氧基)螺[3.3]庚-2-胺(中间体25.1)的制备
步骤1:(6-(吡啶-4-基氧基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。将甲苯(3mL)添加到装有N-{6-羟基螺[3.3]庚-2-基}氨基甲酸叔丁酯(227mg,1.00mmol,1.0当量)、三苯基膦(393mg,1.50mmol,1.5当量)、4-羟基吡啶(142mg,1.50mmol,1.5当量)的小瓶中,然后添加偶氮二甲酸二异丙酯(DIAD,303mg,1.50mmol,1.5当量)。然后在80℃下将反应搅拌3小时。完成后,将反应直接浓缩并通过反相柱色谱法(H2O(0.1% HCO2H)/MeCN(0.1%HCO2H))纯化,得到为无色油状物的(6-(吡啶-4-基氧基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(166mg,54%)。LRMS(APCI+)m/z 305.1(M+H).
步骤1:6-(吡啶-4-基氧基)螺[3.3]庚-2-胺。将HCl(1,4-二噁烷中的4M,1.09mL,4.36mmol,8.0当量)添加到(6-(吡啶-4-基氧基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(166mg,0.545mmol,1.0当量)在CH2Cl2(1mL)中的溶液中。在23℃下,将混合物搅拌20小时。完成后,真空去除挥发物,得到为微淡黄色胶状物的粗制的6-(吡啶-4-基氧基)螺[3.3]庚-2-胺(中间体25.1,110mg,98%),其不经过进一步纯化直接使用。LRMS(APCI+)m/z 205.1(M+H).
中间体25.2以与中间体25.1类似的方式制备,使用下表中提供的试剂。
实施例Z
中间体26.1的合成
6-(甲基磺酰基)螺[3.3]庚-2-胺(中间体26.1)的制备
步骤1:(6-(甲硫基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。在23℃下,将Et3N(202mg,2.00mmol,2.0当量)和TsCl(229mg,1.20mmol,1.2当量)添加到N-{6-羟基螺[3.3]庚-2-基}氨基甲酸叔丁酯(227mg,1.00mmol,1.0当量)在CH2Cl2(3mL)中的溶液中。在23℃下将混合物搅拌3小时,然后将其倒入半饱和NaHCO3溶液中。通过CH2Cl2(5mL×2)萃取水相,并且用盐水洗涤合并的有机相,干燥(MgSO4),过滤,浓缩,并且通过快速柱色谱法(二氧化硅、己烷/EtOAc)纯化,得到期望的甲苯磺酸酯。接下来,将甲硫醇钠(210mg,3.00mmol,3.0当量)添加到上文获得的甲苯磺酸酯在EtOH(3mL)中的悬浮液中。在60℃下,将混合物搅拌18小时。完成后,用半饱和NH4Cl溶液淬灭反应。用EtOAc(5mL×2)萃取水相。用盐水洗涤合并的有机相,干燥(MgSO4),过滤并浓缩,得到为微淡黄色胶状物的粗制的(6-(甲硫基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(183mg,71%)。LRMS(APCI+)m/z 258.1(M+H).
步骤2:(6-(甲磺酰基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。在0℃下,将mCPBA(367mg,2.13mmol,3.0当量)添加到(6-(甲硫基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(183mg,0.71mmol,1.0当量)在CH2Cl2(3mL)中的溶液中。然后在23℃下将反应搅拌3小时。完成后,添加NaHCO3和Na2S2O3的混合溶液以淬灭反应。用CH2Cl2(5mL×3)萃取水相。用盐水洗涤合并的有机相,干燥(MgSO4),过滤并浓缩,得到为白色固体的粗制的(6-(甲磺酰基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(169mg,83%),其不经过进一步纯化直接使用。LRMS(APCI+)m/z 290.2(M+H).
步骤3:6-(甲基磺酰基)螺[3.3]庚-2-胺。将HCl(1,4-二噁烷中的4M,1.17mL,4.67mmol,8.0当量)添加到(6-(甲基磺酰基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(169mg,0.584mmol,1.0当量)在CH2Cl2(1mL)中的溶液中。在23℃下,将混合物搅拌20小时。完成后,真空去除挥发物,得到为微淡黄色胶状物的粗制的6-(甲基磺酰基)螺[3.3]庚-2-胺(中间体26.1,109mg,98%),其不经过进一步纯化直接使用。LRMS(APCI+)m/z 190.1(M+H).
实施例AA
中间体27.1的合成
6-(吡啶-4-基甲氧基)螺[3.3]庚-2-胺(中间体27.1)的制备
步骤1:(6-(吡啶-4-基甲氧基)螺[3.3]庚-2-基)氨基甲酸叔丁酯。在0℃下,将NaH(44mg,矿物油中的60%悬浮液,1.11mmol,2.1当量)添加到(6-羟基螺[3.3]庚-2-基)氨基甲酸叔丁酯(120mg,0.53mmol,1.0当量)在THF(1mL)中的溶液中。在23℃下,将去质子化作用搅拌1小时。然后依次添加碘化钾(18mg,0.11mmol,0.2当量)和4-(氯甲基)吡啶盐酸盐(91mg,0.55mmol,1.05当量)。在23℃下,将反应搅拌4小时。完成后,添加半饱和NH4Cl溶液(5mL)以淬灭反应。用CH2Cl2(3mL×2)萃取水相。用盐水洗涤合并的有机相,干燥(MgSO4),过滤,浓缩,并且通过快速柱色谱法(二氧化硅、CH2Cl2/MeOH)纯化,得到为无色胶状物的(6-(吡啶-4-基甲氧基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(139mg,83%产率)。LRMS(APCI+)m/z319.1(M+H).
步骤2:6-(吡啶-4-基甲氧基)螺[3.3]庚-2-胺。将HCl(1,4-二噁烷中的4M,0.87mL,3.49mmol,8.0当量)添加到(6-(吡啶-4-基甲氧基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(139mg,0.436mmol,1.0当量)在CH2Cl2(1mL)中的溶液中。在23℃下,将混合物搅拌20小时。完成后,真空去除挥发物,得到为微淡黄色胶状物的粗制的6-(吡啶-4-基甲氧基)螺[3.3]庚-2-胺(中间体27.1,95mg,99%),其不经过进一步纯化直接使用。LRMS(APCI+)m/z219.1(M+H).
中间体27.2以与中间体27.1类似的方式制备,使用下表中提供的试剂。
实施例1
1-(2-(3-(2-氯苯基)丙酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲(化合物135)的制备
在室温下,将HATU(207mg,0.545mmol,1.5当量)添加到3-(2-氯苯基)丙酸(101mg,0.545mmol,1.5当量)、1-(4-甲氧基苄基)-3-(2-氮杂螺[3.3]庚-6-基)脲(100mg,0.257mmol,1当量)和NEt3(147μL,0.770mmol,3当量)在DMF(1mL)中的搅拌溶液中。4小时后,用MeOH将反应稀释至总体积为1.8mL,通过0.4μm注射器式过滤器过滤,并且通过反相HPLC(含有0.1%甲酸的0->70%MeCN/H2O)分离出为白色固体的产物(42mg,26%)。LRMS(APCI)m/z442(M+H).1H NMR(400MHz,DMSO-d6)δ7.34(dd,J=7.3,2.7Hz,1H),7.29–7.23(m,1H),7.23–7.12(m,2H),7.07(d,J=7.4Hz,2H),6.87–6.69(m,2H),6.08(dt,J=14.0,6.1Hz,2H),4.02(d,J=5.8Hz,2H),3.95(s,1H),3.84(d,J=12.9Hz,2H),3.77(s,1H),3.65(s,4H),2.80(t,J=7.9Hz,2H),2.39–2.27(m,2H),2.23(q,J=7.7Hz,2H),1.86(ddt,J=12.8,9.3,5.6Hz,2H).
下表中的化合物以与化合物135类似的方式制备,使用列出的中间体和试剂。
实施例2
N-苄基-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺(化合物68)的制备
N-苄基-6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-甲酰胺的制备。
在室温下,将HATU(201mg,0.529mmol,2当量)添加到6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-羧酸(80mg,0.265mmol,1.5当量)、苯甲酰胺(57mg,0.529mmol,2当量)和NEt3(134mg,1.32mmol,5当量)在DMF(0.5mL)中的搅拌溶液中。3小时后,用饱和氯化铵淬灭反应,用CH2Cl2萃取,将有机物组合,在硫酸钠上干燥,过滤,并且通过反相HPLC(含有0.1%甲酸的10->100% MeCN/H2O)分离出为白色固体的产物(10mg,9%)。LRMS(APCI)m/z 408(M+H).1H NMR(400MHz,DMSO-d6)δ8.18(t,J=6.0Hz,1H),7.31(t,J=7.4Hz,2H),7.21(d,J=7.7Hz,3H),7.15(d,J=8.1Hz,2H),6.87(d,J=8.0Hz,2H),6.20–5.97(m,2H),4.24(d,J=5.8Hz,2H),4.10(d,J=5.7Hz,2H),3.92(h,J=8.2Hz,1H),3.72(s,3H),2.93(p,J=8.4Hz,1H),2.35(dt,J=11.9,6.2Hz,1H),2.15(p,J=10.1Hz,4H),2.05–1.88(m,1H),1.80(t,J=9.7Hz,1H),1.71(t,J=9.9Hz,1H).
