TWI429438B - 聚(adp-核糖)聚合酶抑制劑 - Google Patents
聚(adp-核糖)聚合酶抑制劑 Download PDFInfo
- Publication number
- TWI429438B TWI429438B TW096150907A TW96150907A TWI429438B TW I429438 B TWI429438 B TW I429438B TW 096150907 A TW096150907 A TW 096150907A TW 96150907 A TW96150907 A TW 96150907A TW I429438 B TWI429438 B TW I429438B
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- Taiwan
- Prior art keywords
- methyl
- phenyl
- hexahydronaphthyridin
- fluoro
- formula
- Prior art date
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- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 title claims description 28
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 title claims description 28
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 title claims description 25
- 239000003112 inhibitor Substances 0.000 title description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 349
- -1 Pyridin-1-yl Chemical group 0.000 claims description 245
- 150000001875 compounds Chemical class 0.000 claims description 228
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 222
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 16
- 125000003386 piperidinyl group Chemical group 0.000 claims description 15
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 238000001959 radiotherapy Methods 0.000 claims description 12
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 6
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229960002949 fluorouracil Drugs 0.000 claims description 6
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 6
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 5
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 5
- 229960004397 cyclophosphamide Drugs 0.000 claims description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 5
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 5
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 4
- OLBVUFHMDRJKTK-UHFFFAOYSA-N [N].[O] Chemical compound [N].[O] OLBVUFHMDRJKTK-UHFFFAOYSA-N 0.000 claims description 4
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 4
- 229940127089 cytotoxic agent Drugs 0.000 claims description 4
- 229960003901 dacarbazine Drugs 0.000 claims description 4
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 4
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 4
- 229960005277 gemcitabine Drugs 0.000 claims description 4
- 229960001924 melphalan Drugs 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004964 temozolomide Drugs 0.000 claims description 4
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims description 3
- 108010006654 Bleomycin Proteins 0.000 claims description 3
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- 229960001561 bleomycin Drugs 0.000 claims description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 3
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 3
- 229940127093 camptothecin Drugs 0.000 claims description 3
- 229960004562 carboplatin Drugs 0.000 claims description 3
- 229960005243 carmustine Drugs 0.000 claims description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
- 229960004316 cisplatin Drugs 0.000 claims description 3
- 235000008191 folinic acid Nutrition 0.000 claims description 3
- 239000011672 folinic acid Substances 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 229960001691 leucovorin Drugs 0.000 claims description 3
- 229960002247 lomustine Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 3
- 229960000303 topotecan Drugs 0.000 claims description 3
- 229960004768 irinotecan Drugs 0.000 claims description 2
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 408
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 253
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 132
- 229910005965 SO 2 Inorganic materials 0.000 description 131
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
- 229910052731 fluorine Inorganic materials 0.000 description 110
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 109
- 229910052794 bromium Inorganic materials 0.000 description 109
- 229910052801 chlorine Inorganic materials 0.000 description 109
- 238000000034 method Methods 0.000 description 103
- 229910052740 iodine Inorganic materials 0.000 description 95
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 91
- 150000001924 cycloalkanes Chemical class 0.000 description 87
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 85
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- 150000002390 heteroarenes Chemical class 0.000 description 70
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 49
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- 125000000392 cycloalkenyl group Chemical group 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 32
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
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- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 19
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- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 16
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- DIZKLZKLNKQFGB-UHFFFAOYSA-N 1-methylcyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(C)CC1 DIZKLZKLNKQFGB-UHFFFAOYSA-N 0.000 description 14
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
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- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 13
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 13
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 10
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D237/14—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Description
本發明有關聚(ADP-核糖)聚合酶抑制劑、該抑制劑之製法及使用該抑制劑治療患者之方法。
聚(ADP-核糖)聚合酶(PARP)對於幫助DNA修復、控制RNA轉錄、中介細胞死亡及調節免疫反應係屬必要。此種活性使得PARP抑制劑成為許多病症之標靶。PARP抑制劑已證明可使用於治療疾病,諸如局部缺血再灌流損傷、發炎性疾病、逆轉錄病毒感染、局部缺血再灌流損傷、心肌梗塞、中風及其他神經創傷、器官移植、眼睛、腎臟、腸及骨骼肌之再灌流、關節炎、痛風、發炎性腸疾、CNS發炎諸如MS及過敏性腦炎、敗血症、敗血性休克、出血性休克、肺纖維化及葡萄膜炎、糖尿病及帕金森氏症、乙醯胺酚過量後之肝中毒、來自多柔比星(doxorubicin)及以鉑為主之抗腫瘤劑的心臟及腎臟中毒及硫芥子氣繼發之皮膚損傷。PARP抑制劑亦已證明藉由增加癌細胞之細胞死亡、限制腫瘤生長、減少轉移及延長帶有腫瘤之動物的存活性而增強放射及化學療法。
US 2002/0183325 A1描述作為PARP抑制劑之二氮雜萘酮衍生物。US 2004/0023968 A1描述作為PARP抑制劑之二氮雜萘酮衍生物。US 2005/0085476 A1描述作為PARP抑制劑之稠合噠嗪衍生物。US 2005/0059663 A1描述作為PARP抑制劑之二氮雜萘酮衍生物。US 2006/0063767 A1描述作為
PARP抑制劑之二氮雜萘酮衍生物。US 2006/0142293 A1描述作為PARP抑制劑之二氮雜萘酮衍生物。US 2006/0149059 A1描述作為PARP抑制劑之二氮雜萘酮衍生物。US 2007/0093489 A1描述作為PARP抑制劑之二氮雜萘酮衍生物。
因此,醫療界需要PARP抑制劑。該等化合物可用以治療患有癌症之患者,可進一步擴展該等患者可使用之治療選擇範圍。
本發明之一具體實施態樣因此係有關抑制聚(ADP-核糖)聚合酶之活性且具有式I之化合物
及其醫藥上可接受之鹽,其中A1
係為R1
或R2
,其中A1
係未經取代或經一或兩個以下基團所取代:OH、CN、C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基、C5
-烷基、環烷、ORA
或NRA
RA
; RA
係為H或烷基;R1
係為環烷或環烯,其各未稠合或與R1A
稠合;R1A
係為苯、雜芳烴、環烷、環烯、雜環烷或雜環烯;R2
係為雜環烷或雜環烯;其各未稠合或與R2A
稠合;R2A
係為苯、雜芳烴、環烷、環烯、雜環烷或雜環烯;
A2
係為OR4
、NHR4
、N(R4
)2
、SR4
、S(O)R4
、SO2
R4
或R5
;其中各R4
係為C1
-烷基、C2
-烷基或C3
-烷基;其各經R10
所取代;R5
係為C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基或C5
-烷基;其各經R10
所取代,且未進一步經取代或進一步經一或二或三個獨立選自以下之基團所取代:OR10
、NHR10
、N(R10
)2
、SR10
、S(O)R10
、SO2
R10
或CF3
;其中各R10
係為R10A
、R10B
或R10C
;其各須連接於碳原子;R10A
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;
R10B
係為 或;其各未稠合或
與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R10C
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;
其中各R10
係獨立地未經取代或經一或二或三個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、NHR11
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NH2
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NR11
C(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NR11
C(O)OR|1
、NHSO2
NH2
、NHSO2
NHR11
、NHSO2
N(R11
)2
、SO2
NH2
、SO2
NHR11
、SO2
N(R11
)2
、NHC(O)NH2
、NHC(O)NHR11
、NHC(O)N(R11
)2
、NR11
C(O)N(R11
)2
、NO2
、OH、(O)、C(O)H、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;其中各R11
係為R12
、R13
、R14
或R15
; R12
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R13
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R14
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R15
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、
C(O)NH2
、C(O)NHR16
、C(O)N(R16
)2
、NHC(O)R16
、NR16
C(O)R16
、NHC(O)OR16
、NR16
C(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R18
、C(O)OH、NH2
、NHR18
或N(R18
)2
、C(O)R18
、C(O)NH2
、C(O)NHR18
、C(O)N(R18
)2
、NHC(O)R18
、NR18
C(O)R18
、F、Cl、Br或I; R17A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其中各R18
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、S(O)R19
、SO2
R19
、C(O)R19
、CO(O)R19
、OC(O)R19
、OC(O)OR19
、NH2
、NHR19
、N(R19
)2
、NHC(O)R19
、NR19
C(O)R19
、NHS(O)2
R19
、NR19
S(O)2
R19
、NHC(O)OR19
、NR19
C(O)OR19
、NHC(O)NH2
、NHC(O)NHR19
、NHC(O)N(R19
)2
、NR19
C(O)NHR19
、NR19
C(O)N(R19
)2
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)NHOH、C(O)NHOR19
、C(O)NHSO2
R19
、C(O)NR19
SO2
R19
、SO2
NH2
、SO2
NHR19
、SO2
N(R19
)2
、C(O)H、C(O)OH、C(N)NH2
、C(N)NHR19
、C(N)N(R19
)2
、
CNOH、CNOCH3
、OH、(O)、CN、N3
、NO2
、CF3
、CF2
CF3
、OCF3
、OCF2
CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R21
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R22
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R23
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R24
、OR24
、SR24
、S(O)2
R24
、C(O)OH、NH2
、NHR24
、N(R24
)2
、C(O)R24
、C(O)NH2
、C(O)NHR24
、C(O)N(R24
)2
、NHC(O)R24
、NR24
C(O)R24
、NHC(O)OR24
、NR24
C(O)OR24
、NHS(O)2
R24
、NR24
S(O)2
R24
、OH、F、Cl、Br或I;其中各R24
係為R24A
或R24B
; R24A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R24B
係為烷基、烯基或炔基,其各係未經取代或經一或
兩個獨立選自以下之基團所取代:R25
、OR25
、SR25
、S(O)2
R25
、C(O)OH、NH2
、NHR25
、N(R25
)2
、C(O)R25
、C(O)NH2
、C(O)NHR25
、C(O)N(R25
)2
、NHC(O)R25
、NR25
C(O)R25
、NHC(O)OR25
、NR25
C(O)OR25
、OH、F、Cl、Br或I;其中各R25
係為烷基、苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其各係未經取代或經NH2
、NH(CH3
)、N(CH3
)2
、OH或OCH3
所取代;其中由R20
、R21
、R22
及R24
所表示之部分各獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、烯基、炔基、苯基、OH、(O)、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;且R26
係為烷基。
再另一具體實施態樣包含醫藥組合物,其包含具有式I之化合物及賦形劑。
再另一具體實施態樣包含抑制哺乳類PARP之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類癌症之方法,其包含投予治療可接受量之具有式I之化合物
或其鹽,其中
A1
係為R1
或R2
,其中A1
係未經取代或經一或兩個以下基團所取代:OH、CN、C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基、C5
-烷基、環烷、ORA
或NRA
RA
; RA
係為H或烷基;R1
係為環烷或環烯,其各未稠合或與R1A
稠合;R1A
係為苯、雜芳烴、環烷、環烯、雜環烷或雜環烯;R2
係為雜環烷或雜環烯;其各未稠合或與R2A
稠合;R2A
係為苯、雜芳烴、環烷、環烯、雜環烷或雜環烯;A2
係為OR4
、NHR4
、N(R4
)2
、SR4
、S(O)R4
、SO2
R4
或R5
;其中各R4
係為C1
-烷基、C2
-烷基或C3
-烷基;其各經R10
所取代;R5
係為C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基或C5
-烷基;其各經R10
所取代,且未進一步經取代或進一步經一或二或三個獨立選自以下之基團所取代:OR10
、NHR10
、N(R10
)2
、SR10
、S(O)R10
、SO2
R10
或CF3
;其中各R10
係為R10A
、R10B
或R10C
;其各須連接於碳原子;R10A
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;
R10B
係為 或;其各未稠合或
與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R10C
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其中各R10
係獨立地未經取代或經一或二或三個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、NHR11
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NH2
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NR11
C(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NR11
C(O)OR11
、NHSO2
NH2
、NHSO2
NHR11
、NHSO2
N(R11
)2
、SO2
NH2
、SO2
NHR11
、SO2
N(R11
)2
、NHC(O)NH2
、NHC(O)NHR11
、NHC(O)N(R11
)2
、NR11
C(O)N(R11
)2
、NO2
、OH、(O)、C(O)H、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;其中各R11
係為R12
、R13
、R14
或R15
; R12
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R13
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環
烷、環烯、雜環烷或雜環烯稠合;R14
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R15
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NH2
、C(O)NHR16
、C(O)N(R16
)2
、NHC(O)R16
、NR16
C(O)R16
、NHC(O)OR16
、NR16
C(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R18
、C(O)OH、NH2
、NHR18
或N(R18
)2
、C(O)R18
、C(O)NH2
、C(O)NHR18
、C(O)N(R18
)2
、NHC(O)R18
、NR18
C(O)R18
、F、Cl、Br或I; R17A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其中各R18
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、S(O)R19
、SO2
R19
、C(O)R19
、
CO(O)R19
、OC(O)R19
、OC(O)OR19
、NH2
、NHR19
、N(R19
)2
、NHC(O)R19
、NR19
C(O)R19
、NHS(O)2
R19
、NR19
S(O)2
R19
、NHC(O)OR19
、NR19
C(O)OR19
、NHC(O)NH2
、NHC(O)NHR19
、NHC(O)N(R19
)2
、NR19
C(O)NHR19
、NR19
C(O)N(R19
)2
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)NHOH、C(O)NHOR19
、C(O)NHSO2
R19
、C(O)NR19
SO2
R19
、SO2
NH2
、SO2
NHR19
、SO2
N(R19
)2
、C(O)H、C(O)OH、C(N)NH2
、C(N)NHR19
、C(N)N(R19
)2
、CNOH、CNOCH3
、OH、(O)、CN、N3
、NO2
、CF3
、CF2
CF3
、OCF3
、OCF2
CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R21
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R22
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R23
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R24
、OR24
、SR24
、S(O)2
R24
、C(O)OH、NH2
、NHR24
、N(R24
)2
、C(O)R24
、
C(O)NH2
、C(O)NHR24
、C(O)N(R24
)2
、NHC(O)R24
、NR24
C(O)R24
、NHC(O)OR24
、NR24
C(O)OR24
、NHS(O)2
R24
、NR24
S(O)2
R24
、OH、F、Cl、Br或I;其中各R24
係為R24A
或R24B
; R24A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R24B
係為烷基、烯基或炔基,其各係未經取代或經一或兩個獨立選自以下之基團所取代:R25
、OR25
、SR25
、S(O)2
R25
、C(O)OH、NH2
、NHR25
、N(R25
)2
、C(O)R25
、C(O)NH2
、C(O)NHR25
、C(O)N(R25
)2
、NHC(O)R25
、NR25
C(O)R25
、NHC(O)OR25
、NR25
C(O)OR25
、OH、F、Cl、Br或I;其中各R25
係為烷基、苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其各係未經取代或經NH2
、NH(CH3
)、N(CH3
)2
、OH或OCH3
所取代;其中R20
、R21
、R22
及R24
所表示之部分各獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、烯基、炔基、苯基、OH、(O)、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;且R26
係為烷基。
再另一具體實施態樣包含縮減哺乳類腫瘤體積之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含式I化合物之用途,其係用於
製備供治療癌症使用之藥劑。
再另一具體實施態樣包含一種治療哺乳類白血病、結腸癌、膠質母細胞瘤、淋巴瘤、黑色素瘤、乳腺癌或子宮頸癌之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含式I化合物之用途,其係用於製備供治療白血病、結腸癌、膠質母細胞瘤、淋巴瘤、黑色素瘤、乳腺癌或子宮頸癌使用的藥劑。
再另一具體實施態樣包含增強哺乳類之胞毒性癌症療法的方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含增強哺乳類之放射療法的方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類與心肌梗塞、中風、神經創傷或器官移植有關之局部缺血再灌流損傷的方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類眼睛、腎臟、腸或骨骼肌之再灌流的方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類關節炎、痛風、發炎性腸疾、CNS發炎、多發性硬化、過敏性腦炎、敗血症、敗血性休克、出血性休克、肺纖維化或葡萄膜炎之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含一種治療哺乳類類風濕性關節炎或敗血性休克之方法,其包含投予治療可接受量之具有
式I之化合物。
再另一具體實施態樣包含治療哺乳類糖尿病或帕金森氏症之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類血糖過低之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類逆轉錄病毒感染之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類乙醯胺酚過量後之肝中毒的方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類來自多柔比星(doxorubicin)或以鉑為主之抗腫瘤劑的心臟或腎臟中毒之方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含治療哺乳類硫芥子氣繼發之皮膚損傷的方法,其包含投予治療可接受量之具有式I之化合物。
再另一具體實施態樣包含以下化合物2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苄酸;4-(3-胺基-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)胺基)-4-側氧基丁酸;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)
苯基)吡咯啶-2,5-二酮;4-(3-(1,4-二氮-1-基羰基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(胺基甲基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((二甲基胺基)甲基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((異丙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((環己基胺基)甲基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((四氫-2H-哌喃-4-基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((甲基((1-甲基吡咯啶-3-基)甲基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((甲基(((2R)-1-甲基吡咯啶-2-基)甲基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((環丙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((異丙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(嗎啉-4-基甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(吡咯啶-1-基甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-
酮;4-(3-((環己基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((甲基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((乙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-甲基哌啶-1-基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(((2-(4-(三氟甲基)苯基)乙基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((環己基(甲基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((2-乙基吡咯啶-1-基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((環丙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((異丙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-(嗎啉-4-基甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-(吡咯啶-1-基甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((環己基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-
1(2H)-酮;4-(4-((4-苯基哌啶-1-基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((甲基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((乙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((4-甲基哌啶-1-基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-(((2-(3-(三氟甲基)苯基)乙基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((環己基(甲基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((2-甲基吡咯啶-1-基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-((4-甲基-1,4-二氮-1-基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-甲基-1,4-二氮-1-基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-嘧啶-2-基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-吡啶-3-基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-吡啶-4-基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-
酮;N,N-二乙基-2'-氟-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-2-甲醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-哌啶-1-基丙醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-(4-甲基哌嗪-1-基)丙醯胺;2-胺基-N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;3-環己基-N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)哌啶-3-甲醯胺;4-(4-氟-3-(2-側氧基吡咯啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吖丁啶-3-甲醯胺;N-(2-(異丙基胺基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-嗎啉-4-基乙醯胺;N-(2-嗎啉-4-基乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-
吡咯啶-1-基乙基)苯甲醯胺;4-(3-((2-甲基吡咯啶-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-氮-1-基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;4-(3-(哌嗪-1-基羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-吖丁啶-3-基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-哌啶-3-基苯甲醯胺;N-(4-(二甲基胺基)苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(4-甲基哌嗪-1-基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;4-(3-((4-(異噁唑-5-基羰基)哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-苯基哌啶-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(哌啶-2-基甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(哌啶-4-基甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-
哌啶-1-基乙基)苯甲醯胺;N-(1-甲基吖丁啶-3-基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;4-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲酸甲酯;N-甲基-4-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;4-((2-(甲硫基)嘧啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-(甲基磺醯基)嘧啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-(甲基亞磺醯基)嘧啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((3-溴吡啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((6-溴吡啶-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-溴吡啶-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;6-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲酸甲酯;N-乙基-4-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-異丙基-4-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-環己基-4-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;
N-((1-甲基哌啶-2-基)甲基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-((1-甲基哌啶-4-基)甲基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-甲基-6-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-乙基-6-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-異丙基-6-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-環丙基-6-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-環己基-6-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲酸甲酯;5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲酸甲酯;4-((5-溴噻吩-2-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((3-溴噻吩-2-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-胺基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-溴苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(噻吩-2-基甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)噻吩-2-
甲酸甲酯;N-甲基-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-乙基-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-甲基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N-乙基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-甲醯胺;N,N-二甲基-N'-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)磺醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-哌啶-1-基丙醯胺;4-氯-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丁醯胺;4-(3-(2-側氧基吡咯啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-(2-側氧基吖丁啶-1-基)吡啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-(2-側氧基吡咯啶-1-基)吡啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-溴吡啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((6-(2-側氧基吡咯啶-1-基)吡啶-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;
4-((6-(2-側氧基吖丁啶-1-基)吡啶-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-基)苯甲醯胺;N-(5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-基)異菸醯胺;N-(5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-基)菸醯胺;4-((5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-2,2'-聯吡啶-5-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-甲基-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)噻吩-2-甲醯胺;N1
-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)甘胺醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吖丁啶-2-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吖丁啶-3-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)甲烷磺醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙烷-2-磺醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯磺醯胺;
N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡啶-3-磺醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)呋喃-2-磺醯胺;1-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1H-咪唑-4-磺醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)噻吩-2-磺醯胺;4-氰基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯磺醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)萘-1-磺醯胺;4-((6-溴吡啶-2-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((6-(2-側氧基吡咯啶-1-基)吡啶-2-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(6-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)吡啶-2-基)苯甲醯胺;4-((3'-((異丙基胺基)甲基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((3'-((環戊基胺基)甲基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((3'-((2-甲基吡咯啶-1-基)甲基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((3'-((環丙基胺基)甲基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四
氫二氮雜萘-1(2H)-酮;4-((3'-((環丁基胺基)甲基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-溴-1-伸氧基吡啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((1-伸氧基-2-(2-側氧基吡咯啶-1-基)吡啶-4-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)噻吩-3-甲酸甲酯;4-(3-((4-(2-(2-(2-胺基乙氧)乙氧)乙基)-1,4-二氮-1-基)羰基)-4-氟苄基)二氮雜萘-1(2H)-酮;1-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)環丙烷甲醯胺;2-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)環丙烷甲醯胺;3-乙氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙醯胺;5-側氧基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-L-脯胺醯胺;5-側氧基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-D-脯胺醯胺;N1
-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)環丙烷-1,1-二甲醯胺;2-(苄基氧基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-
1-基)甲基)苯基)乙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-苯基丙醯胺;3-(2,5-二甲氧苯基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1-苯基環丙烷甲醯胺;(2S)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-苯基丁醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-苯基丁醯胺;2-(3-甲基苯氧基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;2-(2-甲基苯氧基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;2-(4-甲基苯氧基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;(2R)-2-甲氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-苯基乙醯胺;(2S)-2-甲氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-苯基乙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-苯氧基丙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯
基)-4-噻吩-2-基丁醯胺;1-乙醯基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)哌啶-4-甲醯胺;2-(3,5-二氟苯基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;N2
-乙醯基-N1
-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-L-白胺醯胺;N1
-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-N2
,N2
-二丙基-L-苯胺醯胺;4-側氧基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-苯基丁醯胺;N-(2-側氧基-2-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基胺基)乙基)苯甲醯胺;3-(3-甲氧苯基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙醯胺;3-(4-甲氧苯基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙醯胺;2-(3,4-二甲基苯氧基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;(2R)-2-羥基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-苯基丁醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-苯氧基丁醯胺;4-側氧基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)
甲基)苯基)-4-噻吩-2-基丁醯胺;2-((4-甲基嘧啶-2-基)硫基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;3-(2-氯苯基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙醯胺;3-(4-氯苯基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丙醯胺;3-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-苯基戊醯胺;2-(4-氯-2-甲基苯氧基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-N'-苯基戊烷二醯胺;4-(4-甲氧苯基)-4-側氧基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)丁醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2,2-二苯基乙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-(苯基磺醯基)丙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-(3-苯氧基苯基)乙醯胺;4-乙基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;3-氟-2-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-
基)甲基)苯基)苯甲醯胺;5-氟-2-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;3-氟-4-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2,3-二氟-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2,4-二氟-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2,5-二氟-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;3,5-二氟-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-丙基苯甲醯胺;4-異丙基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2-乙氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;4-異丙氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;4-(二乙基胺基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;4-丁氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲
基)苯基)苯甲醯胺;2-氟-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-5-(三氟甲基)苯甲醯胺;2-氯-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-5-(三氟甲基)苯甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-糠醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-糠醯胺;2,5-二甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-糠醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)噻吩-2-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)噻吩-3-甲醯胺;3-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)噻吩-2-甲醯胺;5-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)噻吩-2-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1H-吡咯-2-甲醯胺;1-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1H-吡咯-2-甲醯胺;2,5-二甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-
基)甲基)苯基)-1H-吡咯-3-甲醯胺;1,2,5-三甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1H-吡咯-3-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1,3-噻唑-2-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1,3-噻唑-4-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1,3-噻唑-5-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)異噁唑-5-甲醯胺;3,5-二甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)異噁唑-4-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)菸醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)異菸醯胺;3-羥基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡啶-2-甲醯胺;2-羥基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)菸醯胺;6-羥基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)菸醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯
基)-2-吡啶-2-基乙醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-吡啶-3-基乙醯胺;5-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡嗪-2-甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1H-吲哚-3-甲醯胺;5-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1-苯基-1H-吡唑-4-甲醯胺;6-氯-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2H-色烯-3-甲醯胺;N3
,N3
-二甲基-N1
-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-β-苯胺醯胺;4-(2-(3-溴苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(3-溴-4-氟苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2,2,2-三氟-1-苯基乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;2-羥基-4-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;4-乙醯基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;3-甲氧-4-甲基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;
4-乙氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;3-氟-4-甲氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-1-萘醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-萘醯胺;5-氯-2-羥基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;4-第三丁基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;4-(乙醯基胺基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-丙氧苯甲醯胺;1-羥基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-萘醯胺;2-氯-5-(甲硫基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;3,4-二乙氧-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2-苄基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;
2-苯胺基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2-苄醯基-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-(2-苯基乙基)苯甲醯胺;5-溴-2-氯-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2-(4-甲基苄醯基)-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;2-碘-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;3-碘-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;4-碘-N-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)苯甲醯胺;N-(2'-氟-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-3-基)乙醯胺;4-((6-氟-3'-(甲基磺醯基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((6-氟-3'-(吡咯啶-1-基羰基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((6-氟-4'-(吡咯啶-1-基羰基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;
2'-氟-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-3-甲醯胺;2'-氟-N,N-二甲基-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-4-甲醯胺;4-(3,3,3-三氟-2-苯基丙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-苯基乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(3-溴苯基)丙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;2-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)哌嗪-1-甲酸第三丁酯;2-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)哌嗪-1,4-二甲酸4-苄酯1-第三丁酯;4-(2-(3-硝基苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(3-胺基苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(哌嗪-2-基甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(3-(2-側氧基吡咯啶-1-基)苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苯基)-2-苯氧基乙醯胺;4-(2-(6-氟-3'-(嗎啉-4-基羰基)-1,1'-聯苯-3-基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苄酸甲酯;3-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙
基)苄酸甲酯;4-(2-(6-氟-4'-(嗎啉-4-基羰基)-1,1'-聯苯-3-基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(6-氟-2'-(吡咯啶-1-基羰基)-1,1'-聯苯-3-基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(6-氟-3'-(吡咯啶-1-基羰基)-1,1'-聯苯-3-基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-環丙基-2'-氟-5'-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;N-(2-(二甲基胺基)乙基)-2'-氟-5'-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;2'-氟-5'-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;N-(2'-氟-5'-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-基)甲烷磺醯胺;N-(2'-氟-5'-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-基)乙醯胺;4-(2-(6-氟-3'-(嗎啉-4-基羰基)-1,1'-聯苯-3-基)丙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(6-氟-3'-(吡咯啶-1-基羰基)-1,1'-聯苯-3-基)丙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-環丙基-2'-氟-5'-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;4-(3-胺基-4-氯苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;
4-(3-胺基-4-甲氧苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-胺基-4-羥基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-胺基-4-甲基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(2-(二甲基胺基)乙基)-3'-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;3'-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;N-(3'-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-基)乙醯胺;3'-(1-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;N-(3'-(1-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-基)乙醯胺;N-(2-(二甲基胺基)乙基)-3'-(1-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;3-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苄酸;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-(4-甲氧苯基)-4-側氧基丁醯胺;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3,4-二甲基-1H-吡咯-2,5-二酮;3-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-氮雜雙環(3.1.0)己烷-2,4-二酮;