下表中的化合物以与化合物68类似的方式制备,使用列出的中间体和试剂。
实施例3
1-(2-((2-氯苯基)磺酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲(化合物116)的制备
1-(2-((2-氯苯基)磺酰基)-2-氮杂螺[3.3]庚-6-基)-3-(4-甲氧基苄基)脲。在室温下,将2-氯苯磺酰氯(114mg,0.544mmol,1.5当量)添加到1-(4-甲氧基苄基)-3-(2-氮杂螺[3.3]庚-6-基)脲(100mg,0.363mmol,1当量)和NEt3(147μL,0.770mmol,3当量)在DMF(1mL)中的搅拌溶液中。2小时后,用MeOH将反应稀释至总体积为1.8mL,通过0.4μm注射器式过滤器过滤,并且通过反相HPLC(含有0.1%甲酸的0->70% MeCN/H2O)分离出为白色固体的产物(21mg,18%)。LRMS(APCI)m/z 450(M+H).1H NMR(400MHz,DMSO-d6)δ7.97(dt,J=8.0,1.8Hz,1H),7.76–7.68(m,2H),7.59(t,J=7.4Hz,1H),7.13(d,J=8.3Hz,2H),6.86(d,J=8.5Hz,2H),6.17(t,J=5.9Hz,1H),6.12(d,J=7.9Hz,1H),4.10(dd,J=16.2,6.9Hz,2H),3.97(s,1H),3.94(s,2H),3.87(s,1H),3.83(s,1H),3.72(s,2H),2.48–2.38(m,1H),2.33(ddd,J=10.2,7.7,3.0Hz,2H),2.27–2.15(m,1H),1.93(t d,J=8.9,3.0Hz,1H).
下表中的化合物以与化合物116类似的方式制备,使用列出的中间体和试剂。
实施例4
1-((3-(4-氯苄基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯(化合物27)的制备
步骤1:1-((3-(4-氯苄基)脲基)甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯。
将1-(氨基甲基)-6-氮杂螺[2.5]辛烷-6-甲酸叔丁酯(0.15g,0.62mmol,1.0当量)滴加到N,N'-二琥珀酰亚胺碳酸酯(0.160mg,0.62mmol,1.0当量)在乙腈(10mL)中的室温溶液中,然后滴加吡啶(0.06mL,0.62mmol,1.0当量)。20分钟后,添加4-氯苄胺(88mg,0.62mmol,1.0当量)在乙腈(2mL)中的溶液,然后添加N,N-二异丙基乙胺(0.11mL,1.24mmol,2.0当量)。将所得混合物在室温下搅拌大约1小时,然后浓缩至干燥。将所得混合物用乙酸乙酯(50mL)稀释,并且用水(2x15mL)和盐水(1x15mL)萃取。将有机相干燥成粘性油状物,通过反相色谱法将其纯化,并且得到为白色泡沫状物的期望产物(148mg,0.36mmol,58.1%产物)。LCMS-APCI(POS.)m/z:308(M-Boc+H)+.1H NMR(400MHz,DMSO-d6)δ7.45–7.32(m,2H),7.25(d,J=8.5Hz,2H),6.37(t,J=6.1Hz,1H),5.94(t,J=5.4Hz,1H),4.18(d,J=6.0Hz,2H),3.43(dddd,J=19.2,12.7,6.6,3.8Hz,2H),3.17(dt,J=13.8,5.9Hz,3H),2.90(ddd,J=13.7,8.5,5.2Hz,1H),1.51(ddd,J=12.3,10.2,6.2Hz,1H),1.40(s,9H),1.31(ddd,J=17.2,7.1,3.5Hz,2H),1.14(ddd,J=13.1,6.5,3.3Hz,1H),0.79(tt,J=8.5,6.2Hz,1H),0.45(dd,J=8.5,4.3Hz,1H),0.16(t,J=4.8Hz,1H).
下表中的化合物以与化合物27类似的方式制备,使用列出的中间体和试剂。
实施例5
N-(6-氰基吡啶-2-基)-6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.3]
庚烷-2-甲酰胺(化合物132)的制备
N-(6-氰基吡啶-2-基)-6-(3-(4-甲氧基苄基)脲基)-2-氮杂螺[3.3]庚烷-2-甲酰胺。在25℃下,将(6-氰基吡啶-2-基)氨基甲酸苯酯(130mg,0.54mmol,1.5当量)添加到1-(4-甲氧基苄基)-3-(2-氮杂螺[3.3]庚-6-基)脲(100mg,0.36mmol,1当量)在DMF(1mL)中的搅拌溶液中。12小时后,用MeOH将反应稀释至总体积为1.8mL,通过0.4μm注射器式过滤器过滤,并且通过反相HPLC(含有0.1%甲酸的0->70% MeCN/H2O)分离出为白色固体的产物(39mg,26%)。1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.14(dd,J=8.7,1.8Hz,1H),7.90–7.75(m,1H),7.51(dd,J=7.3,1.8Hz,1H),7.08(d,J=7.9Hz,2H),6.83–6.76(m,2H),6.17–6.10(m,1H),6.08(d,J=8.1Hz,1H),4.03(d,J=5.8Hz,2H),3.96(s,2H),3.86(d,J=10.2Hz,3H),3.65(s,3H),2.36(t,J=8.8Hz,2H),1.91(t,J=9.5Hz,2H).LRMS(APCI)m/z421.1(M+H).
下表中的化合物以与化合物132类似的方式制备,使用列出的中间体和试剂。
实施例6
1-(4-氯苄基)-3-((2r,4s)-6-(2-甲基吡啶-4-基)-6-氮杂螺[3.4]辛
-2-基)脲(化合物171)的制备
1-(4-氯苄基)-3-((2r,4s)-6-(2-甲基吡啶-4-基)-6-氮杂螺[3.4]辛-2-基)脲。将1-(4-氯苄基)-3-((2r,4s)-6-氮杂螺[3.4]辛-2-基)脲(中间体3.5)(100mg,0.34mmol,1当量)、4-氟-2-甲基吡啶(57mg,0.51mmol,1.5当量)和DI PEA(178μL,1.0mmol,3当量)悬浮在异丙醇(3mL)中,然后在微波炉中加热至150℃,持续30分钟。然后通过旋转蒸发去除溶剂,并且通过反向HPLC(含有0.1%甲酸的05->95% MeCN/H2O)分离出为白色固体的期望产物(30mg,23%)。LRMS(APCI)m/z 385(M+H).1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.98(d,J=6.1Hz,1H),7.40–7.32(m,2H),7.30–7.24(m,2H),6.40–6.28(m,4H),4.18(d,J=6.0Hz,2H),4.12(q,J=8.1Hz,1H),3.31(t,J=6.7Hz,3H),2.32(s,3H),2.29–2.20(m,2H),2.01(t,J=6.7Hz,2H),1.90(td,J=8.8,2.7Hz,2H).
下表中的化合物以与化合物171类似的方式制备,使用列出的中间体和试剂。
实施例7
1-(6-((5,7-二氟-3,4-二氢喹啉-1(2H)-基)甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲(化合物127)的制备
1-(6-((5,7-二氟-3,4-二氢喹啉-1(2H)-基)甲基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲。将(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)甲磺酸甲酯(中间体4.1)(60mg,0.16mmol,1.0当量)和5,7-二氟-1,2,3,4-四氢喹啉(21mg,0.19mmol)溶解在DMF(0.5mL)中,并且添加碳酸钾(1.5当量)。在80℃下,将反应搅拌12小时。滤出碳酸钾,并且通过在Phenomonex Gemini 5u C18柱中运行30分钟、使用10%-100%乙腈水溶液的反相HPLC直接纯化溶液,得到为白色泡沫状物的期望产物(18.0mg,24%产率)。LCMS-APCI(POS.)m/z:456.2(M+H)+.1H NMR(400MHz,DMSO-d6)δ7.17(dd,J=12.2,2.9Hz,2H),6.99(d,J=13.8Hz,2H),6.86(dd,J=8.5,2.9Hz,2H),6.08(d,J=11.9Hz,2H),4.09(d,J=4.6Hz,2H),4.03–3.76(m,1H),3.72(d,J=3.0Hz,3H),3.60(d,J=7.0Hz,2H),2.85(dd,J=7.4,2.4Hz,2H),2.70(d,J=8.4Hz,2H),2.34(s,2H),2.27–1.91(m,5H),1.90–1.56(m,4H).
下表中的化合物以与化合物127类似的方式制备,使用列出的中间体和试剂。
实施例8
1-(4-氯苄基)-3-((2r,4s)-6-(2-甲基吡啶-4-基)-6-氮杂螺[3.4]辛
-2-基)脲(化合物16)的制备
步骤1:(4-(1-苯甲酰基哌啶-4-基)丁基)氨基甲酸苯酯。在0℃下,将NEt3(583mg,5.76mmol,3当量)和氯甲酸苯酯(360.79mg,2.304mmol,1.2当量)添加到4-(1-苯甲酰基哌啶-4-基)丁-1-胺(如先前在“Gillig,A.,Majjigapu,S.R.,Sordat,B.and Vogel,P.(2012),Synthesis of a C-Iminoribofuranoside Analog of the NicotinamidePhosphoribosyltransferase(NAMPT)Inhibitor FK866.HCA,95:34-42”所述的那样制备)(500mg,1.92mmol,1.00当量)在CH2Cl2(5mL)中的搅拌溶液中,然后温热至室温。4小时后,通过旋转蒸发浓缩反应,并且通过制备型TLC(PE/EtOAc 1:1)分离出为黄色油状物的产物(41%)。LRMS(ESI)m/z 381(M+H).