4-((4-(苯氧基乙醯基)哌嗪-2-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(2-(3-溴-4-氟苯基)丙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-側氧基-N-(3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苯基)-4-苯基丁醯胺;2'-氟-5'-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-甲醯胺;N-(2'-氟-5'-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-基)乙醯胺;N-((2'-氟-5'-(1-甲基-2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)-1,1'-聯苯-3-基)甲基)甲烷磺醯胺;2-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)六氫-1H-異吲哚-1,3(2H)-二酮;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3,3-二甲基吡咯啶-2,5-二酮;4-(4-氟-3-(2-甲基-5-側氧基吡咯啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基-1,3-噁唑啶-3-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基氮-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)哌啶-2,6-二酮;
4-(4-氟-3-(2-側氧基咪唑啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(1,1-二氧代異噻唑啶-2-基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基吖丁啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基哌啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(3-呋喃基甲基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(噻吩-2-基甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(噻吩-3-基甲基)苯甲醯胺:3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(吡啶-3-基甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(吡啶-4-基甲基)苯甲醯胺;N-(2-(二甲基胺基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-(二甲基胺基)丙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(3-吡咯啶-1-基丙基)苯甲醯胺;
3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(3-哌啶-1-基丙基)苯甲醯胺;N-(3-嗎啉-4-基丙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(1H-吲哚-3-基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-1,3-噻唑-2-基苯甲醯胺;2-側氧基-2-(3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苯基胺基)乙基胺基甲酸苄酯;4-側氧基-N-(3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苯基)-4-(4-苯氧基苯基)丁醯胺;3-(((3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苯基)胺基)羰基)哌啶-1-甲酸苄酯;2-(4-甲基苯氧基)-N-(3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苯基)乙醯胺;2-(4-甲氧苯氧基)-N-(3-(2-(4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)乙基)苯基)乙醯胺;4-(4-氟-3-(3-甲基-2-側氧基咪唑啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基四氫嘧啶-1(2H)-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(3-第三丁基-2-側氧基咪唑啶-1-基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;
4-(4-氟-3-((1S,4R)-3-側氧基-2-氮雜雙環(2.2.1)庚-2-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(2-乙基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-乙基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-乙基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-丙基苯基)苯甲醯胺;N-(2-異丙基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-異丙基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-第三丁基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-第三丁基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-1,1'-聯苯-4-基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-氟-4-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-氟-4-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;
N-(4-氟-2-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-氟-3-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-氯-4-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-氯-3-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-溴-4-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-溴-3-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-氟-4-甲氧苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-甲氧-5-(三氟甲基)苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-羥基-6-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-羥基-2-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-羥基-4-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-甲氧-5-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;
N-(3-甲氧-4-甲基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-羥基-4-甲氧苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-乙氧苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(4-丙氧苯基)苯甲醯胺;N-(5-第三丁基-2-甲氧苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(5-(乙醯基胺基)-2-甲氧苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-2,3-二氫-1,4-苯并二氧雜環己烯-6-基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(5-氯-2,4-二甲氧苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(3-(甲硫基)苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-(甲硫基)苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(4-哌啶-1-基苯基)苯甲醯胺;N-(4-嗎啉-4-基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;
N-(2-苯胺基苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(4-((4-甲氧苯基)胺基)苯基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-喹啉-6-基苯甲醯胺;N-(5-羥基-1-萘基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-1H-吲唑-6-基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;8-(4-氟苄基)吡啶并(2,3-d)噠嗪-5(6H)-酮;8-(3-氯-4-氟苄基)吡啶并(2,3-d)噠嗪-5(6H)-酮;(3aR)-8-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-2,3,3a,4-四氫-1H-吡咯并(2,1-c)(1,4)苯并噁嗪-1-酮;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-N-甲基甲烷磺醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-羥基-2-甲基丙醯胺;(3aS)-8-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-2,3,3a,4-四氫-1H-吡咯并(2,1-c)(1,4)苯并噁嗪-1-酮;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-苯基乙基)苯甲醯胺;N-(2-(2-甲基苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;
N-(2-(3-甲基苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(4-甲基苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-吡啶-2-基乙基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-吡啶-3-基乙基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-吡啶-4-基乙基)苯甲醯胺;N-(2-(2-甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(3-甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(4-甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2-氟苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(3-氟苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(4-氟苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2-氯苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;
N-(2-(3-氯苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(4-氯苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(3-溴苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(4-溴苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(1,1'-聯苯-4-基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-(3-(三氟甲基)苯基)乙基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-(4-(三氟甲基)苯基)乙基)苯甲醯胺;3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-(4-苯氧基苯基)乙基)苯甲醯胺;N-(2-(3,4-二甲基苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2,4-二甲基苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2,5-二甲基苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(3-乙氧-4-甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;
N-(2-(4-乙氧-3-甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2,3-二甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2,4-二甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2,5-二甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(3,4-二甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(3,5-二甲氧苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(1,3-苯并二氧雜環戊烯-5-基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2,3-二氯苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(3,4-二氯苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(2,6-二氯苯基)乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;(3aS,4R,7S,7aR)-5-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2,2-二甲基四氫-4,7-亞甲(1,3)二氧雜環戊烯并(4,5-c)吡啶-6(3aH)-酮;4-(1-(3-溴-4-氟苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-
酮;4-(1-(4-氟-3-(2-側氧基吡咯啶-1-基)苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;8-(4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;8-(3-溴-4-氟苄基)吡啶并(2,3-d)噠嗪-5(6H)-酮;N-(2-(二甲基胺基)乙基)-N-乙基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-(2-(二乙基胺基)乙基)-N-甲基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-苄基-N-乙基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-苄基-N-異丙基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-苄基-正丁基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N,N-二苄基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-苄基-N-(2-羥基乙基)-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;N-甲基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-N-(2-吡啶-2-基乙基)苯甲醯胺;N-(2-(3,4-二甲氧苯基)乙基)-N-甲基-3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯甲醯胺;4-(3-((4-羥基哌啶-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-
1(2H)-酮;1-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苄醯基)哌啶-3-甲醯胺;1-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苄醯基)哌啶-4-甲醯胺;4-(3-((4-(2-側氧基-2,3-二氫-1H-苯并咪唑-1-基)哌啶-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-甲基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-乙基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苄醯基)哌嗪-1-甲醛;4-(3-((4-乙醯基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-(2-羥基乙基)哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-苯基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-吡啶-2-基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-嘧啶-2-基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-(2-(2-羥基乙氧)乙基)哌嗪-1-基)羰基)苄基)-
5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-(2-氟苯基)哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-(4-氟苯基)哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-(2-氯苯基)哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((4-甲基-1,4-二氮-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(1,1-二氧代-1,2-硫氮雜環己烷-2-基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;8-(4-氟-3-(2-側氧基吖丁啶-1-基)苄基)吡啶并(2,3-d)噠嗪-5(6H)-酮;8-(3-氯-4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;4-(1-(4-氟-3-(2-側氧基吖丁啶-1-基)苯基)乙基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;1-(3-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡咯啶-2,5-二酮;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-(2-側氧基吡咯啶-1-基)乙醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲
基)苯基)-5-側氧基己烷醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-甲氧丙醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-N'-苯基戊烷二醯胺;2-(二甲基胺基)-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基胺基甲酸苄酯;8-(4-氟-3-(2-側氧基吖丁啶-1-基)苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;4-(3-溴-4-氟苯基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基吖丁啶-1-基)苯基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;2-氟-5-((5-側氧基-5,6-二氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯甲醯胺;8-(3-胺基-4-氟苄基)吡啶并(2,3-d)噠嗪-5(6H)-酮;8-(4-氟-3-(2-側氧基吡咯啶-1-基)苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苄酸甲酯;8-(3-胺基-4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苄酸;N-乙基-2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠
嗪-8-基)甲基)苯甲醯胺;N-環丁基-2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯甲醯胺;2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)-N-(2-吡咯啶-1-基乙基)苯甲醯胺;8-(4-氟-3-((4-(嗎啉-4-基羰基)哌嗪-1-基)羰基)苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-N'-苯基戊烷二醯胺;1-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)吡咯啶-2,5-二酮;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-3-甲氧丙醯胺;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-5-側氧基己烷醯胺;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-3-苯氧基丙醯胺;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-4-側氧基-4-苯基丁醯胺;2-(4-(苄基氧基)苯氧基)-N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)乙醯胺;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-2-(4-甲氧苯氧基)乙醯胺;N-環丙基-2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)
噠嗪-8-基)甲基)苯甲醯胺;8-(3-((4-(2-乙氧乙基)哌嗪-1-基)羰基)-4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)-N-(2-哌啶-1-基乙基)苯甲醯胺;2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(3,2-d)噠嗪-8-基)甲基)-N-(2-側氧基-2-(哌啶-1-基)乙基)苯甲醯胺;4-(4-氟-3-((4-嘧啶-2-基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;及4-(4-氟-3-(2-側氧基吡咯啶-1-基)苯基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;及其治療性之鹽、前藥、酯、醯胺、前藥之鹽、酯之鹽及醯胺之鹽。
本發明化合物之可變部分係由識別符號(大寫字母加上數字及/或字母上標)表示且可詳細舉例。
此表示應明瞭本發明之所有組合皆保持適當之價數,具有多於一個原子之單價部分係經由其左端連接。
亦表示應明瞭可變部分之特定具體實施態樣可與具有相同識別符號之另一特定具體實施態樣相同或相異。
以下用以描述流程圖及實施例之縮寫有:BOC為二碳酸二第三丁酯C-18為二甲基-十八碳基矽烷DCI表示直接導入用之化學離子化,
DME表示1,2-二甲氧乙烷,DMSO表示二甲基亞碸,ESI表示電噴霧離子化,HATU表示六氟磷酸O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓,HPLC表示高效液相層析,MS表示質譜,TFA表示三氟乙酸,本發明1
H NMR所使用之符號"δ"係表示1
H NMR化學位移。
本發明1
H NMR所使用之縮寫"br"係表示寬峰之1
H NMR信號。
本發明1
H NMR所使用之縮寫"d"係表示二重1
H NMR波峰。
本發明1
H NMR所使用之縮寫"dd"係表示雙重之二重1
H NMR波峰。
本發明1
H NMR所使用之縮寫"m"係表示多重1
H NMR波峰。
本發明1
H NMR所使用之縮寫"q"係表示四重1
H NMR波峰。
本發明1
H NMR所使用之縮寫"s"係表示單重1
H NMR波峰。
本發明1
H NMR所使用之縮寫"t"係表示三重1
H NMR波峰。
本發明所使用之術語"烯基"係表示具有一或多於一個碳-碳雙鍵之單價、直鏈或分支鏈烴部分,諸如C2
-烯基、C3
-烯基、C4
-烯基、C5
-烯基、C6
-烯基及諸如此類者。
本發明所使用之術語"烷基"係表示單價、飽和、直鏈或分支鏈烴部分,諸如C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基、C5
-烷基、C6
-烷基及諸如此類者。
本發明所使用之術語"炔基"係表示具有一或多於一個碳-碳參鍵之單價、直鏈或分支鏈烴部分,諸如C2
-炔基、C3
-炔基、C4
-炔基、C5
-炔基、C6
-炔基及諸如此類者。
本發明所使用之術語"環烷"係表示飽和環狀或雙環烴部分,諸如C4
-環烷、C5
-環烷、C6
-環烷、C7
-環烷、C8
-環烷、C9
-環烷、C10
-環烷、C11
-環烷、C12
-環烷及諸如此類者。
本發明所使用之術語"環烷基"係表示單價、飽和環狀及雙環烴部分,諸如C3
-環烷基、C4
-環烷基、C5
-環烷基、C6
-環烷基、C7
-環烷基、C8
-環烷基、C9
-環烷基、C10
-環烷基、C11
-環烷基、C12
-環烷基及諸如此類者。
本發明所使用之術語"環烯"係表示具有一或多於一個碳-碳雙鍵之環狀及雙環烴部分,諸如C5
-環烯、C6
-環烯、C7
-環烯、C8
-環烯、C9
-環烯、C10
-環烯、C11
-環烯、C12
-環烯及諸如此類者。
本發明所使用之術語"環烯基"係表示具有一或多於一個碳-碳雙鍵之單價、環狀烴部分,諸如C4
-環烯基、C5
-環烯基、C6
-環烯基、C7
-環烯基、C8
-環烯基、C9
-環烯基、C10
-環烯基、C11
-環烯基、C12
-環烯基及諸如此類者。
本發明所使用之術語"雜芳烴"係表示呋喃、咪唑、異噻唑、異噁唑、1,2,3-噁二唑、1,2,5-噁二唑、1,3,4-噁二
唑、噁唑、吡嗪、吡唑、噠嗪、吡啶、嘧啶、吡咯、噻唑、1,3,4-噻二唑、噻吩、三嗪及1,2,3-三唑。
本發明所使用之術語"雜芳基"係表示呋喃基、咪唑基、異噻唑基、異噁唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑基、吡嗪基、吡唑基、噠嗪基、吡啶基、嘧啶基、吡咯基、四唑基、噻唑基、1,2,3-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻吩基、三嗪基及1,2,3-三唑基。
本發明所使用之術語"雜環烷"係表示有一或二或三個CH2
部分經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分未置換或經N置換之環烷且亦表示有一或二或三個CH2
部分未置換或經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分經N置換之環烷。
本發明所使用之術語"雜環烯"係表示有一或二或三個CH2
部分經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分未置換或經N置換之環烯且亦表示有一或二或三個CH2
部分未置換或經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分經N置換之環烯。
本發明所使用之術語"雜環烷基"係表示有一或二或三個CH2
部分經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分未置換或經N置換之環烷基且亦表示有一或二或三個CH2
部分未置換或經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分經N置換之環烷基。
本發明所使用之術語"雜環烯基"係表示有一或二或三個
CH2
部分經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分未置換或經N置換之環烯基且亦表示有一或二或三個CH2
部分未置換或經獨立選擇之O、S、S(O)、SO2
或NH所置換且一或二個CH部分經N置換之環烯基。
本發明所使用之術語"環狀部分"係表示苯、環烷、環烷基、環烯、環烯基、雜芳烴、雜芳基、雜環烷、雜環烷基、雜環烯、雜環烯基及苯基。
本發明化合物可含有R或S構型之不對稱取代碳原子,其中術語"R"及"S"係如Pure Appl. Chem. (1976)45, 13-10所定義。有等量R及S構型之具有不對稱取代碳原子的化合物在該等原子上係消旋。一種構型超過另一種之原子屬於構型過量,較佳過量約85%-90%,更佳過量約95%-99%,再更佳過量大於約99%。是故,本發明意以涵蓋消旋混合物、相對及絕對非鏡像異構物及其複合物。
本發明化合物亦可含有Z或E構型之碳-碳雙鍵或碳-氮雙鍵,其中本發明所使用之術語"Z"係表示較大之兩取代基位於碳-碳或碳-氮雙鍵之同側,而本發明所使用之術語"E"係表示較大之兩取代基位於碳-碳或碳-氮雙鍵之相對側。本發明化合物亦可存在為"Z"及"E"異構物之混合物形式。
含有NH、C(O)H、C(O)OH、C(O)NH2
、OH或SH部分之本發明化合物可連接有前藥-形成部分。前藥-形成部分係由代謝過程移除且於體內釋出具有游離NH、C(O)H、C(O)OH、C(O)NH2
、OH或SH之化合物。前藥可用以調整如溶解度及/或疏水性、於腸胃道中之吸收、生物可利用
性、組織滲透性及排出率的化合物藥物動力性質。
具有式I之化合物由體外或體內代謝過程所產生之代謝物亦可應用以治療亦可應用於治療因未調節或過度表現之聚(ADP-核糖)聚合酶所致或因而惡化的疾病。
具有式I之化合物之特定前驅物化合物可於體外或體內代謝形成具有式I之化合物,因此亦可應用於治療因未調節或過度表現之聚(ADP-核糖)聚合酶所致或因而惡化的疾病。
具有式I之化合物可存在為酸加成鹽、鹼性加成鹽或兩性離子。具有式I之化合物的鹽係於其單離期間或在其純化之後製備。酸加成鹽係為自具有式I之化合物與酸反應所衍生之鹽。是故,本發明涵蓋鹽包括具有式I之化合物的乙酸鹽、己二酸鹽、藻酸鹽、碳酸氫鹽、檸檬酸鹽、天冬胺酸鹽、苄酸鹽、苯磺酸鹽(besylate)、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡糖酸鹽、甲酸鹽、反丁烯二酸鹽、甘油磷酸鹽、穀胺酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、乳糖醛酸鹽、乳酸鹽、順丁烯二酸鹽、三甲基苯磺酸鹽、甲烷磺酸鹽、萘磺酸鹽、菸鹼酸鹽、草酸鹽、雙羥基萘酸鹽、果膠酸鹽、過硫酸鹽、磷酸鹽、苦味酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫代氰酸鹽、三氯乙酸鹽、三氟乙酸鹽、對-甲苯磺酸鹽及十一碳酸鹽。化合物之鹼性加成鹽係具有式I之化合物與陽離子諸如鋰、鈉、鉀、鈣及鎂之碳酸氫鹽、碳酸鹽、氫氧化物或磷酸鹽反應衍生者。
具有式I之化合物可例如經頰、經眼、經口、滲透、非經腸(肌內、腹膜內、胸骨內、靜脈內、皮下)、直腸、局部、經皮及陰道投藥。
具有式I之化合物的治療有效量係視接受治療者、待治療之疾病及其嚴重性、包含該化合物之組合物、投藥時間、投藥路徑、治療持續時間、效能、排出率及是否共同投予另一種藥物而定。具有式I之化合物用以製造以單一劑量或分次劑量每日投藥於患者之組合物的量係約0.001至約200毫克/公斤體重。單一劑量組合物含有此等量或其約數之組合。
具有式I之化合物可使用或不使用賦形劑投藥。賦形劑係包括例如封包劑及添加劑,諸如加速吸收劑、抗氧化劑、黏合劑、緩衝劑、塗覆劑、著色劑、稀釋劑、崩解劑、乳化劑、增量劑、填料、調味劑、保濕劑、潤滑劑、香料、防腐劑、推進劑、脫模劑、滅菌劑、甜味劑、促溶劑、潤濕劑及其混合物。
具有式I之化合物可使用放射性同位素諸如碳(即13
C)、氫(即3
H)、氮(即15
N)、磷(即32
P)、硫(即35
S)、碘(即125
I)及諸如此類者進行放射標記。放射性同位素可藉由彼者與放射性衍化劑反應或藉著將經放射標記之中間物併入其合成中而併入具有式I之化合物。式I之放射標記化合物同時可用於判斷預後及診斷應用且使用於體內及體外成像兩種應用中。
具有式I之化合物可摻入裝置內,諸如但不限於動靜脈
移植物、膽道支架、分流移植物、導管、中樞神經系統分流器、冠狀動脈支架、藥物輸送氣球、周邊血管支架及輸尿管內支架,其各可使用於諸如但不限於將具有式I之化合物導入所選擇人體組織或器官內的脈管系統之領域。具有式I之化合物的其中一種功效指標係降低或消除與裝置有關之血栓及與其相關之併發症。
具有式I之化合物可作為增進放射療法之功效的放射敏化劑。放射療法之實例包括但不限於體外放射線療法、遠程放射療法、近距離放射療法及密封及開收源放射療法。
用以製備包含具有式I之化合物的待經口投藥組合物之賦形劑係包括例如瓊脂、藻酸、氫氧化鋁、苄醇、苄酸苄酯、1,3-丁二醇、聚羧乙烯製劑、蓖麻油、纖維素、乙酸纖維素、可可脂、玉米澱粉、玉米油、棉籽油、交聯聚乙烯吡咯酮、甘油二酸酯、乙醇、乙基纖維素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明膠、胚芽油、葡萄糖、甘油、花生油、羥基丙基甲基纖維素、異丙醇、等張鹽水、乳糖、氫氧化鎂、硬脂酸鎂、麥芽、甘露糖醇、甘油單酸酯、橄欖油、花生油、磷酸鉀鹽、馬鈴薯澱粉、聚乙烯吡咯酮、丙二醇、林氏溶液(Ringer's solution)、葵花油、芝麻油、羧甲基纖維素鈉、磷酸鈉鹽、硫酸月桂酯鈉、山梨糖醇鈉、大豆油、硬脂酸、反丁烯二酸硬脂酯、蔗糖、界面活性劑、滑石、黃蓍膠、四氫糠醇、甘油三酸酯、水及其混合物。用以製備包含具有式I之化合物的眼用或經口投藥之組合物的賦形劑係包括例如1,3-丁二醇、蓖麻油、
玉米油、棉籽油、乙醇、山梨糖醇之脂肪酸酯、胚芽油、花生油、甘油、異丙醇、橄欖油、聚乙二醇、丙二醇、芝麻油、水及其混合物。用以製備包含具有式I之化合物的滲透投藥組合物的賦形劑係包括例如氯氟-烴、乙醇、水及其混合物。用以製備包含具有式I之化合物的非經腸投藥組合物的賦形劑係包括例如1,3-丁烷二醇、蓖麻油、玉米油、棉籽油、右旋糖、胚芽油、花生油、脂質體、油酸、橄欖油、花生油、林氏溶液(Ringer's solution)、葵花油、芝麻油、大豆油、U.S.P.或等張氯化鈉溶液、水及其混合物。用以製備包含具有式I之化合物的直腸或陰道投藥組合物之賦形劑係包括例如可可脂、聚乙二醇、蠟及其混合物。
亦預期具有式I之化合物可與以下化合物一起使用烷基化劑、血管新生抑制劑、抗體、抗代謝劑、抗有絲分裂劑、抗增殖劑、aurora激酶抑制劑、Bcr-Abl激酶抑制劑、生物反應修飾劑、週期素-依賴性激酶抑制劑、細胞週期抑制劑、環氧合酶-2抑制劑、白血病病毒致癌基因同系物(ErbB2)受體抑制劑、生長因子抑制劑、熱休克蛋白(HSP)-90抑制劑、組織蛋白脫乙醯基酶(HDAC)抑制劑抑制劑、激素療法、免疫製劑、嵌入抗生素、激酶抑制劑、雷波黴素(rapomycin)抑制劑之哺乳類標靶、有絲分裂原活化胞外訊息調節激酶抑制劑、非類固醇消炎藥物(NSAID's)、鉑化療劑、polo樣激酶抑制劑、蛋白酶體抑制劑、嘌呤類似物、嘧啶類似物、受體酪胺酸激酶抑制劑、視網質/楊樹
鹼(deltoids)植物生物鹼、拓撲異構酶抑制劑及諸如此類者。
烷基化劑係包括六甲蜜胺(altretamine)、AMD-473、AP-5280、阿帕奎酮(apaziquone)、苯達莫斯汀(bendamustine)、伯司塔辛(brostallicin)、白消安(busulfan)、卡波昆(carboquone)、卡氮芥(carmustine)(BCNU)、苯丁酸氮芥(chlorambucil)、CloretazineTM
(VNP 40101M)、環磷醯胺(cyclophosphamide)、氮烯咪胺(decarbazine)、雌莫司汀(estramustine)、福莫司汀(fotemustine)、葡磷醯胺(glufosfamide)、異環磷醯胺(ifosfamide)、KW-2170、洛莫司汀(lomustine)(CCNU)、馬磷醯胺(mafosfamide)、美法侖(melphalan)、二溴甘露醇(mitobronitol)、二溴衛矛醇(mitolactol)、尼莫司汀(nimustine)、氮芥子氣N-氧化物、雷莫司汀(ranimustine)、替莫唑胺(temozolomide)、噻替哌(thiotepa)、二羥白消安(treosulfan)、曲洛磷胺(trofosfamide)及諸如此類者。
血管新生抑制劑係包括內皮專一性受體酪胺酸激酶(Tie-2)抑制劑、表皮生長因子受體(EGFR)抑制劑、胰島素生長因子-2受體(IGFR-2)抑制劑、間質金屬結合蛋白酶-2(MMP-2)抑制劑、間質金屬結合蛋白酶-9 (MMP-9)抑制劑、血小板衍生之生長因子受體(PDGFR)抑制劑、凝血酶敏感蛋白(thrombospondin)類似物血管內皮生長因子受體酪胺酸激酶(VEGFR)抑制劑及諸如此類者。
Aurora激酶抑制劑係包括AZD-1152、MLN-8054、VX-680及諸如此類者。
Bcr-Abl激酶抑制劑係包活DASATINIB®
(BMS-354825)、GLEEVEC®
(伊馬替尼(imatinib))及諸如此類者。
CDK抑制劑係包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、黃吡啶酚(flavopyridol)、GPC-286199、MCS-5A、PD0332991、PHA-690509、塞里西里(seliciclib)(CYC-202,R-若司唯汀(R-roscovitine))、ZK-304709及諸如此類者。
COX-2抑制劑係包括ABT-963、ARCOXIA®
(衣托考昔(etoricoxib))、BEXTRA®
(戊地考昔(valdecoxib))、BMS347070、CELEBREXTM
(塞來考昔(celecoxib))、COX-189(魯米考昔(lumiracoxib))、CT-3、DERAMAXX®
(德拉考昔(deracoxib))、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-胺磺醯基苯基-1H-吡咯)、MK-663(衣托考昔(etoricoxib))、NS-398、帕瑞考昔(parecoxib)、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VIOXX®
(rofecoxib)及諸如此類者。
EGFR抑制劑係包括ABX-EGF、抗-EGFr免疫脂質體、EGF-疫苗、EMD-7200、ERBITUX®
(西妥昔單抗(cetuximab))、HR3、IgA抗體、IRESSA®
(吉非替尼(gefitinib))、TARCEVA®
(埃羅替尼(erlotinib)或OSI-774)、TP-38、EGFR融合蛋白、TYKERB®
(拉帕替尼
(lapatinib))及諸如此類者。
ErbB2受體抑制劑係包括CP-724-714、CI-1033(卡奈替尼(canertinib))、Herceptin®
(曲妥珠單抗(trastuzumab))、TYKERB®
(拉帕替尼(lapatinib))、OMNITARG®
(2C4,帕妥珠單抗(petuzumab))、TAK-165、GW-572016(艾那法尼(ionafarnib))、GW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER-2疫苗)、抗-HER/2neu雙專一性抗體、B7.her2IgG3、AS HER2三官能性雙專一性抗體、mAB AR-209、mAB 2B-1及諸如此類者。
組織蛋白脫乙醯基酶抑制劑係包括脂肽、LAQ-824、MS-275、垂帕辛(trapoxin)、辛二醯苯胺異羥肟酸(suberoylanilide hydroxamic acid)(SAHA)、TSA、丙戊酸(valproic acid)及諸如此類者。
HSP-90抑制劑係包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格爾德黴素(geldanamycin)、IPI-504、KOS-953、MYCOGRAB®
、NCS-683664、PU24FCl、PU-3、根赤殼菌素(radicicol)、SNX-2112、STA-9090 VER49009及諸如此類者。
MEK抑制劑係包括ARRY-142886、ARRY-438162、PD-325901、PD-98059及諸如此類者。
mTOR抑制劑係包括AP-23573、CCI-779、依維莫司(everolimus)、RAD-001、雷帕黴素(rapamycin)、替西羅莫司(temsirolimus)及諸如此類者。
非類固醇消炎藥物係包括AMIGESIC®
(雙水楊酸酯
(salsalate))、DOLOBID®
(二氟尼柳(diflunisal))、MOTRIN®
(布洛芬(ibuprofen))、ORUDIS®
(酮洛芬(ketoprofen))、RELAFEN®
(萘丁美酮(nabumetone))、FELDENE®
(吡羅昔康(piroxicam))布洛芬乳霜(ibuprofincream)、ALEVE®
及NAPROSYN®
(萘普生(naproxen))、VOLTAREN®
(雙氯芬酸(diclofenac))、INDOCIN®
(吲哚美辛(indomethacin))、CLINORIL®
(舒林酸(sulindac))、TOLECTIN®
(甲苯醯吡酸(tolmetin))、LODINE®
(依托度酸(etodolac))、TORADOL®
(酮咯酸(ketorolac))、DAYPRO®
(奧沙普嗪(oxaprozin))及諸如此類者。
PDGFR抑制劑係包括C-451、CP-673、CP-868596及諸如此類者。
鉑化療劑係包括順鉑、ELOXATIN®
(奧沙利鉑(oxaliplatin))依鉑(eptaplatin)、洛鉑(lobaplatin)、奈達鉑(nedaplatin)、PARAPLATIN®
(卡鉑(carboplatin))、賽特鉑(satraplatin)及諸如此類者。
Polo樣激酶抑制劑係包括BI-2536及諸如此類者。
凝血酶敏感蛋白(thrombospondin)類似物係包括ABT-510、ABT-567、ABT-898、TSP-1及諸如此類者。
VEGFR抑制劑係包括AVASTIN®
(貝伐珠單抗(bevacizumab))、ABT-869、AEE-788、ANGIOZYMETM
、阿西替尼(axitinib)(AG-13736)、AZD-2171、CP-547,632、IM-862、Macugen(哌加他尼(pegaptamib))、NEXAVAR®
(索拉非尼(sorafenib)、BAY43-9006)、帕若帕
尼(pazopanib)(GW-786034)、(PTK-787, ZK-222584)、SUTENT®
(舒尼替尼(sunitinib), SU-11248)、VEGF阱(VEGF trap)、凡他拉尼(vatalanib)、ZACTIMATM
(凡德他尼(vandetanib), ZD-6474)及諸如此類者。
抗代謝劑係包括ALIMTA®
(培美曲塞二鈉(premetrexed disodium)、LY231514, MTA)、5-阿扎胞苷(5-azacitidine)、XELODA®
(卡培他濱(capecitabine))、卡莫氟(carmofur)、LEUSTAT®
(克拉曲濱(cladribine))、克羅拉賓(clofarabine)、阿糖胞苷(cytarabine)、阿糖胞苷十八烷基磷酸鈉(cytarabine ocfosfate)、阿糖胞苷(cytosine arabinoside)、地西他賓(decitabine)、去鐵胺(deferoxamine)、氟鐵龍(doxifluridine)、依氟鳥胺酸(eflornithine)、EICAR、伊諾他賓(enocitabine)、伊尼胞苷(ethnylcytidine)、氟達拉賓(fludarabine)、羥基脲、單獨或與白葉素(leucovorin)組合之5-氟尿嘧啶(5-FU)、GEMZAR®
(吉西他賓(gemcitabine))、羥基脲、ALKERAN®
(美法侖(melphalan))、巰基嘌呤、6-巰基嘌呤核苷、甲胺喋呤(methotrexate)、黴酚酸(mycophenolic acid)、奈拉賓(nelarabine)、諾拉曲特(nolatrexed)、歐弗司特(ocfosate)、培里曲索(pelitrexol)、噴司他汀(pentostatin)、雷替曲塞(raltitrexed)、病毒唑(Ribavirin)、垂阿平(triapine)、甲曲沙(trimetrexate)、S-1、噻唑呋啉(tiazofurin)、替加氟(tegafur)、TS-1、阿糖腺苷(vidarabine)、UFT及諸如此類者。
抗生素係包括嵌入抗生素阿柔比星(aclarubicin)、放射菌素D、胺柔比星(amrubicin)、安拿黴素(annamycin)、阿黴素(adriamycin)、BLENOXANE®
(平陽黴素(bleomycin))、紅必黴素(daunorubicin)、CAELYX®
或MYOCET®
(多柔比星(doxorubicin))、依沙盧星(elsamitrucin)、伊波布辛(epirbucin)、葛拉布辛(glarbuicin)、ZAVEDOS®
(依達比星(idarubicin))、絲裂黴素(mitomycin)C、奈莫柔比星(nemorubicin)、新制癌素(neocar淨司他汀(zinostatin))、培洛黴素(peplomycin)、吡柔比星(pirarubicin)、蝶黴素(rebeccamycin)、司提馬莫(stimalamer)、鏈脲佐菌素(streptozocin)、VALSTAR®
(戊柔比星(valrubicin))、淨司他汀(zinostatin)及諸如此類者。
拓撲異構酶抑制劑係包括阿柔比星(aclarubicin)、9-胺基喜樹鹼、胺萘非特(amonafide)、胺苯吖啶(amsacrine)、貝卡特啉(becatecarin)、貝洛替康(belotecan)、BN-80915、CAMPTOSAR®
(鹽酸伊利替康(irinotecan hydrochloride))、喜樹鹼、CARDIOXANE®
(脫氧氟尿苷(dexrazoxine))、氟替康(diflomotecan)、伊朵提林(edotecarin)、ELLENCE®
或PHARMORUBICIN®
(表柔比星(epirubicin))、鬼臼乙叉苷(etoposide)、依喜替康(exatecan)、10-羥基喜樹鹼、吉馬替康(gimatecan)、勒托替康(lurtotecan)、米托蒽醌(mitoxantrone)、歐瑞提辛(orathecin)、吡瑞布辛(pirarbucin)、比珊托(pixantrone)、魯比特康(rubitecan)、索布佐生
(sobuzoxane)、SN-38、塔氟波苷(tafluposide)、托泊替康(topotecan)及諸如此類者。
抗體係包括AVASTIN®
(貝伐珠單抗(bevacizumab))、CD40-專一性抗體、chTNT-1/B、得諾舒單抗(denosumab)、ERBITUX®
(西妥昔單抗(cetuximab))、HUMAX-CD4®
(札木單抗(zanolimumab))、IGF1R-專一性抗體、林妥珠單抗(lintuzumab)、PANOREX®
(依決洛單抗(edrecolomab))、RENCAREX®
(WX G250)、RITUXAN®
(利妥昔單抗(rituximab))、提西目單抗(ticilimumab)曲妥吉單抗(trastuzimab)及諸如此類者。
激素療法係包括ARIMIDEX®
(阿那曲唑(anastrozole))、AROMASIN®
(伊西美坦(exemestane))、阿佐普芬(arzoxifene)、CASODEX®
(比卡魯胺(bicalutamide))、CETROTIDE®
(西曲瑞克(cetrorelix))、得加瑞克(degarelix)、得舍瑞林(deslorelin)、DESOPAN®
(曲洛司坦(trilostane))、德沙美松(dexamethasone)、DROGENIL®
、(氟他胺(flutamide))、EVISTA®
(雷洛西芬(raloxifene))、法決唑(fadrozole)、FARESTON®
(托瑞米芬(toremifene))、FASLODEX®
(氟維司群(fulvestrant))、FEMARA®
(來曲唑(letrozole))、福美司坦(formestane)、糖皮質激素、HECTOROL®
或RENAGEL®
(度骨化醇(doxercalciferol))、拉索昔芬(lasofoxifene)、柳培林(leuprolide acetate)、MEGACE®
(甲地孕酮(megesterol))、MIFEPREX®
(美服培酮(mifepristone))、NILANDRONTM
(尼魯米特
(nilutamide))、NOLVADEX®
(檸檬酸他莫昔芬(tamoxifen citrate))、PLENAXISTM
(阿巴瑞克(abarelix))、普瑞氐松(predisone)、PROPECIA®
(非那甾胺(finasteride))、瑞洛司坦(rilostane)、SUPREFACT®
(布舍瑞林(buserelin))、TRELSTAR®
(促黃體生成激素釋放因子(LHRH))、凡塔司(vantas)、VETORYL®
、(曲洛司坦(trilostane)或莫卓司坦(modrastane))、ZOLADEX®
(弗司瑞林(fosrelin)、葛舍瑞林(goserelin))及諸如此類者。
楊樹鹼(deltoids)及視網質係包括西奧骨化醇(seocalcitol)(EB1089、CB1093)、列沙卡西托(lexacalcitrol)(KH1060)、芬維A胺(fenretinide)、PANRETIN®
(阿瑞汀諾(aliretinoin))、ATRAGEN®
(脂質體維他命A酸(liposomal tretinoin))、TARGRETIN®
(倍沙羅汀(bexarotene))、LGD-1550及諸如此類者。
植物生物鹼包括但不限於長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)、長春瑞濱(vinorelbine)及諸如此類者。
蛋白酶體抑制劑係包括VELCADE®
(硼替佐米(bortezomib))、MG132、NPI-0052、PR-171及諸如此類者。
免疫製劑之實例係包括干擾素及其他免疫促進劑。干擾素係包括干擾素α、干擾素α-2a、干擾素α-2b、干擾素β、干擾素γ-1a、ACTIMMUNE®
(干擾素γ-1b)或干擾素γ-n1、其組合及諸如此類者。其他藥劑係包括
ALFAFERONE®
、BAM-002、BEROMUN®
(他索那明(tasonermin))、BEXXAR®
(托西莫單抗(tositumomab))、CamPath®
(阿來組單抗(alemtuzumab))、CTLA4(胞毒性淋巴球抗原4)、氮烯咪胺(decarbazine)、地尼介白素(denileukin)、伊培組單抗(epratuzumab)、GRANOCYTE®
(來革司汀(lenograstim))、香菇多醣(lentinan)、白血球α干擾素、咪奎莫特(imiquimod)、MDX-010、黑色素瘤疫苗、米妥莫單抗(mitumomab)、莫拉司汀(molgramostim)、MYLOTARGTM
(吉妥珠單抗奧唑米星(gemtuzumab ozogamicin))、NEUPOGEN®
(非格司汀(filgrastim))、OncoVAC-CL、OvaRex®
(歐葛瓦單抗(oregovomab))、潘圖莫單抗(pemtumomab)(Y-muHMFG1)、PROVENGE®
、沙革莫司汀(sargaramostim)、裂皺菌素(sizofilan)、替西介白素(teceleukin)、TheraCys®
、烏苯美司(ubenimex)、VIRULIZIN®
、Z-100、WF-10、PROLEUKIN®
(阿地介白素(aldesleukin))、ZADAXIN®
(胸腺法新(thymalfasin))、ZENAPAX®
(達里組單抗(daclizumab))、ZEVALIN®
((90Y-替伊莫單抗(90Y-Ibritumomab tiuxetan))及諸如此類者。
生物反應修飾劑係為修飾活有機體之防衛機制或生物反應(諸如組織細胞之存活、生長或分化)以使其具有抗腫瘤活性的藥劑,包括雲芝多醣K (krestin)、香菇多醣(lentinan)、西佐糖(sizofiran)、畢西巴尼(picibanil)PF-3512676 (CpG-8954)、烏苯美司(ubenimex)及諸如此類者。
嘧啶類似物係包括阿糖胞苷(cytarabine)(ara C)、阿糖胞苷(cytosine arabinoside)、氟鐵龍(doxifluridine)、FLUDARA®
(氟達拉賓(fludarabine))、5-FU(5-氟尿嘧啶)、氟尿苷(floxuridine)、GEMZAR®
(吉西他賓(gemcitabine))、TOMUDEX®
(雷替曲塞(ratitrexed))、TROXATYLTM
(三乙醯基尿苷曲沙他賓(troxacitabine))及諸如此類者。
嘌呤類似物係包括LANVIS®
(硫代鳥嘌呤)及PURI-NETHOL®
(巰基嘌呤)。
抗有絲分裂劑係包括巴塔布林(batabulin)、埃博黴素(epothilone)D (KOS-862)、N-(2-((4-羥基苯基)胺基)吡啶-3-基)-4-甲氧苯磺醯胺、伊沙比隆(ixabepilone)(BMS 247550)、太平洋紫杉醇(paclitaxel)、TAXOTERE®
(多西洋紫杉醇(docetaxel))、PNU100940 (109881)、帕妥匹隆(patupilone)、XRP-9881、長春氟寧(vinflunine)、ZK-EPO及諸如此類者。
本發明化合物亦欲用以作為放射敏化劑,促進放射線療法之效果。放射線療法之實例係包括但不限於體外放射線療法、遠程放射療法、近距離放射療法及密封及開收源放射療法。
此外,具有式I之化合物可與其他化療劑組合,諸如ABRAXANETM
(ABI-007)、ABT-100(法尼基轉移酶抑制劑)、ADVEXIN®
、ALTOCOR®
或MEVACOR®
(洛伐他汀(lovastatin))、AMPLIGEN®
(poly I:poly C12U、合成
RNA)、APTOSYNTM
(伊昔舒林(exisulind))、AREDIA®
(帕米膦酸(pamidronic acid))、爾革拉賓(arglabin)、L-天冬醯胺酶、阿他美坦(atamestane)(1-甲基-3,17-二酮-雄-1,4-二烯)、AVAGE®
(他扎若汀(tazarotne))、AVE-8062、BEC2(米妥莫單抗(mitumomab))、惡病質素(cachectin)或惡藏素(cachexin)(腫瘤壞死因子)、坎唯辛(canvaxin)(疫苗)、CeaVacTM
(癌症疫苗)、CELEUK®
(西莫白介素(celmoleukin))、CEPLENE®
(組織胺二鹽酸鹽)、CERVARIXTM
(人類乳頭瘤病毒疫苗)、CHOP®
(C:CYTOXAN®
(環磷醯胺(cyclophosphamide));H:阿黴素(ADRIAMYCIN)®
(羥基多柔比星(doxorubicin));O:長春新鹼(vincristine)(ONCOVIN®
);P:潑尼松(prednisone))、CyPatTM
、風車子阻生素(combrestatin)A4P、DAB(389)EGF或TransMID-107RTM
(白喉毒素(diphtheria toxin))、達卡巴嗪(dacarbazine)、更生黴素(dactinomycin)、5,6-二甲基咕噸酮-4-乙酸(DMXAA)、乙炔尿嘧啶(eniluracil)、EVIZONTM
(乳酸鯊胺)、DIMERICINE®
(T4N5脂質體洗劑)、海棉內酯(discodermolide)、DX-8951f(甲磺酸依喜替康(exatecan mesylate))、因扎托林(enzastaurin)、EPO906、GARDASIL®
(四價人類乳頭瘤病毒(第6、11、16、18型)重組疫苗)、抗胃泌素免疫原(gastrimmune)、根鈉三思(genasense)、GMK(神經節苷酯共軛物疫苗)、GVAX®
(攝護腺癌症疫苗)、鹵夫酮(halofuginone)、組胺特瑞林
(histerelin)、羥基碳醯胺、伊班膦酸(ibandronic acid)、IGN-101、IL-13-PE38、IL-13-PE38QQR(辛垂得貝索托(cintredekin besudotox))、IL-13-假單胞菌外毒素、干擾素-α、干擾素-γ、JUNOVANTM
或MEPACTTM
(米法莫肽(mifamurtide))、洛那法尼(lonafarnib)、5,10-亞甲基四氫葉酸、滅特復星(miltefosine)(十六烷基磷醯膽鹼)、NEOVASTAT®
(AE-941)、NEUTREXIN®
(糖醛酸甲曲沙)、NIPENT®
(噴司他汀(pentostatin))、ONCONASE®
(核糖核酸酶)、ONCOPHAGE®
(黑色素瘤疫苗處理)、OncoVAX(IL-2疫苗)、歐瑞提辛(ORATHECIN)TM
(魯比特康(rubitecan))、OSIDEM®
(以抗體為主之細胞藥物)、OvaRex®
MAb(鼠類單株抗體)、紫杉酚(paditaxel)、PANDIMEXTM
(來自人蔘之糖苷配基皂素,包含20(S)人蔘二醇(protopanaxadiol)(aPPD)及20(S)人蔘三醇(protopanaxatriol)(aPPT))、帕尼單抗(panitumumab)、PANVAC®
-VF(試驗中癌症疫苗)、培門冬酶(pegaspargase)、PEG干擾素A、吩諾索二醇(phenoxodiol)、丙卡巴肼(procarbazine)、瑞馬司特(rebimastat)、REMOVAB®
(卡妥索單抗(catumaxomab))、REVLIMID®
(來納度胺(lenalidomide))、RSR13(乙丙昔羅(efaproxiral))、SOMATULINE®
LA(蘭瑞肽(lanreotide))、SORIATANE®
(阿曲汀(acitretin))、星孢菌素(staurosporine)(Streptomyces staurospores)、塔拉伯司特(talabostat)(PT100)、TARGRETIN®
(倍沙羅汀
(bexarotene))、Taxoprexin®
(DHA-太平洋紫杉醇(paclitaxel))、TELCYTATM
(TLK286)、特米里吩(temilifene)、TEMODAR®
(替莫唑胺(temozolomide))、特司米里吩(tesmilifene)、沙利度胺(thalidomide)、THERATOPE®
(STn-KLH)、塞米特(thymitaq)(2-胺基-3,4-二氫-6-甲基-4-側氧基-5-(4-吡啶基硫基)喹唑啉二鹽酸鹽)、TNFeradeTM
(腺載體:含有腫瘤壞死因子-α之基因的DNA載體)、TRACLEER®
或ZAVESCA®
(波生坦(bosentan))、維他命A酸(Retin-A)、粉防己鹼(tetrandrine)、TRISENOX®
(三氧化二砷)、VIRULIZIN®
、爾克蘭(ukrain)(白屈菜之生物鹼衍生物)、維塔辛(vitaxin)(抗-αvβ3抗體)、XCYTRIN®
(莫特沙芬釓(motexafin gadolinium))、XINLAYTM
(阿曲生坦(atrasentan))、XYOTAXTM
(聚穀胺紫杉醇(paclitaxel poliglumex))、YONDELISTM
(曲貝特啶(trabectedin))、ZD-6126、ZINECARD®
(右雷佐生(dexrazoxane))、卓骨祂(zometa)(唑來膦酸(zolendronic acid))、佐柔比星(zorubicin)及諸如此類者。
於一具體實施態樣中,具有式I之化合物係使用於一種治療哺乳類癌症之方法中,該方法包含投予治療可接受量之如請求項1之化合物連同選自替莫唑胺(temozolomide)、達卡巴嗪(dacarbazine)、環磷醯胺(cyclophosphamide)、卡氮芥(carmustine)、美法侖(melphalan)、洛莫司汀(lomustine)、卡鉑(carboplatin)、順鉑、5-FU+/-白葉素
(leucovorin)、吉西他賓(gemcitabine)、甲胺喋呤(methotrexate)、平陽黴素(bleomycin)、依利替康(irinotecan)、喜樹鹼或托泊替康(topotecan)之化學療劑。
亦預期具有式I之化合物會抑制自兒童癌症或腫瘤衍生之細胞的生長,包括胚胎性橫紋肌肉瘤、小兒急性淋巴母細胞白血病、小兒急性粒細胞白血病、小兒股骨腺泡狀橫紋肌肉瘤、小兒分化不良性室管膜瘤、小兒分化不良性大細胞淋巴瘤、小兒分化不良性後顱窩腫瘤、中樞神經系統之小兒非典型畸胎/類橫紋肌細胞瘤、小兒混合型急性白血病、小兒貝奇特氏(Burkitts)淋巴瘤、艾恩(Ewing)家族腫瘤之兒童癌症諸如神經外胚層腫瘤、小兒散佈退化型威爾姆氏(Wilm's)腫瘤、小兒組織分化良好威爾姆氏(Wilm's)腫瘤、小兒膠質母細胞瘤、小兒後顱窩腫瘤、小兒神經胚細胞瘤、小兒神經胚細胞瘤-衍生之體髓細胞瘤、小兒前B細胞癌(諸如白血病)、小兒骨肉瘤、小兒類橫紋肌腎臟腫瘤、小兒橫紋肌肉瘤及小兒T-細胞癌諾如淋巴瘤及皮膚癌及諸如此類者(共有之美國申請案序號10/988,338,Cancer Res., 2000, 60, 6101-10);及自體免疫病症,包括後天免疫不全症候群、自體免疫淋巴增生症候群、溶血性貧血、發炎性疾病、血小板減少及諸如此類者(Current Allergy and Asthma Reports 2003, 3:378-384;Br. J. Haematol. 2000 Sep;110(3):584-90;Blood 2000 Feb 15;95(4):1283-92;及New England Journal of Medicine 2004 Sep;351(14):1409-1418)。
菸醯胺[2,5',8-3H]腺嘌呤二核酸及鏈黴抗生物素蛋白(strepavidin)SPA珠粒係購自Amersham Biosiences。自大腸桿菌及6-生物素-17-NAD+
純化之重組人類聚(ADP-核糖)聚合酶(PARP)係購自Trevigen。NAD+
,組蛋白,胺基苯甲醯胺,3-胺基苯甲醯胺及小牛胸腺DNA (dcDNA)係購自Sigma。含MCAT序列之莖環寡核苷係得自Qiagen。寡聚物溶於含有10mM Tris HCl pH 7.5、1mM EDTA及50mM NaCl之韌化(annealing)緩衝劑中至1mM,於95℃培育5分鐘並於45℃韌化45分鐘。組蛋白H1(95%電泳純度)係購自Roche。生物素化組蛋白H1係藉著以得自Pierce之磺基-NHS-LC-生物素處理蛋白質而製備。生物素化反應之進行係在4℃以1分鐘緩緩且斷續地將3當量10mM磺基-NHS-LC-生物素添加於在經磷酸鹽緩衝之鹽水,pH 7.5中之100μM組蛋白H1,接著於4℃培育1小時。塗覆鏈黴抗生物素蛋白(FlashPlate Plus)之微量板係購自Perkin Elmer。
PARP1檢測係於含有50mM Tris pH 8.0、1mM DTT、4mM MgCl2
之PARP檢測緩衝劑中進行。PARP反應含有1.5μM [3
H]-NAD+
(1.6uCi/毫莫耳)、200nM生物素化組蛋白H1、200nM slDNA及1nM PARP酶。採用以SPA珠粒為主之偵測的自動反應係於白色96孔板中在100微升體積中進行。藉著於含有PARP及DNA之50微升2X酶混合物中添加50微升2X NAD+
受質混合物來起始反應。此等反應係藉著添加150微升1.5mM苯甲醯胺(超過其IC50~1000倍)而終
止。將170微升終止反應之混合物移至鏈黴抗生物素蛋白Flash Plate,培育1小時,使用TopCount微量板閃爍計數器計數。例示之本發明化合物的EC50s
係提供於表1。
C41細胞係於96孔板中以本發明化合物處理30分鐘。之後藉由以1mM H2
O2
傷害DNA歷經10分鐘而活化PARP。隨後以冰冷PBS洗滌細胞一次,於-20℃以預先冷卻之甲醇:丙酮(7:3)固定10分鐘。風乾後,該板以PBS再次水合且於室溫以於PBS-TWEEN20® (Sigma, St. Louis, MO)(0.05%)中5%脫脂奶粉(封閉溶液)封閉30分鐘。細胞於37℃以抗-PAR抗體10H於封閉溶液(1:50)中培育60分鐘,接著以PBS-TWEEN20®洗滌5次,在37℃以羊抗鼠螢光素5(6)-異硫代氰酸酯-偶合抗體(1:50)及1微克/毫升在封閉溶液中之4',6-二脒基-2-苯基吲哚(DAPI)培育60分鐘。以PBS-TWEEN20®洗滌5次後,使用FMAX FLUORESCENCE MICROPLATE READER® (Molecular Devices, Sunnyvalle、CA)進行分析,激發波長設定於490奈米且發光波長為528奈米螢光素5(6)-異硫代氰酸酯(FITC)或激發波長355奈米且發光波長為460奈米(DAPI)。PARP活性(FITC信號)係以細胞數目規度化(DAPI)。
細胞檢測係量度細胞內因PARP形成之聚ADP-核糖,證明本發明化合物穿透細胞膜且抑制完整細胞之PARP。因細胞檢測之變化性之故,於每個檢測中各進行2-(1-丙基哌啶-4-基)-1H
-苯并咪唑-4-甲醯胺作為對照組,數據以試驗
化合物EC50
相對於特定檢測所得之2-(1-丙基哌啶-4-基)-1H
-苯并咪唑-4-甲醯胺EC50
之比例來記錄。所進行之所有檢測的平均2-(1-丙基哌啶-4-基)-1H
-苯并咪唑-4-甲醯胺EC50
係為0.0032μM(n=270)且通常係0.001至0.013μM範圍內。(比例EC50
=EC50
試驗化合物/EC50對照組化合物)。EC50
數據(nM)係顯示於表1中。
選擇之式I化合物,其中A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基,進行前述PARP酶抑制檢測及PARP細胞檢測。式I以外之化合物,其中A2
之位置亦以鍵結取代,進行前述PARP酶抑制檢測及PARP細胞檢測。檢測結果描述於下表2:
選擇之式I化合物,其中A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基,其中R5
係經R10
取代,其中R10
係為苯基,或具有對位-取代之F,如式(Is)所示:(Is)或不具有對位-取代之F,進行前述
PARP酶抑制檢測及PARP細胞檢測。
作為PARP抑制劑,本發明化合物具有數種有關局部缺血再灌流損傷、發炎性疾病、退化性疾病、保護防止胞毒性化合物之副作用及增強胞毒性癌症療法的治療應用。尤其,本發明化合物藉由增加癌細胞之細胞死亡、限制腫瘤生長、減少轉移及延長帶有腫瘤之哺乳類的存活性而增強放射及化學療法。具有式I之化合物可治療白血病、結腸癌、膠質母細胞瘤、淋巴瘤、黑色素瘤、乳腺癌及子宮頸癌。
其他治療應用係包括逆轉錄病毒感染、關節炎、痛風、發炎性腸疾、CNS發炎、多發性硬化、過敏性腦炎、敗血症、敗血性休克、出血性休克、肺纖維化、葡萄膜炎、糖尿病,帕金森氏症、心肌梗塞、中風、其他神經創傷、器官移植、眼睛再灌流、腎臟再灌流、腸再灌流、骨骼肌再灌流、乙醯胺酚過量後之肝中毒、來自多柔比星(doxorubicin)及以鉑為主之抗腫瘤劑的心臟及腎臟中毒及硫芥子氣繼發之皮膚損傷。(G. Chen等人,Cancer Chemo. Pharmacol. 22 (1988), 303;C. Thiemermann等人,Proc.
Natl. Acad. Sci. USA 94 (1997), 679-683 D. Weltin等人,Int. J. Immunopharmacol. 17 (1995), 265-271;H. Kröger 等人,Inflammation 20 (1996), 203-215;W. Ehrlich等人,Rheumatol. Int. 15 (1995), 171-172;C. Szabo等人,Proc. Natl. Acad. Sci. USA 95 (1998), 3867-3872;S. Cuzzocrea等人,Eur. J. Pharmacol. 342 (1998), 67-76;V. Burkhart等人,Nature Medicine (1999), 5314-19)。
式I之一具體實施態樣中
或其鹽,其中A1
係為R1
或R2
,其中A1
係未經取代或經一或兩個以下基團所取代:OH、CN、C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基、C5
-烷基、環烷、ORA
或NRA
RA
; RA
係為H或烷基;R1
係為環烷或環烯,其各未稠合或與R1A
稠合;R1A
係為苯、雜芳烴、環烷、環烯、雜環烷或雜環烯;R2
係為雜環烷或雜環烯;其各未稠合或與R2A
稠合;R2A
係為苯、雜芳烴、環烷、環烯、雜環烷或雜環烯;A2
係為OR4
、NHR4
、N(R4
)2
、SR4
、S(O)R4
、SO2
R4
或R5
;
其中各R4
係為C1
-烷基、C2
-烷基或C3
-烷基;其各經R10
所取代;R5
係為C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基或C5
-烷基;其各經R10
所取代,且未進一步經取代或進一步經一或二或三個獨立選自以下之基團所取代:OR10
、NHR10
、N(R10
)2
、SR10
、S(O)R10
、SO2
R10
或CF3
;其中各R10
係為R10A
、R10B
或R10C
;其各須連接於碳原子;R10A
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;
R10B
係為;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R10C
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其中各R10
係獨立地未經取代或經一或二或三個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、
SO2
R11
、NH2
、NHR11
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NH2
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NR11
C(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NR11
C(O)OR11
、NHSO2
NH2
、NHSO2
NHR11
、NHSO2
N(R11
)2
、SO2
NH2
、SO2
NHR11
、SO2
N(R11
)2
、NHC(O)NH2
、NHC(O)NHR11
、NHC(O)N(R11
)2
、NR11
C(O)N(R11
)2
、NO2
、OH、(O)、C(O)H、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;其中各R11
係為R12
、R13
、R14
或R15
; R12
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R13
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R14
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R15
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NH2
、C(O)NHR16
、C(O)N(R16
)2
、NHC(O)R16
、NR16
C(O)R16
、NHC(O)OR16
、NR16
C(O)OR16
、OH、F、
Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R18
、C(O)OH、NH2
、NHR18
或N(R18
)2
、C(O)R18
、C(O)NH2
、C(O)NHR18
、C(O)N(R18
)2
、NHC(O)R18
、NR18
C(O)R18
、F、Cl、Br或I; R17A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其中各R18
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、S(O)R19
、SO2
R19
、C(O)R19
、CO(O)R19
、OC(O)R19
、OC(O)OR19
、NH2
、NHR19
、N(R19
)2
、NHC(O)R19
、NR19
C(O)R19
、NHS(O)2
R19
、NR19
S(O)2
R19
、NHC(O)OR19
、NR19
C(O)OR19
、NHC(O)NH2
、NHC(O)NHR19
、NHC(O)N(R19
)2
、NR19
C(O)NHR19
、NR19
C(O)N(R19
)2
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)NHOH、C(O)NHOR19
、C(O)NHSO2
R19
、C(O)NR19
SO2
R19
、SO2
NH2
、SO2
NHR19
、SO2
N(R19
)2
、C(O)H、C(O)OH、C(N)NH2
、C(N)NHR19
、C(N)N(R19
)2
、CNOH、CNOCH3
、OH、(O)、CN、N3
、NO2
、CF3
、CF2
CF3
、OCF3
、OCF2
CF3
、F、Cl、Br或I;
其中各R19
係為R20
、R21
、R22
或R23
;R20
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R21
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R22
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R23
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R24
、OR24
、SR24
、S(O)2
R24
、C(O)OH、NH2
、NHR24
、N(R24
)2
、C(O)R24
、C(O)NH2
、C(O)NHR24
、C(O)N(R24
)2
、NHC(O)R24
、NR24
C(O)R24
、NHC(O)OR24
、NR24
C(O)OR24
、NHS(O)2
R24
、NR24
S(O)2
R24
、OH、F、Cl、Br或I;其中各R24
係為R24A
或R24B
; R24A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R24B
係為烷基、烯基或炔基,其各係未經取代或經一或兩個獨立選自以下之基團所取代:R25
、OR25
、SR25
、S(O)2
R25
、C(O)OH、NH2
、NHR25
、N(R25
)2
、C(O)R25
、
C(O)NH2
、C(O)NHR25
、C(O)N(R25
)2
、NHC(O)R25
、NR25
C(O)R25
、NHC(O)OR25
、NR25
C(O)OR25
、OH、F、Cl、Br或I;其中各R25
係為烷基、苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其各係未經取代或經NH2
、NH(CH3
)、N(CH3
)2
、OH或OCH3
所取代;其中由R20
、R21
、R22
及R24
所表示之每一部分各獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、烯基、炔基、苯基、OH、(O)、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;且R26
係為烷基。
以下所述之各具體實施態樣係顯示式I化合物範圍內之特定重要化合物亞群,其中A1
、R1
、RA
、R1A
、R2
、R2A
,A2
、R4
、R5
、R10
、R10A
、R10B
、R10C
、R11
、R12
、R13
、R14
、R15
、R16
、R17
、R17A
、R18
、R19
、R20
、R21
、R22
、R23
、R24
、R24A
、R24B
、R25
及R26
可如式I化合物所定義且如本發明全文所述之各具體實施態樣中所定義。
式I之一具體實施態樣中,A1
係為R1
或R2
,其中R1
係為未稠合環烷且R2
係為未稠合雜環烷,其中A1
係未經取代或係經一或兩個以下基團所取代:OH、CN、C1
-烷基、C2
-烷基、C3
-烷基、C4
-烷基、C5
-烷基、環烷、ORA
或NRA
RA
;其中RA
係為H或烷基。式I之另一具體實施態樣
中,A1
係為R1
或R2
,其中R1
係為環己烷且R2
係為哌啶基,其中A1
係未經取代或係經一或兩個以下基團所取代:C1
-烷基、C2
-烷基或C3
-烷基。式I之另一具體實施態樣中,A1
係為R1
或R2
,其中R1
係未經取代環己烷且R2
係未經取代哌啶基。式I之另一具體實施態樣中,A1
係為R1
,且R1
係未經取代環己烷,如式(Ia)所示:
式I之一具體實施態樣中,A2
係為OR4
、NHR4
、N(R4
)2
、SR4
、S(O)R4
、SO2
R4
或R5
;其中各R4
係為C1
-烷基、C2
-烷基或C3
-烷基;其各如式I所述般地經R10
所取代;且R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R5
係如式I所述般地經取代。式I之另一具體實施態樣中,A2
係為R5
,且R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R5
係如式I所述般地經取代。式I之另一具體實施態樣中,A2
係為R5
,其中R5
係為C1
-烷基,其係經R10
取代,且未進一步經取代或進一步經一或二或三個獨立選自以下之基團所取代:NHR10
、N(R10
)2
、SR10
、S(O)R10
、SO2
R10
或CF3
,其中R10
係如式I所述。式I之另一具體實施態樣中,A2
係為R5
,其中R5
係為C1
-烷基,如式I所述般地經R10
取代且如式(Ib)所示未進一步經取代:。式I之另一具體實施態樣中,A2
係為
R5
,其中R5
係為C2
-烷基,如式I所述般地經R10
取代且未如式(Ic)及(Id)所示地進一步經取代:。式I之另一具體實施態
樣中,A2
係為R5
,其中R5
係為C3
-烷基,如式I所述般地經R10
取代且未進一步經取代。式I之另一具體實施態樣中,A2
係為R5
,其中R5
係為C1
-烷基或C2
-烷基;其各如式I所述般地經R10
取代且進一步經CF3
所取代。
式I之一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為
稠合雜環烷,R10B
係為,且
R10C
係為未稠合雜環烷基,其中R10
係視情況如式I所述般經取代。式I之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠合雜環烷,R10B
係為,且R10C
係為未稠合雜環烷
基;其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11、
NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br,其中R11
係如式I所述。式I之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠
合雜環烷,R10B
係為,且R10C
係為未稠合雜環烷基;其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中各R11
係為R12
、R13
、R14
或R15
;其中R12
係為未稠合或與苯、雜芳烴、雜環烷或雜環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、
C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I,其中R16
係如式I所述。式I之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠合雜環烷,R10B
係為,且R10C
係為未稠合雜環烷
基;其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中各R11
係為R12
、R13
、R14
或R15
;其中R12
係為未稠合或與苯、雜芳烴、雜環烷或雜環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;且R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分
係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述。式I之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠合雜環
烷,R10B
係為,且R10C
係為未
稠合雜環烷基;其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中各R11
係為R12
、R13
、R14
或R15
;其中R12
係為未稠合或與苯、雜芳烴、雜環烷或雜環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各
R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;且R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
N(R24
)2
、NHS(O)2
R24
或OH,其中R24
係如式I所述。式I之另一具體實施態樣中,R10
R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠合雜環
烷,R10B
係為,且R10C
係為未
稠合雜環烷基;其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中各R11
係為R12
、R13
、R14
或R15
;其中R12
係為未稠合或與苯、雜芳烴、雜環烷或雜
環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;且R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其未稠合或與雜環烷稠合;R24B
係為未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為未經取代或經NH2
取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分
係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
(O)、F、Cl、Br或I;且R26
係為烷基。式I之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中
R10A
係為、R10B
係為,且R10C
係為,其中R10
係視情況如式I所述般經取代。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係視情況如式I所述般經取代。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中各R11
係為R12
、R13
、R14
或R15
;其中R12
係為未稠合或與苯、雜芳烴、雜環烷或雜環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、
NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;且R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其未稠合或與雜環烷稠合;R24B
係為未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為未經取代或經NH2
取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
(O)、F、Cl、Br或I;且R26
係為烷基。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係經F取代且進一步經NHC(O)R11
取代,其中R11
係為R15
,其中R16
係視情況如式I所述般經取代。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係經F取代且進一步經R11
取代,其中R11
係為R12
或R14
,其中R14
係為未經取代或經一或二或三或四個獨立選自以下之基團所取代的雜環烷基:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係經F取代且進一步經R11
取代,其中R11
係為苯基、吡咯啶基、氮雜雙環(3.1.0)己烷基、六氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係經F取代且進一步經R11
取代,其中R11
係為苯基、吡咯啶基、氮雜雙環(3.1.0)己烷基、六氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地經一或兩個(O)所取代。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,
其中R10
係經F取代且進一步經R11
取代,其中R11
係為R14
,其中R14
係為雜環烷基,其未經取代或經一或兩個(O)所取代。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係經F取代且進一步經R11
取代,其中R11
係為R14
,其中R14
係為吡咯啶基,其係經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述且其中R14
係經至少一個(O)所取代。式I之另一具體實施態樣中,R10
係為R10A
,其中R10A
係為未稠合之苯基,其中R10
係經F取代且進一步經R11
取代,其中R11
係為R14
,其中R14
係為經一或兩個(O)所取代之吡咯啶基。
以下係式I化合物之其他具體實施態樣。除非另有陳述,否則取代基係如式I所述。
式I之一具體實施態樣中,R1
係為未稠合之環烷;R2
係為未稠合之雜環烷,且A2
係為R5
。
式I之一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為如式I所述之R5
。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷
基,其中R5
係如式I所述般地經取代。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R10
係為R10A
,其中R10A
係為未稠合且經F取代之苯基,且進一步經NHC(O)R11
取代,其中R11
係為R15
。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R10
係為R10A
,其中R10A
係為未稠合且經F取代之苯基,且進一步經NHC(O)R11
取代,其中R11
係為R15
其中R15
係為未經取代或經一或兩個獨立選自以下之基團所取代的烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經一或兩個獨立選自R18
之基團所取代的烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;其中各R18
係為苯基或雜環烷基;其中由R17A
及R18
所表示之部分各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;R23
係為未經取代或經一或兩個獨立選自以下之基團所取代的烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其各未稠合或與雜環烷稠合;R24B
係為未經取代或經一或兩個獨立選自OR25
或OH之基團所取代的烷基;其中各R25
係為未經取代或經NH2
取代之烷基;其中各R20
係未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、(O)、F、Cl、Br或I;且R26
係為烷基。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R10
係經F取代且進一步經R14
取代,其中各R10
係獨立地未經取代或經一或二或三個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、NHR11
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NH2
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NR11
C(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NR11
C(O)OR11
、NHSO2
NH2
、NHSO2
NHR11
、NHSO2
N(R11
)2
、SO2
NH2
、SO2
NHR11
、SO2
N(R11
)2
、NHC(O)NH2
、NHC(O)NHR11
、NHC(O)N(R11
)2
、NR11
C(O)N(R11
)2
、NO2
、OH、(O)、C(O)H、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;其中R14
係為吡咯啶基、吖丁啶基、吡咯基、1,3-噁唑啶基、氮基、哌啶基、咪唑啶基、四氫嘧啶(2H)-基、氮雜雙環(2.2.1)庚基或1,6-二氫噠嗪基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未
稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;且其中由R14
表示之部分係經一或兩個(O)取代基所取代。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R5
係經R10
取代,且未進一步經取代或進一步經一或二或三個獨立選自以下之基團所取代:NHR10
、N(R10
)2
、SR10
、S(O)R10
、SO2
R10
或CF3
,其中R10
係如式I所述。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R5
係經R10
取代,且未進一步經取代或經一個CF3
取代,其中R10
係如式I所述。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為選自下式(Ie)、(If)、(Ig)、(Ih)、(Ii)或(Ij)之R5
: 。式
(Ii)之一具體實施態樣中,R10
係為R10A
、R10B
或R10C
;其各須連接於碳原子;R10A
係為未稠合或與雜環烷稠合之苯
基,該雜環烷係與雜環烷稠合;R10B
係為;R10C
係為未稠合雜環烷基;
其中R10
係經以下基團取代:C(O)R11
、C(O)NHR11
、C(O)N(R11
)2
或NHC(O)R11
,且未進一步經取代或經一或二或三個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl、Br或I;其中各R11
係為R12
、R13
、R14
或R15
; R12
係為未稠合或與苯、雜芳烴、雜環烷或雜環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;R15
係為未經取代或經一或兩個獨立選自以下之基團所取代的烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為烷基,其未經取代或經R18
所取代;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、
NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基,其各未稠合或與苯稠合;R23
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
、OH、F、Cl、Br或I;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基;其各未稠合或與雜環烷稠合;R24B
係為係未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為各未經取代或經NH2
所取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、(O)、F、Cl、Br或I;且R26
係為烷基。式I之另一具體實施態樣中,A1
係為R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為C1
-烷基,其中R5
係經R10
取代,其中R10
係如式I所述,如式(Ie)所描述。式I之另一具體實施態樣中,A1
係為
R1
,其中R1
係未經取代之未稠合環己烷,且A2
係為R5
,R5
係為未分支鏈C2
-烷基,其中R5
係經R10
取代,其中R10
係如
式I所述,如式(If)所描述。
式(Ie)之一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠合雜環烷,R10B
係為,且
R10C
係為未稠合雜環烷基;其中R10
係如式I所述般地經取代。式(Ie)之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠合雜環烷,R10B
係為,且R10C
係為未稠合雜環烷
基;其中R10
係經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係如式I所述。式(Ie)之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠
合之苯基,該雜環烷係為稠合雜環烷,R10B
係為,且R10C
係為未稠合雜環烷
基;其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O或
R11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係如式I所述。式(Ie)之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,其中R10A
係為未稠合或與雜環烷稠合之苯基,該雜環烷係為稠
合雜環烷,R10B
係為,且R10C
係為未稠合雜環烷基;其中R10
係經F取代且未進一步經取代或經一或兩個獨立選自以下之基團所取代:R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係為R12
、R13
、R14
或R15
; R12
係為未稠合或與苯、雜芳烴、雜環烷或雜環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、
C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R33
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其未稠合或與雜環烷稠合;R24B
係為未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為未經取代或經NH2
取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
(O)、F、Cl、Br或I;且R26
係為烷基。式(Ie)之另一具體實施態樣中,R10
係為R10A
、R10B
或R10C
,
其中R10A
係為未稠合之苯基、或,R10B
係為,且
R10C
係為,其中R10
係視情況如式I所述般經取代。
式(Ie)之另一具體實施態樣中,R10
係為如式(Ik)、(Il)、(Im)、(In)、(Io)或(Ip)所述之R10A
、R10B
或R10C ,其
中R101
、R102
、R103
、R104
及R105
係獨立地選自R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係如式I所述。
式(Ie)之另一具體實施態樣中,R10
係為R10A
或R10B
,如式(Ik)、(Il)、(Im)、(In)、(Io)或(Ip)所述。式(Ie)之另一具體實施態樣中,R10
係為苯基,如式(Ik)所示:,其中R101
、R102
、R103
、R104
及
R105
係獨立地選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係如式I所述。式(Ik)之另一具體實施態樣中,R101
、R102
、R103
、R104
及R105
中至少一基團係為F,且至少一基團係為R11
,其中R11
係為苯基、吡咯基、氮雜雙環(3.1.0)己烷基、六氫-1H-異吲哚基、1,3-噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、1,6-二氫噠嗪基、四氫嘧啶(2H)-基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或二或三個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基,其各未稠合或與苯稠合;R23
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R24
、OR24
、
NHR24
、N(R24
)2
、NHS(O)2
R19
、OH、F、Cl、Br或I;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基;其各未稠合或與雜環烷稠合;R24B
係為係未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為各未經取代或經NH2
所取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、(O)、F、Cl、Br或I;且R26
係為烷基。式(Ik)之另一具體實施態樣中,R101
、R104
及R105
係為H,且R102
係為R11
,其中R11
係選自吡咯啶基、噁唑基、咪唑啶基、異噻唑啶基、哌啶基及氮基,其中R102
係經一或兩個(O)取代基所取代。式(Ik)之另一具體實施態樣中,R101
、R104
及R105
係為H,且R102
係為R11
,其中R11
係為吡咯啶基。
式(Ik)之一具體實施態樣中,R102
係為NHC(O)R11
,如式(Iq)所述:,其中R101
、R103
、R104
及R105
係獨立選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、
C(O)OH、F、Cl或Br;其中R11
係如式I所述。式(Iq)之一具體實施態樣中,R11
係為R15
,其中R16
係視情況如式I所述般經取代且R101
、R103
、R104
及R105
係如式(Iq)所述。式(Iq)之另一具體實施態樣中,R103
係為F,且R101
、R104
及R105
係獨立選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;且R11
係為R15
,其中R16
係視情況如式I所述般經取代。式(Iq)之另一具體實施態樣中,R101
、R103
、R104
及R105
中之一係為F、R11
係為R15
,其中R16
係視情況如式I所述般經取代。式(Iq)之另一具體實施態樣中,R101
、R104
及R105
係為F。式(Iq)之另一具體實施態樣中,R103
係為F。式(Iq)之另一具體實施態樣中,R101
、R103
、R104
及R105
中之一係為F,R11
係為R15
,其中R16
係為未經取代或經一或兩個獨立選自以下之基團所取代的烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經一或兩個獨立選自R18
之基團所取代的烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;其中各R18
係為苯基或雜環烷基;其中由R17A
及R18
所表示之部分各獨立地未經取代或經一或二或三或四個獨立選自以下之
基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;R23
係為未經取代或經一或兩個獨立選自以下之基團所取代的烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24BA
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其各未稠合或與雜環烷稠合;R24B
係為未經取代或經一或兩個獨立選自OR25
或OH之基團所取代的烷基;其中各R25
係為未經取代或經NH2
取代之烷基;其中各R20
係未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、(O)、F、Cl、Br或I;且R26
係為烷基。式(Iq)之另一具體實施態樣中,R103
係為F,且R101
、R104
及R105
各係為H,R11
係為R15
,其中R16
係視情況如式I所述般經取代。式(Iq)之另一具體實施態樣中,R11
係為R12
或R14
,其中R14
係為未經取代或經一或二或三或四個獨立選自以下之基團所取代的雜環烷基:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中R19
係如式I所述。式(Iq)之另一具體實施態樣中,R11
係選自苯基、吡咯啶基、氮雜雙環(3.1.0)己烷基、六
氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中R19
係如式I所述。
式(Ik)之一具體實施態樣中,R102
係為R11
,其中R11
係為吡咯啶基,如式(Ir)所述:,其中R101
、R103
、R104
及R105
係獨立地選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係如式I所述,且R201
、R202
、R203
及R204
係獨立地為H、R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或
I;其中R19
係如式I所述。式(Ir)之一具體實施態樣中,R103
係為F,且R101
、R104
及R105
係為H,其中R201
、R202
、R203
及R204
係獨立地為H、R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中R19
係如式I所述。式(Ir)之一具體實施態樣中,R201
、R202
、R203
及R204
中之一或兩基團係為(O)。式(Ir)之另一具體實施態樣中,R201
、R202
、R203
及R204
中兩基團係為(O)。式(Ir)之另一具體實施態樣中,R201
及R204
係為(O)且R202
及R203
係為H,如式(Ir1
)所述:。式(Ir1
)之一具體實施態樣中,
R103
係為F且R101
、R104
及R105
係獨立地選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係如式I所述。
式(Ik)之一具體實施態樣中,R103
係為F,如式(Is)所
述:,其中R101
、R102
、R104
及R105
係獨立地選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中R11
係如式I所述。式(Is)之另一具體實施態樣中,R101
、R102
、R104
及R105
係獨立地選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中各R11
係為R12
、R13
、R14
或R15
;其中R12
係為未稠合或與苯、雜芳烴、雜環烷或雜環烯稠合之苯基;R13
係為未稠合之雜芳基;R14
係為環烷基、雜環烷基或雜環烯基;其各未稠合或與苯、環烷、雜環烷或雜環烯稠合;其各未稠合或與苯稠合;且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;且R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其未稠合或與雜環烷稠合;R24B
係為未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為未經取代或經NH2
取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
(O)、F、Cl、Br或I;且R26
係為烷基。式(Is)之另一具體實施態樣中,R11
係選自苯基、吡咯啶基、氮雜雙環(3.1.0)己烷基、六氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取
代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中R19
係如式I所述。式(Is)之另一具體實施態樣中,R102
係為R11
、其中R11
係選自吡咯啶基、噁唑基、咪唑啶基、異噻唑啶基、哌啶基、哌嗪基及氮基,其中R102
係經一或兩個(O)取代基所取代。式(Is)之另一具體實施態樣中,R102
係為R11
,其中R11
係選自經一或兩個(O)取代基所取代之吡咯啶基。式(Is)之另一具體實施態樣中,R101
、R104
及R105
係為H,且R102
係選自R11
、OR11
、NHC(O)R11
或C(O)NHR11
;其中R11
係如式I所述。式(Is)之另一具體實施態樣中,其中R101
、R104
及R105
係為H,且R102
係選自R11
、OR11
、NHC(O)R11
或C(O)NHR11
;其中R11
係為苯基、吡咯啶基、氮雜雙環(3.1.0)己烷基、六氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述。式(Is)之另一具體實施態樣中,其中R101
、R104
及R105
係為H,且R102
係選自R11
、OR11
、NHC(O)R11
或C(O)NHR11
;其中R11
係為苯基、吡咯啶基、氮雜雙環
(3.1.0)己烷基、六氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述。式(Is)之另一具體實施態樣中,其中R101
、R104
及R105
係為H,且R102
係選自R11
、OR11
、NHC(O)R11
或C(O)NHR11
;其中R11
係為R15
且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷
基或雜環烷基;其各未稠合或與苯稠合;且R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其未稠合或與雜環烷稠合;R24B
係為未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為未經取代或經NH2
取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
(O)、F、Cl、Br或I;且R26
係為烷基。
於一具體實施態樣中,式(Is)化合物係選自:2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苄酸;4-(3-胺基-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)胺基)-4-側氧基丁酸;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡咯啶-2,5-二酮;4-(3-(1,4-二氮-1-基羰基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(胺基甲基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-((二甲基胺基)甲基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((異丙基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-
1(2H)-酮;4-(3-((環己基胺基)甲基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((四氫-2H-哌喃-4-基胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((甲基((1-甲基吡咯啶-3-基)甲基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((甲基(((2R)-1-甲基吡咯啶-2-基)甲基)胺基)甲基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-嘧啶-2-基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-吡啶-3-基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-吡啶-4-基苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N,N-二乙基-2'-氟-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-2-甲醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-哌啶-1-基丙醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-(4-甲基哌嗪-1-基)丙醯胺;2-胺基-N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)乙醯胺;3-環己基-N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-
1-基)甲基)苯基)丙醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)哌啶-3-甲醯胺;4-(4-氟-3-(2-側氧基吡咯啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吖丁啶-3-甲醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-嗎啉-4-基乙醯胺;N-(2'-氟-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-3-基)乙醯胺;4-((6-氟-3'-(甲基磺醯基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((6-氟-3'-(吡咯啶-1-基羰基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-((6-氟-4'-(吡咯啶-1-基羰基)-1,1'-聯苯-3-基)甲基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N,N-二乙基-2'-氟-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-3-甲醯胺;2'-氟-N,N-二甲基-5'-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)-1,1'-聯苯-4-甲醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-4-(4-甲氧苯基)-4-側氧基丁醯胺;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)
苯基)-3,4-二甲基-1H-吡咯-2,5-二酮;3-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-氮雜雙環(3.1.0)己烷-2,4-二酮;2-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)六氫-1H-異吲哚-1,3(2H)-二酮;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3,3-二甲基吡咯啶-2,5-二酮;4-(4-氟-3-(2-甲基-5-側氧基吡咯啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基-1,3-噁唑啶-3-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基氮-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)哌啶-2,6-二酮;4-(4-氟-3-(2-側氧基咪唑啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(1,1-二氧根異噻唑啶-2-基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基吖丁啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基哌啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(3-甲基-2-側氧基咪唑啶-1-基)苄基)-5,6,7,8-四
氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基四氫嘧啶-1(2H)-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(3-(3-第三丁基-2-側氧基咪唑啶-1-基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-((1S,4R)-3-側氧基-2-氮雜雙環(2.2.1)庚-2-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-N-甲基甲烷磺醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-羥基-2-甲基丙醯胺;(3aS,4R,7S,7aR)-5-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2,2-二甲基四氫-4,7-亞甲(1,3)二氧雜環戊烯并(4,5-c)吡啶-6(3aH)-酮;4-(3-(1,1-二氧代-1,2-硫氮雜環己烷-2-基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-2-(2-側氧基吡咯啶-1-基)乙醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-5-側氧基己烷醯胺;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-甲氧丙醯胺;
N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-N'-苯基戊烷二醯胺;4-(4-氟-3-((4-嘧啶-2-基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;或4-(4-氟-3-(2-側氧基吡咯啶-1-基)苯基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮。
另一具體實施態樣中,式(Is)化合物係選自4-((2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)胺基)-4-側氧基丁酸;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡咯啶-2,5-二酮;4-(4-氟-3-(2-側氧基吡咯啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;N-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-(4-甲基哌嗪-1-基)丙醯胺;3-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3-氮雜雙環(3.1.0)己烷-2,4-二酮;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)-3,3-二甲基吡咯啶-2,5-二酮;4-(4-氟-3-(2-側氧基-1,3-噁唑啶-3-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(3-甲基-2-側氧基咪唑啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基氮-1-基)苄基)-5,6,7,8-四氫二氮雜
萘-1(2H)-酮;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)哌啶-2,6-二酮;4-(3-(1,1-二氧代異噻唑啶-2-基)-4-氟苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基哌啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;或4-(4-氟-3-((4-嘧啶-2-基哌嗪-1-基)羰基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮。
式(Ik)之一具體實施態樣中,R102
係為C(O)R11
,如式(It)所述:,其中R11
係如式I所述。式(It)之一具
體實施態樣中,R101
、R103
、R104
及R105
係為H。式(It)之另一具體實施態樣中,R103
係為F且R101
、R104
及R105
係為H。式(It)之另一具體實施態樣中,R11
係為R15
且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合
或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷基或雜環烷基;其各未稠合或與苯稠合;且R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其未稠合或與雜環烷稠合;R24B
係為未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為未經取代或經NH2
取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
(O)、F、Cl、Br或I;且R26
係為烷基。式(It)之另一具體實施態樣中,R11
係為苯基、吡咯啶基、氮雜雙環(3.1.0)己烷基、六氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、
C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述。
式(Ik)之一具體實施態樣中,R102
係為C(O)NHR11
,如式
(Iu)所述:,其中R11
係如式I所述。
式(Iu)之一具體實施態樣中,R101
、R103
、R104
及R105
係為H。式(Iu)之另一具體實施態樣中,R103
係為F且R101
、R104
及R105
係為H。式(Iu)之另一具體實施態樣中,R11
係為R15
且R15
係為未經取代或經一或兩個獨立選自以下之基團所取代之烷基:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NHR16
、NHC(O)R16
、NHC(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為未經取代或經R18
取代之烷基;R17A
係為苯基、雜芳基、環烷基、雜環烷基或雜環烯基,其各未稠合或與苯或雜環烷稠合;R18
係為未稠合之苯基或雜環烷基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合之苯基;R21
係為未稠合之雜芳基;R22
係為環烷
基或雜環烷基;其各未稠合或與苯稠合;且R23
係為係未經取代或經以下基團取代之烷基:R24
、OR24
、NHR24
、N(R24
)2
、NHS(O)2
R24
或OH;其中各R24
係為R24A
或R24B
; R24A
係為苯基、環烷基、雜環烷基或雜環烯基,其未稠合或與雜環烷稠合;R24B
係為未經取代或經以下基團取代之烷基:OR25
、OH、F、Cl、Br或I; R25
係為未經取代或經NH2
取代之烷基;其中由R20
、R21
、R22
及R24
所表示之部分係獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
(O)、F、Cl、Br或I;且R26
係為烷基。式(Iu)之另一具體實施態樣中,R11