步骤2:1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(4-氯苄基)脲。在室温下,将NEt3((119mg,1.2mmol,3.00当量)添加到N-[4-(1-苯甲酰基哌啶-4-基)丁基]氨基甲酸苯酯(150mg,0.4mmol,1.00当量)和1-(4-氯苯基)甲胺(167mg,1.18mmol,3.00当量)在CH2Cl2(2mL)中的搅拌溶液中。12小时后,通过旋转蒸发去除溶剂并且通过反相HPLC(含有0.1%甲酸铵的30%->60% MeCN/H2O)分离出为白色固体的产物(31%)。LRMS(ESI)m/z 428(M+H).1H NMR(300MHz,DMSO-d6)δ7.48(m,3H),7.31(m,4H),7.21(m,2H),6.30(t,J=6.1Hz,1H),5.92(t,J=5.7Hz,1H),4.46(s,1H),4.17(d,J=6.0Hz,2H),3.55(s,1H),3.00(q,J=6.4Hz,3H),2.81(m,1H),1.70(s,2H),1.48(s,1H),1.36(s,2H),1.24(s,4H),1.06(s,2H).
下表中的化合物以与化合物16类似的方式制备,使用列出的中间体和试剂。
实施例9
1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(4-甲氧基苄基)脲(化合物20)的制备
步骤1:(4-氨基甲酰基苄基)氨基甲酸苯酯。在0℃下,将NEt3(1.6g,16.1mmol,3.0当量)和氯甲酸苯酯(1.0g,5.9mmol,1.10当量)添加到4-(氨基甲基)苯甲酰胺盐酸盐(1.0g,5.4mmol,1.0当量)在CH2Cl2(10mL)中的搅拌溶液中。2小时后,用水(20mL)淬灭反应,用CH2Cl2(2x20mL)萃取,将有机物组合,用饱和氯化钠(20mL)洗涤,在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂,得到为白色固体的粗制的产物(1.2g),其不经过进一步纯化用于后续步骤。LRMS(ESI)m/z 271(M+H).
步骤2:1-(4-(1-苯甲酰基哌啶-4-基)丁基)-3-(4-甲氧基苄基)脲。在室温下,将NEt3(291mg,2.9mmol,5当量)添加到4-(1-苯甲酰基哌啶-4-基)丁-1-胺(150mg,0.6mmol,1.00当量)和N-[(4-甲氧基苯基)甲基]氨基甲酸苯酯(518mg,2.0mmol,3.5当量)在DMF(3mL)中的搅拌溶液中。12小时后,用水(20mL)淬灭反应,用EtOAc(2x20mL)萃取。将有机物合并,用饱和氯化钠(20mL)洗涤,在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂。然后通过反相HPLC(含有0.1%甲酸铵的30%->60% MeCN/H2O)分离出为淡黄色固体的产物(82mg)。LRMS(ESI)m/z 424(M+H).1H NMR(400MHz,甲醇-d4)δ7.49(m,3H),7.42(m,2H),7.23(m,2H),6.88(m,2H),4.60(d,J=13.1Hz,1H),4.22(s,2H),3.75(s,3H),3.69(d,J=13.3Hz,1H),3.13(t,J=6.8Hz,3H),2.84(d,J=13.1Hz,1H),1.83.
下表中的化合物以与化合物20类似的方式制备,使用列出的中间体和试剂。
实施例10
1-(4-甲氧基苄基)-3-(5-苯氧基戊基)脲(化合物149)的制备
步骤1:1-(5-羟基戊基)-3-(4-甲氧基苄基)脲。将N-[(4-甲氧基苯基)甲基]氨基甲酸苯酯(250mg,1.0mmol,1.00当量)、5-氨基戊醇(120mg,1.2mmol,1.2当量)和NEt3(295mg,2.9mmol,3当量)溶解在THF(5mL)中并加热至65℃。1小时后,将反应冷却至室温,用H2O(20mL)淬灭,用EtOAc(2x20mL)萃取,将有机物合并且用饱和氯化钠(20mL)洗涤。然后将有机层在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂,得到为白色固体的粗制的产物(250mg)。LRMS(ESI)m/z 267(M+H).
步骤2:5-(3-(4-甲氧基苄基)脲基)甲磺酸戊酯。在0℃下,将MsCl(226mg,1.9mmol,2.50当量)添加到3-(5-羟基戊基)-1-[(4-甲氧基苯基)甲基]脲(210mg,0.79mmol,1.00当量)和NEt3(399mg,3.9mmol,5当量)在CH2Cl2(5mL)中的搅拌溶液中,然后温热至室温。1小时后,用H2O(20mL)淬灭反应,用EtOAc(2x20mL)萃取,将有机物组合并且用饱和氯化钠(20mL)洗涤。然后将有机层在硫酸钠上干燥,过滤,并且通过旋转蒸发去除溶剂,得到为白色固体的粗制的产物(440mg)。LRMS(ESI)m/z 345(M+H).
步骤3:1-(4-甲氧基苄基)-3-(5-苯氧基戊基)脲。将5-([[(4-甲氧基苯基)甲基]氨基甲酰基]氨基)甲磺酸戊酯(350mg,1.0mmol,1.00当量)、K2CO3(351mg,2.5mmol,2.5当量)、苯酚(115mg,1.2mmol,1.2当量)和KI(16.9mg,0.10mmol,0.1当量)悬浮在DMSO(5mL)中,然后加热至80℃。2小时后,将反应冷却至室温,并且通过反相HPLC(含有0.5%甲酸铵的50% MeCN/H2O)分离出为白色固体的产物(15mg)。LRMS(ESI)m/z 343(M+H).1H NMR(300MHz,DMSO-d6)δ7.32–7.21(m,2H),7.15(d,J=8.6Hz,2H),6.95–6.81(m,5H),6.16(t,J=6.2Hz,1H),5.86(s,1H),4.11(d,J=5.8Hz,2H),3.93(t,J=6.4Hz,2H),3.71(s,3H),3.02(d,J=6.0Hz,2H),1.70(t,J=6.8Hz,2H),1.41(s,4H).
下表中的化合物以与化合物149类似的方式制备,使用列出的中间体和试剂。
实施例11
N-苄基-2-(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)-N-甲基乙酰胺(化合物67)的制备
步骤1:(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)甲基氰化物的制备。
将(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)甲磺酸甲酯(中间体4.1)(0.1g,0.27mmol,1.0当量)溶解在DMF(1mL)中并且添加氰化钠(5eq)。在80℃下,将溶液搅拌过夜并通过LCMS分析监测。将溶液冷却至0℃,并且添加饱和氯化铵水溶液(8mL)和EtOAc(5mL),并且将溶液剧烈搅拌10分钟。分离有机层,并且用10mL EtOAc萃取水层。用盐水洗涤组合的有机层,干燥,过滤并浓缩,得到为白色固体的产物(72mg,87%产率)。LCMS-APCI(POS.)m/z:314.0(M+H)+.
步骤2:N-苄基-2-(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)-N-甲基乙酰胺。
将(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)甲基氰化物(50mg,0.17mmol,1.0当量)和N-甲基苄胺(19mg,0.17mmol,1.0当量)溶解在甲苯(0.5mL)中,并且添加甲磺酸(16mg,0.17mmol,1.0当量)。在110℃下,将反应搅拌24小时。将溶液冷却至室温,并且用饱和碳酸氢钠水溶液淬灭。用DCM萃取反应,并且将组合的有机层干燥、过滤并浓缩。将有机相干燥成粘性油状物,并且通过在Phenomonex Gemini 5u C18柱中运行30分钟、使用10%-100%乙腈水溶液的反相HPLC纯化所述粘性油状物,得到为白色固体的期望产物(51.0mg,0.12mmol,69%产率)。LCMS-APCI(POS.)m/z:436.0(M+H)+.1H NMR(400MHz,DMSO-d6)δ7.33(tt,J=24.0,7.5Hz,3H),7.16(dd,J=13.3,7.3Hz,4H),6.86(d,J=8.0Hz,2H),6.22–5.97(m,2H),4.55(s,1H),4.47(s,1H),4.09(t,J=4.3Hz,2H),3.90(dq,J=15.0,8.0Hz,1H),3.72(d,J=1.6Hz,3H),2.88(s,2H),2.78(s,2H),2.45(d,J=16.9Hz,3H),2.34(q,J=9.3,7.5Hz,1H),2.16(s,1H),2.04(dd,J=15.8,9.5Hz,1H),1.68(dh,J=37.2,9.6Hz,4H).
实施例12
1-(4-氯苄基)-3-(6-(二苄基氨基)螺[3.3]庚-2-基)脲(化合物119)的制备
步骤1:1-(4-氯苄基)-3-(6-(二苄基氨基)螺[3.3]庚-2-基)脲的制备。
在室温下,将苄基溴(18μL,0.159mmol,1当量)添加到1-(6-氨基螺[3.3]庚-2-基)-3-(4-氯苄基)脲(70mg,0.238mmol,1.5当量)和DIPEA(83μL,0.477mmol,3当量)在CH2Cl2(2mL)中的搅拌溶液中。3小时后,通过旋转蒸发去除溶剂,并且通过反相HPLC(含有0.1%甲酸的5->95% MeCN/H2O)分离出为白色固体的产物(28mg,40%)。LRMS(APCI)m/z474(M+H).1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.41–7.15(m,14H),6.25(t,J=6.1Hz,1H),6.15(d,J=8.1Hz,1H),4.14(d,J=6.0Hz,2H),3.90(q,J=8.0Hz,1H),3.40(s,3H),3.18(d,J=3.9Hz,1H),2.99(q,J=7.9Hz,1H),2.24(dt,J=11.3,5.8Hz,1H),2.09(dq,J=10.0,5.2,4.5Hz,2H),1.89(dt,J=11.5,5.8Hz,1H),1.75(qd,J=13.0,11.8,9.0Hz,3H).
实施例13
4-(4-(6-(苄基氨基)螺[3.3]庚-2-基)-3-氧代丁基)苯甲酰胺(化合物24)的制备
步骤1:(6-(4-(4-氨基甲酰基苯基)-2-氧代丁基)螺[3.3]庚-2-基)氨基甲酸叔丁酯的制备。将N-[(4-氨基甲酰基苯基)甲基]氨基甲酸苯酯(657mg,2.4mmol,1.1当量)和NEt3(671mg,6.6mmol,3.00当量)添加到N-[6-氨基螺[3.3]庚-2-基]氨基甲酸酯(500mg,2.2mmol,1.00当量)在DMF(5.00mL)中的搅拌溶液中,然后加热至50℃。2小时后,将反应冷却至室温,并且通过旋转蒸发去除挥发物。通过反相HPLC(含有0.1%甲酸铵的60% MeCN/H2O)分离出为白色固体的产物(45%)。LRMS(ESI)m/z 403(M+H).
步骤2:4-(4-(6-氨基螺[3.3]庚-2-基)-3-氧代丁基)苯甲酰胺盐酸盐的制备。在室温下,将HCl(二噁烷中的10mL,4M)添加到(6-(4-(4-氨基甲酰基苯基)-2-氧代丁基)螺[3.3]庚-2-基)氨基甲酸叔丁酯(380mg,0.94mmol,1.00当量)在CH2Cl2(40mL)中的搅拌溶液中。1小时后,通过旋转蒸发浓缩反应,得到为白色固体的粗制的产物(560mg),其不经过进一步纯化使用。LRMS(ESI)m/z 303(M+H).
步骤3:4-(4-(6-(苄基氨基)螺[3.3]庚-2-基)-3-氧代丁基)苯甲酰胺的制备
在室温下,将AcOH(29mg,0.54mmol,2当量)和NaHB(OAc)3(103mg,0.54mmol,2.00当量)添加到4-[[([6-氨基螺[3.3]庚-2-基]氨基甲酰基)氨基]甲基]苯甲酰胺盐酸盐(82mg,0.27mmol,1.00当量)和苯甲醛(29mg,0.27mmol,1.00当量)在CH2Cl2(5mL)中的搅拌溶液中。3小时后,通过旋转蒸发去除溶剂并且通过反相HPLC(含有0.1%甲酸铵的15%->45% MeCN/H2O)分离出为白色固体的产物(15%)。LRMS(ESI)m/z 393(M+H).1H NMR(300MHz,甲醇-d4)δ7.90(s,1H),7.80(d,J=7.8Hz,2H),7.28(s,6H),7.23–7.09(m,1H),6.26(s,1H),6.16(d,J=8.1Hz,1H),4.21(d,J=4.6Hz,2H),3.92(d,J=7.9Hz,1H),3.57(s,2H),3.32(s,3H),3.11–2.92(m,1H),2.23(s,2H),2.12(s,1H),2.03(d,J=7.6Hz,1H),1.73(dt,J=20.4,10.2Hz,3H).
实施例14
4-((3-(6-((吡啶-2-基甲基)氨基)螺[3.3]庚-2-基)脲基)甲基)苯甲酰胺(化合物34)的制备
步骤1:6-氨基螺[3.3]庚-2-酮盐酸盐的制备。将HCl(二噁烷中的5mL,4M)添加到N-[6-氧代螺[3.3]庚-2-基]氨基甲酸叔丁酯(500mg,2.2mmol,1.00当量)在CH2Cl2(5.00mL)中的搅拌溶液中。然后通过旋转蒸发浓缩反应,得到为白色固体的粗制的产物(350mg)。LRMS(ESI)m/z 126(M+H).
步骤2:4-((3-(6-氧代螺[3.3]庚-2-基)脲基)甲基)苯甲酰胺的制备。将N-[(4-氨基甲酰基苯基)甲基]氨基甲酸酯(241mg,0.90mmol,1.2当量)和NEt3(300mg,2.97mmol,4当量)添加到6-氨基螺[3.3]庚-2-酮盐酸盐(120mg,0.74mmol,1.00当量)在MeCN(4mL)中的搅拌溶液中,并且加热至65℃。2小时后,将反应冷却至室温并且通过旋转蒸发浓缩,得到为黄色固体的粗制的产物(280mg)。LRMS(ESI)m/z 302(M+H).
步骤3:4-((3-(6-((吡啶-2-基甲基)氨基)螺[3.3]庚-2-基)脲基)甲基)苯甲酰胺的制备。将2-吡啶甲胺(145mg,1.34mmol,1.5当量)和4-[[([6-氧代螺[3.3]庚-2-基]氨基甲酰基)氨基]甲基]苯甲酰胺(270mg,0.90mmol,1.00当量)溶解在DCE(5mL)中,并且在室温下搅拌30分钟,然后添加NaHB(OAc)3(285mg,1.34mmol,1.5当量)。1小时后,通过旋转蒸发浓缩反应,并且通过反相HPLC(含有甲酸铵的3%->15% MeCN/H2O)分离出为黄色固体的产物(20mg)。LRMS(ESI)m/z 394(M+H).1H NMR(400MHz,DMSO-d6)δ8.50(d,J=4.9Hz,1H),8.25(s,1H),7.91(s,1H),7.85–7.71(m,3H),7.42(d,J=7.9Hz,1H),7.36–7.22(m,5H),6.30(t,J=6.2Hz,1H),6.21(d,J=8.0Hz,1H),4.22(d,J=6.0Hz,2H),3.94(q,J=7.9Hz,1H),3.16(p,J=7.7Hz,1H),2.32–2.19(m,2H),2.15(dt,J=11.9,6.4Hz,1H),2.06(dt,J=11.7,5.9Hz,1H),1.84–1.71(m,4H).
实施例15
4-((3-(6-((吡啶-2-基甲基)氨基)螺[3.3]庚-2-基)脲基)甲基)苯甲酰胺(化合物187和182)的制备
1-(4-氯苄基)-3-(6-(4-(2-羟基-2-甲基丙基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲的制备。在室温下,将HATU(1.4g,3.7mmol,1.5当量)添加到6-(3-(4-氯苄基)脲基)螺[3.3]庚烷-2-羧酸(中间体2.1)(1g,0.36mmol,1当量)、2-甲基-1-(哌嗪-1-基)丙-2-醇(980mg,6.2mmol,2当量)和NEt3(1.3mL,9.3mmol,3当量)在EtOAc(50mL)中的搅拌溶液中。12小时后,将反应干燥加载到二氧化硅上,并且通过二氧化硅色谱法(含有0.1%甲酸的0->15%MeOH/CH2CL2)分离出为白色固体的外消旋产物。
1-(4-氯苄基)-3-(6-(4-(2-羟基-2-甲基丙基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲的手性分离。
通过SFC(Chiralcel OX-H柱,50%共溶剂[含有0.25%异丙胺的25%MeOH/MeCN],速率为70克/分钟)分离1-(4-氯苄基)-3-(6-(4-(2-羟基-2-甲基丙基)哌嗪-1-羰基)螺[3.3]庚-2-基)脲的1g混合物,得到为白色固体的两种异构体:化合物187(0.32g,46%)和化合物182(0.33g,47%)。每种异构体的绝对立体化学没有确定并且任意地指定。首先使用规定的条件将化合物187从SFC中洗脱,然后是化合物182。
化合物187:LRMS(APCI)m/z 464.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.32(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),4.28(s,2H),4.03(p,J=8.0Hz,1H),3.62–3.52(m,2H),3.47–3.39(m,2H),3.27(q,J=8.6Hz,1H),2.55(ddt,J=18.0,11.5,5.1Hz,5H),2.37–2.22(m,6H),2.12(ddd,J=11.5,8.5,3.2Hz,1H),1.87(ddd,J=36.9,11.1,8.6Hz,2H),1.21(s,6H).
化合物182:LRMS(APCI)m/z 464.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.31(d,J=8.5Hz,2H),7.26(d,J=8.4Hz,2H),4.28(s,2H),4.03(p,J=8.0Hz,1H),3.57(q,J=4.6Hz,2H),3.43(t,J=4.9Hz,2H),3.27(t,J=8.6Hz,1H),2.54(ddt,J=18.2,11.7,5.0Hz,5H),2.38–2.21(m,6H),2.21–2.07(m,1H),1.87(ddd,J=37.2,11.2,8.6Hz,2H),1.21(s,6H).
下表中的化合物以与化合物187和182类似的方式制备,使用列出的中间体和试剂。
实施例16
1-(4-氯苄基)-3-(6-((4-甲基-3-氧代哌嗪-1-基)甲基)螺[3.3]庚-2-基)脲(化合物238)的制备
1-(4-氯苄基)-3-(6-((4-甲基-3-氧代哌嗪-1-基)甲基)螺[3.3]庚-2-基)脲。在室温下,将NaBH(OAc)3(249mg,1.17mmol,2当量)添加到1-(4-氯苄基)-3-(6-甲酰基螺[3.3]庚-2-基)脲(中间体11.1,180mg,0.587mmol,1当量)和1-甲基哌嗪-2-酮(134mg,1.17mmol,2当量)在CH2Cl2(2mL)中的搅拌溶液中。12小时后,通过旋转蒸发去除溶剂,将粗产物悬浮在MeOH(3mL)中,通过0.4μm注射器式过滤器过滤,并且通过反相HPLC(含有0.1%甲酸的0->30%MeCN/水)分离出为白色固体的产物(60mg,25%)。LRMS(ESI)m/z405.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.20(d,J=8.2Hz,2H),7.14(d,J=8.2Hz,2H),4.16(s,2H),3.90(p,J=8.0Hz,1H),3.25(t,J=5.6Hz,2H),2.97(s,2H),2.83(s,3H),2.60(t,J=5.7Hz,2H),2.42–2.28(m,4H),2.20–2.08(m,2H),1.96(ddd,J=11.1,7.0,4.1Hz,1H),1.81–1.73(m,1H),1.73–1.57(m,3H).