係為苯基、吡咯啶基、氮雜雙環(3.1.0)己烷基、六氫-1H-異吲哚基、噁唑啶基、氮基、哌啶基、咪唑啶基、噻唑啶基、噻嗪基、吖丁啶基、四氫嘧啶基或氮雜雙環(2.2.1)庚-2-基;其各獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R19
、OR19
、SR19
、SO2
R19
、C(O)R19
、CO(O)R19
、NHR19
、N(R19
)2
、NHC(O)R19
、NHS(O)2
R19
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)H、OH、(O)、CN、CF3
、F、Cl、Br或I,其中R19
係如式I所述。
式(Ik)之一具體實施態樣中,R102
係為未經取代或經一或二或三或四個獨立選自以下之基團所取代的苯基:R19
、OR19
、SR19
、S(O)R19
、SO2
R19
、C(O)R19
、CO(O)R19
、OC(O)R19
、OC(O)OR19
、NH2
、NHR19
、N(R19
)2
、NHC(O)R19
、NR19
C(O)R19
、NHS(O)2
R19
、NR19
S(O)2
R19
、NHC(O)OR19
、NR19
C(O)OR19
、NHC(O)NH2
、
NHC(O)NHR19
、NHC(O)N(R19
)2
、NR19
C(O)NHR19
、NR19
C(O)N(R19
)2
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)NHOH、C(O)NHOR19
、C(O)NHSO2
R19
、C(O)NR19
SO2
R19
、SO2
NH2
、SO2
NHR19
、SO2
N(R19
)2
、C(O)H、C(O)OH、C(N)NH2
、C(N)NHR19
、C(N)N(R19
)2
、CNOH、CNOCH3
、OH、(O)、CN、N3
、NO2
、CF3
、CF2
CF3
、OCF3
、OCF2
CF3
、F、Cl、Br或I;其中R19
係如式I所述。
式(Ik)之一具體實施態樣中,R102
係為未經取代或經一或二或三或四個獨立選自以下之基團所取代的雜環烷基:R19
、OR19
、SR19
、S(O)R19
、SO2
R19
、C(O)R19
、CO(O)R19
、OC(O)R19
、OC(O)OR19
、NH2
、NHR19
、N(R19
)2
、NHC(O)R19
、NR19
C(O)R19
、NHS(O)2
R19
、NR19
S(O)2
R19
、NHC(O)OR19
、NR19
C(O)OR19
、NHC(O)NH2
、NHC(O)NHR19
、NHC(O)N(R19
)2
、NR19
C(O)NHR19
、NR19
C(O)N(R19
)2
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)NHOH、C(O)NHOR19
、C(O)NHSO2
R19
、C(O)NR19
SO2
R19
、SO2
NH2
、SO2
NHR19
、SO2
N(R19
)2
、C(O)H、C(O)OH、C(N)NH2
、C(N)NHR19
、C(N)N(R19
)2
、CNOH、CNOCH3
、OH、(O)、CN、N3
、NO2
、CF3
、CF2
CF3
、OCF3
、OCF2
CF3
、F、Cl、Br或I;其中R19
係如式I所述。
式(I)之一具體實施態樣中,A1
係為R2
,其中R2
係未經取
代之未稠合哌啶,且A2
係為R3
,如式I所述。式I之另一具體實施態樣中,A1
係為R2
,其中R2
係未經取代之未稠合哌啶,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R5
係經R10
取代,且未進一步經取代或進一步經一或二或三個獨立選自以下之基團所取代:NHR10
、N(R10
)2
、SR10
、S(O)R10
、SO2
R10
或CF3
,其中R10
係如式I所述。式I之另一具體實施態樣中,A1
係為R2
,其中R2
係未經取代之未稠合哌啶,且A2
係為R5
,R5
係為C1
-烷基、C2
-烷基或C3
-烷基,其中R5
係經R10
取代,且未進一步經取代或經一個CF3
取代,其中R10
係如式I所述。式I之另一具體實施態樣中,A1
係為R2
,其中R2
係未經取代之未稠合哌啶,A2
係為C1
-烷基及R10
係為苯基,如式(Iv)所示:,其中R101
、R102
、R103
、R104
及
R105
係獨立地選自H、R11
、OR11
、SR11
、S(O)R11
、SO2
R11
、NH2
、N(R11
)2
、C(O)R11
、C(O)OR11
、C(O)NHR11
、C(O)N(R11
)2
、NHC(O)R11
、NHSO2
R11
、NR11
SO2
R11
、NHC(O)OR11
、NHSO2
N(R11
)2
、NO2
、OH、(O)、C(O)OH、F、Cl或Br;其中各R11
係為R12
、R13
、R14
或R15
; R12
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、
環烷、環烯、雜環烷或雜環烯稠合;R13
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R14
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R15
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R16
、OR16
、SR16
、S(O)2
R16
、C(O)OH、NH2
、NHR16
、N(R16
)2
、C(O)R16
、C(O)NH2
、C(O)NHR16
、C(O)N(R16
)2
、NHC(O)R16
、NR16
C(O)R16
、NHC(O)OR16
、NR16
C(O)OR16
、OH、F、Cl、Br或I;其中各R16
係為R17
或R17A
; R17
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R18
、C(O)OH、NH2
、NHR18
或N(R18
)2
、C(O)R18
、C(O)NH2
、C(O)NHR18
、C(O)N(R18
)2
、NHC(O)R18
、NR18
C(O)R18
、F、Cl、Br或I; R17A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其中各R18
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其中由R12
、R13
、R14
、R17A
及R18
所表示之部分各獨立地未經取代或經一或二或三或四個獨立選自以下之基團所取代:R19
、OR19
、SR19
、S(O)R19
、SO2
R19
、C(O)R19
、CO(O)R19
、OC(O)R19
、OC(O)OR19
、NH2
、NHR19
、N(R19
)2
、NHC(O)R19
、NR19
C(O)R19
、
NHS(O)2
R19
、NR19
S(O)2
R19
、NHC(O)OR19
、NR19
C(O)OR19
、NHC(O)NH2
、NHC(O)NHR19
、NHC(O)N(R19
)2
、NR19
C(O)NHR19
、NR19
C(O)N(R19
)2
、C(O)NH2
、C(O)NHR19
、C(O)N(R19
)2
、C(O)NHOH、C(O)NHOR19
、C(O)NHSO2
R19
、C(O)NR19
SO2
R19
、SO2
NH2
、SO2
NHR19
、SO2
N(R19
)2
、C(O)H、C(O)OH、C(N)NH2
、C(N)NHR19
、C(N)N(R19
)2
、CNOH、CNOCH3
、OH、(O)、CN、N3
、NO2
、CF3
、CF2
CF3
、OCF3
、OCF2
CF3
、F、Cl、Br或I;其中各R19
係為R20
、R21
、R22
或R23
; R20
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之苯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R21
係為未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合之雜芳基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R22
係為環烷基、環烯基、雜環烷基或雜環烯基;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R23
係為烷基、烯基或炔基;其各係未經取代或經一或兩個獨立選自以下之基團所取代:R24
、OR24
、SR24
、S(O)2
R24
、C(O)OH、NH2
、NHR24
、N(R24
)2
、C(O)R24
、C(O)NH2
、C(O)NHR24
、C(O)N(R24
)2
、NHC(O)R24
、NR24
C(O)R24
、NHC(O)OR24
、NR24
C(O)OR24
、NHS(O)2
R24
、NR24
S(O)2
R24
、OH、F、Cl、Br或I;其中各R24
係為R24A
或R24B
; R24A
係為苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,
其各未稠合或與苯、雜芳烴、環烷、環烯、雜環烷或雜環烯稠合;R24B
係為烷基、烯基或炔基,其各係未經取代或經一或兩個獨立選自以下之基團所取代:R25
、OR25
、SR25
、S(O)2
R25
、C(O)OH、NH2
、NHR25
、N(R25
)2
、C(O)R25
、C(O)NH2
、C(O)NHR25
、C(O)N(R25
)2
、NHC(O)R25
、NR25
C(O)R25
、NHC(O)OR25
、NR25
C(O)OR25
、OH、F、Cl、Br或I;其中各R25
係為烷基、苯基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;其各係未經取代或經NH2
、NH(CH3
)、N(CH3
)2
、OH或OCH3
所取代;其中由R20
、R21
、R22
及R24
所表示之每一部分各獨立地未經取代或經一或兩個獨立選自以下之基團所取代:R26
、OR26
、烯基、炔基、苯基、OH、(O)、C(O)OH、CN、CF3
、OCF3
、CF2
CF3
、F、Cl、Br或I;且R26
係為烷基。另一具體實施態樣中,式(Iv)化合物係選自8-(4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;8-(4-氟-3-(2-側氧基吖丁啶-1-基)苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;8-(3-氯-4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;8-(4-氟-3-(2-側氧基吡咯啶-1-基)苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苄酸甲酯;8-(3-胺基-4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;
2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苄酸;N-乙基-2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯甲醯胺;N-環丁基-2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯甲醯胺;2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)-N-(2-吡咯啶-1-基乙基)苯甲醯胺;8-(4-氟-3-((4-(嗎啉-4-基羰基)哌嗪-1-基)羰基)苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-N'-苯基戊烷二醯胺;1-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)吡咯啶-2,5-二酮;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-3-甲氧丙醯胺;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-5-側氧基己烷醯胺;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-3-苯氧基丙醯胺;N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-4-側氧基-4-苯基丁醯胺;2-(4-(苄基氧基)苯氧基)-N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)乙醯胺;
N-(2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯基)-2-(4-甲氧苯氧基)乙醯胺;N-環丙基-2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)苯甲醯胺;8-(3-((4-(2-乙氧乙基)哌嗪-1-基)羰基)-4-氟苄基)-2,3,4,6-四氫吡啶并(2,3-d)噠嗪-5(1H)-酮;或2-氟-5-((5-側氧基-1,2,3,4,5,6-六氫吡啶并(2,3-d)噠嗪-8-基)甲基)-N-(2-哌啶-1-基乙基)苯甲醯胺。
本發明所使用之起始物質係市售品或可藉一般技術者熟知之慣用方法製備。本發明化合物可使用以下詳述之一般合成流程圖及實驗方法中所例示的方法製備。該等一般合成流程圖係供作說明,而非限制。
如流程圖1所示,雙環酐(1)
可使用還原劑(諸如但不限於硼氫化鈉)還原成醇(2)
。反應一般係於溶劑(諸如但不限於四氫呋喃)中在低於室溫至回流下進行。將(2)
轉化成鏻鹽(3)
可藉著使前者與三烷基膦(諸如但不限於三正丁基膦)於氫溴酸存在下進行反應而進行。反應一般係於溶劑(諸如但不限於乙酸)中在回流下進行。(3)
與式(4)
硝基苯甲醛(其中R11A
係如本發明所述為位於R10
之取代基)於鹼(諸如但不限於三乙基胺)存在下反應提供式(5)
之內酯。反應一般係於溶劑(諸如但不限於二氯甲烷)中在室溫下進行。以還原劑(諸如但不限於鐵粉及NH4
Cl)還原式(5)
化合物之硝基提供對應之式(6)
苯胺。反應一般係於溶劑(諸如但不限於乙醇)中在回流下進行。式(6)
之苯胺與肼反應提供式(7)
之四氫二氮雜萘酮。反應一般於溶劑(諸如但不限於乙醇)中在高溫下進行。式(7)
化合物與式(8)
之酐或式(11)
之酸於熟習此技術者已知且廣泛使用於文獻中之標準胜肽偶合條件下的反應個別提供式(9)
及(12)
之化合物。式(9)
之酸可使用標準胜肽偶合條件進一步修飾成式(10)
之醯亞胺,包括使用1,1'-羰基二咪唑(CDI)作為偶合劑。
或者,如流程圖2所示,鏻鹽(3)
可與式(13)
氰基苯甲醛反應以提供式(14)
之內酯。反應一般在鹼性條件下於溶劑(諸如但不限於二氯甲烷)中於室溫下進行。式(14)
之腈水解成對應之酸,接著添加肼,提供式(15)
之四氫二氮雜萘酮。水解步驟一般係使用鹼水溶液(諸如但不限於氫氧化鈉)於高溫下進行。第二步驟亦於水性條件在高溫下進行。式(15)
之酸與式(16)
之胺(其中各R11
係如本發明式I所述或係為H或係為雜環胺R14
)於熟習此技術者已知且廣泛使用於文獻中之標準胜肽偶合條件下偶合,提供式(17)
之醯胺。或者,式(14)
之化合物可如前文所述般使用肼轉化成四氫二氮雜萘酮,接著於阮來(Raney)-鎳還原條件下還原成式(18)
之一級胺。於標準還原胺化條件下使用醛R16
CHO或酮R16
C(O)R16
處理式(18)
之化合物,隨後視情況使用第二醛R16
CHO或酮R16
C(O)R16
進行處理,提供式(19)
之二級或三級胺(其中各R16
可為H或如式(I)所定義)。
依類似流程圖1所述方法的方式,鏻鹽(3)
可與式(20)
之苯甲醛反應,其中R11B
係為烷基,諸如但不限於乙基且R11A
係如先前流程圖1所定義。式(21)
之化合物與肼如流程圖1所述般地進行反應,接著使用酸水溶液(諸如但不限於硫酸)水解,提供式(22)
之化合物。反應一般係於高溫下在溶劑(諸如但不限於乙醇)中進行。式(22)
化合物與式(23)
之胺於熟習此技術者已知且廣泛使用於文獻中之還原胺化條件下進行反應,提供式(19)
之四氫二氮雜萘酮。
如流程圖4所示,鏻鹽(3)
可使用流程圖1所述條件與式(24)
之溴苯甲醛反應,以提供式(25)
之化合物。式(25)
化合物與肼如流程圖1所述般地反應,提供式(26)
之四氫二氮雜萘酮,其可與式(27)
之錫烷或式(28)
之硼酸酯偶合,以提供式(29)
化合物,其中R11
係為經取代或未經取代苯基或雜芳基。偶合條件係包括熟習此技術者熟知且廣泛使用於Suzuki及Stille型偶合之文獻中者。
式(30)
之苄基溴,其中R11
係如本發明所述,可轉化成格利雅(Grignard)試劑且隨後添加於二酯(31)
,如流程圖5所示般地產生式(32)
之酮-酯。格利雅(Grignard)試劑之添加
一般係於冷溫下進行,之後將反應加溫至室溫。反應一般係於溶劑諸如但不限於四氫呋喃、乙醚及諸如此類者或其混合物中進行。格利雅(Grignard)試劑可購得或可使用文獻中之標準條件自Mg製備。在室溫下於流程圖1所述條件下將肼添加於式(32)
之化合物,提供式(33)
之二氮雜萘酮。溴化物可於鈀催化羧化條件下轉化成式(34)
之酯。該轉變一般需要在一氧化碳及甲醇外另外使用鈀觸媒及鹼,諸如但不限於三乙基胺。典型鈀觸媒係包括[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷及諸如此類者。反應一般係於高溫下進行且可能需使用溶劑,諸如但不限於N,N-二甲基甲醯胺。式(34)
之酯可使用氨轉化成式(35)
之一級醯胺,接著以溴及氫氧化鉀水溶液進行霍夫曼(Hoffman)重排,以提供式(36)
之苯胺。第一步驟一般需要高溫,第二步驟一般需要低溫以進行添加,接著加熱。吡啶環可於催化條件(諸如但不限於使用氫氣及碳上鉑)下還原,以提供式(37)
之化合物。使用式R11
C(O)Cl之醯基氯或式R11
C(O)OH之酸於熟習此技術者已知且廣泛使用於文獻中之標準胜肽偶合條件下進行醯胺形成,提供式(38)
之化合物。或者,式(34)
之酯可使用前述條件還原成式(39)
之化合物,接著水解,以提供式(40)
之酸。典型水解條件係包括但不限於在高溫下使用鹼水溶液,諸如氫氧化鋰。使用式NH2
R11
或NH(R11
)2
之一級或二級胺採用熟習此技術者已知且廣泛使用於文獻中之標準胜肽偶合條件進行的醯胺形成,提供式(41)
之醯胺。
以下實施例係用以提供相信是本發明方法及觀念態樣之最有效且可輕易瞭解的描述。例示化合物係使用ACD/ChemSketch第5.06版(2001年6月5日,Advanced Chemistry Development Inc., Toronto, Ontario)命名,實施例160、320及487除外,係使用ChemDraw®第9.0.5版(CambridgeSoft, Cambridge, MA)命名。中間物係使用IUPAC標準命名。
1-環己烯-1,2-二甲酸酐(25.2克)於四氫呋喃(125毫升)中之溶液於0℃添加硼氫化鈉(1.51克)。混合物溫至環境溫度歷經30分鐘,於回流下加熱5小時,冷卻,以1N鹽酸處理並濃縮。濃縮物分溶於乙酸乙酯與鹽水之間,且有機層以鹽水及水洗滌並濃縮。濃縮物以快速層析使用50%於己烷中之乙酸乙酯純化。
實施例1A(3克)於乙酸(10毫升)中之溶液於環境溫度以三正丁基膦(4.81毫升)及33%於乙酸中之氫溴酸(3.34毫升)進行橡膠,於回流下加熱21小時,冷卻並濃縮。濃縮物於
矽膠上以快速層析使用10%於二氯甲烷中之甲醇純化。
實施例1B(3.05克)於二氯甲烷(30毫升)中之溶液中添加2-氟-5-甲醯基苄腈(1.08克)及三乙基胺(1.02毫升)。混合物於環境溫度攪拌歷經16小時並濃縮。濃縮物分溶於乙酸乙酯與鹽水之間。有機層以鹽水洗滌並濃縮。濃縮物於矽膠上以快速層析使用50%於己烷中之乙酸乙酯純化。
實施例1C(1.46克)於水(15毫升)中之懸浮液中添加50%氫氧化鈉。混合物於90℃加熱1小時。冷卻至70℃後,添加單水合肼(0.54毫升),溶液於70℃攪拌17小時。溶液冷卻至環境溫度且以6N鹽酸調至pH 4。過濾沉澱物,以水洗滌並乾燥。1
H NMR (DMSO-d6
)δ1.55-1.69 (m, 4H), 2.31-2.42 (m, 4H), 3.93 (s, 2H), 7.24 (dd, J=10.8, 8.5 Hz, 1H), 7.40-7.48 (m, 1H), 7.68 (dd, J=6.9, 2.2 Hz, 1H), 12.61 (s, 1H), 13.22 (brs, 1H)。
此實施例係如實施例1C所述般製備,以4-氟-3-硝基苯甲醛取代2-氟-5-甲醯基苄腈。
實施例2A(2.25克)及氯化銨(0.83克)於乙醇(35毫升)及水(25毫升)中之溶液於70℃以鐵粉(4.35克)處理,攪拌3小時且經矽藻土(CELITE®
, World Minerals, Santa Barbara, CA)以熱乙醇過濾。將濾液濃縮,濃縮物與水一起攪拌30分鐘並過濾。固體以水洗滌並乾燥。
實施例2B(1.42克)於乙醇(10毫升)中之溶液中添加單水合肼(0.27毫升)。混合物於回流下攪拌1小時,冷卻至0℃並過濾。固體以水洗滌並乾燥。1
H NMR (CD3
OD)δ 1.63-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.84 (s, 2H), 6.42-6.49 (m, 1H), 6.64 (dd, J=8.6, 2.2 Hz, 1H), 6.86 (dd, J=11.2, 8.1 Hz, 1H)。
實施例2(872毫克)於乙腈中之溶液中添加琥珀酸酐(370毫克)。混合物於回流下加熱17小時,冷卻並濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙
酸之乙腈/水)。1
H NMR (DMSO-d6
)δ1.53-1.66 (m, 4H), 2.30-2.43 (m, 4H), 2.55-2.67 (m, 2H), 3.26-3.31 (m, 2H), 3.85 (s, 2H), 6.85-6.99 (m, 1H), 7.15 (dd, J=10.8, 8.5 Hz, 1H), 7.74 (d, J=6.4 Hz, 1H), 9.70 (brs, 1H), 12.09 (brs, 1H), 12.61 (s, 1H)。
實施例3(905毫克)於二氯甲烷(30毫升)及N,N-二甲基甲醯胺(6毫升)中添加1,1'-羰基二咪唑(785毫克)。混合物於環境溫度攪拌歷經3小時並濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。1
H NMR (DMSO-d6
):δ 1.57-1.69 (m, 4H), 2.32-2.42 (m, 4H), 2.78-2.89 (m, 4H), 3.93 (s, 2H), 7.09-7.13 (m, 1H), 7.32-7.33 (m, 1H), 7.34 (d, J=1.2 Hz, 1H), 12.62 (s, 1H)。
實施例1(294毫克)於1:1 N,N-二甲基甲醯胺/吡啶(6毫升)中添加1,1'-羰基二咪唑(166毫克)。混合物於環境溫度
攪拌歷經30分鐘,添加1-高哌嗪甲酸第三丁酯(189微升)。混合物攪拌18小時並濃縮。濃縮物藉矽膠上快速層析使用5%甲醇之乙酸乙酯溶液純化。
實施例5A(330毫克)於二氯甲烷(8毫升)中之溶液於0℃下添加三氟乙酸(8毫升)。溶液溫至環境溫度,添加乙腈。濃縮混合物。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。產物溶解於甲醇/二氯甲烷且以1M於二乙醚中之鹽酸處理,過濾產生鹽酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ 1.70-1.76 (m, 4H), 2.02-2.11 (m, 2H), 2.52 (d, J=27.5 Hz, 4H), 3.32-3.36 (m, 2H), 3.40-3.46 (m, 2H), 3.51 (t, J=6.1 Hz, 2H), 3.95-4.01 (m, 2H), 4.06 (s, 2H), 7.19 (t, J=9.0 Hz, 1H), 7.29-7.34 (m, 1H), 7.36-7.41 (m, 1H)。
此實施例係如實施例2C所述般製備,以實施例1C取代實施例2B。
實施例6A(1.5克)於20%於甲醇中之氨(150毫升)中之溶液中添加阮來鎳(15克)。混合物於氫(60psi)下在環境溫度搖盪歷經2小時,過濾並濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)產生三氟乙酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ1.55-1.65 (m, 4H), 2.33-2.41 (m, 4H), 3.90 (s, 2H), 4.04 (s, 2H), 7.21-7.25 (m, 1H), 7.27-7.29 (m, 1H), 7.31 (d, J=7.0 Hz, 1H), 8.20-8.27 (brs, 2H)。
實施例6(75毫克)於甲醇(8毫升)中之溶液中添加37重量%於水中之甲醛(39微升)及三乙基胺(36微升)。溶液於環境溫度攪拌歷經1小時。添加氰基硼氫化鈉(49毫克)及氯化鋅(35毫克),混合物攪拌60小時並濃縮。濃縮物溶解於三氟乙酸/甲醇中並藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。產物溶解於甲醇/二氯甲烷且以1M於二乙醚中之鹽酸處理,產生鹽酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ1.68-1.80 (m, 4H), 2.50-2.60 (m, 4H), 2.88 (s, 6H), 4.10 (s, 2H), 4.39 (s, 2H), 7.22-7.27 (m, 1H), 7.40-7.44 (m, 1H), 7.46 (dd, J=6.9, 2.0 Hz, 1H)。
此實施例係如實施例7所述般地製備為鹽酸鹽形式,以丙酮取代甲醛。1
H NMR (CD3
OD)δ1.39 (d, J=6.7 Hz, 6H), 1.68-1.77 (m, 4H), 2.43-2.59 (m, 4H), 3.41-3.50 (m, 1H), 4.05 (s, 2H), 4.24 (s, 2H), 7.18-7.24 (m, 1H), 7.35-7.38 (m, 1H), 7.38-7.42 (m, 1H)。
此實施例係如實施例7所述般地製備為鹽酸鹽形式,以環己酮取代甲醛。1
H NMR (CD3
OD)δ 1.32-1.46 (m, 4H), 1.68-1.81 (m, 6H), 1.84-1.94 (m, 2H), 2.13-2.22 (m, 2H), 2.43-2.61 (m, 4H), 3.08-3.18 (m, 1H), 4.07 (s, 2H), 4.26 (s, 2H), 7.18-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.40-7.43 (m, 1H)。
此實施例係如實施例7所述般地製備為鹽酸鹽形式,以四氫-4H-哌喃-4-酮取代甲醛。1
H NMR (CD3
OD)δ 1.66-1.76 (m, 6H), 2.04-2.14 (m, 2H), 2.40-2.57 (m, 4H), 3.40-3.51 (m, 3H), 4.03 (s, 2H), 4.05 (d, J=4.6 Hz, 2H), 4.29 (s, 2H), 7.18-7.25 (m, 1H), 7.36-7.39 (m, 1H), 7.40 (d, J=1.8
Hz, 1H)。
實施例6(75毫克)於甲醇(8毫升)中之溶液中添加3-甲醯基-吡咯啶-1-甲酸第三丁酯(104毫克)及三乙基胺(36微升)。混合物於環境溫度攪拌歷經1小時。添加氰基硼氫化鈉(49毫克)及氯化鋅(35毫克)。混合物攪拌60小時,添加三氟乙酸,混合物攪拌一小時並濃縮。濃縮物溶解於水/乙腈中並藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。殘留物如前述般地以37重量%於水中之甲醛(39微升)處理,接著以1M於二乙醚中之鹽酸處理,以得到HCl鹽形式之標題化合物。1
H NMR (CD3
OD)δ1.69-1.74 (m, 6H), 1.80-1.88 (m, 3H), 2.10-2.20 (m, 2H), 2.44-2.58 (m, 6H), 3.10 (dd, J=11.4, 7.5 Hz, 2H), 3.22-3.26 (m, 1H), 3.34-3.38 (m, 2H), 3.52-3.56 (m, 1H), 4.03 (s, 2H), 4.31 (s, 2H), 7.18-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.49 (dd, J=6.9, 2.0 Hz, 1H)。
此實施例係如實施例11所述般地製備成鹽酸鹽形式,以N-(第三丁氧羰基)-D-丙醛取代3-甲醯基-吡咯啶-1-甲酸第
三丁酯。1
H NMR (CD3
OD)δ 1.74-1.83 (m, 4H), 1.95-2.07 (m, 1H), 2.10-2.28 (m, 2H), 252-2.70 (m, 5H), 2.91 (s, 3H), 3.04 (s, 3H), 3.21-3.29 (m, 1H), 3.63-3.69 (m, 1H), 3.73-3.81 (m, 1H), 3.90-4.00 (m, 1H), 4.05-4.13 (m, 1H), 4.20 (s, 2H), 4.50-4.62 (m, 2H), 7.27 (t, J=9.1 Hz, 1H), 7.44-7.49 (m, 1H), 7.64 (d, J=5.2 Hz, 1H)。
此實施例係如實施例1C所述般製備,以3-(二乙氧甲基)苯甲醛取代2-氟-5-甲醯基苄腈。
此實施例係如實施例2C所述般製備,以實施例13A取代實施例2B。
實施例13B(681毫克)於乙醇/水1:1混合物(20毫升)中之溶液中添加濃硫酸(0.4毫升)。混合物回流16小時。將混合物冷卻並濃縮,且濃縮物以飽和碳酸氫鈉濕磨。過濾固體,以水洗滌並乾燥。
實施例13C(80毫克)及環丙基胺(51毫克)於甲醇(8毫升)中之溶液於環境溫度攪拌歷經1小時。添加氰基硼氫化鈉(57毫克),溶液攪拌18小時並濃縮。濃縮物溶解於甲醇/三氟乙酸並藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。產物溶解於甲醇/二氯甲烷,以1M於二乙醚中之鹽酸處理並濃縮,產生鹽酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ 0.82-0.92 (m, 4H), 1.65-1.77 (m, 4H), 2.41-2.60 (m, 4H), 2.69-2.79 (m, 1H), 4.11 (s, 2H), 4.28 (s, 2H), 7.31 (d, J=6.7 Hz, 1H), 7.34-7.40 (m, 2H), 7.41-7.45 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以異丙基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.38 (d, J=6.7 Hz, 6H), 1.68-1.79 (m, 4H), 2.41-2.65 (m, 4H), 3.38-3.48 (m, 1H), 4.12 (s, 2H), 4.17 (s, 2H), 7.31 (d, J=7.1 Hz, 1H), 7.35-7.38 (m, 1H), 7.38-7.41 (m, 1H), 7.41-7.46 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以嗎啉取代環丙基胺。1
H NMR (CD3
OD)δ 1.67-1.78 (m, 4H), 2.39-2.57 (m, 4H), 3.13-3.24 (m, 2H), 3.32-3.39 (m, 2H), 3.71-3.80 (m, 2H), 4.03 (dd, J=13.3, 3.2 Hz, 2H), 4.08 (s, 2H), 4.34 (s, 2H), 7.37 (d, J=6.7 Hz, 1H), 7.39-7.42 (m, 1H), 7.41-7.44 (m, 1H), 7.44-7.48 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以吡咯啶取代環丙基胺。1
H NMR (CD3
OD)δ1.67-1.79 (m, 4H), 1.95-2.07 (m, 2H), 2.11-2.24 (m, 2H), 2.44-2.65 (m, 4H), 3.09-3.26 (m, 2H), 3.41-3.54 (m, 2H), 4.15 (s, 2H), 4.35 (s, 2H), 7.32-7.37 (m, 1H), 7.39-7.47 (m, 3H).
此實施例係如實施例13所述般製備為鹽酸鹽形式,以環己基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.20-1.27 (m, 1H), 1.31-1.45 (m, 4H), 1.66-1.78 (m, 5H), 1.85-1.93 (m, 2H), 2.12-2.20 (m, 2H), 2.45-2.60 (m, 4H), 3.08 (dd, J=14.6, 7.6 Hz, 1H), 4.11 (s, 2H), 4.19 (s, 2H), 7.32 (d, J=7.0 Hz, 1H), 7.34-7.38 (m, 1H), 7.38-7.42 (m, 1H), 7.41-7.45 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以2M於甲醇中之甲基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.69-1.78 (m, 4H), 2.45-2.59 (m, 4H), 2.70 (s, 3H), 4.13 (s, 2H), 4.16 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.37 (m, 1H), 7.37-7.40 (m, 1H), 7.43 (t, J=7.4 Hz, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以2M於甲醇中之乙基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.33 (t, J=7.2 Hz, 3H), 1.66-1.80 (m, 4H), 2.42-2.62 (m, 4H), 3.10 (q, J=7.4 Hz, 2H), 4.13 (s, 2H), 4.16 (s, 2H), 7.31 (d, J=7.1 Hz, 1H), 7.34-7.37 (m, 1H), 7.38-7.40 (m, 1H), 7.41-7.45 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以4-甲基哌啶取代環丙基胺。1
H NMR (CD3
OD)δ 0.99 (d, J=6.4 Hz, 3H), 1.39-1.54 (m, 2H), 1.67-1.76 (m, 5H), 1.83-1.95 (m, 2H), 2.44-2.63 (m, 4H), 2.92-3.04 (m, 2H), 3.35-
3.46 (m, 2H), 4.15 (s, 2H), 4.26 (s, 2H), 7.34-7.37 (m, 1H), 7.40-7.44 (m, 2H), 7.44-7.47 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以3-(三氟甲基)苯乙基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.64-1.72 (m, 4H), 2.40-2.57 (m, 4H), 3.06-3.14 (m, 2H), 3.27-3.29 (m, 2H), 4.07 (s, 2H), 4.22 (s, 2H), 7.33 (d, J=7.3 Hz, 1H), 7.35-7.38 (m, 1H), 7.38-7.42 (m, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.55-7.58 (m, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.60-7.62 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以N-甲基環己基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.23-1.40 (m, 3H), 1.53-1.65 (m, 2H), 1.67-1.79 (m, 5H), 1.90-2.00 (m, 2H), 2.02-2.18 (m, 2H), 2.40-2.49 (m, 2H), 2.49-2.58 (m, 2H), 2.71 (s, 3H), 3.16-3.28 (m, 1H), 4.07 (s, 2H), 4.17 (d, J=12.9 Hz, 1H), 4.45 (d, J=13.2 Hz, 1H), 7.34-7.36 (m, 1H), 7.37-7.39 (m, 1H), 7.41 (s, 1H), 7.43-7.49 (m, 1H)。
此實施例係如實施例13所述般製備為鹽酸鹽形式,以2-乙基吡咯啶取代環丙基胺。1
H NMR (CD3
OD)δ 0.94 (t, J=7.5 Hz, 3H), 1.52-1.63 (m, 1H), 1.69-1.77 (m, 4H), 1.78-1.87 (m, 2H), 1.91-2.04 (m, 1H), 2.05-2.17 (m, 1H), 2.31-2.44 (m, 1H), 2.45-2.64 (m, 4H), 3.19-3.28 (m, 1H), 3.34-3.47 (m, 2H), 4.15 (s, 2H), 4.21 (d, J=12.9 Hz, 1H), 4.50 (d, J=13.2 Hz, 1H), 7.33-7.38 (m, 1H), 7.40-7.44 (m, 2H), 7.44-7.48 (m, 1H)。
此實施例係如實施例1C所述般製備,以4-(二乙氧甲基)苯甲醛取代2-氟-5-甲醯基苄腈。
此實施例係如實施例2C所述般製備,以實施例24A取代實施例2B。
此實施例係如實施例13C所述般製備,以實施例24B取代實施例13B。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C。1
H NMR (CD3
OD)δ 0.82-0.88 (m, 2H), 0.89-0.94 (m, 2H), 1.62-1.77 (m, 4H), 2.35-2.44 (m, 2H), 2.45-2.55 (m, 2H), 2.70-2.82 (m, 1H), 4.02 (s, 2H), 4.27 (s, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以2-丙基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.38 (d, J=6.4 Hz, 6H), 1.65-1.72 (m, 4H), 2.37-2.45 (m, 2H), 2.46-2.52 (m, 2H), 3.39-3.50 (m, 1H), 4.01 (s, 2H), 4.17 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以嗎啉取代環丙基胺。1
H
NMR (CD3
OD)δ 1.65-1.76 (m, 4H), 2.43-2.48 (m, 2H), 2.49-2.58 (m, 2H), 3.13-3.24 (m, 2H), 3.33-3.37 (m, 2H), 3.36-3.41 (m, 1H), 3.70-3.80 (m, 2H), 3.99-4.03 (m, 1H), 4.06 (s, 2H), 4.34 (s, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以吡咯啶取代環丙基胺。1
H NMR (CD3
OD)δ 1.63-1.76 (m, 4H), 1.94-2.06 (m, 2H), 2.10-2.24 (m, 2H), 2.37-2.46 (m, 2H), 2.46-2.55 (m, 2H), 3.11-3.23 (m, 2H), 3.38-3.58 (m, 2H), 4.02 (s, 2H), 4.34 (s, 2H), 7.33 (d, J=7.7 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以環己基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.21-1.29 (m, 1H), 1.33-1.43 (m, 4H), 1.64-1.75 (m, 5H), 1.86-1.93 (m, 2H), 2.13-2.21 (m, 2H), 2.37-2.44 (m, 2H), 2.49 (t, J=4.9 Hz, 2H), 3.05-3.16 (m, 1H), 4.01 (s, 2H), 4.18 (s, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以4-苯基哌啶取代環丙基胺。1
H NMR (CD3
OD)δ 1.64-1.76 (m, 4H), 1.93-2.03 (m, 2H), 2.05-2.15 (m, 2H), 2.40-2.49 (m, 2H), 2.48-2.55 (m, 2H), 2.81-2.94 (m, 1H), 3.10-3.23 (m, 2H), 3.54-3.64 (m, 2H), 4.04 (s, 2H), 4.33 (s, 2H), 7.19-7.22 (m, 1H), 7.24 (d, J=7.1 Hz, 2H), 7.28-7.33 (m, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.51 (d, J=7.7 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以2M於甲醇中之甲基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.64-1.73 (m, 4H), 2.38-2.44 (m, 2H), 2.47-2.54 (m, 2H), 2.71 (s, 3H), 4.02 (s, 2H), 4.15 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以
實施例24C取代實施例13C且以2M於甲醇中之乙基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.32 (t, J=7.4 Hz, 3H), 1.64-1.72 (m, 4H), 2.37-2.44 (m, 2H), 2.45-2.52 (m, 2H), 3.10 (q, J=7.4 Hz, 2H), 4.01 (s, 2H), 4.15 (s, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以4-甲基哌啶取代環丙基胺。1
H NMR (CD3
OD)δ 0.99 (d, J=6.4 Hz, 3H), 1.33-1.48 (m, 2H), 1.66-1.75 (m, 5H), 1.85-1.95 (m, 2H), 2.40-2.48 (m, 2H), 2.48-2.57 (m, 2H), 2.90-3.05 (m, 2H), 3.44 (d, J=12.3 Hz, 2H), 4.04 (s, 2H), 4.25 (s, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以3-(三氟甲基)苯乙基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.62-1.72 (m, 4H), 2.38-2.44 (m, 2H), 2.46-2.52 (m, 2H), 3.06-3.14 (m, 2H), 3.27-3.35 (m, 2H), 4.02 (s, 2H), 4.22 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.53-7.57 (m, 2H), 7.57-7.62
(m, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以N-甲基環己基胺取代環丙基胺。1
H NMR (CD3
OD)δ 1.20-1.31 (m, 1H), 1.32-1.44 (m, 2H), 1.54-1.63 (m, 2H), 1.65-1.75 (m, 5H), 1.91-2.01 (m, 2H), 2.05-2.18 (m, 2H), 2.39-2.46 (m, 2H), 2.47-2.53 (m, 2H), 2.71 (s, 3H), 3.23-3.29 (m, 1H), 4.03 (s, 2H), 4.13 (d, J=13.2 Hz, 1H), 4.47 (d, J=13.2 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.43-7.46 (m, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以2-甲基吡咯啶取代環丙基胺。1
H NMR (CD3
OD)δ 1.39 (d, J=6.7 Hz, 3H), 1.66-1.78 (m, 5H), 1.93-2.02 (m, 1H), 2.03-2.13 (m, 1H), 2.29-2.38 (m, 1H), 2.39-2.45 (m, 2H), 2.47-2.53 (m, 2H), 3.15-3.27 (m, 1H), 3.34-3.40 (m, 1H), 3.51-3.62 (m, 1H), 4.02 (s, 2H), 4.09-4.17 (m, 1H), 4.43-4.55 (m, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以實施例24C取代實施例13C且以1-甲基高哌嗪取代環丙基胺。1
H NMR (CD3
OD)δ 1.68-1.79 (m, 4H), 2.29-2.42 (m, 2H), 2.46-2.53 (m, 2H), 2.53-2.62 (m, 2H), 2.97 (s, 3H), 3.35-3.44 (m, 1H), 3.47-3.65 (m, 2H), 3.67-3.96 (m, 5H), 4.11 (s, 2H), 4.46 (s, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H)。
此實施例係如實施例13D所述般製備為鹽酸鹽形式,以1-甲基高哌嗪取代環丙基胺。1
H NMR (CD3
OD)δ 1.68-181 (m, 4H), 2.29-2.41 (m, 2H), 2.44-2.53 (m, 2H), 2.55-2.64 (m, 2H), 2.98 (s, 3H), 3.33-3.40 (m, 1H), 3.40-3.56 (m, 2H), 3.58-3.72 (m, 1H), 3.73-3.97 (m, 4H), 4.15 (s, 2H), 4.46 (s, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.51 (d, J=6.1 Hz, 2H)。
此實施例係如實施例1C所述般製備,以3-溴-4-氟苯甲
醛取代2-氟-5-甲醯基苄腈。
此實施例係如實施例2D所述般製備,以實施例38A取代實施例2B。
於N,N-二甲基甲醯胺(8毫升)中之實施例38B(75毫克)中添加2-三丁基錫烷基嘧啶(81毫克)、三(二亞苄基丙酮)二鈀(0)(20毫克)、三-鄰-甲苯基膦(20毫克)及三乙基胺(92微升)。混合物於70℃攪拌17小時。冷卻後,過濾混合物並將濾液濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。產物溶解於甲醇/二氯甲烷且以1M於二乙醚中之鹽酸處理並濃縮,以提供鹽酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ 1.69-1.78 (m, 4H), 2.48-2.60 (m, 4H), 4.11 (s, 2H), 7.27 (dd, J=10.8, 8.5 Hz, 1H), 7.43-7.50 (m, 1H), 7.61 (t, J=5.1 Hz, 1H), 7.87 (dd, J=7.1, 2.4 Hz, 1H), 9.01 (d, J=5.1 Hz, 2H)。
於7:3:2 1,2-二甲氧乙烷/水/乙醇(3毫升)中之實施例38B(75毫克)、3-吡啶酸(54毫克)及二氯雙(三苯基膦)鈀(II)(28毫克)中添加2M碳酸鈉(0.22毫升)。混合物在150℃
於CEM Explorer®微波反應器(Matthews, NC)中攪拌10分鐘。冷卻後,過濾混合物並將濾液濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。產物溶解於甲醇/二氯甲烷,以1M於二乙醚中之鹽酸處理並濃縮,以提供鹽酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ1.70-1.80 (m, 4H), 2.50-2.62 (m, 4H), 4.17 (s, 2H), 7.33 (dd, J=10.7, 8.5 Hz, 1H), 7.40-7.48 (m, 1H), 7.60 (dd, J=7.3, 1.8 Hz, 1H), 8.22 (dd, J=8.2, 5.8 Hz, 1H), 8.87 (d, J=8.2 Hz, 1H), 8.90 (d, J=5.5 Hz, 1H), 9.12 (s, 1H)。
此實施例係如實施例39所述般地製備為鹽酸鹽形式,以4-吡啶酸取代3-吡啶酸。1
H NMR (CD3
OD)δ 1.68-1.84 (m, 4H), 2.46-2.64 (m, 4H), 4.15 (s, 2H), 7.35 (dd, J=11.0, 8.5 Hz, 1H), 7.48-7.53 (m, 1H), 7.69 (dd, J=7.2, 2.0 Hz, 1H), 8.32 (d, J=5.8 Hz, 2H), 8.91 (d, J=6.7 Hz, 2H)。
此實施例係如實施例39所述般地製備為鹽酸鹽形式,以(2-(N,N-二乙基胺基羰基)苯基)酸取代3-吡啶酸。1
H NMR (CD3
OD)δ 0.83 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz,
3H), 1.72-1.83 (m, 4H), 2.51-2.66 (m, 4H), 2.73-3.01 (m, 2H), 3.02-3.25 (m, 2H), 4.11 (s, 2H), 7.13-7.17 (m, 1H), 7.17-7.19 (m, 1H), 7.26-7.31 (m, 1H), 7.38-7.41 (m, 2H), 7.47-7.50 (m, 1H), 7.51-7.54 (m, 1H)。
於二氯甲烷(3毫升)中之3-(1-哌啶基)丙酸(28毫克)中添加草醯氯(24微升)及一滴N,N-二甲基甲醯胺。混合物於環境溫度攪拌歷經1小時並濃縮。濃縮物溶解於二氯甲烷(3毫升)並添加於實施例2C(50毫克)於四氫呋喃(3毫升)中之溶液。亦添加三乙基胺(31微升)。混合物於環境溫度攪拌歷經16小時並濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。產物溶解於甲醇/二氯甲烷且以1M於二乙醚中之鹽酸處理並濃縮,以提供鹽酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ 1.50-1.59 (m, 1H), 1.68-1.75 (m, 4H), 1.76-1.87 (m, 3H), 1.92-2.01 (m, 2H), 2.41-2.57 (m, 4H), 2.94-2.98 (m, 2H), 2.98-3.03 (m, 2H), 3.45 (t, J=6.9 Hz, 2H), 3.57 (d, J=12.2 Hz, 2H), 3.99 (s, 2H), 6.99-7.05 (m, 1H), 7.11 (dd, J=10.4, 8.5 Hz, 1H), 7.81 (dd, J=7.3, 1.8 Hz, 1H)。
此實施例係如實施例42所述般地製備為鹽酸鹽形式,以3-(4-甲基哌嗪-1-基)丙酸取代3-(1-哌啶基)丙酸。1
H NMR (CD3
OD)δ 1.65-1.79 (m, 4H), 2.38-2.58 (m, 4H), 3.03 (s, 3H), 3.07 (t, J=6.7 Hz, 2H), 3.60-3.65 (m, 2H), 3.65-3.68 (m, 3H), 3.70-3.89 (m, 4H), 3.97-4.06 (m, 1H), 4.00 (s, 2H), 6.99-7.04 (m, 1H), 7.12 (dd, J=10.7, 8.5 Hz, 1H), 7.83 (dd, J=7.3, 1.8 Hz, 1H)。
實施例2(50毫克)及Boc-L-甘胺酸N-羥基琥珀醯亞胺酯(54毫克)於四氫呋喃(4毫升)中之溶液於環境溫度攪拌歷經16小時並濃縮。於二氯甲烷(2毫升)中之此固體中添加三氟乙酸(1毫升),混合物於環境溫度攪拌歷經1小時並濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)以提供三氟乙酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ 1.65-1.74 (m, 4H), 2.38-2.55 (m, 4H), 3.89 (s, 2H), 3.96 (s, 2H), 7.00-7.06 (m, 1H), 7.09-7.16 (m, 1H), 7.87 (dd, J=7.4, 2.1 Hz, 1H)。