下表中的化合物以与化合物238类似的方式制备,使用列出的中间体和试剂。
实施例17
1-(4-氯苄基)-3-(6-((5-苯基-1H-1,2,3-三唑-1-基)甲基)螺[3.3]庚-2-基)脲(化合物242)的制备
1-(4-氯苄基)-3-(6-((5-苯基-1H-1,2,3-三唑-1-基)甲基)螺[3.3]庚-2-基)脲。将1-(6-(叠氮甲基)螺[3.3]庚-2-基)-3-(4-氯苄基)脲(100mg,0.30mmol,1当量)、乙炔苯(46mg,0.449mmol,1.5当量)和Cp*RuCl(cod)(11mg,0.03mmol,0.1当量)悬浮在THF(5mL)中,然后加热至60℃。12小时后,将反应冷却至室温,通过旋转蒸发去除溶剂,并通过反相HPLC(5->95% MeCN/水0.1%甲酸)分离出为白色固体的产物(20mg,15%)。LRMS(ESI)m/z436.1(M+H).1H NMR(400MHz,氯仿-d)δ7.10(d,J=5.5Hz,3H),6.99–6.92(m,2H),6.88(d,J=10.0Hz,5H),6.81(d,J=8.0Hz,2H),4.28(t,J=5.9Hz,1H),4.19(d,J=7.4Hz,1H),3.92(d,J=6.5Hz,4H),3.64–3.50(m,1H),2.24(dt,J=15.3,7.5Hz,1H),2.02(dt,J=11.9,6.4Hz,1H),1.83(dt,J=12.1,6.4Hz,1H),1.74–1.65(m,1H),1.60–1.47(m,3H).
实施例18
1-(4-(1-(2H-四唑-5-基)哌啶-4-基)丁基)-3-(4-氯苄基)脲(化合物318)的制备
步骤1:1-(4-氯苄基)-3-(4-(1-氰基哌啶-4-基)丁基)脲。在0℃下,将CNBr(154mg,1.46mmol,1.05当量)添加到1-(4-氯苄基)-3-(4-(哌啶-4-基)丁基)脲(中间体3.8,500mg,1.39mmol,1当量)和饱和碳酸氢钠(4.2mL)在CH2Cl2(10mL)中的搅拌溶液中。14小时后,用CH2Cl2(3x5mL)萃取反应,将有机物组合,在硫酸钠上干燥,通过硅胶垫过滤,并且通过旋转蒸发去除溶剂,得到粗制的产物,其不经过进一步纯化用于下一步(267mg,55%)。LRMS(ESI)m/z 349.1(M+H).
步骤2:1-(4-(1-(2H-四唑-5-基)哌啶-4-基)丁基)-3-(4-氯苄基)脲。将1-(4-氯苄基)-3-(4-(1-氰基哌啶-4-基)丁基)脲(102mg,0.29mmol,1当量)、叠氮化钠(21mg,0.322mmol,1.1当量)和溴化锌(66mg,0.293mmol,1当量)悬浮在DMF(2mL)中,然后加热至100℃,持续3小时。将反应冷却至室温,并且通过反相HPLC(含有0.1%甲酸的10->60%MeCN/水)分离出为白色固体的产物。LRMS(ESI)m/z 392.1(M+H).1H NMR(400MHz,DMSO-d6)δ7.37(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,2H),6.31(t,J=6.1Hz,1H),5.93(t,J=5.6Hz,1H),4.18(d,J=5.9Hz,2H),3.80(d,J=12.7Hz,2H),3.05–2.90(m,4H),1.71(d,J=14.1Hz,2H),1.36(t,J=7.0Hz,3H),1.32–1.07(m,7H).
实施例19
1-(4-甲氧基苄基)-3-(6-(5-苯基-1,3,4-噁二唑-2-基)螺[3.3]庚
-2-基)脲(化合物325)的制备
1-(4-甲氧基苄基)-3-(6-(5-苯基-1,3,4-噁二唑-2-基)螺[3.3]庚-2-基)脲。将6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-羧酸(200mg,0.628mmol,1当量)和苯甲酰肼(86mg,0.628mmol,1当量)悬浮在三氯氧磷(5mL)中,然后在室温下搅拌14小时。通过旋转蒸发去除溶剂并通过反相HPLC(含有0.1%甲酸的5->95% MeCN/水)分离出为白色固体的产物(17mg,5%)。LRMS(ESI)m/z 419.1(M+H).1H NMR(400MHz,甲醇-d4)δ8.04(d,J=8.3Hz,2H),7.59(q,J=7.5,6.5Hz,3H),7.20(d,J=8.1Hz,2H),6.88(d,J=7.1Hz,2H),4.24(s,2H),4.10(p,J=8.0Hz,1H),3.78(s,4H),2.71–2.53(m,3H),2.47(dd,J=21.5,7.2Hz,3H),1.98(dt,J=23.2,10.0Hz,2H).
实施例20
1-(4-甲氧基苄基)-3-(6-(4-苯基噁唑-2-基)螺[3.3]庚-2-基)脲(化合物326)的制备
1-(4-甲氧基苄基)-3-(6-(4-苯基噁唑-2-基)螺[3.3]庚-2-基)脲。在室温下,将DCC(143mg,0.693mmol,1.05当量)添加到6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-羧酸(210mg,0.660mmol,1当量)、2-羟基-1-苯基乙-1-酮(90mg,0.660mmol,1当量)和DMAP(1mg,0.007mmol,0.01当量)在CH2Cl2(20mL)中的搅拌溶液中。14小时后,通过硅藻土垫过滤反应,并且通过旋转蒸发去除溶剂。将粗制的物质悬浮在甲苯(50mL)中,然后添加乙酸铵(101mg,1.32mmol,2当量)和AcOH(2mL),并且将反应加热回流2小时。将反应冷却至室温,通过旋转蒸发去除溶剂,并通过反相HPLC(含有0.1%甲酸的5->95% MeCN/水)分离出为白色固体的产物(55mg,20%)。LRMS(ESI)m/z 418.1(M+H).1H NMR(400MHz,甲醇-d4)δ8.15(s,1H),7.73(d,J=7.7Hz,2H),7.41(t,J=7.6Hz,2H),7.32(t,J=7.4Hz,1H),7.21(d,J=8.2Hz,2H),6.88(d,J=8.2Hz,2H),4.24(s,2H),4.09(p,J=8.1Hz,1H),3.78(s,3H),3.61(p,J=8.6Hz,1H),2.61(dt,J=11.5,5.7Hz,1H),2.57–2.48(m,2H),2.48–2.33(m,3H),2.04–1.95(m,1H),1.95–1.85(m,1H).
实施例21
1-(6-(苯并[d]噁唑-2-基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲
(化合物327)的制备
1-(6-(苯并[d]噁唑-2-基)螺[3.3]庚-2-基)-3-(4-甲氧基苄基)脲。在室温下,将DCC(136mg,0.660mmol,1.05当量)添加到6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚烷-2-羧酸(200mg,0.628mmol,1当量)、2-氨基苯酚(75mg,0.691mmol,1当量)和DMAP(1mg,0.007mmol,0.01当量)在CH2Cl2(20mL)中的搅拌溶液中。14小时后,通过硅藻土垫过滤反应,并且通过旋转蒸发去除溶剂。将粗制的物质悬浮在甲苯(20mL)中,然后添加4-甲基苯磺酸(11mg,0.063mmol,0.1当量),并且将反应加热回流2小时。将反应冷却至室温,通过旋转蒸发去除溶剂,并通过反相HPLC(含有0.1%甲酸的5->95% MeCN/水)分离出为白色固体的产物(35mg,14%)。LRMS(ESI)m/z 392.1(M+H).1H NMR(400MHz,甲醇-d4)δ7.68–7.53(m,2H),7.41–7.32(m,2H),7.20(d,J=7.6Hz,2H),6.88(d,J=7.5Hz,2H),4.24(s,2H),4.10(p,J=8.4,7.7Hz,1H),3.83–3.67(m,4H),2.70–2.35(m,6H),1.97(dt,J=33.1,10.0Hz,2H).
实施例22
1-(4-氯苄基)-3-(6-(羟基(苯基)甲基)螺[3.3]庚-2-基)脲(化合物
328)的制备
1-(4-氯苄基)-3-(6-(羟基(苯基)甲基)螺[3.3]庚-2-基)脲。在0℃下,将苯基溴化镁(THF中的1M,652mL,0.652mmol,2当量)添加到1-(4-氯苄基)-3-(6-甲酰基螺[3.3]庚-2-基)脲(中间体11.1,100mg,0.326mmol,1当量)在THF(5mL)中的搅拌溶液中。2小时后,用饱和氯化铵(50mL)淬灭反应,用CH2Cl2(3x25mL)萃取,将有机物组合,在硫酸钠上干燥,过滤,并通过旋转蒸发去除溶剂。通过反相HPLC(含有0.1%甲酸的5->95% MeCN/水)分离出为白色固体的产物(13mg,10%)。LRMS(ESI)m/z 385.2(M+H).1H NMR(400MHz,甲醇-d4)δ7.34–6.94(m,9H),4.32(d,J=8.3Hz,1H),4.16(s,2H),3.88(dt,J=17.2,8.3Hz,2H),2.34(dt,J=15.8,7.8Hz,2H),2.19–2.05(m,2H),1.99–1.83(m,2H),1.79–1.58(m,4H).
下表中的化合物以与化合物328类似的方式制备,使用列出的中间体和试剂。
实施例23
1-(4-甲氧基苄基)-3-(6-(4-甲基苄基)螺[3.3]庚-2-基)脲(化合物334)的制备
1-(4-甲氧基苄基)-3-(6-(4-甲基苄基)螺[3.3]庚-2-基)脲。将(6-(3-(4-甲氧基苄基)脲基)螺[3.3]庚-2-基)4-甲基苯磺酸甲酯(中间体19.1,100mg,0.218mmol,1当量)、1-溴-4-甲苯(56mg,0.327mmol,1.5当量)、四丁基碘化铵(121mg,0.327mmol,1.5当量)、锌(43mg,0.654mmol,3当量)和Ni预催化剂(如Mennie,Katrina;Vara,Brandon;Levi,Samuel.Reductive sp3-sp2 Coupling Reactions Enable Late-Stage Modification ofPharmaceuticals.Organic Letters.2020,22,556-559中制备)(6mg,0.011mmol,0.05当量)在循环N2下放置5分钟,然后添加MeCN(5mL),将小瓶密封,并且将反应加热至90℃。14小时后,将反应冷却至室温,通过旋转蒸发去除溶剂,并通过反相HPLC(含有0.1%甲酸的5->95% MeCN/水)分离出为白色固体的产物。LRMS(ESI)m/z379.2(M+H).1H NMR(400MHz,甲醇-d4)δ7.19(d,J=8.2Hz,2H),7.06(d,J=7.7Hz,2H),7.00(d,J=7.7Hz,2H),6.87(d,J=8.1Hz,2H),4.22(s,2H),4.01(p,J=8.1Hz,1H),3.78(s,3H),2.61(d,J=7.6Hz,2H),2.41(dq,J=15.4,7.7,6.9Hz,2H),2.29(s,4H),2.15(t,J=10.0Hz,1H),2.02–1.92(m,1H),1.81(dd,J=16.7,7.6Hz,3H),1.75–1.66(m,1H).
下表中的化合物以与化合物334类似的方式制备,使用列出的中间体和试剂。
实施例24
1-(4-氯苄基)-3-(6-(吡啶-4基甲基)螺[3.3]庚-2-基)脲(化合物329)的制备
1-(4-氯苄基)-3-(6-(吡啶-4基甲基)螺[3.3]庚-2-基)脲。在23℃下,将Et3N(75mg,0.74mmol,2.0当量)和1-氯-4-(异氰酸甲基)苯(93mg,0.56mmol,1.5当量)添加到6-(吡啶-4-基甲基)螺[3.3]庚-2-胺(中间体22.1)(75mg,0.37mmol,1.0当量)在CH2Cl2(1mL)中的溶液中。在此温度下,将反应搅拌30分钟,然后将其直接浓缩,并且通过制备型HPLC(H2O(0.1% HCO2H)/MeCN(0.1% HCO2H))纯化,得到为无色油状物的1-(4-氯苄基)-3-(6-(吡啶-4基甲基)螺[3.3]庚-2-基)脲(70mg,51%)。LRMS(APCI+)m/z 370.10(M+H).1H NMR(400MHz,DMSO-d6)δ8.48(s,2H),7.35(d,J=8.4Hz,2H),7.30–7.17(m,4H),6.25(t,J=6.1Hz,1H),6.17(d,J=8.0Hz,1H),4.15(d,J=6.0Hz,2H),3.90(h,J=8.1Hz,1H),2.68(dd,J=7.6,1.8Hz,2H),2.40(p,J=7.9Hz,1H),2.30(ddd,J=10.8,7.3,5.2Hz,1H),2.17(ddd,J=12.1,7.3,5.2Hz,1H),2.09(ddd,J=11.3,7.7,3.9Hz,1H),1.93(ddd,J=11.6,7.7,4.0Hz,1H),1.75(q,J=9.0Hz,3H),1.68(dd,J=11.2,8.2Hz,1H).
下表中的化合物以与化合物329类似的方式制备,使用列出的中间体和试剂。
实施例25
1-(4-氯苄基)-3-(6-((4-氰基-1H-吡唑-1-基)甲基)螺[3.3]庚-2-基)脲(化合物333)的制备
1-(4-氯苄基)-3-(6-((4-氰基-1H-吡唑-1-基)甲基)螺[3.3]庚-2-基)脲。将Et3N(118mg,1.17mmol,3.0当量)和MsCl(89mg,0.777mmol,2.0当量)依次添加到1-(4-氯苄基)-3-(6-(羟基甲基)螺[3.3]庚-2-基)脲(中间体10.1,120mg,0.389mmol,1.0当量)在CH2Cl2(2mL)中的溶液中。在23℃下将混合物搅拌3小时,然后将其倒入半饱和NaHCO3溶液中。用CH2Cl2(5mL×2)萃取水相,并且用盐水洗涤合并的有机相,干燥(MgSO4),过滤并浓缩,得到不经过进一步纯化直接使用的粗制的甲磺酸酯。接下来,将K2CO3(107mg,0.777mmol,2.0当量)和1H-吡唑-4-甲腈(72mg,0.777mmol,2.0当量)添加到如此获得的甲磺酸酯(至多0.389mmol)在DMF(1mL)中的溶液中。在80℃下,将反应加热3小时。完成后,直接对反应进行制备型HPLC(H2O(0.1% HCO2H)/MeCN(0.1% HCO2H),得到为白色固体的1-(4-氯苄基)-3-(6-((4-氰基-1H-吡唑-1-基)甲基)螺[3.3]庚-2-基)脲(61mg,2步骤中40%)。LRMS(APCI+)m/z 384.15(M+H).1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.04(s,1H),7.36(d,J=8.4Hz,2H),7.24(d,J=8.2Hz,2H),6.25(t,J=6.1Hz,1H),6.17(d,J=8.0Hz,1H),4.15(d,J=6.7Hz,4H),3.90(h,J=8.2Hz,1H),2.60(hept,J=7.7Hz,1H),2.31(ddd,J=10.7,7.3,5.1Hz,1H),2.16(ddd,J=12.1,7.4,5.2Hz,1H),2.07(ddd,J=11.3,7.9,3.5Hz,1H),1.92(ddd,J=11.5,7.9,3.4Hz,1H),1.80(dd,J=11.3,8.2Hz,2H),1.74(dd,J=11.3,8.4Hz,2H).