此實施例係如實施例42所述般製備,以環己烷丙酸取代3-(1-哌啶基)丙酸。1
H NMR (CD3
OD)δ 0.90-1.00 (m, 2H)1.16-1.33 (m, 4H)1.53-1.61 (m, 2H)1.63-1.68 (m, 1H)1.70-1.74 (m, 5H)1.74-1.82 (m, 3H)2.39-2.46 (m, 4H)2.48-2.51 (m, 2H)3.94 (s, 2H)6.96-7.01 (m, 1H)7.07 (dd, J=10.7, 8.5 Hz, 1H)7.69 (dd, J=7.2, 1.7 Hz, 1H)。
此實施例係如實施例42所述般製備為三氟乙酸鹽形式,以1-(第三丁氧羰基)-3-哌啶甲酸取代3-(1-哌啶基)丙酸。1
H NMR (CD3
OD)δ 1.66-1.76 (m, 4H), 1.79-1.87 (m, 1H), 1.89-2.03 (m, 2H), 2.12 (dd, J=9.3, 4.9 Hz, 1H), 2.38-2.56 (m, 4H), 2.96-3.04 (m, 1H), 3.08-3.15 (m, 1H), 3.17-3.25 (m, 2H), 3.33-3.35 (m, 1H), 3.95 (s, 2H), 6.99-7.06 (m, 1H), 7.07-7.15 (m, 1H), 7.71 (dd, J=7.5, 2.0 Hz, 1H)。
實施例2(200毫克)於二氯甲烷(5毫升)中之溶液中添加4-氯丁醯氯(103毫克)及三乙基胺(0.12毫升)。溶液於環境溫度攪拌歷經16小時並濃縮。濃縮物溶解於乙醇(2毫升)並添加於乙醇鈉於乙醇中之21重量%溶液(0.47毫升)。混合物於環境溫度攪拌歷經16小時,以2M鹽酸處理(1毫升)並濃
縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)。1
H NMR (CD3
OD)δ 1.66-1.77 (m, 4H), 2.15-2.27 (m, 2H), 2.40-2.51 (m, 4H), 2.51-2.58 (m, 2H), 3.78-3.86 (m, 2H), 3.97 (s, 2H), 7.11-7.15 (m, 1H), 7.16-7.19 (m, 1H), 7.22-7.27 (m, 1H)。
此實施例係如實施例42所述般製備為三氟乙酸鹽形式,以1-(第三丁氧羰基)-3-吖丁啶甲酸取代3-(1-哌啶基)丙酸。1
H NMR (CD3
OD)δ 1.64-1.78 (m, 4H), 2.40-2.49 (m, 2H), 2.47-2.55 (m, 2H), 3.81-3.93 (m, 1H), 3.96 (s, 2H), 4.20-4.33 (m, 4H), 6.99-7.06 (m, 1H), 7.07-7.15 (m, 1H), 7.87 (dd, J=7.3, 2.2 Hz, 1H)。
此實施例係如實施例1C所述般製備,以甲基-3-甲醯基苄酸酯取代2-氟-5-甲醯基苄腈。
於1:1四氫呋喃/水(60毫升)中之實施例49A(6.09克)在環境溫度下以氫氧化鋰單水合物處理(1.8克)並攪拌16小時。混合物以2N鹽酸加以酸化,分溶於乙酸乙酯與鹽水之間。有機層以水洗滌並濃縮,且濃縮物藉矽膠上快速層析使用乙酸乙酯純化。
此實施例係如實施例2C所述般製備,以實施例49B取代實施例2B。
實施例49C(75毫克)於N,N-二甲基甲醯胺(3毫升)中之溶液中添加N-異丙基伸乙二胺(27毫克)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺鹽酸鹽(50毫克)、1-羥基苯并三唑水合物(35毫克)及三乙基胺(0.11毫升)。混合物於環境溫度攪拌歷經16小時且分溶於鹽水與水之間。有機物以鹽水洗滌並濃縮。濃縮物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0至100%含有0.1%三氟乙酸之乙腈/水)以提供三氟乙酸鹽形式之標題化合物。1
H NMR (CD3
OD)δ 1.34 (d, J=6.7 Hz, 6H), 1.65-1.74 (m, 4H), 2.37-2.44 (m, 2H), 2.47-2.54 (m, 2H), 3.23 (t,
J=5.9 Hz, 2H), 3.39-3.47 (m, 1H), 3.67 (t, J=5.9 Hz, 2H), 4.05 (s, 2H), 7.41-7.44 (m, 2H), 7.71-7.74 (m, 2H)。
此實施例係如實施例41所述般地製備為三氟乙酸鹽形式,以嗎啉-4-基-乙酸取代3-(1-哌啶基)丙酸。1
H NMR (CD3
OD)δ 1.65-1.73 (m, 4H), 2.38-2.46 (m, 2H), 2.46-2.52 (m, 2H), 3.34-3.52 (m, 4H), 3.90-4.03 (m, 6H), 4.19 (s, 2H), 7.03-7.09 (m, 1H), 7.10-7.17 (m, 1H), 7.85 (dd, J=7.3, 2.1 Hz, 1H)。
標題化合物係依實施例1之方法製備,以3-甲醯基苄腈取代實施例1C中之2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 285 (M+H)+
。
實施例51A(75毫克,0.26毫莫耳)於無水二氯甲烷(5毫升)中之溶液於氮下添加4-(2-胺基乙基)嗎啉(68毫克,0.52
毫莫耳)、六氟磷酸苯并三唑-1-基-氧基三吡咯啶鏻(271毫克,0.52毫莫耳)及N,N'-二異丙基乙基胺(0.18毫莫耳,1.04毫莫耳)。反應混合物於室溫攪拌16小時並濃縮。藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 397 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.64-1.75 (m, 4H), 2.37-2.45 (m, 2H), 2.45-2.55 (m, 2H), 3.15-3.27 (m, 2H), 3.40 (t,J
=5.80 Hz, 2H), 3.63-3.71 (m, 2H), 3.74-3.81 (m, 4H), 4.02-4.13 (m, 4H), 7.42-7.46 (m, 2H), 7.71-7.75 (m, 2H)。
標題化合物係依實施例51之方法製備為三氟乙酸鹽形式,以1-(2-胺基乙基)吡咯啶取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 381 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.65-1.74 (m, 4H), 1.97-2.08 (m, 2H), 2.13-2.22 (m, 2H), 2.39-2.45 (m, 2H), 2.46-2.54 (m, 2H), 3.10-3.20 (m, 2H), 3.42 (t,J
=5.80 Hz, 2H), 3.73 (t,J
=5.95 Hz, 2H), 3.75-3.82 (m, 2H), 4.05 (s, 2H), 7.42-7.46 (m, 2H), 7.70-7.74 (m, 2H)。
標題化合物係依實施例51之方法製備為三氟乙酸鹽形式,以2-甲基吡咯啶取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 352 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 0.86 (d,J
=6.41 Hz, 1H), 1.33 (d,J
=6.41 Hz, 2H), 1.60-1.67 (m, 2H), 1.70 (d,J
=2.75 Hz, 3H), 1.73-1.80 (m, 1H), 1.90-1.99 (m, 1H), 2.11-2.22 (m, 1H), 2.39-2.47 (m, 2H), 2.46-2.56 (m, 2H), 3.43-3.51 (m, 1H), 3.57-3.67 (m, 1H), 4.02 (s, 2H), 4.21-4.28 (m, 1H), 7.24-7.33 (m, 2H), 7.33-7.36 (m, 1H), 7.37-7.42 (m, 1H)。
標題化合物係依實施例51之方法製備為三氟乙酸鹽形式,以1-胺基高哌啶取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 381 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.68-1.74 (m, 4H), 1.73-1.81 (m, 4H), 1.92-2.01 (m, 4H), 2.41-2.46 (m, 2H), 2.48-2.54 (m, 2H), 3.53-3.60 (m, 4H), 4.06 (s, 2H), 7.45-7.50 (m, 2H), 7.70-7.73 (m, 2H)。
標題化合物係依實施例51之方法製備,以1-哌嗪甲酸第三丁酯取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 453 (M+H)+
。
實施例55A(480毫克,1.76毫莫耳)於二氯甲烷(10毫升)中之溶液中添加三氟乙酸(5毫升)。溶液於室溫攪拌1小時並濃縮。殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 353 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.68-1.74 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.19-3.29 (m, 3H), 3.67-3.97 (m, 5H), 4.04 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.36 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (t,J
=7.48 Hz, 1H)。
標題化合物係依實施例55之方法製備為三氟乙酸鹽,以3-胺基-1-N-Boc-吖丁啶取代1-哌嗪甲酸第三丁酯。MS (DCI/NH3
)m/z 339 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.63-1.76 (m, 4H), 2.37-2.45 (m, 2H), 2.46-2.55 (m, 2H), 4.05 (s, 2H), 4.28-4.37 (m, 4H), 4.76-4.82
(m, 1H), 7.41-7.45 (m, 2H), 7.69-7.74 (m, 2H)。
標題化合物係依實施例55之方法製備為三氟乙酸鹽,以(+/-)-3-胺基-1-N-Boc-哌啶取代1-哌嗪甲酸第三丁酯。MS (DCI/NH3
)m/z 367 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.68-1.72 (m, 4H), 1.72-1.77 (m, 1H), 1.80-1.89 (m, 1H), 2.02-2.15 (m, 2H), 2.37-2.46 (m, 2H), 2.47-2.54 (m, 2H), 2.85-3.00 (m, 2H), 3.33-3.39 (m, 1H), 3.52 (dd,J
=12.21, 4.27 Hz, 1H), 4.04 (s, 2H), 4.18-4.26 (m, 1H), 7.40-7.43 (m, 2H), 7.66-7.71 (m, 2H)。
標題化合物係依實施例51之方法製備為三氟乙酸鹽形式,以N,N-二甲基-1,4-苯二胺取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 403 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.67-1.73 (m, 4H), 2.42-2.48 (m, 2H), 2.47-2.55 (m, 2H), 3.28 (s, 6H), 4.08 (s, 2H), 7.43-7.45 (m, 1H), 7.45-7.49 (m, 1H), 7.55 (d,J
=8.85 Hz, 2H), 7.77-7.80 (m, 1H), 7.79-7.82 (m, 1H), 7.89-7.93 (m, 2H)。
標題化合物係依實施例51之方法製備為三氟乙酸鹽形式,以2-(4-甲基-哌嗪-1-基)-乙基胺取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 410 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.67-1.73 (m, 4H), 2.41-2.46 (m, 2H), 2.48-2.54 (m, 2H), 2.82 (t,J
=6.41 Hz, 2H), 2.87 (s, 3H), 2.89-3.09 (m, 3H), 3.17-3.26 (m, 2H), 3.33-3.41 (m, 1H), 3.57 (t,J
=6.26 Hz, 2H), 4.04 (s, 2H), 4.72-4.83 (m, 2H), 7.39-7.44 (m, 2H), 7.63-7.66 (m, 1H), 7.66-7.69 (m, 1H)。
異噁唑-5-甲酸(32毫克,0.28毫莫耳)於無水N,N-二甲基甲醯胺(2毫升)與吡啶(2毫升)之混合物中的溶液於40℃以1,1'-羰基二咪唑(48毫克,0.30毫莫耳)處理2小時。添加實施例55(50毫克,0.14毫莫耳),反應混合物於60℃加熱3小時。冷卻後,反應混合物於旋轉蒸發器上濃縮且殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 448 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.65-1.76 (m, 4H), 2.41-2.47 (m, 2H), 2.48-2.56 (m, 2H), 3.51-3.66 (m, 3H), 3.66-3.79 (m, 3H), 3.79-3.94 (m, 2H), 4.04 (s, 2H), 7.27-7.30 (m, 1H), 7.32-7.35
(m, 1H), 7.36-7.39 (m, 1H), 7.43 (t,J
=7.48 Hz, 1H), 7.61-7.66 (m, 1H), 7.86-7.91 (m, 1H)。
標題化合物係依實施例51之方法製備為三氟乙酸鹽形式,以4-苯基哌啶取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 428 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.54-1.65 (m, 1H), 1.64-1.71 (m, 4H), 1.72-1.82 (m, 2H), 1.91-1.99 (m, 1H), 2.40-2.45 (m, 2H), 2.49-2.51 (m, 2H), 2.80-2.89 (m, 1H), 2.89-2.98 (m, 1H), 3.15-3.26 (m, 1H), 3.71-3.82 (m, 1H), 4.04 (s, 2H), 4.72-4.81 (m, 1H), 7.16-7.20 (m, 1H), 7.22-7.26 (m, 3H), 7.27-7.30 (m, 2H), 7.30-7.32 (m, 1H), 7.34 (d,J
=7.93 Hz, 1H), 7.42 (t,J
=7.63 Hz, 1H)。
標題化合物係依實施例55之方法製備為三氟乙酸鹽,以2-(胺基甲基)哌啶-1-甲酸第三丁酯取代1-哌嗪甲酸第三丁酯。MS (DCI/NH3
)m/z 381 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ1.46-1.56 (m, 2H), 1.60-1.78 (m, 6H), 1.79-1.93 (m, 2H), 2.38-2.47 (m, 2H), 2.47-2.55 (m, 2H), 3.14 (dd,J
=13.27, 4.42 Hz, 2H), 3.46-3.52 (m, 1H), 3.55-3.64 (m,
1H), 4.04 (s, 2H), 4.91-5.05 (m, 1H), 7.27-7.32 (m, 1H), 7.35-7.40 (m, 2H), 7.43 (t,J
=7.48 Hz, 1H)。
標題化合物係依實施例55之方法製備為三氟乙酸鹽,以4-胺基甲基-哌啶-1-甲酸第三丁酯取代1-哌嗪甲酸第三丁酯。MS (DCI/NH3
)m/z 381 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.40-1.52 (m, 2H), 1.64-1.74 (m, 4H), 1.91-2.03 (m, 3H), 2.37-2.47 (m, 2H), 2.47-2.55 (m, 2H), 2.93-3.02 (m, 2H), 3.32-3.36 (m, 2H), 3.37-3.44 (m, 2H), 4.04 (s, 2H), 7.38-7.43 (m, 2H), 7.65-7.69 (m, 2H)。
標題化合物係依實施例51之方法製備為三氟乙酸鹽形式,以2-(哌啶-1-基)乙胺取代4-(2-胺基乙基)嗎啉。MS (DCI/NH3
)m/z 395 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.50-1.58 (m, 1H), 1.67-1.73 (m, 4H), 1.76-1.88 (m, 3H), 1.97 (d,J
=14.34 Hz, 2H), 2.38-2.47 (m, 2H), 2.46-2.54 (m, 2H), 2.93-3.04 (m, 2H), 3.32-3.37 (m, 2H), 3.68 (d,J
=12.21 Hz, 2H), 3.74 (t,J
=6.10 Hz, 2H), 4.05 (s, 2H), 7.42-7.45 (m, 2H), 7.70-7.74 (m, 2H)。
實施例56(25毫克,0.07毫莫耳)於甲醇(2毫升)中之溶液中添加甲醛(於水中37%,16微升,0.21毫莫耳)及三乙基胺(10微升,0.07毫莫耳)。混合物於室溫攪拌2小時,之後添加氰基硼氫化鈉(13毫克,0.21毫莫耳)及氯化鋅(10毫克)。反應混合物於室溫攪拌16小時並濃縮。殘留物溶解於乙腈與水1:1混合物中並藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 353 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.63-1.74 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.01 (d,J
=17.70 Hz, 3H), 4.06 (d,J
=10.68 Hz, 2H), 4.21-4.28 (m, 1H), 4.31 (dd,J
=11.44, 8.70 Hz, 1H), 4.56-4.66 (m, 2H), 5.51 (s, 1H), 7.41-7.44 (m, 1H), 7.44-7.48 (m, 1H), 7.70-7.78 (m, 2H)。
標題化合物係依實施例1C之方法製備,以2-溴-吡啶-4-甲醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 307
(M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例66A取代實施例2B。MS (DCI/NH3
)m/z 321 (M+H)+
。
實施例66B(800毫克,2.5毫莫耳)、二氯(1,1'-二茂鐵基雙(二苯基-膦))鈀(II)二氯甲烷(125毫克,0.15毫莫耳)及三乙基胺(1毫升)於甲醇(40毫升)及N,N-二甲基甲醯胺(16毫升)之混合物中的混合物於110℃在加壓容器中於30psi一氧化碳下加熱16小時。冷卻後,濾除固體物質並將濾液濃縮。殘留固體以甲醇洗滌並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 300 (M+H)+
。
實施例66(100毫克,0.33毫莫耳)於甲醇(5毫升)中之溶液於50℃以甲基胺(於甲醇中2.0N,2毫升)處理24小時並濃縮。殘留物以甲醇洗滌並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 299 (M+H)+
。
標題化合物係依實施例1C之方法製備,以2-甲硫基-4-嘧啶-甲醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 275 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例68A取代實施例2B。MS (DCI/NH3
)m/z 289 (M+H)+
。
實施例68(280毫克,1毫莫耳)於二氯甲烷(5毫升)中之懸浮液中添加間-氯過氧苄酸(256毫克,1.5毫莫耳)。反應混合物於室溫攪拌4小時並濃縮。殘留固體於矽膠上藉快速層析分離(80%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 321 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.61-1.89 (m, 4 H), 2.37-2.71 (m, 4 H), 3.32 (s, 3H), 4.29 (s, 2H), 7.65 (d,J
=5.09 Hz, 1 H), 8.88 (d,J
=5.43 Hz, 1 H)。
標題化合物係實施例69單離之副產物。MS (ESI)m/z 305 (M+H)+
。
標題化合物係依實施例1C之方法製備,以3-溴異菸醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 306 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例71A取代實施例2B。MS (DCI/NH3
)m/z 321 (M+H)+
。
標題化合物係依實施例1C之方法製備,以6-溴菸醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 306 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例72A取代實施例2B。MS (DCI/NH3
)m/z 321 (M+H)+
。
標題化合物係依實施例1C之方法製備,以2-溴菸醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 306 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例72A取代實施例2B。MS (DCI/NH3
)m/z 321 (M+H)+
。
標題化合物係依實施例1C之方法製備,以6-溴-吡啶-2-甲醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 300 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例74A取代實施例2B。MS (DCI/NH3
)m/z 321 (M+H)+
。
標題化合物係依實施例66C之方法製備,以實施例74B取代實施例66B。MS (DCI/NH3
)m/z 300 (M+H)+
。
標題化合物係依實施例67之方法製備,以乙基胺取代甲基胺。MS (ESI)m/z 313 (M+H)+
。
標題化合物係依實施例67之方法製備,以異丙基胺取代甲基胺。MS (ESI)m/z 327 (M+H)+
。
標題化合物係依實施例67之方法製備,以環己胺取代甲基胺。MS (ESI)m/z 367 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.23-1.45 (m, 6 H), 1.60-1.64 (m, 4 H), 1.65-1.86 (m, 5 H), 2.30-2.40 (m, 4 H), 4.03 (s, 2 H), 7.41
(dd,J
=4.92, 1.86 Hz, 1 H), 7.86 (s, 1 H), 8.41 (d,J
=8.82 Hz, 1 H), 8.53 (d,J
=5.09 Hz, 1 H), 12.64 (s, 1 H)。
標題化合物係依實施例65之方法製備為三氟乙酸鹽形式,以實施例62取代實施例56。MS (DCI/NH3
)m/z 409 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.47-1.57 (m, 1H), 1.58-1.67 (m, 1H), 1.67-1.77 (m, 6H), 1.77-1.87 (m, 1H), 1.85-1.95 (m, 1H), 2.43-2.51 (m, 2H), 2.53-2.63 (m, 2H), 2.99 (s, 3H), 3.08 (s, 3H), 3.26 (dd,J
=13.73, 3.36 Hz, 2H), 3.51-3.61 (m, 1H), 3.95 (dd,J
=13.27, 11.44 Hz, 1H), 4.13 (s, 2H), 5.11-5.24 (m, 1H), 7.35-7.40 (m, 2H), 7.41-7.47 (m, 2H)。
標題化合物係依實施例65之方法製備為三氟乙酸鹽形式,以實施例63取代實施例56。MS (DCI/NH3
)m/z 395 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.49-1.61 (m, 2H), 1.69-1.78 (m, 4H), 1.90-1.98 (m, 1H), 1.97-2.08 (m, 2H), 2.43-2.53 (m, 2H), 2.54-2.65 (m, 2H), 2.85 (s, 3H), 2.95-3.04 (m, 2H), 3.32-3.38 (m, 2H), 3.53 (dd,J
=10.53, 1.98 Hz, 2H), 4.15 (s, 2H), 7.39-7.41 (m, 1H), 7.43 (t,J
=7.63 Hz, 1H), 7.68 (s, 1H), 7.70-7.73 (m, 1H)。
標題化合物係依實施例67之方法製備,以實施例74取代實施例66。MS (ESI)m/z 299 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.61-1.81 (m, 4 H), 2.38-2.61 (m, 4 H), 2.95 (s, 3 H), 4.22 (s, 2 H), 7.41 (dd,J
=7.46, 1.36 Hz, 1 H), 7.88 (t,J
=7.63 Hz, 1 H), 7.91-7.98 (m, 1 H)。
標題化合物係依實施例67之方法製備,以實施例74取代實施例66且以乙基胺取代甲基胺。MS (ESI)m/z 313 (M+H)+
。
標題化合物係依實施例67之方法製備,以實施例74取代實施例66且以異丙基胺取代甲基胺。MS (ESI)m/z 327 (M+H)+
。
標題化合物係依實施例67之方法製備,以實施例74取代實施例66且以環丙基胺取代甲基胺。MS (ESI)m/z 325 (M+H)+
。
標題化合物係依實施例67之方法製備,以實施例74取代實施例66且以環己基胺取代甲基胺。MS (ESI)m/z 367 (M+H)+
。
標題化合物係依實施例66C之方法製備,以實施例73B取代實施例66B。MS (DCI/NH3
)m/z 300 (M+H)+
。
標題化合物係依實施例66C之方法製備,以實施例72B取代實施例66B。MS (DCI/NH3
)m/z 300 (M+H)+
。
標題化合物係依實施例1C之方法製備,以5-溴噻吩-2-甲醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 312 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例87A取代實施例2B。MS (DCI/NH3
)m/z 326 (M+H)+
。
標題化合物係依實施例1C之方法製備,以3-溴噻吩-2-甲醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 312 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例88A取代實施例2B。MS (DCI/NH3
)m/z 326 (M+H)+
。
標題化合物係依實施例2之方法製備,以3-硝基苯甲醛取代實施例2A中之4-氟-3-硝基苯甲醛。MS (DCI/NH3
)m/z 256 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.62-1.75
(m, 4H), 2.37-2.44 (m, 2H), 2.46-2.54 (m, 2H), 3.86 (s, 2H), 6.46-6.54 (m, 2H), 6.57 (dd,J
=7.93, 1.98 Hz, 1H), 7.01 (t,J
=7.73 Hz, 1H)。
標題化合物係依實施例2C之方法製備,以3-溴苯甲醛取代4-氟-3-硝基苯甲醛。MS (DCI/NH3
)m/z 256 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.64-1.77 (m, 4H), 2.37-2.46 (m, 2H), 2.47-2.55 (m, 2H), 3.96 (s, 2H), 7.13-7.18 (m, 1H), 7.18-7.24 (m, 1H), 7.35-7.40 (m, 2H)。
實施例87(100毫克,0.31毫莫耳)及乙醯胺(1克)之混合物於180℃攪拌隔夜。冷卻後,混合物溶解於甲醇,藉HPLC分離(Zorbax® C-8充填材料[Agilent Technologies, Santa Clara, CA]0.1%三氟乙酸/CH3
CN/H2
O)以提供標題化合物。MS (DCI/NH3
)m/z 247 (M+H)+
。
標題化合物係依實施例66C之方法製備,以實施例87取代實施例66B。MS (DCI/NH3
)m/z 305 (M+H)+
。
標題化合物係依實施例67之方法製備,以實施例86取代66。MS (ESI)m/z 299 (M+H)+
,1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.51-1.73 (m, 4 H), 2.40 (d,J
=14.92 Hz, 4 H), 2.81 (d,J
=5.09 Hz, 3 H), 4.02 (s, 2 H), 7.75 (dd,J
=7.97, 2.20 Hz, 1 H), 7.96 (d,J
=8.14 Hz, 1 H), 8.49 (d,J
=1.70 Hz, 1 H), 8.70 (d,J
=4.75 Hz, 1 H), 12.60 (s, 1 H)。
標題化合物係依實施例67之方法製備,以實施例86取代實施例66且以乙基胺取代甲基胺。MS (ESI)m/z 313 (M+H)+
。
標題化合物係依實施例67之方法製備,以實施例85取代66。MS (ESI)m/z 299 (M+H)+
,1
H NMR(300 MHz,二甲基亞碸-d 6
)δ 1.53-1.79 (m, 4 H), 2.29-2.44 (m, 4 H), 2.73 (d,J
=5.16 Hz, 3 H), 4.35 (s, 2 H), 7.50 (dd,J
=7.73, 4.56 Hz, 1 H), 7.66 (dd,J
=7.93, 1.59 Hz, 1 H), 8.49 (dd,J
=4.36, 1.59 Hz, 1 H), 8.65 (d,J
=5.16 Hz, 1 H), 12.35 (s, 1 H)。
標題化合物係依實施例67之方法製備,以實施例85取代實施例66且以乙基胺取代甲基胺。MS (ESI)m/z 313 (M+H)+
。
實施例89(50毫克,0.2毫莫耳)於二氯甲烷(4毫升)中之溶液中添加二甲基胺磺醯氯(31毫克,0.22毫莫耳)及吡啶(17毫升,0.22莫耳)。溶液於室溫攪拌16小時並濃縮。藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 363 (M+H)+
;1
H NMR (400 MHz, CD3
OD):δ 1.64-1.76 (m, 4H), 2.37-2.46 (m, 2H), 2.47-2.54 (m, 2H), 2.72 (s, 6H), 3.95 (s, 2H), 6.91-6.96 (m, 1H), 7.02-7.06 (m, 2H), 7.19-7.24 (m, 1H)。
3-(哌啶-1-基)丙酸(31毫克)於無水二氯甲烷(2毫升)中之溶液中添加草醯氯(25.7微升)及一滴N,N-二甲基甲醯胺。溶液攪拌1小時並濃縮。殘留物再溶解於無水二氯甲烷(2毫升)中,迅速添加於實施例89(50毫克)於無水四氫呋喃
(2毫升)中之溶液中。添加三乙基胺(32.8微升),反應混合物於室溫攪拌隔夜。濃縮混合物。殘留物分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮。殘留固體於HPLC上分離(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 395 (M+H)+
;1
H NMR (400 MHz, CD3
OD):δ 1.48-1.60 (m, 1H), 1.65-1.71 (m, 4H), 1.73-1.87 (m, 3H), 1.92-2.01 (m, 2H), 2.38-2.45 (m, 2H), 2.46-2.53 (m, 2H), 2.87 (t,J
=6.60 Hz, 2H), 2.93-3.03 (m, 2H), 3.44 (t,J
=6.75 Hz, 2H), 3.57 (d,J
=12.58 Hz, 2H), 3.97 (s, 2H), 6.95-7.00 (m, 1H), 7.26 (t,J
=7.83 Hz, 1H), 7.36-7.39 (m, 1H), 7.41-7.48 (m, 1H)。
實施例89(150毫克,0.59毫莫耳)及4-氯丁醯氯(83毫克,0.59毫莫耳)於二氯甲烷(5毫升)中之溶液於室溫攪拌16小時並濃縮。殘留物分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮,以提供標題化合物。MS (DCI/NH3
)m/z 360 (M+H)+
;1
H NMR (400 MHz, CD3
OD):δ 1.66-1.73 (m, 4H), 2.07-2.15 (m, 2H), 2.40-2.46 (m, 2H), 2.48-2.51 (m, 2H), 2.50-2.56 (m, 2H), 3.63 (t,J
=6.44 Hz, 2H), 3.96 (s, 2H), 6.93 (d,J
=7.67 Hz, 1H), 7.21-7.26 (m, 1H),
7.36 (s, 1H), 7.38-7.46 (m, 1H)。
實施例90(150毫克,0.47毫莫耳)、吡咯啶-2-酮(80毫克,0.94毫莫耳)、三(二亞苄基丙酮)二鈀(0)(43毫克,0.05毫莫耳)、Xantphos(4,5-雙(二苯基膦基)-9,9-二甲基咕噸)(4,5-雙(二苯基膦基)-9,9-二甲基咕噸)(41毫克,0.07毫莫耳)及碳酸銫(214毫克,0.66毫莫耳)於無水二噁烷(2毫升)中之懸浮液於CEM Explorer®微波反應器(Matthews, NC)中在200℃加熱30分鐘。冷卻後,將反應混合物濃縮。藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 324 (M+H)+
;1
H NMR (400 MHz, CD3
OD):δ 1.65-1.75 (m, 4H), 2.11-2.23 (m, 2H), 2.41-2.47 (m, 2H), 2.48-2.53 (m, 2H), 2.57 (t,J
=7.98 Hz, 2H), 3.83-3.92 (m, 2H), 3.99 (s, 2H), 7.01 (d,J
=7.67 Hz, 1H), 7.31 (t,J
=7.98 Hz, 1H), 7.38-7.42 (m, 1H), 7.51 (t,J
=1.69 Hz, 1H)。
在微波管中置入三(二亞苄基丙酮)二鈀(0)(5.4毫克,
0.006毫莫耳)、Xantphos(4,5-雙(二苯基膦基)-9,9-二甲基咕噸)(5.4毫克,0.01毫莫耳)、實施例103(50毫克,0.16毫莫耳),吖丁啶-2-酮(53毫克,0.62毫莫耳)及Cs2
CO3
(70毫克,0.21毫莫耳)。添加無水二噁烷,懸浮液於CEM Explorer®微波反應器(Matthews, NC)中在200℃加熱30分鐘。濃縮後,殘留物分溶於乙酸乙酯與鹽水之間。將有機相濃縮。殘留固體於矽膠上藉快速層析分離(100%乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 311 (M+H)+
。
標題化合物係依實施例101之方法製備,以吡咯啉-2-酮取代吖丁啶-2-酮。MS (ESI)m/z 339 (M+H)+
。
標題化合物係如實施例66B所述般製備。MS (DCI/NH3
)m/z 321 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例72取代基實施例103且以吡咯啉-2-酮取代吖丁啶-2-酮。MS (ESI)m/z 325 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例72取代實施例103。MS (ESI)m/z 311 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例72取代基實施例103且以苯甲醯胺取代吖丁啶-2-酮。MS (ESI)m/z 361 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.48-1.70 (m, 4 H), 2.41 (d,J
=17.29 Hz, 4 H), 3.92 (s, 2 H), 7.86 (t,J
=1.86 Hz, 3 H), 7.86-7.90 (m, 2 H), 7.99-8.06 (m, 1 H), 8.12 (d,J
=8.48 Hz, 1 H), 8.24 (d,J
=2.37 Hz, 1 H), 10.72 (s, 1 H)12.60 (s, 1 H)。
標題化合物係依實施例101之方法製備,以實施例72取代基實施例103且以異菸醯胺取代吖丁啶-2-酮。MS (ESI)m/z 362 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.65 (d,J
=5.09 Hz, 4 H), 2.41 (d,J
=16.28 Hz, 4 H), 3.93 (s, 2 H), 7.68 (dd,J
=8.48, 2.37 Hz, 1 H), 7.90-8.00 (m, 2 H), 8.11 (d,J
=8.48 Hz, 1 H), 8.27 (d,J
=2.03 Hz, 1 H), 8.76-8.82 (m, 2 H), 11.12 (s, 1 H), 12.60 (s, 1 H)。
標題化合物係依實施例101之方法製備,以實施例72取代基實施例103且以菸醯胺取代吖丁啶-2-酮。MS (ESI)m/z 362 (M+H)+
。
標題化合物係為實施例108之副產物。MS (ESI)m/z 481 (M+H)+
。
標題化合物係依實施例67之方法製備,以實施例92取代66。MS (ESI)m/z 304 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.63 (d,J
=3.05 Hz, 4 H), 2.29-2.46 (m, 4 H), 2.72 (d,J
=4.41 Hz, 3 H), 4.09 (s, 2 H), 6.88 (d,J
=3.73 Hz, 1 H), 7.51 (d,J
=3.73 Hz, 1 H), 8.31 (d,J
=4.41 Hz, 1 H), 12.66 (s, 1 H)。
實施例89(50毫克,0.2毫莫耳)及2-(第三丁氧羰基胺基)
乙酸2,5-二側氧基吡咯啶-1-酯(59毫克,0.22毫莫耳)於無水四氫呋喃(4毫升)中之溶液於室溫攪拌16小時並濃縮。殘留固體溶解於二氯甲烷(4毫升)且於室溫以三氟乙酸(2毫升)處理1小時。將反應混合物濃縮且藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 313 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.64-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.54 (m, 2H), 3.80 (s, 2H), 3.98 (s, 2H), 7.00 (d,J
=7.80 Hz, 1H), 7.28 (t,J
=7.97 Hz, 1H), 7.37-7.40 (m, 1H), 7.42-7.47 (m, 1H)。
標題化合物係依實施例98之方法製備,以1-(第三丁氧羰基)吖丁啶-2-甲酸取代3-(哌啶-1-基)丙酸。MS (DCI/NH3
)m/z 439 (M+H)+
。
實施例112A(64毫克)於二氯甲烷(4毫升)中之溶液於室
溫以三氟乙酸(2毫升)處理1小時。將反應混合物濃縮且殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 339 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.64-1.73 (m, 4H), 2.36-2.44 (m, 2H), 2.46-2.53 (m, 2H), 2.57-2.69 (m, 1H), 2.81-2.93 (m, 1H), 3.94-4.04 (m, 1H), 3.98 (s, 2H), 4.08-4.20 (m, 1H), 5.07 (dd,J
=9.49, 7.80 Hz, 1H), 7.03 (d,J
=8.14 Hz, 1H), 7.30 (t,J
=7.80 Hz, 1H), 7.41 (t,J
=1.70 Hz, 1H), 7.49 (dd,J
=7.97, 1.53 Hz, 1H)。
標題化合物係依實施例112之方法製備,以1-(第三丁氧羰基)吖丁啶-3-甲酸取代1-(第三丁氧羰基)吖丁啶-2-甲酸。MS (DCI/NH3
)m/z 339 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ1.62-1.75 (m, 4H), 2.36-2.44 (m, 2H), 2.46-2.54 (m, 2H), 3.69-3.83 (m, 1H), 3.97 (s, 2H), 4.17-4.33 (m, 4H), 7.00 (dd,J
=7.14, 1.19 Hz, 1H), 7.27 (t,J
=7.93 Hz, 1H), 7.40 (t,J
=1.59 Hz, 1H), 7.45-7.51 (m, 1H)。
標題化合物係依實施例97之方法製備,以甲烷磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 334 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.53-1.67 (m, 4H), 2.29-2.42 (m, 4H), 2.95 (s, 3H), 3.88 (s, 2H), 6.92 (d,J
=7.63 Hz, 1H), 7.00 (s, 1H), 7.06 (dd,J
=7.93, 1.22 Hz, 1H), 7.26 (t,J
=7.78 Hz, 1H), 9.68 (br s, 1H), 12.63 (br s, 1H)。
標題化合物係依實施例97之方法製備,以丙烷-2-磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 362 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.19 (d,J
=7.02 Hz, 6H), 1.53-1.66 (m, 4H), 2.25-2.33 (m, 2H), 2.34-2.41 (m, 2H), 3.08-3.22 (m, 1H), 3.87 (s, 2H), 6.88-6.91 (m, 1H), 7.01 (s, 1H), 7.08 (dd,J
=8.24, 1.22 Hz, 1H), 7.23 (t,J
=7.78 Hz, 1H), 9.68 (br s, 1H), 12.64 (br s, 1H)。
標題化合物係依實施例97之方法製備,以苯磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 396 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.48-1.60 (m, 4H), 2.10-2.21 (m, 2H), 2.29-2.39 (m, 2H), 3.78 (s, 2H), 6.83-
6.87 (m, 2H), 6.92 (dd,J
=8.09, 1.37 Hz, 1H), 7.15 (t,J
=7.78 Hz, 1H), 7.48 (t,J
=7.78 Hz, 2H), 7.58 (t,J
=7.48 Hz, 1H), 7.64-7.69 (m, 2H), 10.24 (br s, 1H), 12.64 (br s, 1H)。
標題化合物係依實施例97之方法製備,以吡啶-3-磺醯氯鹽酸鹽取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 397 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.50-1.61 (m, 4H), 2.12-2.21 (m, 2H), 2.33-2.40 (m, 2H), 3.80 (s, 2H), 6.85 (s, 1H), 6.92 (d,J
=7.63 Hz. 1H), 6.96 (dd,J
=7.93, 1.22 Hz, 1H), 7.19 (t,J
=7.78 Hz, 1H), 7.55 (dd,J
=8.09, 4.73 Hz, 1H), 8.02-8.06 (m, 1H), 8.75 (dd,J
=4.88, 1.53 Hz, 1H), 8.77 (d,J
=1.83 Hz, 1H), 10.43 (br s, 1H), 12.63 (br s, 1H)。
標題化合物係依實施例97之方法製備,以呋喃-2-磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 386 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.52-1.63 (m, 4H), 2.19-2.28 (m, 2H), 2.32-2.40 (m, 2H), 3.82 (s, 2H), 6.57 (dd,J
=3.66, 1.83 Hz, 1H), 6.89 (d,J
=1.53 Hz, 1H), 6.91 (d,J
=7.63 Hz, 1H), 6.95-6.99 (m, 1H), 7.04 (d.J
=3.36 Hz, 1H), 7.20 (t,J
=7.78 Hz, 1H), 7.90 (dd,J
=1.83, 0.92 Hz, 1H), 10.60 (br s, 1H), 12.65 (br s, 1H)。
標題化合物係依實施例97之方法製備,以1-甲基-1H-咪唑-4-磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 400 (M+H)+
。1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.55-1.61 (m, 4H), 2.24-2.32 (m, 2H), 2.32-2.40 (m, 2H), 3.63 (s, 3H), 3.80 (s, 2H), 6.80 (d,J
=7.93 Hz, 1H), 6.92 (s, 1H), 6.99 (dd,J
=8.09, 1.37 Hz, 1H), 7.13 (t,J
=7.78 Hz, 1H), 7.70 (d,J
=1.22 Hz, 1H), 7.73 (d,J
=1.22 Hz, 1H), 10.15 (br s, 1H), 12.64 (br s, 1H)。
標題化合物係依實施例97之方法製備,以噻吩-2-磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 402 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.41-1.64 (m, 4H), 2.18-2.24 (m, 2H), 2.34-2.40 (m, 2H), 3.82 (s, 2H), 6.90-6.94 (m, 2H), 6.97 (d,J
=7.93 Hz, 1H), 7.06 (dd,J
=5.03, 3.81 Hz, 1H), 7.17-7.24 (m, 1H), 7.45 (dd,J
=3.81, 1.37 Hz, 1H), 7.85 (dd,J
=5.03, 1.37 Hz, 1H), 10.36 (br s, 1H), 12.65
(br s, 1H)。
標題化合物係依實施例97之方法製備,以4-氰基苯-1-磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 421 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.49-1.62 (m, 4H), 2.14-2.20 (m, 2H), 2.31-2.39 (m, 2H), 3.80 (s, 2H), 6.84 (s, 1H), 6.90 (d,J
=7.63 Hz, 1H), 6.94 (dd,J
=7.93, 1.22 Hz, 1H), 7.19 (t,J
=7.93 Hz, 1H), 7.83 (d,J
=8.85 Hz, 2H), 8.00 (d,J
=8.54 Hz, 2H), 10.52 (br s, 1H), 12.65 (br s, 1H)。
標題化合物係依實施例97之方法製備,以萘-1-磺醯氯取代二甲基胺磺醯氯。MS (DCI/NH3
)m/z 421 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.41-1.47 (m, 2H), 1.47-1.56 (m, 2H), 2.00-2.10 (m, 2H), 2.30-2.39 (m, 2H), 3.71 (s, 2H), 6.75-6.80 (m, 2H), 6.83-6.89 (m, 1H), 7.07 (t,J
=7.78 Hz, 1H), 7.50-7.56 (m, 1H), 7.64 (t,J
=7.02 Hz, 1H), 7.67-7.72 (m, 1H), 8.04 (d,J
=7.63 Hz, 1H), 8.06-8.10 (m, 1H), 8.18 (d,J
=8.24 Hz, 1H), 8.67 (d,J
=8.54 Hz, 1H), 10.65 (br s, 1 H), 12.64 (br s, 1H)。
標題化合物係如實施例74B所述般製備。MS (DCI/NH3
)m/z 321 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例123取代基實施例103且以吡咯啉-2-酮取代吖丁啶-2-酮。MS (ESI)m/z 325 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例123取代基實施例103且以苄基醯胺取代吖丁啶-2-酮。MS (ESI)m/z 361 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.63 (m, 4 H), 2.40 (m, 4 H), 4.02 (s, 2 H), 6.95 (d,J
=7.46 Hz, 1 H), 7.38-7.54 (m, 2 H), 7.50-7.62 (m, 1 H), 7.67-7.84 (m, 1 H), 7.90-8.12 (m, 3 H), 10.69 (s, 1 H), 12.61 (s, 1 H)。
實施例90(500毫克,1.57毫莫耳)、3-甲醯基苯基酸(352毫克,2.35毫莫耳)、二氯雙(三苯基膦)鈀(II)(112毫克,0.16毫莫耳)及碳酸鈉(2M溶液,3.13毫莫耳,1.6毫升)於1,2-二甲氧乙烷/水/乙醇7/3/3混合物(23毫升)中之懸浮液以氮換氣,於70℃加熱16小時。冷卻至室溫後,反應混合物於旋轉蒸發器上濃縮。粗製固體係藉HPLC分離(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供標題化合物。MS (DCI/NH3
)m/z 345 (M+H)+
。
標題化合物係依實施例65之方法製備為三氟乙酸鹽形式,以實施例127A取代甲醛且以丙烷-2-胺取代實施例56。MS (DCI/NH3
)m/z 388 (M+H)+
;1
H NMR (500 MHz, CD3
OD):δ 1.41 (d,J
=6.71 Hz, 6H), 1.64-1.76 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.53 (m, 2H), 3.42-3.52 (m, 1H), 4.06 (s, 2H), 4.27 (s, 2H), 7.22 (d,J
=7.93 Hz, 1H), 7.41 (t,J
=7.63 Hz, 1H), 7.45-7.50 (m, 2H), 7.51-7.56 (m, 2H), 7.64-7.69 (m, 1H), 7.71-7.74 (m, 1H)。