下表中的化合物以与化合物333类似的方式制备,使用列出的中间体和试剂。
生物学实施例1
NMN荧光生化和NAD细胞测定
A.人重组酶测定
测定本文所述的化合物通过酶NAMPT刺激烟酰胺单核苷酸(NMN)合成的能力。人重组酶测定在缓冲的无细胞系统中使用重组酶和底物来测量化合物对酶活性的激活。测定条件密切模拟细胞环境。使用检测烟酰胺单核苷酸形成的测定来测量剂量反应。所有实验均以384孔格式执行。一般来讲,将含有不同浓度的测试化合物的0.5μL DMSO与10μL酶试剂溶液混合。通过添加10μL含有底物的溶液开始酶反应。最终测定条件如下:50mM HEPES,pH7.2、1mM DTT、1mM CHAPS50mM NaCl、100mM MgCl2中的6nM人NAMPT、2.5mM ATP、20μM PRPP和150μM烟酰胺。在环境温度下孵育60分钟后,添加10μL的20%苯乙酮在DMSO中的溶液,然后添加10μL的2M KOH和40μL的甲酸。在环境温度下孵育40分钟后,使用EnVision酶标仪读取板的荧光(激发/发射=355nm/460nm)。将化合物的效力测量值量化并且表示为AC1.4(生成比基础高40%的活性的化合物浓度)和EC50(产生半最大激活的化合物浓度)。表A示出了测试的化合物的AC1.4和EC50数据。
表A
ND=未确定
B.细胞NAD+调节测定。
还测定了本文所述的化合物在细胞NAD+调节测定中在天然细胞环境中刺激内源性NAMPT的能力,所述细胞NAD+调节测定测量化合物调节细胞NAD水平的能力。渗透细胞并激活内源性NAMPT的催化活性的化合物预期会增加NAD水平。
在37℃下,在具有95%空气和5% CO2的气氛的加湿孵育箱中,使神经母细胞瘤SH-SY5Y细胞在Eagle最低必需培养基(Eagle's Minimum Essential Medium)和F12培养基的1:1混合物以及10%胎牛血清中生长。通过将具有0.1%胎牛血清的培养基中的20μL SH-SY5Y细胞以5000个细胞/孔的密度接种到384孔CorningTM BioCoatTMPoly-D-Lysine多孔板中来开始测定。在37℃的孵育箱中,将板孵育5小时。使用Labcyte Echo Liquid Handler将DMSO中的化合物以120nL的体积添加到板中。将测定培养基中的5μL的1.5uM多柔比星(Doxorubicin)溶液添加到每个孔中。然后将板孵育40小时。30μL的读数溶液含有0.2U/mL心肌黄酶(Diaphorase enzyme)、40uM刃天青(resazurin)、10uM FMN、0.8U/mL乙醇脱氢酶、3%乙醇、0.4mg/mL牛血清白蛋白、100mM Tris-HCl中的0.2% Triton X-100、30mM EDTA,pH 8.4。在环境温度下孵育60分钟后,使用EnVision酶标仪读取板的荧光(激发/发射=540nm/590nm)。表B示出了测试的化合物的AC0.3和EC50数据。
表B
ND=未确定
本文提及的所有出版物、专利申请、专利和其他参考文献均明确地以引用方式整体并入,其程度如同每篇单独地以引用方式并入。
应当理解,虽然已经结合上述实施方案描述了本文提供的公开内容,但前述描述和实例旨在说明并且不限制本公开内容的范围。本公开范围内的其他方面、优点和修改对于本公开所属领域的技术人员将是显而易见的。
Claims (104)
1.一种式(II)的化合物:
或其药学上可接受的盐,
其中:
n为0至6;
或者
或者
Y1为-C(O)-N(Rq)-(Rs),其中Rq为H或C1-C6烷基,并且Rs为C3-C8环烷基、任选取代的C6-C14芳基、任选取代的5元至18元杂芳基、或-(C1-C6亚烷基)-(任选取代的C6-C14芳基),并且R1选自由以下组成的组:
或者
或者
或者
R2a和R2b各自独立地为卤基、-O(C1-C6烷基)、被-OH取代的C1-C6烷基、-C(O)NR2cR2d或-N(R2e)C(O)(C1-C6烷基);并且
R2c、R2d和R2e各自独立地为氢或C1-C6烷基;
G1为CH或N;
p1和p2各自独立地为0、1或2;
q1和q2各自独立地为1或2;
r为1、2或3;
R3选自由以下组成的组:
i.未取代的C1-C6烷基;
ii.C6-C14芳基;
iii.任选取代的5元至18元杂芳基;
iv.-NR3aR3b,其中
R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基);
v.-OR3c,其中
R3c为C6-C14芳基、5元至18元杂芳基、或-(C1-C6亚烷基)-(5元至18元杂芳基);
vi.-C(O)R3d,其中
R3d选自由以下组成的组:-NR3fR3g;C3-C8环烷基;被任选取代的C6-C14芳基取代的C3-C8环烷基;C3-C8环烯基;任选取代的C6-C14芳基;任选取代的–(C1-C6亚烷基)-(C6-C14芳基);任选取代的3元至18元杂环烷基;和任选取代的5元至18元杂芳基,
其中
R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选取代的C1-C6烷基,
(c)C6-C14芳基,
(d)任选取代的3元至18元杂环烷基,
(e)任选取代的5元至18元杂芳基,
(f)任选取代的C3-C10环烷基;和
(g)任选取代的C3-C10环烯基;
vii.被一个或多个-OH、-C(O)NR3hR3i、任选取代的C6-C14芳基、任选取代的3元至18元杂环烷基、任选取代的5元至18元杂芳基、-N(R3p)-C(O)R3q、-S(O)2-R3r或-C(O)-R3s取代的C1-C6烷基,
其中
R3h和R3i各自独立地选自C1-C6烷基和-(C1-C6亚烷基)-(C6-C14芳基),
R3p为H或C1-C6烷基,
R3q为C3-C8环烷基、任选取代的3元至18元杂环烷基、或任选取代的5元至18元杂芳基,
R3r为C6-C14芳基或5元至18元杂芳基,并且
R3s为任选取代的3元至18元杂环烷基;
viii.-C(O)OR3j,其中
R3j为氢或C1-C6烷基;
ix.-NHC(O)R3k,其中
R3k为任选取代的C6-C14芳基、任选取代的–(C1-C6亚烷基)-(C6-C14芳基)、或任选取代的5元至18元杂芳基;
x.-NHC(O)OR3l,其中
R3l为氢或C1-C6烷基;
xi.-NHSO2R3m,其中
R3m为任选取代的5元至18元杂芳基、任选取代的C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中每一种都是任选取代的;和
xii.-SO2R3n;其中
R3n为C1-C6烷基、任选取代的C3-C10环烷基、任选取代的C6-C14芳基、或任选取代的–(C1-C6亚烷基)-(C6-C14芳基);
R4为苯基或-C(O)NH-CH2-苯基;
R5a和R5b独立地选自由以下组成的组:氢、甲基、和-NHC(O)O(C1-C6烷基);并且
R6选自由以下组成的组:-C(O)OC(CH3)3、-NHC(O)O(C1-C6烷基)、-C(O)-(任选取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)、和5元至18元杂芳基,
前提条件是,当R6为-C(O)-(取代的苯基)、-C(O)-(C1-C6亚烷基)-(任选取代的苯基)、-C(O)-(任选取代的3元至18元杂环烷基)、-C(O)-(任选取代的5元至18元杂芳基)、-C(O)-(C1-C6亚烷基)-(任选取代的5元至18元杂芳基)、或5元至18元杂芳基时,那么(1)n为4或5,并且(2)R1选自由以下组成的组:
其中
3.如权利要求1或权利要求2所述的化合物或其药学上可接受的盐,其中p1为1并且q1为1。
4.如权利要求1或权利要求2所述的化合物或其药学上可接受的盐,其中p1为2并且q1为1。
5.如权利要求1或权利要求2所述的化合物或其药学上可接受的盐,其中p1为2并且q1为2。
6.如权利要求1-5中任一项所述的化合物或其药学上可接受的盐,其中p2为1并且q2为1。
7.如权利要求1-5中任一项所述的化合物或其药学上可接受的盐,其中p2为0并且q2为1。
8.如权利要求1-5中任一项所述的化合物或其药学上可接受的盐,其中p2为1并且q2为2。
9.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为未取代的C1-C6烷基。
10.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为C6-C14芳基。
11.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为任选被一个或多个Ra取代基取代的5元至18元杂芳基,其中Ra为C1-C6烷基、C6-C14芳基或5元至18元杂芳基,其中Ra的所述5元至18元杂芳基任选被一个或多个C1-C6烷基取代基取代。
12.如权利要求11所述的化合物或其药学上可接受的盐,其中R3为任选被一个或多个Ra取代基取代的吡啶基、嘧啶基、1,3,4-噁二唑基、噁唑基或苯并[d]噁唑基。
14.如权利要求1-8中任一项所述的化合物,或其药学上可接受的盐,其中R3为-NR3aR3b,其中R3a和R3b各自独立地选自由以下组成的组:氢、C6-C14芳基、5元至18元杂芳基、–(C1-C6亚烷基)-(C6-C14芳基)和–(C1-C6亚烷基)-(5元至18元杂芳基)。
16.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为OR3c,其中R3c为C6-C14芳基、5元至18元杂芳基或-(C1-C6亚烷基)-(5元至18元杂芳基)。
17.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-C(O)R3d。
18.如权利要求17所述的化合物或其药学上可接受的盐,其中R3d为-NR3fR3g,并且R3f和R3g各自独立地选自由以下组成的组:
(a)氢,
(b)任选被独立地选自由-OH、C6-C14芳基和5元至18元杂芳基组成的组的一个或多个取代基取代的C1-C6烷基,其中所述C6-C14芳基和5元至18元杂芳基各自独立地为未取代的或被独立地选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、羟基、C1-C6烷氧基、C1-C6卤代烷氧基和CN。
(c)C6-C14芳基,
(d)3元至18元杂环烷基,
(e)任选被甲基或CN取代的5元至18元杂芳基,
(f)任选被独立地自由以下组成的组的一个或多个取代基取代的C3-C10环烷基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基;和
(g)任选被独立地选自由以下组成的组的一个或多个取代基取代的C3-C10环烯基:卤基、羟基、任选被羟基取代的C1-C6烷基、C6-C14芳基和5元至18元杂芳基。
20.如权利要求17所述的化合物或其药学上可接受的盐,其中R3d为C3-C8环烷基。
21.如权利要求17所述的化合物或其药学上可接受的盐,其中R3d为被C6-C14芳基取代的C3-C8环烷基,其中所述C6-C14芳基任选被独立地选自由以下组成的组的一个或多个取代基取代:卤基、C1-C6烷基、C1-C6卤代烷基和C1-C6烷氧基。
23.如权利要求17所述的化合物或其药学上可接受的盐,其中R3d为C3-C8环烯基。
25.如权利要求案17所述的化合物或其药学上可接受的盐,其中R3d为任选被独立地选自由以下组成的组的一个或多个取代基取代的C6-C14芳基:羟基、卤基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、-(C1-C6亚烷基)-OH、-C(O)O(C1-C6烷基)、-NR3e1R3e2、-S(O)2(C1-C6烷基)、5元至18元杂芳基和任选被氧代基取代的3元至18元杂环烷基,其中R3e1和R3e2各自独立地为H或C1-C6烷基。
27.如权利要求17所述的化合物或其药学上可接受的盐,其中R3d为任选被独立地选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14芳基):卤基、C1-C6烷基、C1-C6卤代烷基、和C1-C6烷氧基。
29.如权利要求17所述的化合物或其药学上可接受的盐,其中R3d为任选被独立地选自由以下组成的组的一个或多个取代基取代的3元至18元杂环烷基:
(a)任选被独立地选自由以下组成的组的一个或多个取代基取代的C1-C6烷基:羟基、卤基、C3-C10环烷基和任选被一个或多个C1-C6烷基取代基取代的5元至18元杂芳基,
(b)C6-C14芳基,
(c)3元至18元杂环烷基,
(d)-C(O)O(C1-C6烷基),
(e)-C(O)(C6-C14烷基),
(f)卤基,
(g)任选被一个或多个卤基取代基取代的C1-C6烷氧基,和
(h)氧代基。
31.如权利要求17所述的化合物或其药学上可接受的盐,其中R3d为任选被独立地选自由以下组成的组的一个或多个取代基取代的5元至18元杂芳基:C1-C6烷基、羟基、氧代基和3元至18元杂环烷基。
33.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被C(O)NR3hR3i取代的C1-C6烷基,其中R3h和R3i各自独立地选自C1-C6烷基和–(C1-C6亚烷基)-(C6-C14芳基)。
35.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被3元至18元杂环烷基取代的C1-C6烷基,其中所述3元至18元杂环烷基任选被独立地选自卤基、氧代基、C1-C6烷基、C6-C14芳基和5元至18元杂芳基的一个或多个取代基取代。
37.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为C1-C6烷基,其中R3的所述C1-C6烷基(i)被5元至18元杂芳基取代,其中所述5元至18元杂芳基任选被一个或多个C1-C6烷基、C6-C14芳基或氰基取代,并且(ii)任选被一个或多个–OH取代。
39.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-C(O)OR3j,其中R3j为氢或C1-C6烷基。
41.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-NHC(O)R3k。
42.如权利要求41所述的化合物或其药学上可接受的盐,其中R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的C6-C14芳基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基、和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。
44.如权利要求41所述的化合物或其药学上可接受的盐,其中R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的–(C1-C6亚烷基)-(C6-C14芳基):C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基、和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。
46.如权利要求41所述的化合物或其药学上可接受的盐,其中R3k为任选被独立地选自由以下组成的组的一个或多个取代基取代的5元至18元杂芳基:C1-C6烷基、氰基、-NR3k1R3k2、羟基、烷氧基、和S(O)2(烷基),其中R3k1和R3k2各自独立地为氢或C1-C6烷基。
48.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-NHC(O)OR3l,其中R3l为氢或C1-C6烷基。
50.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-NHSO2R3m,其中R3m为5元至18元杂芳基、C6-C14芳基、或–(C1-C6亚烷基)-(C6-C14芳基),其中所述5元至18元杂芳基、所述C6-C14芳基和所述–(C1-C6亚烷基)-(C6-C14芳基)各自任选被独立地选自卤基和C1-C6烷氧基的一个或多个取代基取代。
52.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为-SO2R3n并且R3n为C1-C6烷基、C3-C10环烷基、C6-C14芳基或–(C1-C6亚烷基)-(C6-C14芳基),其中R3n的所述C3-C10环烷基、所述C6-C14芳基和所述–(C1-C6亚烷基)-(C6-C14芳基)各自独立地任选被独立地选自卤基和-C(O)O(C1-C6烷基)的一个或多个取代基取代。
54.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被一个或多个-N(R3p)-C(O)R3q取代的C1-C6烷基,其中R3p为H或C1-C6烷基,并且R3q为(i)C3-C8环烷基、(ii)任选被一个或多个独立选择的氧代基取代基取代的3元至18元杂环烷基、或(iii)任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至18元杂芳基。
56.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被一个或多个-S(O)2-R3r取代的C1-C6烷基,其中R3r为C6-C14芳基或5元至18元杂芳基。
58.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为被一个或多个-C(O)-R3s取代的C1-C6烷基,其中R3s为任选被一个或多个独立选择的C1-C6烷基取代基取代的3元至18元杂环烷基,其中所述C1-C6烷基独立地任选被一个或多个-OH取代。
60.如权利要求1-8中任一项所述的化合物或其药学上可接受的盐,其中R3为C1-C6烷基,其中R3的所述C1-C6烷基(i)被一个或多个独立选择的C6-C14芳基取代基取代,其中所述C6-C14芳基任选被一个或多个独立选择的C1-C6烷基取代基取代,并且(ii)任选被一个或多个-OH取代。
62.如权利要求1-61中任一项所述的化合物或其药学上可接受的盐,其中G1为CH。
63.如权利要求1-61中任一项所述的化合物或其药学上可接受的盐,其中G1为N。
66.如权利要求65所述的化合物或其药学上可接受的盐,其中r为1。
67.如权利要求65所述的化合物或其药学上可接受的盐,其中r为2。
69.如权利要求68所述的化合物或其药学上可接受的盐,其中R4为苯基。
70.如权利要求68所述的化合物或其药学上可接受的盐,其中R4为-C(O)NH-CH2-苯基。
72.如权利要求71所述的化合物或其药学上可接受的盐,其中R5a选自由以下组成的组:氢、甲基和-NHC(O)O(C1-C6烷基)。
73.如权利要求71或权利要求72所述的化合物或其药学上可接受的盐,其中R5b选自由以下组成的组:氢、甲基和-NHC(O)O(C1-C6烷基)。
75.如权利要求74所述的化合物或其药学上可接受的盐,其中R6选自由以下组成的组:
(a)-C(O)OC(CH3)3;
(b)-NHC(O)O(C1-C6烷基);
(c)-C(O)-(苯基),其中所述苯基任选被独立地选自C1-C6烷基、C1-C6卤代烷基和5元至18元杂芳基的一个或多个取代基取代;
(d)-C(O)-(C1-C6亚烷基)-(苯基),其中所述苯基任选被一个或多个独立选择的C1-C6烷基取代基取代;
(e)-C(O)-(3元至18元杂环烷基),其中所述3元至18元杂环烷基任选被一个或多个独立选择的氧代基或C1-C6烷基取代基取代;
(f)-C(O)-(5元至18元杂芳基),其中所述5元至18元杂芳基任选被一个或多个独立选择的C1-C6烷基取代基取代;
(g)-C(O)-(C1-C6亚烷基)-(5元至18元杂芳基),其中所述5元至18元杂芳基任选被一个或多个独立选择的C1-C6烷基取代基取代;和
(h)5元至18元杂芳基。
76.如权利要求75所述的化合物或其药学上可接受的盐,其中R6为-C(O)-(苯基),其中所述苯基任选被一个或多个C1-C6烷基、C1-C6卤代烷基或5元至18元杂芳基取代。
78.如权利要求1所述的化合物或其药学上可接受的盐,其中Y1为-C(O)-N(Rq)-(Rs),其中Rq为H或C1-C6烷基,并且Rs为
(a)C3-C8环烷基;
(b)任选被独立地选自卤基、C1-C6烷基和C6-C14芳基的一个或多个取代基取代的C6-C14芳基;
(c)任选被一个或多个C1-C6烷基取代的5元至18元杂芳基;或
(d)-(C1-C6亚烷基)-(C6-C14芳基),其中所述-(C1-C6亚烷基)-(C6-C14芳基)的所述C6-C14芳基任选被一个或多个C1-C6烷基取代。
80.如权利要求1所述的化合物或其药学上可接受的盐,其中Y1为-C(O)-Rb,其中Rb为任选被一个或多个C1-C6烷基取代的3元至18元杂环烷基,其中所述C1-C6烷基任选被一个或多个-OH取代。
82.如权利要求1所述的化合物或其药学上可接受的盐,其中Y1为-N(Rt)-C(O)Ru,其中Rt为H或C1-C6烷基,并且Ru为
(a)任选被一个或多个独立选择的C1-C6烷基或卤基取代基取代的C6-C14芳基;
(b)任选被一个或多个独立选择的C1-C6烷基取代基取代的5元至18元杂芳基;或
(c)-(C1-C6亚烷基)-(5元至18元杂芳基)。
85.如权利要求1-63、65、66和68-77中任一项所述的化合物或其药学上可接受的盐,其中n为0。
86.如权利要求1-63、65、66和68-77中任一项所述的化合物或其药学上可接受的盐,其中n为1。
87.如权利要求1-63和65-77中任一项所述的化合物或其药学上可接受的盐,其中n为2。
88.如权利要求1-63和65-77中任一项所述的化合物或其药学上可接受的盐,其中n为3。
89.如权利要求1-84中任一项所述的化合物或其药学上可接受的盐,其中n为4。
90.如权利要求1-84中任一项所述的化合物或其药学上可接受的盐,其中n为5。
91.如权利要求1-77中任一项所述的化合物或其药学上可接受的盐,其中n为6。
100.一种化合物,其选自由表1的化合物或其药学上可接受的盐组成的组。
101.一种药物组合物,其包含根据权利要求1-100中任一项所述的化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂。
102.一种治疗有需要的受试者的由NAMPT活性介导的疾病或疾患的方法,其包括向所述受试者施用权利要求1-100中任一项所述的化合物或其药学上可接受的盐、或权利要求101所述的药物组合物。
103.如权利要求102所述的方法,其中所述疾病或疾患选自由以下组成的组:癌症、过度增殖性疾病或疾患、炎性疾病或疾患、代谢障碍、心脏疾病或疾患、化疗诱导的组织损伤、肾脏疾病、代谢疾病、神经系统疾病或损伤、神经退行性病症或疾病、干细胞功能受损引起的疾病、DNA损伤引起的疾病、原发性线粒体病症、或肌肉疾病或肌肉萎缩症。
104.如权利要求102所述的方法,其中疾病或疾患选自由以下组成的组:肥胖症、动脉粥样硬化、胰岛素抵抗、2型糖尿病、心血管疾病、阿尔茨海默病、亨廷顿病、帕金森病、肌萎缩侧索硬化症、抑郁症、唐氏综合症、新生儿神经损伤、衰老、轴索变性、腕管综合征、格林-巴利综合征、神经损伤、脊髓灰质炎和脊髓损伤。
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