標題化合物係依實施例65之方法製備為三氟乙酸鹽形式,以實施例127A取代甲醛且以環戊胺取代實施例56。MS (DCI/NH3
)m/z 414 (M+H)+
。
標題化合物係依實施例65之方法製備為三氟乙酸鹽形式,以實施例127A取代甲醛且以2-甲基吡咯啶取代實施例56。MS (DCI/NH3
)m/z 414 (M+H)+
。
標題化合物係依實施例65之方法製備為三氟乙酸鹽形式,以實施例127A取代甲醛且以環丙胺取代實施例56。MS (DCI/NH3
)m/z 386 (M+H)+
。
標題化合物係依實施例65之方法製備為三氟乙酸鹽形式,以實施例127A取代甲醛且以環丁胺取代實施例56。MS (DCI/NH3
)m/z 400 (M+H)+
。
實施例103(100毫克,0.31毫莫耳)於二氯甲烷(15毫升)中之溶液於室溫以間
-氯過氧苄酸(100毫克,0.58毫莫耳)隔夜並濃縮。殘留物溶解於甲醇,藉HPLC分離(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 336 (M+H)+
。
標題化合物係依實施例132之方法製備,以實施例102取代實施例103。MS (ESI)m/z 341 (M+H)+
。
標題化合物係依實施例1C之方法製備,以5-溴噻吩-2-甲醛取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 312 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例134A
取代實施例2B。MS (DCI/NH3
)m/z 326 (M+H)+
。
標題化合物係依實施例66之方法製備,以實施例134B取代實施例66B。MS (DCI/NH3
)m/z 305 (M+H)+
。
2-(2-(t-Boc-胺基乙氧)乙氧)乙基溴(Toronto, 137毫克,0.44毫莫耳)於N,N-二甲基甲醯胺(4毫升)中之溶液中添加實施例5(84毫克,0.22毫莫耳)及碳酸鉀(91毫克,0.66毫莫耳)。反應混合物於35℃加熱隔夜,分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮。藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],250x2.54管柱,移動相A:0.1%於H2
O中之三氟乙酸;B:0.1%於CH3
CN中之三氟乙酸;0至100%梯度)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 612 (M+H)+
。
實施例135A(43毫克,0.06毫莫耳)於二氯甲烷(5毫升)中之懸浮液於室溫添加三氟乙酸(1毫升)。溶液保持室溫歷經1小時並濃縮。殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],250x2.54管柱,移動相A:0.1%於H2
O中之三氟乙酸;B:0.1%於CH3
CN中之三氟乙酸;0至100%梯度)以提供三氟乙酸鹽形式之標題化合物。該三氟乙酸鹽溶解於二氯甲烷與甲醇之混合物中,以1 M HCl於乙醚中之溶液處理。移除揮發物產生HCl鹽形式之標題化合物。MS (DCI/NH3
)m/z 338 (M+H)+
。
實施例89(20毫克,0.08毫莫耳)、1-甲基環丙烷甲酸(10毫克,0.096毫莫耳)、HATU(六氟磷酸2-(1H-7-氮雜苯并三唑-1-基)-1,1,3,3-四甲基脲鎓methanaminium)(38毫克,0.1毫莫耳)及三乙基胺(20毫克,0.2毫莫耳)於二甲基乙醯胺(2.5毫升)中之溶液於室溫攪拌18小時並濃縮。殘留物溶解於二甲基亞碸/甲醇1:1混合物中,藉HPLC分離(Waters Sunfire® C-8分析管柱[Milford, MA],0.1%三氟乙酸/水/CH3
CN)以提供標題化合物。MS (DCI/NH3
)m/z 338 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 0.57-
0.69 (m, 2H), 1.02-1.10 (m, 2H), 1.38 (s, 3H), 1.57-1.65 (m, 4H), 2.29-2.44 (m, 4H), 3.87 (s, 2H), 6.89 (d,J
=7.63 Hz, 1H), 7.23 (t,J
=7.93 Hz, 1H), 7.42 (s, 1H), 7.46 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以2-甲基環丙烷甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 338 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-乙氧丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 356 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ1
H NMR(500MHz,溶劑)δ 1.08 (t,J
=7.02 Hz, 3H), 1.54-1.64 (m, 4H), 2.32-2.42 (m, 4H), 2.51 (t,J
=6.26 Hz, 2H), 3.43 (q,J
=7.02 Hz, 2H), 3.64 (t,J
=6.26 Hz, 2H), 3.88 (s, 2H), 6.90 (d,J
=7.63 Hz, 1H), 7.24 (t,J
=7.78 Hz, 1H), 7.36 (s, 1H), 7.48 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例136之方法製備,以(S)-5-側氧基吡咯啶-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 367 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ1
H NMR(500 MHz,溶劑)δ 1.56-1.66 (m, 4H), 1.93-2.03 (m, 1H), 2.14-2.27 (m, 2H), 2.32-2.43 (m, 5H), 3.96 (s, 2H), 4.19 (dd,J
=8.70, 4.42 Hz, 1H), 6.94 (d,J
=7.63 Hz, 1H), 7.27 (t,J
=7.93 Hz, 1H), 7.40 (s, 1H), 7.49 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例136之方法製備,以(R)-5-側氧基吡咯啶-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 367 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.56-1.66 (m, 4H), 1.93-2.02 (m, 1H), 2.13-2.25 (m, 2H), 2.32-2.42 (m, 5H), 3.89 (s, 2H), 4.18 (dd,J
=8.70, 4.42 Hz, 1H), 6.94 (d,J
=7.63 Hz, 1H), 7.27 (t,J
=7.93 Hz, 1H), 7.39 (s, 1H), 7.49 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以1-胺基甲醯基環丙烷甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 367 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ
1.35-1.44 (m, 4H), 1.55-1.67 (m, 4H), 2.31-2.44 (m, 4H), 3.88 (s, 2H), 6.91 (d,J
=7.63 Hz, 1H), 7.26 (t,J
=7.78 Hz, 1H), 7.40 (s, 1H), 7.43 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例136之方法製備,以2-(苄基氧基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.56-1.64 (m, 4H), 2.32-2.42 (m, 4H), 3.89 (s, 2H), 4.06 (s, 2H), 4.60 (s, 2H), 6.93 (d,J
=7.63 Hz, 1H), 7.26 (t,J
=7.78 Hz, 1H), 7.31-7.34 (m, 1H), 7.36-7.42 (m, 5H), 7.50 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例136之方法製備,以3-苯基丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 388 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.65 (m, 4H), 2.32-2.42 (m, 4H), 2.60 (t,J
=7.63 Hz, 2H), 2.89 (t,J
=7.63 Hz, 2H), 3.87 (s, 2H), 6.89 (d,J
=7.63 Hz, 1H), 7.18 (t,J
=7.17 Hz, 1H), 7.21-7.26 (m, 3H), 7.28 (t,J
=7.48 Hz, 2H), 7.32 (s, 1H), 7.45 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以3-(2,5-二甲氧苯基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例136之方法製備,以1-苯基環丙烷甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 400 (M+H)+
。
標題化合物係依實施例136之方法製備,以(S)-2-苯基丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-苯基丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-(間-甲苯基氧基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-(鄰-甲苯基氧基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-(對-甲苯基氧基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.56-1.65 (m, 4H), 2.23 (s, 3H), 2.33-2.44 (m, 4H), 3.89 (s, 2H), 4.61 (s, 2H), 6.88 (d,J
=8.54 Hz, 2H), 6.94 (d,J
=7.63 Hz, 1H), 7.11 (d,J
=8.24 Hz, 2H), 7.27 (t,J
=7.78 Hz, 1H), 7.41 (s, 1H), 7.50 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以(R)-2-甲氧-
2-苯基乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.53-1.66 (m, 4H), 2.29-2.44 (m, 4H), 3.35 (s, 3H), 3.87 (s, 2H), 4.81 (s, 1H), 6.91 (d,J
=7.63 Hz, 1H), 7.25 (t,J
=7.93 Hz, 1H), 7.33-7.36 (m, 1H), 7.39 (t,J
=7.17 Hz, 2H), 7.45-7.49 (m, 3H), 7.52 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以(S)-2-甲氧-2-苯基乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d6
):δ 1.53-1.66 (m, 4H), 2.30-2.42 (m, 4H), 3.34 (s, 3H), 3.87 (s, 2H), 4.81 (s, 1H), 6.91 (d,J
=7.63 Hz, 1H), 7.25 (t,J
=7.93 Hz, 1H), 7.32-7.36 (m, 1H), 7.39 (t,J
=7.17 Hz, 2H), 7.44-7.49 (m, 3H), 7.51 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以3-苯氧基丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-(噻吩-2-基)丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 408 (M+H)+
。
標題化合物係依實施例136之方法製備,以1-乙醯基哌啶-4-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 409 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.36-1.46 (m, 1H), 1.52-1.67 (m, 5H), 1.79 (t,J
=14.19 Hz, 2H), 2.02 (s, 3H), 2.30-2.43 (m, 4H), 2.56-2.63 (m, 1H), 3.06 (t,J
=12.97 Hz, 1H), 3.85-3.90 (m, 2H), 3.97 (s, 2H), 4.39 (d,J
=13.43 Hz, 1H), 6.89 (d,J
=7.63 Hz, 1H), 7.24 (t,J
=7.78 Hz, 1H), 7.38 (s, 1H), 7.48 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以2-(3,5-二氟苯基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 410 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.53-1.67 (m, 4H), 2.31-2.42 (m, 4H), 3.67 (s, 2H), 3.88 (s, 2H), 6.91 (d,J
=7.63 Hz, 1H), 7.04 (d,J
=6.41 Hz, 1H), 7.07-7.13 (m, 1H), 7.25 (t,J
=7.93 Hz, 1H), 7.36 (s, 1H), 7.46 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以(S)-2-乙醯胺基-4-甲基戊酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 411 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 0.88 (d,J
=6.71 Hz, 3H), 0.90 (d,J
=6.71 Hz, 3H), 1.43-1.53 (m, 2H), 1.56-1.66 (m, 5H), 1.87 (s, 3 H), 2.29-2.43 (m, 4H), 3.88 (s, 2H), 4.39 (dd,J
=9.61, 5.34 Hz, 1H), 6.91 (d,J
=7.63 Hz, 1H), 7.25 (t,J
=7.78 Hz, 1H), 7.38 (s, 1H), 7.49 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以(S)-2-(二丙基胺基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 411 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-側氧基-4-苯基丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 411 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-
1.66 (m, 4H), 2.31-2.42 (m, 4H), 2.70 (t,J
=6.26 Hz, 2H), 3.32 (t,J
=6.26 Hz, 2H), 3.87 (s, 2H), 6.88 (d,J
=7.63 Hz, 1H), 7.23 (t,J
=7.93 Hz, 1H), 7.37 (s, 1H), 7.45 (d,J
=8.24 Hz, 1H), 7.55 (t,J
=7.63 Hz, 2H), 7.66 (t,J
=7.32 Hz, 1H), 7.99 (t,J
=6.41 Hz, 2H)。
標題化合物係依實施例136之方法製備,以2-苯醯胺基乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 417 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.66 (m, 4H), 2.31-2.40 (m, 4H), 3.89 (s, 2H), 4.04 (s, 2H), 6.92 (d,J
=7.93 Hz, 1H), 7.26 (t,J
=7.93 Hz, 1H), 7.38 (s, 1H), 7.47 (d,J
=8.24 Hz, 1H), 7.49-7.54 (m, 2H), 7.58 (t,J
=7.32 Hz, 1H), 7.85-7.90 (m, 2H)。
標題化合物係依實施例136之方法製備,以3-(3-甲氧苯基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-(4-甲氧苯基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-(3,4-二甲基苯氧基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例136之方法製備,以(R)-2-羥基-4-苯基丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 418 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.65 (m, 4H), 1.80-1.90 (m, 1H), 1.95-2.03 (m, 1H), 2.31-2.44 (m, 4H), 2.69 (t,J
=7.93 Hz, 2H), 3.88 (s, 2H), 3.96 (s, 1H), 4.01 (dd,J
=8.09, 4.12 Hz, 1H), 6.91 (d,J
=7.63 Hz, 1H), 7.17-7.23 (m, 3H), 7.25 (t,J
=7.78 Hz, 1H), 7.29 (t,J
=7.48 Hz, 2H), 7.49 (s, 1H), 7.53 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例136之方法製備,以4-苯氧基丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 418 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.67 (m, 4H), 1.96-2.06 (m, 2H), 2.31-2.42 (m, 4H), 2.47 (t,J
=7.48 Hz, 2H), 3.88 (s, 2H), 3.99 (t,J
=6.26 Hz, 2H), 6.87-6.91 (m, 2H), 6.91-6.96 (m, 2H), 7.24 (t,J
=7.78 Hz, 1H), 7.26-7.30 (m, 2H), 7.36 (s, 1H), 7.48 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以4-側氧基-4-(噻吩-2-基)丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 422 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.65 (m, 4H), 2.32-2.42 (m, 4H), 2.69 (t,J
=6.41 Hz, 2H), 3.26 (t,J
=6.41 Hz, 2H), 3.87 (s, 2H), 6.88 (d,J
=7.63 Hz, 1H), 7.23 (t,J
=7.93 Hz, 1H), 7.25-7.29 (m, 1H), 7.37 (s, 1H), 7.44 (d,J
=8.24 Hz, 1H), 7.97 (d,J
=4.88 Hz, 1H), 7.99 (d,J
=2.75 Hz, 1H)。
標題化合物係依實施例136之方法製備,以2-(4-甲基嘧啶-2-基硫基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 422 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-(2-氯苯基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 422 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-(4-氯苯基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 422 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-甲基-2-苯基戊酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 430 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-(4-氯-2-甲基苯氧基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 438 (M+H)+
。
標題化合物係依實施例136之方法製備,以5-側氧基-5-(苯基胺基)戊酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 445 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.65 (m, 4H), 1.84-1.94 (m, 2H), 2.31-2.42 (m, 8H), 3.87 (s, 2H), 6.89 (d,J
=7.63 Hz, 1H), 7.05 (t,J
=7.32 Hz, 1H), 7.24 (t,J
=7.93 Hz, 1H), 7.30 (t,J
=8.09 Hz, 2H), 7.36 (s, 1H), 7.48 (d,J
=8.24 Hz, 1H), 7.57 (d,J
=7.63 Hz, 2 H)。
標題化合物係依實施例136之方法製備,以4-(4-甲氧苯基)-4-側氧基丁酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 446 (M+H)+
。
標題化合物係依實施例136之方法製備,以2,2-二苯基乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 450 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-(苯基磺醯基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 452 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.52-1.70 (m, 4H), 2.29-2.42 (m, 4H), 2.66 (t,J
=7.32 Hz, 2H), 3.59 (t,J
=7.32 Hz, 2H), 3.87 (s, 2H), 6.90 (d,J
=7.32 Hz, 1H), 7.20-7.26 (m, 2H), 7.37 (d,J
=8.54 Hz, 1H), 7.66 (t,J
=7.63 Hz, 2H), 7.74 (t,J
=7.48 Hz, 1H), 7.91 (d,J
=7.32 Hz, 2H)。
標題化合物係依實施例136之方法製備,以2-(3-苯氧基苯基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 466 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.65 (m, 4H), 2.29-2.42 (m, 4H), 3.60 (s, 2H), 3.87 (s, 2H), 6.86-6.92 (m, 2H), 6.98-7.03 (m, 3H), 7.10 (d,J
=7.93 Hz, 1H), 7.16 (t,J
=7.48 Hz, 1H), 7.24 (t,J
=7.78 Hz, 1H), 7.32-7.37 (m, 2H), 7.38-7.42 (m, 2H), 7.46 (d,J
=8.24 Hz, 1H)。
標題化合物係依實施例136之方法製備,以4-乙基苄酸
取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 388 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-氟-2-甲基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 392 (M+H)+
。
標題化合物係依實施例136之方法製備,以5-氟-2-甲基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 392 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-氟-4-甲基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 392 (M+H)+
。
標題化合物係依實施例136之方法製備,以2,3-二氟苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 396 (M+H)+
。
標題化合物係依實施例136之方法製備,以2,4-二氟苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 396 (M+H)+
。
標題化合物係依實施例136之方法製備,以2,5-二氟苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 396 (M+H)+
。
標題化合物係依實施例136之方法製備,以3,5-二氟苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 396 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-丙基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-異丙基苄
酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-乙氧苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-異丙氧苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 418 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.30 (d,J
=6.10 Hz, 6H), 1.53-1.67 (m, 4H), 2.33-2.46 (m, 4H), 3.91 (s, 2H), 4.67-4.80 (m, 1H), 6.94 (d,J
=7.63 Hz, 1H), 7.02 (d,J
=8.85 Hz, 2H), 7.29 (t,J
=7.78 Hz, 1H), 7.55 (s, 1H), 7.62 (d,J
=8.24 Hz, 1H), 7.89 (d,J
=8.85 Hz, 2H)。
標題化合物係依實施例136之方法製備,以4-(二乙基胺基)苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 431 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.11 (t,J
=7.02 Hz, 6H), 1.57-1.66 (m, 4H), 2.34-2.44 (m, 4H),
3.45 (q,J
=7.02 Hz, 4H), 3.91 (s, 2H), 6.87 (d,J
=8.85 Hz, 2H), 6.91 (d,J
=7.63 Hz, 1H), 7.27 (t,J
=7.93 Hz, 1H), 7.55 (s, 1H), 7.62 (d,J
=8.24 Hz, 1H), 7.85 (d,J
=8.85 Hz, 2H)。
標題化合物係依實施例136之方法製備,以4-丁氧苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 432 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-氟-5-(三氟甲基)苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 446 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-氯-5-(三氟甲基)苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 461 (M+H)+
。
標題化合物係依實施例136之方法製備,以呋喃-2-甲酸
取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 350 (M+H)+
。
標題化合物係依實施例136之方法製備,以呋喃-3-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 350 (M+H)+
。
標題化合物係依實施例136之方法製備,以2,5-二甲基呋喃-3-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 378 (M+H)+
。
標題化合物係依實施例136之方法製備,以噻吩-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 366 (M+H)+
。
標題化合物係依實施例136之方法製備,以噻吩-3-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 366 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.66 (m, 4H), 2.32-2.44 (m, 4H), 3.92 (s, 2H), 6.96 (d,J
=7.63 Hz,
1H), 7.30 (t,J
=7.93 Hz, 1H), 7.53 (s, 1H), 7.59-7.65 (m, 3H), 8.31 (dd,J
=2.75, 1.53 Hz, 1H)。
標題化合物係依實施例136之方法製備,以3-甲基噻吩-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 380 (M+H)+
。
標題化合物係依實施例136之方法製備,以5-甲基噻吩-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 380 (M+H)+
。
標題化合物係依實施例136之方法製備,以吡咯-3-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 349 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.56-1.66 (m, 4H), 2.33-2.44 (m, 4H), 3.91 (s, 2H), 6.18 (dd,J
=3.51, 2.29 Hz, 1H), 6.92 (d,J
=7.63 Hz, 1H), 6.98 (d,J
=1.53 Hz, 1H), 7.03-7.07 (m, 1H), 7.27 (t,J
=7.93 Hz, 1H), 7.53 (s, 1H), 7.60 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例136之方法製備,以1-甲基-1H-吡咯-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 363 (M+H)+
。
標題化合物係依實施例136之方法製備,以2,5-二甲基-1H-吡咯-3-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 377 (M+H)+
。
標題化合物係依實施例136之方法製備,以1-甲基-1H-吡咯-3-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 363 (M+H)+
。
標題化合物係依實施例136之方法製備,以噻唑-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 367 (M+H)+
。
標題化合物係依實施例136之方法製備,以噻唑-4-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 367 (M+H)+
。
標題化合物係依實施例136之方法製備,以噻唑-5-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 367 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.67 (m, 2H), 2.32-2.44 (m, 2H), 3.92 (s, 2H), 7.00 (d,J
=7.63 Hz, 1H), 7.32 (t,J
=7.93 Hz, 1H), 7.49 (s, 1H), 7.59 (d,J
=8.24 Hz, 1H), 8.66 (s, 1H), 9.27 (s, 1H)。
標題化合物係依實施例136之方法製備,以異噁唑-5-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 351 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.68 (m, 4H), 2.33-2.45 (m, 4H), 3.93 (s, 2H), 7.03 (d,J
=7.63 Hz, 1H), 7.22 (d,J
=2.14 Hz, 1H), 7.34 (t,J
=7.93 Hz, 1H), 7.54 (s, 1H), 7.63 (d,J
=7.93 Hz, 1H), 8.77 (d,J
=1.83 Hz, 1H)。
標題化合物係依實施例136之方法製備,以3,5-二甲基異噁唑-4-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 379 (M+H)+
。
標題化合物係依實施例136之方法製備,以菸鹼酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 361 (M+H)+
。
標題化合物係依實施例136之方法製備,以異菸鹼酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 361 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.57-1.68 (m, 4H), 2.33-2.45 (m, 4H), 3.94 (s, 2H), 7.04 (d,J
=7.63 Hz, 1H), 7.36 (t,J
=7.78 Hz, 1H), 7.56 (s, 1H), 7.66 (d,J
=8.24 Hz, 1H), 8.10 (d,J
=6.41 Hz, 2H), 8.90 (d,J
=6.10 Hz, 2H)。
標題化合物係依實施例136之方法製備,以3-羥基吡啶
甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 377 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-羥基菸鹼酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 377 (M+H)+
。
標題化合物係依實施例136之方法製備,以6-羥基菸鹼酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 377 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.53-1.65 (m, 4H), 2.32-2.43 (m, 4H), 3.91 (s, 2H), 6.45 (d,J
=10.07 Hz, 1H), 6.95 (d,J
=7.63 Hz, 1H), 7.29 (t,J
=7.93 Hz, 1H), 7.46 (s, 1H), 7.57 (d,J
=8.24 Hz, 1H), 7.98 (dd,J
=9.76, 2.75 Hz, 1H), 8.16 (d,J
=2.14 Hz, 1H)。
標題化合物係依實施例136之方法製備,以2-(吡啶-2-基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 375 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-(吡啶-3-基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 375 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.66 (m, 4H), 2.30-2.42 (m, 4H), 3.88 (s, 2H), 3.98 (s, 2H), 6.94 (d,J
=7.32 Hz, 1H), 7.27 (t,J
=7.93 Hz, 1H), 7.38 (s, 1H), 7.46 (d,J
=8.85 Hz, 1H), 8.04 (dd,J
=7.93, 5.80 Hz, 1H), 8.52 (d,J
=8.24 Hz, 1H), 8.81 (d,J
=5.49 Hz, 1H), 8.85 (s, 1H)。
標題化合物係依實施例136之方法製備,以5-甲基吡嗪-2-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 376 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.69 (m, 4H), 2.34-2.46 (m, 4H), 2.63 (s, 3H), 3.93 (s, 2H), 7.00 (d,J
=7.63 Hz, 1H), 7.33 (t,J
=8.09 Hz, 1H), 7.68-7.74 (m, 2H), 8.68 (s, 1H), 9.13 (d,J
=1.22 Hz, 1H)。
標題化合物係依實施例136之方法製備,以1H-吲哚-3-
甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 399 (M+H)+
。
標題化合物係依實施例136之方法製備,以5-甲基-1-苯基-1H-吡唑-4-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 440 (M+H)+
。
標題化合物係依實施例136之方法製備,以6-氯-2H-色烯-3-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-(二甲基胺基)丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 355 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.66 (m, 4H), 2.30-2.43 (m, 4H), 2.77-2.93 (m, 10H), 3.93 (s, 2H), 6.74 (s, 1H), 6.90 (dd,J
=8.09, 1.37 Hz, 1H), 7.06 (d,J
=7.63 Hz, 1H), 7.37 (t,J
=7.78 Hz, 1H)。
2-(3-溴苯基)乙酸(4.4克,20.56毫莫耳)於N,N-二甲基甲醯胺(125毫升)中之溶液中連續添加N,O-二甲基羥基胺(4.5克,46.26毫莫耳)、三乙基胺(10毫升)、1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(8.9克,46.26毫莫耳)及1-羥基苯并三唑(6.24克,46.26毫莫耳)。反應混合物於室溫攪拌隔夜,分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮。殘留物藉矽膠上快速層析純化(50%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 258 (M+H)+
。
實施例222A(2.5克,9.7毫莫耳)於無水四氫呋喃(50毫升)中之溶液於0℃以LiAlH4
(0.37克,9.7毫莫耳)處理10分鐘,且以水中止反應。混合物分溶於乙酸乙酯及飽和氯化銨之間。有機相以水洗滌並濃縮。殘留物藉矽膠上快速層析純化(20%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 199 (M+H)+
。
標題化合物係依實施例1C之方法製備,以實施例222B取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 319
(M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例222C取代實施例2B。MS (DCI/NH3
)m/z 333 (M+H)+
。
標題化合物係依實施例222之方法製備,以2-(3-溴-4-氟苯基)乙酸取代實施例223B中之2-(3-溴苯基)乙酸。MS (DCI/NH3
)m/z 216 (M+H)+
。
標題化合物係依實施例1C之方法製備,以實施例223A取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 351 (M+H)+
。
標題化合物係依實施例1C之方法製備,以2,2,2-三氟-1-苯基乙酮取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 295
(M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例224A取代實施例2B。MS (DCI/NH3
)m/z 309 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-羥基-4-甲基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 390 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-乙醯基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 402 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.69 (m, 4H), 2.34-2.46 (m, 4H), 2.64 (s, 3H), 3.93 (s, 2H), 6.99 (d,J
=7.63 Hz, 1H), 7.32 (t,J
=7.93 Hz, 1H), 7.57 (s, 1H), 7.65 (d,J
=7.93 Hz, 1H), 8.01-8.05 (m, 2H), 8.05-8.10 (m, 2H)。
標題化合物係依實施例136之方法製備,以3-甲氧-4-甲基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-乙氧苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-氟-4-甲氧苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 408 (M+H)+
。
標題化合物係依實施例136之方法製備,以1-萘甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 410 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-萘甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 410 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-羥基-5-甲基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 390 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-第三丁基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 416 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-乙醯胺基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 417 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.53-1.68 (m, 4H), 2.10 (s, 3H), 2.33-2.44 (m, 4H), 3.92 (s, 2H), 6.95 (d,J
=7.93 Hz, 1H), 7.30 (t,J
=7.93 Hz, 1H), 7.56 (s, 1H), 7.63 (d,J
=7.63 Hz, 1H), 7.70 (d,J
=8.85 Hz, 2H), 7.90 (d,J
=8.85 Hz, 2H)。
標題化合物係依實施例136之方法製備,以4-丙氧苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例136之方法製備,以1-羥基-2-萘甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 426 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-氯-5-(甲硫基)苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 440 (M+H)+
。
標題化合物係依實施例136之方法製備,以3,4-二乙氧苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-苄基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 450 (M+H)+
。
標題化合物係依實施例136之方法製備成三氟乙酸鹽,以2-(苯基胺基)苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 451 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.55-1.68 (m, 4H), 2.31-2.45 (m, 4H), 3.91 (s, 2H), 6.91-6.99 (m, 3H), 7.13 (d,J
=7.63 Hz, 2H), 7.27-7.34 (m, 4H), 7.38-7.42 (m, 1H), 7.49 (s, 1H), 7.58 (d,J
=8.85 Hz, 1H), 7.71-7.75 (m, 1H)。
標題化合物係依實施例136之方法製備,以2-苄醯基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 464 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-苯乙基苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 464 (M+H)+
。
標題化合物係依實施例136之方法製備,以5-溴-2-氯苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 472 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-(4-甲基苄醯基)苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 478 (M+H)+
。
標題化合物係依實施例136之方法製備,以2-碘苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 486 (M+H)+
。
標題化合物係依實施例136之方法製備,以3-碘苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 486 (M+H)+
。
標題化合物係依實施例136之方法製備,以4-碘苄酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 486 (M+H)+
。
標題化合物係依實施例39之方法製備為游離鹼形式,以3-乙醯胺基苯基酸取代3-吡啶酸,但取消最後HCl鹽形成步驟。MS (DCI/NH3
)m/z 392 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.58-1.67 (m, 4H), 2.05 (s, 3H), 2.33-2.39 (m, 2H), 2.40-2.46 (m, 2H), 3.95 (s, 2H), 7.16 (d,J
=7.02 Hz, 1H), 7.18-7.21 (m, 1H), 7.22-7.27 (m, 1H), 7.30 (dd,J
=7.63, 2.14 Hz, 1H), 7.38 (t,J
=7.93 Hz, 1H), 7.59 (d,J
=7.32 Hz, 1H), 7.76 (s, 1H), 10.04 (br s, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例39之方法製備為游離鹼形式,以3-(甲基磺醯基)苯基酸取代3-吡啶酸,但取消最後HCl鹽形成步驟。MS (DCI/NH3
)m/z 413 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.57-1.73 (m, 4H), 2.34-2.41 (m, 2H), 2.41-2.48 (m, 2H), 3.28 (s, 3H), 3.98 (s, 2H), 7.24-7.28 (m, 1H), 7.28-7.33 (m, 1H), 7.47 (dd,J
=7.63,
2.14 Hz, 1H), 7.77 (t,J
=7.78 Hz, 1H), 7.90 (d,J
=7.93 Hz, 1H), 7.96-8.00 (m, 1H), 8.04 (s, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例39之方法製備為游離鹼形式,以3-(吡咯啶-1-羰基)苯基酸取代3-吡啶酸,但取消最後HCl鹽形成步驟。MS (DCI/NH3
)m/z 432 (M+H)+
。
標題化合物係依實施例39之方法製備為游離鹼形式,以4-(吡咯啶-1-羰基)苯基酸取代3-吡啶酸,但取消最後HCl鹽形成步驟。MS (DCI/NH3
)m/z 432 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.57-1.68 (m, 4H), 1.78-1.93 (m, 4H), 2.32-2.39 (m, 2H), 2.40-2.47 (m, 2H), 3.39-3.53 (m, 4H), 3.95 (s, 2H), 7.21-7.24 (m, 1H), 7.24-7.31 (m, 1H), 7.39 (dd,J
=7.63, 1.86 Hz, 1H), 7.55-7.59 (m, 2H), 7.60-7.64 (m, 2H), 12.60 (br s, 1H)。
標題化合物係依實施例39之方法製備為游離鹼形式,以3-胺基甲醯基苯基酸取代3-吡啶酸,但取消最後HCl鹽
形成步驟。MS (DCI/NH3
)m/z 378 (M+H)+
;1
H NMR (500 MHz,二甲基亞碸-d 6
):δ 1.55-1.72 (m, 4H), 2.33-2.41 (m, 2H), 2.41-2.47 (m, 2H), 3.97 (s, 2H), 7.19-7.24 (m, 1H), 7.24-7.30 (m, 1H), 7.42 (dd,J
=7.63, 2.14 Hz, 1H), 7.44 (s, 1H), 7.56 (t,J
=7.78 Hz, 1H), 7.68 (d,J
=7.63 Hz, 1H), 7.88-7.92 (m, 1H), 8.02 (s, 1H), 8.07 (s, 1H), 12.61 (s, 1H)。
標題化合物係依實施例39之方法製備為游離鹼形式,以4-(二甲基胺基甲醯基)苯基酸取代3-吡啶酸,但取消最後HCl鹽形成步驟。MS (DCI/NH3
)m/z 406 (M+H)+
。1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.56-1.69 (m, 4H), 2.31-2.40 (m, 2H), 2.40-2.47 (m, 2H), 2.95 (s, 3H), 3.00 (s, 3H), 3.96 (s, 2H), 7.20-7.24 (m, 1H), 7.24-7.30 (m, 1H), 7.40 (dd,J
=7.48, 1.98 Hz, 1H), 7.49-7.52 (m, 1H), 7.56-7.59 (m, 2H), 7.60-7.65 (m, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例1C之方法製備,以1,1,1-三氟-3-苯基丙烷-2-酮取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z
309 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例254A取代實施例2B。MS (DCI/NH3
)m/z 323 (M+H)+
。
標題化合物係依實施例101方法製備之副產物,以實施例222取代實施例103。MS (DCI/NH3
)m/z 255 (M+H)+
。
實施例222A(3.5克,13.56毫莫耳)於無水四氫呋喃(50毫升)中之溶液於-78℃以1 N二氰胺化鈉於四氫呋喃(16毫升,16.27毫莫耳)中之溶液處理1小時。經注射筒添加碘甲烷(3.85克,27.1毫莫耳),混合物溫至室溫歷經2小時。濃縮混合物,且殘留物分溶於乙酸乙酯與鹽水之間。將有機相濃縮,殘留物藉快速管柱層析純化(30%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 273 (M+H)+
。
標題化合物係依實施例222B之方法製備,以實施例
256A取代實施例222A。MS (DCI/NH3
)m/z 214 (M+H)+
。
標題化合物係依實施例1C之方法製備,以256B取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 334 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例256C取代實施例2B。MS (DCI/NH3
)m/z 348 (M+H)+
。
標題化合物係依實施例222A方法製備,以4-(苄基氧基羰基)-1-(第三丁氧羰基)哌嗪-2-甲酸取代2-(3-溴苯基)乙酸。MS (DCI/NH3
)m/z 408 (M+H)+
。
標題化合物係依實施例222B之方法製備,以實施例257A取代實施例222A。MS (DCI/NH3
)m/z 349 (M+H)+
。
標題化合物係依實施例1C之方法製備,以實施例257B取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 469 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例257C取代實施例2B。MS (DCI/NH3
)m/z 483 (M+H)+
。
實施例257D(0.77克,1.6毫莫耳)於四氫呋喃(100毫升)中之溶液於室溫在氫(氣球)下以10%碳上鈀處理(85毫克,0.8毫莫耳)隔夜。濾除觸媒並將濾液濃縮。殘留物藉快速層析純化(0至15%於CH2
Cl2
中甲醇梯度)以提供標題化合物。MS (DCI/NH3
)m/z 349 (M+H)+
。
標題化合物係如實施例257D所述般地製備。MS (DCI/NH3
)m/z 483 (M+H)+
。
標題化合物係依實施例222A方法製備,以3-硝基苄酸取代2-(3-溴苯基)乙酸。MS (DCI/NH3
)m/z 225 (M+H)+
。
標題化合物係依實施例222B之方法製備,以實施例259A取代實施例222A。
標題化合物係依實施例1C之方法製備,以實施例259B取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 286 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例259C取代實施例2B。MS (DCI/NH3
)m/z 300 (M+H)+
。
實施例259(110毫克,0.17毫莫耳)於甲醇(20毫升)中之懸浮液於室溫在氫(氣球)下以阮來鎳(20毫克)處理隔夜。濾除固體物質並將濾液濃縮,產生標題化合物。MS (DCI/NH3
)m/z 270 (M+H)+
。
實施例258(35毫克,0.1毫莫耳)於三氟乙酸(5毫升)中之溶液於室溫攪拌1小時並濃縮。殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 249 (M+H)+
。
實施例260(100毫克,0.37毫莫耳)於二氯甲烷(5毫升)中之溶液中添加4-氯丁醯氯(52.3毫克,0.37毫莫耳)及三乙基胺(0.12毫升,0.45毫莫耳)。混合物於室溫攪拌隔夜並濃縮。殘留物溶解於無水乙醇(5毫升)中,於室溫以乙醇鈉(0.2毫升,於乙醇中21重量%)處理16小時。添加1毫升2N HCl並濃縮混合物。藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 338 (M+H)+
。
2-苯氧基乙酸(28毫克,0.186毫莫耳)於無水二氯甲烷(3毫升)中之溶液於室溫以草醯氯(35.3毫克,0.186毫莫耳)及
一滴N,N-二甲基甲醯胺處理1小時並濃縮。殘留物再溶解於無水二氯甲烷(5毫升)中。之後添加實施例260(50毫克,0.186毫莫耳)於無水四氫呋喃(2毫升)中之懸浮液。反應混合物於室溫攪拌隔夜並濃縮。殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 404 (M+H)+
;1
H NMR (300 MHz,二甲基亞碸-d 6
):δ 1.60-1.70 (m, 4 H), 2.35-2.39 (m, 2 H), 2.42-2.50 (m, 2 H), 2.66-2.93 (m, 4 H), 4.68 (s, 2 H), 6.82-7.09 (m, 4 H), 7.23 (t,J
=7.80 Hz, 1 H), 7.24-7.38 (m, 2 H), 7.40-7.60 (m, 2 H), 10.01 (s, 1 H)12.54 (s, 1 H)。
置有實施例223(50毫克,0.14毫莫耳)、二氯雙(三苯基膦)鈀(II)(10毫克,0.014毫莫耳)、3-(嗎啉-4-羰基)苯基酸(40毫克,0.17毫莫耳)、DME(7)/水(3)/乙醇(2)混合物(3毫升)及碳酸鈉溶液(2M,0.1毫升)之微波管瓶在CEM Explorer®微波反應器(Matthews, NC)中於150℃加熱15分鐘。冷卻後,反應混合物以甲醇(20毫升)稀釋並過濾。將濾液濃縮,且藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供標題化合物。MS (DCI/NH3
)m/z
462 (M+H)+
;1
H NMR (300 MHz,二甲基亞碸-d 6
):δ 1.60-1.67 (m, 4 H), 2.35-2.39 (m, 2 H), 2.44-2.50 (m, 2 H), 2.75-3.01 (m, 4 H), 3.44-3.73 (m, 8 H), 7.17-7.28 (m, 1 H), 7.27-7.34 (m, 1 H), 7.38-7.47 (m, 1 H), 7.50-7.67 (m, 4 H), 12.55 (s, 1 H)。
標題化合物係依實施例66之方法製備,以實施例222取代實施例66B。MS (DCI/NH3
)m/z 313 (M+H)+
。
標題化合物係依實施例66之方法製備,以實施例256取代實施例66B。MS (DCI/NH3
)m/z 237 (M+H)+
。
標題化合物係依實施例264之方法製備,以4-(嗎啉-4-羰基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 462 (M+H)+
。
標題化合物係依實施例264之方法製備,以2-(吡咯啶-1-羰基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 446 (M+H)+
。
標題化合物係依實施例264之方法製備,以3-(吡咯啶-1-羰基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 446 (M+H)+
;1
H NMR (300 MHz, CDCl3
):δ 1.64-1.81 (m, 4 H), 1.83-2.03 (m, 4 H), 2.43-2.47 (m, 2 H), 2.56-2.59 (m, 2 H), 2.76-2.88 (m, 2 H), 2.93-3.06 (m, 2 H), 3.48 (t,J
=6.54 Hz, 2 H), 3.67 (t,J
=6.74 Hz, 2 H), 7.01-7.11 (m, 1 H), 7.11-7.21 (m, 1 H), 7.29 (dd,J
=7.54, 2.38 Hz, 1 H), 7.39-7.54 (m, 2 H), 7.55-7.62 (m, 1 H), 7.69 (s, 1 H), 10.10 (s, 1 H)。
標題化合物係依實施例264之方法製備,以3-(環丙基胺基甲醯基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 432 (M+H)+
。
標題化合物係依實施例264之方法製備,以3-(2-(二甲基胺基)乙基胺基甲醯基)苯基酸取代3-(嗎啉-4-羰基)-苯基酸。MS (DCI/NH3
)m/z 463 (M+H)+
;1
H NMR (300 MHz, CDCl3
):δ 2.28-2.39 (m, 2 H), 2.35 (m, 3 H), 2.45 (s, 6 H), 2.60-2.69 (m, 2 H), 2.73-2.82 (m, 2 H), 2.87 (t,J
=7.14 Hz, 2 H), 3.01 (t,J
=7.14 Hz, 2 H), 3.54-3.64 (m, 1 H), 3.69 (q,J
=5.29 Hz, 2 H), 6.95-7.10 (m, 1 H), 7.10-7.20 (m, 1 H), 7.35-7.53 (m, 2 H), 7.65-7.80 (m, 2 H), 7.79-7.88 (m, 1 H)。
標題化合物係依實施例264之方法製備,以3-胺基甲醯基苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 392 (M+H)+
;1
H NMR (500 MHz,吡啶-d 5
):δ 1.54 (s, 4 H), 2.27 (s, 2 H), 2.70 (s, 2 H), 2.76-2.95 (m, 2 H), 2.98-3.21 (m, 2 H), 7.19-7.27 (m, 2 H), 7.31 (s, 1 H), 7.49 (d,J
=7.02 Hz, 1 H), 7.82 (d,J
=7.32 Hz, 1 H), 8.42 (d,J
=7.63 Hz, 1 H), 8.47 (s, 1 H), 8.68 (s, 1 H), 9.02 (s, 1 H), 14.05 (s, 1 H)。
標題化合物係依實施例264之方法製備,以3-(甲基磺醯
胺基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 442 (M+H)+
;1
H NMR (300 MHz, CDCl3
):δ 2.31-2.48 (m, 4 H), 2.59 (m, 4 H), 2.77-2.96 (m, 4 H), 3.02 (t,J
=7.80 Hz, 3 H), 6.92-7.03 (m, 1 H), 7.02-7.12 (m, 1 H), 7.10-7.22 (m, 2 H), 7.27-7.33 (m, 1 H), 7.32-7.47 (m, 2 H), 10.96 (s, 1 H)。
標題化合物係依實施例264之方法製備,以3-乙醯胺基苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 406 (M+H)+
;1
H NMR (300 MHz, CDCl3
):δ 2.06-2.21 (m, 4 H), 2.25 (s, 3 H), 2.34 (m, 2 H), 2.58 (m, 2 H), 2.80-2.94 (m, 2 H), 2.92-3.06 (m, 2 H), 6.93-7.10 (m, 2 H), 7.10-7.19 (m, 1 H), 7.23 (d,J
=4.36 Hz, 1 H), 7.27-7.33 (m, 1 H), 7.38 (t,J
=7.73 Hz, 1 H), 7.67-7.76 (m, 1 H), 11.25 (s, 1 H)。
標題化合物係依實施例264之方法製備,以實施例293取代實施例223。MS (DCI/NH3
)m/z 476 (M+H)+
。
標題化合物係依實施例264之方法製備,以實施例293取代實施例223且以3-(吡咯啶-1-羰基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 460 (M+H)+
;1
H NMR (300 MHz, CDCl3
):δ 1.36 (d,J
=6.74 Hz, 3 H), 1.61-1.78 (m, 4 H), 1.76-2.06 (m, 4 H), 2.26-2.45 (m, 2 H), 2.49-2.67 (m, 2 H), 2.84 (m, 2 H), 3.21-3.36 (m, 1 H), 3.40-3.57 (m, 2 H), 3.59-3.83 (m, 2 H), 7.13-7.23 (m, 1 H), 7.36 (t,J
=7.93 Hz, 1 H), 7.40-7.51 (m, 3 H), 7.55-7.64 (m, 1 H), 7.73 (s, 1 H)9.98 (s, 1 H)。
標題化合物係依實施例264之方法製備,以實施例293取代實施例223且以3-(環丙基胺基甲醯基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 446 (M+H)+
。
標題化合物係依實施例2之方法製備,以4-氯-3-硝基苯甲醛取代4-氟-3-硝基苯甲醛。MS (DCI/NH3
)m/z 290 (M+H)+
。
標題化合物係依實施例2之方法製備,以4-甲氧-3-硝基
苯甲醛取代4-氟-3-硝基苯甲醛。MS (DCI/NH3
)m/z 286 (M+H)+
。
標題化合物係依實施例2之方法製備,以4-羥基-3-硝基苯甲醛取代4-氟-3-硝基苯甲醛。MS (DCI/NH3
)m/z 272 (M+H)+
。
標題化合物係依實施例2之方法製備,以4-甲基-3-硝基苯甲醛取代4-氟-3-硝基苯甲醛。MS (DCI/NH3
)m/z 270 (M+H)+
。
標題化合物係依實施例264之方法製備,以實施例256取代實施例223且以3-(2-(二甲基胺基)乙基胺基甲醯基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 459 (M+H)+
。
標題化合物係依實施例264之方法製備,以實施例256取代實施例223且以3-胺基甲醯基苯基酸取代3-(嗎啉-4-羰
基)苯基酸。MS (DCI/NH3
)m/z 388 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.40 (d,J
=7.14 Hz, 3 H), 1.53-1.81 (m, 4 H), 2.25-2.59 (m, 4 H), 2.91 (d,J
=7.14 Hz, 2 H), 3.31-3.41 (m, 1 H), 7.23 (d,J
=7.54 Hz, 1 H), 7.36 (t,J
=7.93 Hz, 1 H), 7.42-7.51 (m, 2 H), 7.50-7.59 (m, 1 H), 7.73 (d,J
=7.93 Hz, 1 H), 7.79-7.91 (m, 1 H), 8.09 (s, 1 H)。
標題化合物係依實施例264之方法製備,以實施例256取代實施例223且以3-乙醯胺基苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 402 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.40 (d,J
=7.12 Hz, 3 H), 1.50-1.78 (m, 4 H), 2.16 (s, 3 H), 2.36-2.53 (m, 4 H), 2.83 (m, 1 H), 2.88 (d,J
=7.46 Hz, 2 H), 7.16-7.23 (m, 1 H), 7.22-7.29 (m, 1 H), 7.29-7.36 (m, 2 H), 7.36-7.45 (m, 2 H), 7.47-7.67 (m, 1 H), 7.72 (t,J
=1.86 Hz, 1 H)。
3-溴乙基苯(2克,11毫莫耳)、N-溴琥珀醯亞胺(91.9
克,11毫莫耳)及偶氮基雙異丁腈(10毫克,0.06毫莫耳)於氯仿(30毫升)中之溶液於65℃在氮下攪拌18小時。冷卻後,反應混合物濃縮,且殘留物分溶於乙酸乙酯與鹽水之間。有機層以鹽水洗滌並濃縮。殘留物於矽膠上藉快速層析分離(10%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 262 (M+H)+
。
實施例285A(1.0克,3.8毫莫耳)及三苯基膦(1.1克,4.2毫莫耳)於甲苯(15毫升)中之溶液於120℃在氮下加熱三日。冷卻至室溫後,過濾收集固體物質,以甲苯洗滌,並乾燥,以提供標題化合物。
實施例285B(1.88克,3.4毫莫耳)於四氫呋喃(100毫升)中之懸浮液在-78℃以第三丁醇鉀(於四氫呋喃中之1 N溶液,3.4毫升,3.4毫莫耳)處理1小時,以30分鐘使之溫熱至0℃。之後添加4,5,6,7-四氫異苯并呋喃-1,3-二酮(0.54克,3.4毫莫耳)於四氫呋喃(10毫升)中之溶液。反應混合物溫熱至室溫,於室溫攪拌另外4小時。以水中止反應後,反應混合物分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮。殘留物藉快速層析分離(20%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 320 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例285C取代實施例2B。MS (DCI/NH3
)m/z 334 (M+H)+
。
標題化合物係依實施例264之方法製備,以實施例285D取代實施例223且以3-胺基甲醯基苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 374 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.59 (d,J
=7.12 Hz, 3 H), 1.61-1.81 (m, 4 H), 2.10-2.22 (m, 1H), 2.39-2.55 (m, 2 H), 2.61-2.73 (m, 1 H), 4.32 (q,J
=6.78 Hz, 1 H), 7.08-7.21 (m, 1 H), 7.35-7.43 (m, 1 H), 7.48-7.59 (m, 3 H), 7.75 (d,J
=7.80 Hz, 1 H), 7.80-7.87 (m, 1 H), 8.06-8.11 (m, 1 H)。
標題化合物係依實施例264之方法製備,以實施例285D取代實施例223且以3-乙醯胺基苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 388 (M+H)+
;1
H NMR (300 MHz, CD3
OD):δ 1.58 (d,J
=7.12 Hz, 3 H), 1.60-1.82 (m, 4 H), 2.14 (s, 3 H), 2.10-2.23 (m, 1H), 2.47-2.55 (m, 2 H), 2.60-2.73 (m, 1H), 4.30 (q,J
=6.78 Hz, 1 H), 7.15 (d,J
=7.46 Hz, 1 H), 7.23-7.30 (m, 1 H), 7.31-7.40 (m, 2 H),
7.41-7.47 (m, 1 H), 7.47-7.56 (m, 1 H), 7.56-7.69 (m, 1 H), 7.77 (t,J
=1.86 Hz, 1 H)。
標題化合物係依實施例264之方法製備,以實施例285D取代實施例223且以3-(2-(二甲基胺基)乙基胺基甲醯基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 445 (M+H)+
。
實施例266(50毫克,0.16毫莫耳)於四氫呋喃(10毫升)中之溶液於50℃以LiOH▪H2
O(100毫克,4毫莫耳)於水(4毫升)中之溶液處理隔夜。濃縮混合物,且殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供標題化合物。MS (DCI/NH3
)m/z 313 (M+H)+
。
4-(4-甲氧苯基)-4-側氧基丁酸(29毫克,0.14毫莫耳)於二噁烷(1.5毫升)中之溶液中添加六氟磷酸2-(1H-7-氮雜苯并三唑-1-基)-1,1,3,3-四甲基脲鎓三甲銨乙內酯(HATU)(42
毫克)及N,N'-二異丙基乙基胺(32微升)。混合物於室溫攪拌15分鐘,添加實施例2(25毫克,0.091毫莫耳)。反應混合物於室溫攪拌16小時並濃縮。粗製物係藉HPLC分離(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 464 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.53-1.66 (m, 4H), 2.29-2.40 (m, 4H), 2.74 (t,J
=6.41 Hz, 2H), 3.25 (t,J
=6.56 Hz, 2H), 3.84 (s, 2H), 3.85 (s, 3H), 6.88-6.96 (m, 1H), 7.05 (d,J
=8.85 Hz, 2H), 7.12-7.20 (m, 1H), 7.74 (d,J
=6.41 Hz, 1H), 7.97 (d,J
=9.15 Hz, 2H), 9.75 (br s, 1H), 12.60 (br s, 1H)。
實施例2(100毫克,0.37毫莫耳)於乙酸(8毫升)中之溶液中添加3,4-二甲基呋喃-2,5-二酮(46毫克,0.37毫莫耳)。反應混合物於80℃加熱16小時並濃縮。藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 382 (M+H)+
;1
H NMR(500 MHz,二甲基亞碸-d 6
):δ 1.56-1.68 (m, 4H), 1.98 (s, 6H), 2.30-2.43 (m, 4H), 3.93 (s, 2H), 7.18 (dd,J
=7.02, 1.53 Hz, 1H), 7.31-7.35 (m, 2H), 12.63 (br s, 1H)。
實施例2(210毫克,0.77毫莫耳)於乙腈(8毫升)中之懸浮液中添加3-氧雜雙環(3.1.0)己烷-2,4-二酮(95毫克,0.85毫莫耳)且於80℃攪拌16小時。將反應混合物冷卻並於旋轉蒸發器上濃縮。殘留固體溶解於二噁烷(4毫升),於室溫以六氟磷酸O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓(380毫克,0.99毫莫耳)及N,N'-二異丙基乙基胺(0.3毫升,1.69毫莫耳)處理另外16小時。將反應混合物濃縮,藉HPLC分離(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供三氟乙酸鹽形式之標題化合物。MS (DCI/NH3
)m/z 368 (M+H)+
;1
H NMR(400 MHz,二甲基亞碸-d 6
):δ 1.57-1.64 (m, 4H), 1.66-1.72 (m, 2H), 2.32-2.41 (m, 4H), 2.75 (dd,J
=7.82, 3.22 Hz, 2H), 3.91 (s, 1H), 7.16 (d,J
=7.36 Hz, 1H), 7.27-7.29 (m, 1H), 7.29-7.32 (m, 1H), 12.61 (br s, 1H)。
實施例258(138毫克,0.29毫莫耳)於二氯甲烷(10毫升)中之溶液於40℃以三氟乙酸(2毫升)處理2小時並濃縮。殘留物藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent
Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供TFA鹽形式之標題化合物。MS (DCI/NH3
)m/z 383 (M+H)+
。
標題化合物係依實施例222A方法製備,以2-(3-溴-4-氟苯基)乙酸取代2-(3-溴苯基)乙酸。MS (DCI/NH3
)m/z 276 (M+H)+
。
標題化合物係依實施例256A之方法製備,以實施例293A取代實施例222A。MS (DCI/NH3
)m/z 291 (M+H)+
。
標題化合物係依實施例256B之方法製備,以實施例293B取代實施例256A。MS (DCI/NH3
)m/z 232 (M+H)+
。
標題化合物係依實施例1C之方法製備,以293C取代2-氟-5-甲醯基苄腈。MS (DCI/NH3
)m/z 352 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例293D取代實施例2B。MS (DCI/NH3
)m/z 366 (M+H)+
。
4-側氧基-4-苯基丁酸(50毫克,0.28毫莫耳)、六氟磷酸2-(3H-(1,2,3)三唑并(4,5-b)吡啶-3-基)-1,1,3,3-四甲基異脲鎓(V)(106毫克,0.28毫莫耳)及Hunig氏鹼(120毫克,0.9毫莫耳)於無水N,N-二甲基甲醯胺(0.5毫升)中之混合物於室溫攪拌10分鐘,一次添加實施例260(50毫克,0.18毫莫耳)。反應混合物於室溫攪拌另外1小時,以5毫升甲醇稀釋。過濾收集固體物質,以甲醇洗滌並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 430 (M+H)+
。1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.54-1.77 (m, 4 H), 2.30-2.42 (m, 2 H), 2.42-2.49 (m, 2 H), 2.65-2.79 (m, 4 H), 2.79-2.89 (m, 2 H), 3.30-3.38 (m, 2 H), 6.90 (d,J
=7.80 Hz, 1 H), 7.19 (t,J
=7.80 Hz, 1 H), 7.38-7.49 (m, 2 H), 7.54 (t,J
=7.46 Hz, 2 H), 7.61-7.69 (m, 1 H), 7.99 (t,J
=6.61 Hz, 2 H), 9.96 (s, 1 H), 12.52 (s, 1 H)。
標題化合物係依實施例264之方法製備,以實施例293取
代實施例223且以3-胺基甲醯基苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 406 (M+H)+
。
標題化合物係依實施例264之方法製備,以實施例293取代實施例223且以3-乙醯胺基苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 420 (M+H)+
。
標題化合物係依實施例264之方法製備,以實施例293取代實施例223且以3-(甲基磺醯胺基甲基)苯基酸取代3-(嗎啉-4-羰基)苯基酸。MS (DCI/NH3
)m/z 470 (M+H)+
。
標題化合物係依實施例291之方法製備,以六氫異苯并呋喃-1,3-二酮取代氧雜雙環(3.1.0)己烷-2,4-二酮。MS (DCI/NH3
)m/z 410 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.31-1.53 (m, 5H), 1.57-1.68 (m, 4H), 1.66-1.78 (m, 3H), 1.76-1.92 (m, 2H), 2.29-2.43 (m, 4H), 3.93 (s, 2H), 7.12-7.17 (m, 1H), 7.28-7.33 (m, 1H), 7.33-7.37 (m, 1H), 12.63 (br s, 1H)。
標題化合物係依實施例291之方法製備,以3,3-二甲基二氫呋喃-2,5-二酮取代氧雜雙環(3.1.0)己烷-2,4-二酮。MS (DCI/NH3
)m/z 384 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.31 (s, 6H), 1.54-1.70 (m, 4H), 2.30-2.44 (m, 4H), 2.78 (s, 2H), 3.94 (s, 2H), 7.19 (d,J
=7.46 Hz, 1H), 7.30-7.33 (m, 1H), 7.35 (s, 1H), 12.62 (br s, 1H)。
100毫升圓底燒瓶中置入3-溴-4-氟苯甲醛(1.0克,4.93毫莫耳)、三(二亞苄基丙酮)二鈀(0)(450毫克,0.493毫莫耳)、Xantphos(4,5-雙(二苯基膦基)-9,9-二甲基呫噸)(428毫克,0.739毫莫耳)及碳酸銫(2.4克,7.39毫莫耳)。混合物以氮換氣,且添加無水二噁烷(15毫升)及5-甲基吡咯啶酮(0.586克,5.91毫莫耳)。反應混合物再次以氮換氣且於100℃加熱20小時。冷卻至室溫後,反應混合物分溶於乙酸乙酯與鹽水之間。有機相以MgSO4
乾燥,過濾並濃縮。殘留物藉快速層析分離(50%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 222 (M+H)+
。
實施例1B(486毫克,1.16毫莫耳)、實施例300A(265毫克)及三乙基胺(0.16毫升)於二氯甲烷(8毫升)中之溶液於室溫攪拌16小時並濃縮。殘留物溶解於乙醇(5毫升)中且於80℃以單水合肼(0.11毫升)處理2小時。使混合物冷卻,過濾沉澱固體並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 356 (M+H)+
;1
H NMR(400 MHz,二甲基亞碸-d 6
):δ 1.02(d,J
=6.14 Hz, 3H), 1.57-1.63 (m, 4H), 1.64-1.72 (m, 1N), 2.27-2.34 (m, 1H), 2.34-2.40 (m, 4H), 2.41-2.46 (m, 2H), 3.90 (s, 2H), 4.08 (q,J
=6.44 Hz, 1H), 7.10-7.14 (m, 1H), 7.14-7.18 (m, 1H), 7.20-7.27 (m, 1H), 12.61 (s, 1H)。
標題化合物係依實施例300A之方法製備,以噁唑啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 210 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例
301A取代實施例300A。MS (DCI/NH3
)m/z 344 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.55-1.75 (m, 4H), 2.30-2.45 (m, 4H), 3.90 (s, 2H), 3.98 (t,J
=7.93 Hz, 2H), 4.45 (dd,J
=8.72, 7.14 Hz, 2H), 7.11-7.17 (m, 1H), 7.25 (dd,J
=10.91, 8.53 Hz, 1H), 7.36 (dd,J
=7.54, 2.38 Hz, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例300A之方法製備,以氮-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 236 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例302A取代實施例300A。MS (DCI/NH3
)m/z 370 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.54-1.65 (m, 4H), 1.65-1.80 (m, 6H), 2.32-2.45 (m, 4H), 2.54-2.63 (m, 2H), 3.57-3.72 (m, 2H), 3.88 (s, 2H), 7.04-7.12 (m, 2H), 7.13-7.22 (m, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例291之方法製備,以二氫-2H-哌喃-2,6(3H)-二酮取代氧雜雙環(3.1.0)己烷-2,4-二酮。MS (DCI/NH3
)m/z 370 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.53-1.69 (m, 4H), 1.84-1.97 (m, 1H), 1.98-2.11 (m, 1H), 2.29-2.42 (m, 4H), 2.75 (t,J
=6.44 Hz, 4H), 3.90 (s, 2H), 7.04 (d,J
=7.80 Hz, 1H), 7.24 (s, 1H), 7.26 (d,J
=1.36 Hz, 1H), 12.63 (s, 1H)。
標題化合物係依實施例300A之方法製備,以咪唑啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 209 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例304A取代實施例300A。MS (DCI/NH3
)m/z 343 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.55-1.69 (m, 4H), 2.31-2.44 (m, 4H), 3.39 (t,J
=7.97 Hz, 2H), 3.75-3.83 (m, 2H), 3.86 (s, 2H), 6.86 (br s, 1H), 6.94-7.03 (m, 1H), 7.16 (dd,J
=11.19, 8.48 Hz, 1H), 7.31 (dd,J
=7.63, 2.20 Hz, 1H),
12.61 (br s, 1H)。
實施例2(150毫克,0.55毫莫耳)於二氯甲烷(5毫升)中之溶液中添加3-氯丙烷-1-磺醯氯(97毫克,0.55毫莫耳),混合物攪拌16小時。將反應混合物濃縮,殘留固體溶解於二噁烷(3毫升)。隨後添加乙醇鈉(0.14毫升,於乙醇中21重量%),溶液於80℃加熱16小時。冷卻後,將反應混合物濃縮。藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1%三氟乙酸/CH3
CN/H2
O)以提供游離鹼形式之標題化合物。MS (DCI/NH3
)m/z 378 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.56-1.70 (m, 4H), 2.33-2.47 (m, 6H), 3.40 (t,J
=7.29 Hz, 2H), 3.72 (t,J
=6.44 Hz, 2H), 3.90 (s, 2H), 7.09-7.16 (m, 1H), 7.23 (d,J
=8.48 Hz, 1H), 7.25-7.28 (m, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例300A之方法製備,以吖丁啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 194 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例306A取代實施例300A。MS (DCI/NH3
)m/z 328 (M+H)+
。1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.55-1.68(m, 4H), 2.31-2.43 (m, 4H), 3.11 (t,J
=4.58 Hz, 2H), 3.82 (q,J
=4.41 Hz, 2H), 3.86 (s, 2H), 6.86-6.94 (m, 1H), 7.18 (dd,J
=11.87, 8.48 Hz, 1H), 7.74 (dd,J
=7.63, 2.20 Hz, 1H), 12.60 (br s, 1H)。
標題化合物係依實施例300A之方法製備,以哌啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 222 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例307A取代實施例300A。MS (DCI/NH3
)m/z 356 (M+H)+
;1
H NMR(300 MHz,二甲基亞碸-d 6
):δ 1.54-1.67 (m, 4H), 1.77-1.93 (m, 4H), 2.31-2.44 (m, 6H), 3.44-3.53 (m, 2H),
3.88 (s, 2H), 7.10-7.14 (m, 1H), 7.15 (d,J
=6.35 Hz, 1H), 7.17-7.23 (m, 1H), 12.62 (s, 1H)。
實施例1B(25.8克,61.5毫莫耳)、甲基-3-甲醯基苄酸酯(10.01克,61.0毫莫耳)及三乙基胺(8.7毫升,62.4毫莫耳)於二氯甲烷(125毫升)中之溶液於室溫攪拌16小時並濃縮。殘留物與乙酸乙酯及水之混合物一起攪拌。過濾沉澱之固體,以水洗滌並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 285 (M+H)+
。
實施例308A(9.9克,35毫莫耳)於四氫呋喃/水1:1混合物(100毫升)中之溶液在室溫下以氫氧化鋰單水合物(2.93克,70毫莫耳)處理16小時。添加乙酸乙酯(100毫升),混合物以2M HCl(100毫升)洗滌。於真空下將結合之有機物濃縮並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 271 (M+H)+
。
實施例308B(9.0克,33.33毫莫耳)於無水乙醇(120毫升)中之溶液在80℃與單水合肼(3.3毫升,66.66毫莫耳)一起加熱16小時。冷卻至室溫後,過濾沉澱之固體並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 285 (M+H)+
。
實施例308C(2.73克,9.6毫莫耳)於無水四氫呋喃(30毫升)中之溶液於室溫以草醯氯(1.3毫升,14.4毫莫耳)及數滴N,N-二甲基甲醯胺處理10分鐘且於50℃處理1小時。將反應混合物濃縮並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 303 (M+H)+
。
實施例308D(19毫克,0.06毫莫耳)、呋喃-3-基甲胺(0.07毫莫耳)及三乙基胺(14.6毫克,0.14毫莫耳)於四氫呋喃(1.0毫升)中之溶液於室溫攪拌16小時。將反應混合物濃縮。殘留物溶解於二甲基亞碸/甲醇1:1混合物並藉HPLC純化(Waters Sunfire® C-8分析管柱[Milford, MA]/0.1%三氟乙酸/水/100% CH3
CN)以提供標題化合物。MS (DCI/NH3
)m/z 363 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.54-1.69 (m, 4H), 2.32-2.45 (m, 4H), 3.96 (s, 2H), 4.29 (s, 2H), 6.41-6.49 (m, 1H), 7.32-7.37 (m, 1H),
7.41 (t,J
=7.63 Hz, 1H), 7.52-7.60 (m, 2H), 7.64-7.72 (m, 2H)。
標題化合物係依實施例308之方法製備,以噻吩-2-基甲胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 380 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.56-1.70 (m, 4H), 2.32-2.43 (m, 4H), 3.97 (s, 2H), 4.61 (s, 2H), 6.97 (dd,J
=5.03, 3.51 Hz, 1H), 7.02 (d,J
=2.44 Hz, 1H), 7.34-7.39 (m, 2H), 7.42 (t,J
=7.63 Hz, 1H), 7.67 (s, 1H), 7.70 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以噻吩-3-基甲胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 380 (M+H)+
。
標題化合物係依實施例308之方法製備,以吡啶-3-基甲胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 375 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.53-1.70 (m, 4H), 2.31-2.45 (m, 4H), 3.98 (s, 2H), 4.61 (s, 2H), 7.37-
7.41 (m, 1H), 7.45 (t,J
=7.63 Hz, 1H), 7.69 (s, 1H), 7.74 (d,J
=7.63 Hz, 1H), 7.91 (dd,J
=7.93, 5.49 Hz, 1H), 8.37 (d,J
=7.93 Hz, 1H), 8.72 (d,J
=5.19 Hz, 1H), 8.78 (s, 1H)。
標題化合物係依實施例308之方法製備,以吡啶-4-基甲胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 375 (M+H)+
。
標題化合物係依實施例308之方法製備,以N1
,N1
-二甲基乙烷-1,2-二胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 355 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.56-1.66 (m, 4H), 2.33-2.44 (m, 4H), 2.84 (s, 6H), 3.26 (t,J
=5.95 Hz, 2H), 3.60 (t,J
=5.95 Hz, 2H), 3.98 (s, 2H), 7.38-7.41 (m, 1H), 7.45 (t,J
=7.63 Hz, 1H), 7.67 (s, 1H), 7.71 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以N1
,N1
-二甲基丙烷-1,3-二胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 369 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-(吡咯啶-1-基)丙烷-1-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 395 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-(哌啶-1-基)丙烷-1-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 409 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-嗎啉丙烷-1-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 411 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.56-1.68 (m, 4H), 1.87-1.97 (m, 2H), 2.31-2.45 (m, 4H), 3.08 (t,J
=12.05 Hz, 2H), 3.11-3.17 (m, 2H), 3.33 (t,J
=6.71 Hz, 2H), 3.42 (d,J
=12.51 Hz, 2H), 3.65 (t,J
=12.05 Hz, 2H), 3.96-4.02 (m, 2H), 3.97 (s, 2H), 7.35-7.39 (m, 1H), 7.43 (t,J
=7.63 Hz, 1H), 7.65 (s, 1H), 7.69 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以2-(1H-吲哚-3-基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 427 (M+H)+
。
標題化合物係依實施例308之方法製備,以噻唑-2-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 367 (M+H)+
;1
H NMR(500 MHz, D2
O/二甲基亞碸-d 6
):δ 1.59-1.68 (m, 4H), 2.35-2.46 (m, 4H), 4.01 (s, 2H), 7.28 (d,J
=3.66 Hz, 1H), 7.45-7.48 (m, 1H), 7.50 (t,J
=7.48 Hz, 1H), 7.56 (d,J
=3.66 Hz, 1H), 7.87 (s, 1H), 7.93 (d,J
=7.63 Hz, 1H)。
標題化合物係依實施例294之方法製備,以2-(苄基氧基羰基胺基)乙酸取代4-側氧基-4-苯基丁酸。MS (DCI/NH3
)m/z 461 (M+H)+
。
標題化合物係依實施例294之方法製備,以4-側氧基-4-(4-苯氧基苯基)丁酸取代4-側氧基-4-苯基丁酸。MS
(DCI/NH3
)m/z 522 (M+H)+
。
標題化合物係依實施例294之方法製備,以1-(苄基氧基羰基)哌啶-3-甲酸取代4-側氧基-4-苯基丁酸。MS (DCI/NH3
)m/z 515 (M+H)+
。
標題化合物係依實施例294之方法製備,以2-(對-甲苯基氧基)乙酸取代4-側氧基-4-苯基丁酸。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例294之方法製備,以2-(4-甲氧苯氧基)乙酸取代4-側氧基-4-苯基丁酸。MS (DCI/NH3
)m/z 434 (M+H)+
。
標題化合物係依實施例300A之方法製備,以1-甲基咪唑啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 223 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例325A取代實施例300A。MS (DCI/NH3
)m/z 357 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.54-1.69 (m, 4H), 2.32-2.43 (m, 4H), 2.74 (s, 3H), 3.39-3.44 (m, 2H), 3.67-3.76 (m, 2H), 3.86 (s, 2H), 6.97-7.05 (m, 1H), 7.17 (dd,J
=11.19, 8.48 Hz, 1H), 7.31 (dd,J
=7.63, 2.20 Hz, 1H), 12.60 (s, 1H)。
標題化合物係依實施例300A之方法製備,以四氫嘧啶-2(1H)-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 223 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例326A取代實施例300A。MS (DCI/NH3
)m/z 357 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.57-1.68 (m, 4H), 1.87-2.00 (m, 2H), 2.33-2.43 (m, 4H), 3.23 (t,J
=5.76 Hz, 2H), 3.44-3.52 (m, 2H), 3.86 (s, 2H), 6.60 (s, 1H), 7.00-7.07 (m, 1H), 7.09-7.18 (m, 2H), 12.61 (s, 1H)。
標題化合物係依實施例300A之方法製備,以1-第三丁基咪唑啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 265 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例327A取代實施例300A。MS (DCI/NH3
)m/z 399 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.3 (s, 9H), 1.53-1.68 (m, 4H), 2.31-2.45 (m, 4H), 3.43-3.48 (m, 2H), 3.58-3.69 (m, 2H), 3.86 (s, 2H), 6.95-7.02 (m, 1H), 7.15 (dd,J
=11.36, 8.31 Hz, 1H), 7.28 (dd,J
=7.46, 2.03 Hz, 1H), 12.59 (s, 1H)。
標題化合物係依實施例300A之方法製備,以(1S,4R)-2-氮雜雙環[2.2.1]庚烷-3-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 234 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例328A取代實施例300A。MS (DCI/NH3
)m/z 368 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.49-1.56 (m, 2H), 1.57-1.65 (m, 4H), 1.69-1.76 (m, 1H), 1.79-1.86 (m, 1H), 1.89-1.96 (m, 1H), 1.97-2.03 (m, 1H), 2.32-2.45 (m, 4H), 2.74-2.82 (m, 1H), 3.87 (s, 2H), 4.25 (s, 1H), 7.01-7.08 (m, 1H), 7.16-7.23 (m, 1H), 7.23-7.28 (m, 1H), 12.59 (br s, 1H)。
標題化合物係依實施例308之方法製備,以2-乙基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 388 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-乙基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 388 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-乙基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 388 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-丙基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-異丙基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-異丙基苯
胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 402 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.20 (d,J
=7.02 Hz, 6H), 1.55-1.72 (m, 4H), 2.34-2.47 (m, 4H), 2.82-2.96 (m, 1H), 4.01 (s, 2H), 7.23 (d,J
=8.24 Hz, 2H), 7.39 (d,J
=7.63 Hz, 1H), 7.47 (t,J
=7.63 Hz, 1H), 7.63 (d,J
=8.54 Hz, 2H), 7.74 (s, 1H), 7.80 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以3-第三丁基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 416 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-第三丁基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 416 (M+H)+
。
標題化合物係依實施例308之方法製備,以聯苯-4-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 436 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.57-1.70 (m, 4H),
2.34-2.48 (m, 4H), 4.02 (s, 2H), 7.36 (t,J
=7.32 Hz, 1H), 7.42 (d,J
=7.93 Hz, 1H), 7.45-7.48 (m, 2H), 7.49-7.52 (m, 1H), 7.66-7.71 (m, 4H), 7.78 (s, 1H), 7.81-7.87 (m, 3H).
標題化合物係依實施例308之方法製備,以2-氟-4-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 392 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-氟-4-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 392 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-氟-2-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 392 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-氟-3-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 392 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-氯-4-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 408 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-氯-3-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 408 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-溴-4-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 452 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-溴-3-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 452 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-氟-4-甲氧苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 408 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.55-1.69 (m, 4H), 2.33-2.49 (m, 4H), 3.83 (s, 3H), 4.01 (s, 2H), 7.16 (t,J
=9.31 Hz, 1H), 7.40 (d,J
=7.93 Hz, 1H), 7.44-7.50 (m, 2H), 7.69 (dd,J
=13.58, 2.59 Hz, 1H), 7.73 (s, 1H), 7.79 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以3-甲氧-5-(三氟甲基)苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 458 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-胺基-3-甲基酚取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 390
(M+H)+
。
標題化合物係依實施例308之方法製備,以3-胺基-2-甲基酚取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 390 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-胺基-5-甲基酚取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 390 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-甲氧-5-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例308之方法製備,以5-甲氧-2-甲基苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 404
(M+H)+
。
標題化合物係依實施例308之方法製備,以5-胺基-2-甲氧酚取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 406 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-乙氧苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 404 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-丙氧苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例308之方法製備,以5-第三丁基-2-甲氧苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 446 (M+H)+
。
標題化合物係依實施例308之方法製備,以N-(3-胺基-4-甲氧苯基)乙醯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 447 (M+H)+
。
標題化合物係依實施例308之方法製備,以2,3-二氫苯并[b][1,4]二氧雜環己烯-6-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 418 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.56-1.68 (m, 4H), 2.34-2.48 (m, 4H), 4.00 (s, 2H), 4.15-4.32 (m, 4H), 6.84 (d,J
=8.85 Hz, 1H), 7.16 (dd,J
=8.85, 2.44 Hz, 1H), 7.34 (d,J
=2.44 Hz, 1H), 7.38 (d,J
=7.93 Hz, 1H), 7.46 (t,J
=7.63 Hz, 1H), 7.72 (s, 1H), 7.77 (d,J
=7.63 Hz, 1H)。
標題化合物係依實施例308之方法製備,以5-氯-2,4-二甲氧苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 454 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-(甲硫基)苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 406 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-(甲硫基)苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 406 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-(哌啶-1-基)苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 443 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-嗎啉苯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 445 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.57-1.68 (m, 4H), 2.34-2.46 (m, 4H), 3.15-3.23 (m, 4H), 3.79-3.82 (m, 4H), 4.01 (s, 2H), 7.10 (d,J
=9.15 Hz, 2H), 7.39 (d,J
=7.63 Hz, 1H), 7.45-7.50 (m, 1H), 7.66 (d,J
=9.15 Hz, 2H), 7.72-7.77 (m, 1H), 7.80 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以N1
-苯基苯-1,2-二胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 451 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.54-1.69 (m, 4H), 2.31-2.44 (m, 4H), 3.95 (s, 2H), 6.78 (t,J
=7.32 Hz, 1H), 6.86 (d,J
=7.63 Hz, 2H), 7.02-7.09 (m, 1H), 7.15-7.23 (m, 3H), 7.28-7.32 (m, 1H), 7.35-7.39 (m, 1H), 7.42 (t,J
=7.63 Hz, 1H), 7.59 (d,J
=7.32 Hz, 1H), 7.63 (s, 1H), 7.69 (d,J
=7.63 Hz, 1H)。
標題化合物係依實施例308之方法製備,以N1
-(4-甲氧苯基)苯-1,2-二胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 481 (M+H)+
。
標題化合物係依實施例308之方法製備,以喹啉-7-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 411 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.57-1.72 (m, 4H), 2.36-2.49 (m, 4H), 4.04 (s, 2H), 7.44-7.50 (m, 1H), 7.54 (t,J
=7.63 Hz, 1H), 7.82 (s, 1H), 7.88 (dd,J
=8.24, 5.19 Hz, 2H), 8.19 (d,J
=9.15 Hz, 1H), 8.27 (dd,J
=9.15, 2.14 Hz, 1H), 8.74 (d,J
=2.44 Hz, 1H), 8.88 (d,J
=7.93 Hz, 1H), 9.04 (d,J
=4.88 Hz, 1H)。
標題化合物係依實施例308之方法製備,以5-胺基萘-1-酚取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 426 (M+H)+
。
標題化合物係依實施例308之方法製備,以1H-吲唑-6-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 400 (M+H)+
。
吡啶-2,3-二甲酸二甲酯(1.0克,5.1毫莫耳)於四氫呋喃(50毫升)中之溶液於-78℃經注射筒添加氯化(4-氟苄基)鎂(於四氫呋喃中0.25 M,20毫升,5.1毫莫耳)。反應混合物於相同溫度攪拌30分鐘且藉添加水中止反應。溫熱至室溫後,反應混合物分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮。殘留物藉快速層析純化(15%於己烷中之乙
酸乙酯)產生標題化合物。MS (DCI/NH3
)m/z 274 (M+H)+
。
實施例369A(0.46克,1.68毫莫耳)於乙醇(20毫升)中之溶液在室溫下以肼(108毫克,3.37毫莫耳)處理5小時。將反應混合物濃縮至約5毫升。過濾收集固體,以乙醇洗滌並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 256 (M+H)+
。
標題化合物係依實施例369A之方法製備,以氯化(2-氯-4-氟苄基)鎂取代氯化(4-氟苄基)鎂。MS (DCI/NH3
)m/z 308 (M+H)+
。
標題化合物係依實施例369B之方法製備,以實施例370A取代實施例369A。MS (DCI/NH3
)m/z 290 (M+H)+
。
標題化合物係依實施例300A之方法製備,以(R)-5-(羥基甲基)吡咯啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 232 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例371A取代實施例300A。MS (DCI/NH3
)m/z 352 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.54-1.63 (m, 4H), 1.64-1.72 (m, 1H), 2.13-2.22 (m, 1H), 2.23-2.31 (m, 1H), 2.33-2.44 (m, 4H), 2.54-2.64 (m, 1H), 3.72 (t,J
=10.17 Hz, 1H), 3.78-3.84 (m, 2H), 3.91-4.05 (m, 1H), 4.48 (dd,J
=10.51, 3.05 Hz, 1H), 6.77-6.82 (m, 1H), 6.84-6.89 (m, 1H), 8.26 (d,J
=2.03 Hz, 1H), 12.58 (br s, 1H)。
標題化合物係依實施例300A之方法製備,以N-甲基甲烷磺醯胺取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 232 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例372A取代實施例300A。MS (DCI/NH3
)m/z 366 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.57-1.71 (m, 4H), 2.34-2.47 (m, 4H), 3.13 (s, 6H), 3.93 (s, 2H), 7.25 (dd,J
=8.33, 1.98 Hz, 1H), 7.51 (d,J
=7.93 Hz, 1H), 7.58 (d,J
=1.98 Hz, 1H), 12.62 (br s, 1H)。
標題化合物係依實施例300A之方法製備,以5,5-二甲基噁唑啶-2,4-二酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 226 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例373A取代實施例300A。MS (DCI/NH3
)m/z 360 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.34 (s, 6H), 1.53-1.70 (m, 4H), 2.29-2.45 (m, 4H), 3.87 (s, 2H), 6.85-7.02 (m,
1H), 7.20 (dd,J
=10.91, 8.53 Hz, 1H), 7.91 (dd,J
=7.54, 1.98 Hz, 1H), 9.24 (s, 1H), 12.62 (s, 1H)。
標題化合物係依實施例300A之方法製備,以(S)-5-(羥基甲基)吡咯啶-2-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 232 (M+H)+
。
標題化合物係依實施例300A之方法製備,以實施例374A取代實施例300B。MS (DCI/NH3
)m/z 352 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.54-1.62 (m, 4H), 1.63-1.76 (m, 1H), 2.13-2.22 (m, 1H), 2.23-2.31 (m, 2H), 2.32-2.40 (m, 4H), 3.72 (t,J
=10.31 Hz, 1H), 3.81 (s, 2H), 3.90-4.04 (m, 1H), 4.48 (dd,J
=10.71, 3.17 Hz, 1H), 6.77-6.83 (m, 1H), 6.84-6.91 (m, 1H), 8.26 (d,J
=1.98 Hz, 1H), 12.58 (br s, 1H)。
標題化合物係依實施例308之方法製備,以2-苯基乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 388 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.56-1.69 (m, 4H), 2.33-2.45 (m, 4H), 2.84 (t,J
=7.48 Hz, 2H), 3.43-3.51 (m, 2H), 3.96 (s, 2H), 7.21 (t,J
=7.17 Hz, 1H), 7.23-7.26 (m, 2H), 7.27-7.32 (m, 2H), 7.32-7.36 (m, 1H), 7.40 (t,J
=7.63 Hz, 1H), 7.60 (s, 1H), 7.64 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以2-鄰-甲苯基乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-間-甲苯基乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-對-甲苯基
乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 402 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(吡啶-2-基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 389 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.57-1.68 (m, 4H), 2.31-2.43 (m, 4H), 3.24 (t,J
=6.56 Hz, 2H), 3.69 (t,J
=6.41 Hz, 2H), 3.95 (s, 2H), 7.33-7.37 (m, 1H), 7.40 (t,J
=7.63 Hz, 1H), 7.53 (s, 1H), 7.57 (d,J
=7.63 Hz, 1H), 7.86-7.89 (m, 1H), 7.90-7.94 (m, 1H), 8.40-8.49 (m, 1H), 8.75 (d,J
=4.88 Hz, 1H)。
標題化合物係依實施例308之方法製備,以3-(吡啶-2-基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 389 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-(吡啶-2-基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 389
(M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2-甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例308之方法製備,以3-(2-甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 418 (M+H)+
。
標題化合物係依實施例308之方法製備,以4-(2-甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 418 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.55-1.68 (m, 4H), 2.32-2.45 (m, 4H), 2.77 (t,J
=7.48 Hz, 2H), 3.27-3.47 (m, 2H), 3.71 (s, 3H), 3.96 (s, 2H), 6.83-6.88 (m, 2H), 7.14-7.20 (m, 2H), 7.32-7.36 (m, 1H), 7.40 (t,J
=7.63 Hz, 1H), 7.61 (s, 1H), 7.64 (d,J
=7.63 Hz, 1H)。
標題化合物係依實施例308之方法製備,以2-(2-氟苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 406 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(3-氟苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 406 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(4-氟苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 406 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2-氯苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 422 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(3-氯苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 422 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(4-氯苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 422 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(3-溴苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 467 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(4-溴苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 467 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(聯苯-4-基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 464 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.54-1.67 (m, 4H), 2.30-2.44 (m, 4H), 2.89 (t,J
=7.48 Hz, 2H), 3.52 (t,J
=7.32 Hz, 2H), 3.96 (s, 2H), 7.33-7.37 (m, 4H), 7.41 (t,J
=7.63 Hz, 1H), 7.44-7.50 (m, 2H), 7.59 (d,J
=8.24 Hz, 2H), 7.64 (d,J
=8.24 Hz, 2H), 7.64-7.68 (m, 2H)。
標題化合物係依實施例308之方法製備,以2-(3-(三氟甲基)苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 456 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(4-(三氟甲基)苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 456 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(4-苯氧基苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 480 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.55-1.66 (m, 4H), 2.32-2.43 (m, 4H), 2.83 (t,J
=7.32 Hz, 2H), 3.48 (t,J
=7.32 Hz, 2H), 3.96 (s, 2H), 6.91-6.94 (m, 2H), 6.96 (d,J
=7.63 Hz, 2H), 7.12 (t,J
=7.48 Hz, 1H), 7.26 (d,J
=8.54 Hz, 2H), 7.32-7.35 (m, 1H), 7.35-7.38 (m, 2H), 7.38-7.43 (m, 1H), 7.62 (s, 1H), 7.64 (d,J
=7.63 Hz, 1H)。
標題化合物係依實施例308之方法製備,以2-(3,4-二甲基苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 416 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2,4-二甲基苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 416 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2,5-二甲
基苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 416 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(3-乙氧-4-甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 462 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(4-乙氧-3-甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 462 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2,3-二甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2,4-二甲
氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2,5-二甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(3,4-二甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(3,5-二甲氧苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 448 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(苯并
[d][1,3]二氧雜環戊烯-5-基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 432 (M+H)+
;1
H NMR (500 MHz, D2
O/DMSO-d 6
):δ 1.54-1.72 (m, 4H), 2.32-2.44 (m, 4H), 2.75 (t,J
=7.32 Hz, 2H), 3.43 (t,J
=7.32 Hz, 2H), 3.96 (s, 2H), 5.94 (s, 2H), 6.70 (dd,J
=7.93, 1.53 Hz, 1H), 6.80 (s, 1H), 6.81-6.83 (m, 1H), 7.32-7.36 (m, 1H), 7.40 (t,J
=7.63 Hz, 1H), 7.61 (s, 1H), 7.64 (d,J
=7.93 Hz, 1H)。
標題化合物係依實施例308之方法製備,以2-(2,3-二氯苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 457 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(3,4-二氯苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 457 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(2,6-二氯苯基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 457
(M+H)+
。
標題化合物係依實施例300A之方法製備,以(1S, 2R, 6S, 7R)-4,4-二甲基-3,5-二氧雜-8-氮雜三環[5.2.1.0(2,6)]癸烷-9-酮取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 306 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例411A取代實施例300B。MS (DCI/NH3
)m/z 440 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.29-1.34 (m, 3H), 1.42 (s, 3H), 1.55-1.67 (m, 4H), 2.01-2.11 (m, 1H), 2.12-2.21 (m, 1H), 2.32-2.45 (m, 4H), 2.77-2.84 (m, 1H), 3.88 (s, 2H), 4.16-4.24 (m, 1H), 4.58-4.64 (m, 1H), 4.64-4.69 (m, 1H), 7.02-7.09 (m, 1H), 7.22 (dd,J
=11.19, 8.48 Hz, 1H), 7.31 (dd,J
=7.46, 2.03 Hz, 1H), 12.59 (s, 1H)。
1-(3-溴-4-氟苯基)乙酮(15.0克,69毫莫耳)於四氫呋喃(200毫升)中之溶液於0℃以硼氫化鈉(5.3克,138毫莫耳)處理。添加後,移除冰浴,混合物於室溫攪拌30分鐘並於回流下隔夜。冷卻後,緩緩添加1 N HCl(10毫升)並將反應混合物濃縮。殘留物分溶於乙酸乙酯與鹽水之間。有機相以水洗滌並濃縮。殘留物藉快速層析純化(30%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 220 (M+H)+
。
實施例412A(1.5克,6.8毫莫耳)及三苯基膦(1.9克,7.2毫莫耳)於二甲基甲醯胺(20毫升)中之溶液經注射筒添加溴(1.1克,6.8毫莫耳)。添加後,反應混合物於室溫攪拌另外15分鐘,分溶於水(100毫升)及乙酸乙酯(200毫升)之間。有機相以鹽水洗滌並濃縮。殘留物藉快速層析純化(2.6%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 282 (M+H)+
。
標題化合物係依實施例285B之方法製備,以實施例
412A取代實施例285A。
標題化合物係依實施例285C之方法製備,以實施例412B取代實施例285B。MS (DCI/NH3
)m/z 338 (M+H)+
。
標題化合物係依實施例2C之方法製備,以實施例412C取代實施例2B。MS (DCI/NH3
)m/z 352 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例412取代基實施例103且以吡咯啉-2-酮取代吖丁啶-2-酮。MS (ESI)m/z 356 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.42 (d,J
=6.74 Hz, 3 H), 1.46-1.70 (m, 4 H), 1.93-2.16 (m, 4 H), 2.29-2.67 (m, 6 H), 4.25 (q,J
=6.74 Hz, 1 H), 7.07-7.15 (m, 1 H), 7.18 (s, 1 H), 7.19-7.29 (m, 1 H), 12.70 (s, 1 H)。
實施例369(150毫克,0.6毫莫耳)、5%碳上鉑(30毫克)、濃HCl水溶液(50毫升)及二甲基甲醯胺(5毫升)之混合
物在加壓容器中於室溫在50 psi氫下攪拌16小時。過濾混合物並將濾液濃縮。殘留固體藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1% TFA/CH3
CN/H2
O)以提供TFA鹽形式之標題產物。MS (ESI)m/z 260 (M+H)+
。
鎂削屑(880毫克,37毫莫耳)及2-溴-4-(溴甲基)-1-氟苯(1.0克,3.7毫莫耳)於無水二乙醚(15毫升)中之混合物以一片碘處理。混合物隨後加熱至溫和回流,直至混合物顏色消失,之後持續加熱另外一小時。將懸浮液冷卻至室溫,以導管導入-78℃吡啶-2,3-二甲酸二甲酯(1.0克,5.1毫莫耳)於四氫呋喃(50毫升)中之溶液中。反應混合物於該溫度保持30分鐘,且藉添加水中止反應。溫熱至室溫後,反應混合物分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮。殘留物藉快速層析純化(15%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 353 (M+H)+
。
標題化合物係依實施例369B之方法製備,以實施例415A取代實施例369A。MS (DCI/NH3
)m/z 335 (M+H)+
。
標題化合物係依實施例308之方法製備,以N1
-乙基-N2
,N2
-二甲基乙烷-1,2-二胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 383 (M+H)+
。
標題化合物係依實施例308之方法製備,以N1
,N1
-二乙基-N2
-甲基乙烷-1,2-二胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 397 (M+H)+
。
標題化合物係依實施例308之方法製備,以N-苄基乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 402 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 0.97-1.11 (m, 3H), 1.36-1.57 (m, 4H), 2.22-2.30 (m, 2H), 2.50-2.66 (m, 2H), 3.27-3.45 (m, 2H), 3.98 (s, 2H), 4.61-4.74 (m, 2H), 7.26-7.31 (m, 1H), 7.32-7.40 (m, 6H), 7.42-7.47 (m, 1H), 7.52 (s, 1H)。
標題化合物係依實施例308之方法製備,以N-苄基丙烷-2-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 416 (M+H)+
。
標題化合物係依實施例308之方法製備,以N-苄基丁烷-1-胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 430 (M+H)+
。
標題化合物係依實施例308之方法製備,以二苄基胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 464 (M+H)+
。
標題化合物係依實施例308之方法製備,以2-(苄基胺基)乙醇取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 418 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.40-1.54 (m, 4H), 2.21-2.33 (m, 2H), 2.50-2.61 (m, 2H), 3.62-3.78 (m, 2H), 3.89-4.02 (m, 2H), 3.96 (s, 2H), 4.82-4.97 (m, 2H), 7.25-7.29 (m, 1H), 7.30-7.36 (m, 5H), 7.36-7.43 (m, 1H), 7.43-7.47 (m, 1H), 7.50 (d,J
=7.32 Hz, 1H)。
標題化合物係依實施例308之方法製備,以N-甲基-2-(吡啶-2-基)乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 403 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.42-1.52 (m, 4H), 2.24-2.34 (m, 2H), 2.51-2.62 (m, 2H), 2.97 (s, 3H), 3.07-3.21 (m, 2H), 3.83-3.94 (m, 2H), 3.99 (s, 2H), 7.12 (dd,J
=7.32, 5.49 Hz, 1H), 7.14-7.20 (m, 1H), 7.28-7.32 (m, 2H), 7.32-7.37 (m, 1H), 7.37-7.45 (m, 1H), 7.57 (t,J
=7.63 Hz, 1H), 8.55 (d,J
=3.66 Hz, 1H)。
標題化合物係依實施例308之方法製備,以2-(3,4-二甲氧苯基)-N-甲基乙胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 462 (M+H)+
。
標題化合物係依實施例308之方法製備,以哌啶-4-醇取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 368 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.42-1.52 (m, 4H), 1.63-1.75 (m, 2H), 1.87-1.98 (m, 2H), 2.27-2.35 (m, 2H), 2.54-
2.62 (m, 2H), 3.25-3.40 (m, 2H), 4.01 (s, 2H), 4.01-4.04 (m, 2H), 4.05-4.07 (m, 1H), 7.35 (t,J
=7.17 Hz, 1H), 7.37-7.40 (m, 1H), 7.40-7.44 (m, 1H), 7.51 (s, 1H)。
標題化合物係依實施例308之方法製備,以哌啶-3-甲醯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 395 (M+H)+
。
標題化合物係依實施例308之方法製備,以哌啶-4-甲醯胺取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 395 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.41-1.55 (m, 4H), 1.82-1.97 (m, 4H), 2.27-2.37 (m, 2H), 2.54-2.61 (m, 2H), 2.63-2.73 (m, 1H), 2.94-3.06 (m, 2H), 4.00 (s, 2H), 4.16-4.32 (m, 2H), 7.32-7.36 (m, 1H), 7.36-7.40 (m, 2H), 7.48-7.51 (m, 1H)。
標題化合物係依實施例308之方法製備,以1-(哌啶-4-基)-1H-苯并[d]咪唑-2(3H)-酮取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 484 (M+H)+
。
標題化合物係依實施例308之方法製備,以1-甲基哌嗪取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 367 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.46-1.52 (m, 4H), 2.24 (s, 3H), 2.29-2.34 (m, 2H), 2.37-2.42 (m, 4H), 2.54-2.62 (m, 2H), 3.61-3.73 (m, 4H), 4.02 (s, 2H), 7.35-7.39 (m, 1H), 7.39-7.43 (m, 2H), 7.51 (s, 1H)。
標題化合物係依實施例308之方法製備,以1-乙基哌嗪取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 381 (M+H)+
。
標題化合物係依實施例308之方法製備,以哌嗪-1-甲醛取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 381 (M+H)+
。
標題化合物係依實施例308之方法製備,以1-(哌嗪-1-基)乙酮取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 395
(M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.44-1.57 (m, 4H), 2.09 (s, 3H), 2.28-2.39 (m, 2H), 2.51-2.66 (m, 2H), 3.39-3.73 (m, 8H), 4.03 (s, 2H), 7.36-7.39 (m, 1H), 7.43 (t,J
=7.02 Hz, 2H), 7.54 (s, 1H)。
標題化合物係依實施例308之方法製備,以2-(哌嗪-1-基)乙醇取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 397 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.42-1.55 (m, 4H), 2.27-2.37 (m, 2H), 2.50-2.62 (m, 6H), 2.69 (t,J
=5.80 Hz, 2H), 3.54-3.75 (m, 4H), 3.89 (t,J
=5.80 Hz, 2H), 4.02 (s, 2H), 7.35-7.38 (m, 1H), 7.39-7.43 (m, 2H), 7.50 (s, 1H)。
標題化合物係依實施例308之方法製備,以1-苯基哌嗪取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 429 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.44-1.57 (m, 4H), 2.27-2.42 (m, 2H), 2.52-2.66 (m, 2H), 3.08-3.20 (m, 4H), 3.68-3.83 (m, 4H), 4.04 (s, 2H), 6.91 (t,J
=7.32 Hz, 1H), 6.98 (d,J
=7.93 Hz, 2H), 7.28-7.34 (m, 2H), 7.37-7.41 (m, 1H), 7.44 (t,J
=7.48 Hz, 1H), 7.46-7.49 (m, 1H), 7.57 (s, 1H)。
標題化合物係依實施例308之方法製備,以1-(吡啶-2-基)哌嗪取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 430 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.46-1.55 (m, 4H), 2.29-2.40 (m, 2H), 2.52-2.65 (m, 2H), 3.53-3.63 (m, 4H), 3.64-3.78 (m, 4H), 4.03 (s, 2H), 6.66 (dd,J
=6.71, 4.58 Hz, 1H), 6.73 (d,J
=8.54 Hz, 1H), 7.37-7.41 (m, 1H), 7.43 (d,J
=7.63 Hz, 1H), 7.45-7.48 (m, 1H), 7.49-7.54 (m, 1H), 7.57 (s, 1H), 8.29 (dd,J
=4.88, 1.22 Hz, 1H)。
標題化合物係依實施例308之方法製備,以2-(哌嗪-1-基)嘧啶取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 431 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.42-1.59 (m, 4H), 2.26-2.40 (m, 2H), 2.50-2.66 (m, 2H), 3.62-3.74 (m, 4H), 3.82-3.91 (m, 4H), 4.03 (s, 2H), 6.55 (t,J
=4.73 Hz, 1H), 7.38 (d,J
=5.80 Hz, 1H), 7.40-7.45 (m, 1H), 7.45-7.49 (m, 1H), 7.57 (s, 1H), 8.38 (d,J
=4.88 Hz, 2H)。
標題化合物係依實施例308之方法製備,以2-(2-(哌嗪-1-基)乙氧)乙醇取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 441 (M+H)+
。
標題化合物係依實施例308之方法製備,以1-(2-氟苯基)哌嗪取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 447 (M+H)+
。
標題化合物係依實施例308之方法製備,以1-(4-氟苯基)哌嗪取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 447 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.44-1.56 (m, 4H), 2.30-2.39 (m, 2H), 2.53-2.63 (m, 2H), 3.02-3.12 (m, 4H), 3.68-3.81 (m, 4H), 4.05 (s, 2H), 6.93-6.97 (m, 2H), 7.04-7.09 (m, 2H), 7.37-7.41 (m, 1H), 7.44 (t,J
=7.32 Hz, 1H), 7.46-7.51 (m, 1H), 7.57 (s, 1H)。
標題化合物係依實施例308之方法製備,以1-(2-氯苯基)哌嗪取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 463
(M+H)+
。
標題化合物係依實施例308之方法製備,以1-甲基-4-(哌嗪-1-基)氮取代呋喃-3-基甲胺。MS (DCI/NH3
)m/z 381 (M+H)+
;1
H NMR(500 MHz, D2
O/吡啶-d 5
):δ 1.44-1.48 (m, 1H), 1.48-1.51 (m, 4H), 1.92-2.01 (m, 2H), 2.28-2.36 (m, 2H), 2.51-2.55 (m, 2H), 2.58 (s, 3H), 2.64 (t,J
=5.65 Hz, 1H), 2.84-2.94 (m, 2H), 3.64-3.71 (m, 3H), 3.88-3.92 (m, 1H), 4.01 (s, 2H), 7.33-7.39 (m, 1H), 7.39-7.41 (m, 1H), 7.41-7.45 (m, 1H), 7.51 (s, 1H)。
標題化合物係依實施例300A之方法製備,以1,4-丁烷萘迫磺內醯胺取代5-甲基吡咯啶酮。MS (DCI/NH3
)m/z 258 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例
448A取代實施例300A。MS (DCI/NH3
)m/z 392 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.57-1.71 (m, 4H), 1.75-1.87 (m, 2H), 2.13-2.24 (m, 2H), 2.34-2.46 (m, 4H), 3.16-3.28 (m, 2H), 3.46-3.58 (m, 2H), 3.92 (s, 2H), 7.23 (dd,J
=8.13, 2.18 Hz, 1H), 7.48 (d,J
=7.93 Hz, 1H), 7.57 (d,J
=1.59 Hz, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例101之方法製備,以實施例415取代實施例103。MS (ESI)m/z 325 (M+H)+
。
標題化合物係依實施例414之方法製備為TFA鹽形式,以實施例370取代實施例369。MS (ESI)m/z 294 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例412取代實施例103。MS (ESI)m/z 342 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.41 (d,J
=7.12 Hz, 3 H), 1.44-1.67 (m, 4 H), 1.84-2.08 (m, 1 H), 2.34 (m, 2 H), 2.53-2.74 (m, 1 H), 3.11 (t,J
=4.58 Hz, 2 H), 3.72-3.88 (m, 2 H), 4.22 (q,J
=6.78 Hz, 1 H), 6.81-6.95 (m, 1 H), 7.18 (dd,J
=11.87, 8.48 Hz, 1 H), 7.76 (dd,J
=7.46, 2.37 Hz, 1 H), 12.70 (s, 1 H)。
標題化合物係依實施例2、3及4之方法製備,以3-硝基苯甲醛取代4-氟-3-硝基苯甲醛。MS (DCI/NH3
)m/z 256 (M+H)+
。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例2取代實施例89且以2-(2-側氧基吡咯啶-1-基)乙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 356 (M+H)+
。MS (DCI/NH3
)m/z 399 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.53-1.67 (m, 4H), 1.89-2.06 (m, 2H), 2.26 (t,J
=7.97 Hz, 2H), 2.31-2.43 (m, 4H), 3.39-3.47 (m, 2H), 3.86 (s, 2H), 4.07 (s, 2H), 6.93-6.99 (m, 1H), 7.18 (dd,J
=10.85, 8.48 Hz, 1H), 7.71 (dd,J
=7.46, 2.03 Hz, 1H), 9.82 (br s, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例2取代實施例89且以5-甲基-1-苯基-1H-吡唑-4-甲酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 356 (M+H)+
。MS (DCI/NH3
)m/z 458 (M+H)+
。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例2取代實施例89且以5-側氧基己酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 386 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.53-1.65 (m, 4H), 1.67-1.80 (m, 2H), 2.08 (s, 3H), 2.28-2.34 (m, 2H), 2.34-2.41 (m, 4H), 2.42-2.49 (m, 2H), 3.85 (s, 2H), 6.82-6.96 (m, 1H), 7.15 (dd,J
=10.85, 8.48 Hz, 1H), 7.67 (dd,J
=7.46, 1.70 Hz, 1H), 9.60 (br s, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例2取代實施例89且以3-甲氧丙酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 360 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.55-1.66 (m, 4H), 2.30-2.43 (m, 4H), 2.60 (t,J
=6.10 Hz, 2H), 3.23 (s, 3H), 3.59 (t,J
=6.27 Hz, 2H), 3.86 (s, 2H), 6.85-6.99 (m, 1H), 7.16 (dd,J
=10.85,
8.48 Hz, 1H), 7.74 (dd,J
=7.46, 1.70 Hz, 1H), 9.64 (br s, 1H), 12.61 (br s, 1H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例2取代實施例89且以5-側氧基-5-(苯基胺基)戊酸取代1-甲基環丙烷甲酸。MS (DCI/NH3
)m/z 463 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.55-1.67 (m, 4H), 1.83-1.94 (m, 2H), 2.31-2.40 (m, 6H), 2.40-2.45 (m, 2H), 3.85 (s, 2H), 6.89-6.96 (m, 1H), 6.98-7.06 (m, 1H), 7.15 (dd,J
=10.85, 8.48 Hz, 1H), 7.24-7.32 (m, 2H), 7.59 (d,J
=7.46 Hz, 2H), 7.71 (dd,J
=7.97, 1.53 Hz, 1H), 9.67 (br s, 1H), 9.88 (br s, 1H), 12.62 (br s, 1H)。
4-氟-3-硝基苄酸(5克,27.0毫莫耳)於二甲基甲醯胺(100毫升)中之溶液中添加N,O-二甲基羥基胺鹽酸鹽(5.93克,60.8毫莫耳)及三乙基胺(17.0毫升,122毫莫耳)。添加1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(11.65克,60.8毫莫耳)及羥基苯并三唑(9.31克,60.8毫莫耳),反應
混合物於室溫攪拌3日。將反應混合物濃縮,分溶於乙酸乙酯(150毫升)及鹽水(150毫升)之間。有機物於旋轉蒸發器上濃縮,粗製物藉快速層析純化,以40%於己烷中之乙酸乙酯溶離,以提供標題產物。MS (DCI/NH3
)m/z 254 (M+H)+
。
實施例458A (2.34克,9.24毫莫耳)於四氫呋喃(40毫升)中之溶液於室溫在氫(氣球)下以阮來Ni(2.0克,Raney 2800,於水中之漿液)處理16小時。濾除觸媒,並將濾液濃縮。殘留物不進一步純化地使用於後續步驟。
實施例458B於四氫呋喃(20毫升)及水(20毫升)之混合物中的溶液中添加碳酸銫(6.02克,18.58毫莫耳)及氯甲酸苄酯(1.5毫升,10.16毫莫耳)。反應混合物於室溫攪拌16小時並濃縮。殘留物分溶於乙酸乙酯(100毫升)及鹽水(75毫升)之間。有機層以鹽水洗滌並濃縮。殘留油藉快速層析純化,以40%於己烷中之乙酸乙酯溶離,以提供標題產物。MS (DCI/NH3
)m/z 358 (M+H)+
。
實施例458C(2.89克,8.1毫莫耳)於無水四氫呋喃(20毫
升)中之溶液於0℃以氫化鋰鋁(四氫呋喃中1.0 M溶液,8.1毫升,8.1毫莫耳)處理10分鐘。反應以水中止,混合物分溶於乙酸乙酯及稀HCl溶液之間。有機層以鹽水洗滌並於旋轉蒸發器上濃縮。殘留油藉快速層析純化,以20%於己烷中之乙酸乙酯溶離,以提供標題產物。MS (DCI/NH3
)m/z 299 (M+H)+
。
標題化合物係依實施例300B之方法製備,以實施例458D取代實施例300A。MS (DCI/NH3
)m/z 433 (M+H)+
。
標題化合物係依實施例414之方法製備,以實施例449取代實施例369。MS (ESI)m/z 329 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.61-1.76 (m, 2 H), 2.33 (t,J
=6.35 Hz, 2 H), 3.12 (t,J
=4.56 Hz, 2 H), 3.17 (m, 2 H), 3.77 (s, 2 H), 3.81 (q,J
=4.36 Hz, 2 H), 6.32 (s, 1 H), 6.87-7.01 (m, 1 H), 7.17 (dd,J
=11.90, 8.33 Hz, 1 H), 7.78 (dd,J
=7.54, 2.38 Hz, 1 H), 11.80 (s, 1 H)。
2-溴-1-氟-4-碘苯(13.23克,44毫莫耳)於無水四氫呋喃(30毫升)中之溶液於-20℃添加氯化異丙基鎂(於四氫呋喃中2.0 M溶液,24.18毫升,48.4毫莫耳)。添加後,反應混合物於0℃攪拌3小時,且於-78℃添加於3,4,5,6-四氫苯二甲酸酐(6.08克,40毫莫耳)於無水四氫呋喃(60毫升)中之溶液。混合物攪拌2小時,將飽和氯化銨水溶液添加於反應混合物,隨之於室溫攪拌30分鐘。將無水硫酸鎂添加於反應混合物,過濾混合物。將濾液濃縮。亞磺醯氯(10.4毫升,142莫耳)於-10℃逐滴添加於甲醇(40毫升),溶液於0℃攪拌30分鐘。隨後於該亞磺醯氯溶液中添加來自濾液於無水甲醇中之殘留物(15毫升)。反應混合物於室溫攪拌隔夜並濃縮。殘留物溶解於二氯甲烷(40毫升)中,於0℃以三乙基胺(5.58毫升)處理1小時。添加水,混合物以碳酸氫鈉、鹽水及水洗滌。有機相以硫酸鎂乾燥,過濾並濃縮。殘留物藉快速層析分離(10至35%於己烷中之乙酸乙酯的梯度)以提供標題化合物。MS (DCI/NH3
)m/z 341, 343 (M+H)+
。
實施例460A(9.5克,27.8毫莫耳)及單水合肼(1.76毫升,36.2毫莫耳)於乙醇(70毫升)中之溶液於回流下加熱4小時。冷卻至室溫後,過濾收集固體,以乙醇洗滌並乾
燥,以提供標題化合物。MS (DCI/NH3
)m/z 323, 325 (M+H)+
;1
H NMR (300 MHz, DMSO-D6
):δ 1.57-1.65 (m, 2 H), 1.66-1.74 (m, 2 H), 2.34 (t,J
=5.75 Hz, 2 H), 2.45 (t,J
=6.15 Hz, 2 H), 7.45 (t,J
=8.72 Hz, 1 H), 7.49-7.55 (m, 1 H), 7.80 (dd,J
=6.74, 2.38 Hz, 1 H), 12.85 (br s, 1H)。
實施例460(2.0克,6.19毫莫耳)於無水二甲基甲醯胺(30毫升)中之溶液中添加第三丁醇鉀(於四氫呋喃中1 M溶液,6.50毫升,6.5毫莫耳)。溶液於室溫攪拌30分鐘,添加苄基氯甲基醚(1.163克,7.43毫莫耳)。反應混合物於室溫攪拌隔夜。以水中止反應後,反應混合物分溶於水及乙酸乙酯之間。有機相以水洗滌並濃縮。殘留物藉快速層析分離(20至60%於己烷中之乙酸乙酯的梯度)以提供標題化合物。MS (DCI/NH3
)m/z 443 (M+H)+
。
微波反應器管內置入實施例461A(137毫克,0.309毫莫耳)、三(二亞苄基丙酮)二鈀(0)(28.3毫克,0.031毫莫
耳)、4,5-雙(二苯基膦基)-9,9-二甲基咕噸(Xantphos)(26.9毫克,0.046毫莫耳)、2-吖丁啶酮(44毫克,0.619毫莫耳)及磷酸三鉀(98毫克,0.464毫莫耳)。添加無水二噁烷(3毫升)。懸浮液以氮換氣,蓋上微波隔板。反應混合物於CEM Explorer®微波反應器(Matthews, NC)中在200℃加熱50分鐘。冷卻後,反應混合物分溶於乙酸乙酯與鹽水之間。有機相以水洗滌並濃縮。殘留物藉快速層析分離(20至70%於己烷中之乙酸乙酯的梯度)以提供標題化合物。MS (DCI/NH3
)m/z 434 (M+H)+
。
實施例461B(140毫克,0.323毫莫耳)於甲醇(10毫升)中之溶液於氮下添加20%碳上氫氧化鈀(80毫克)。此懸浮液以氫換氣,於氫(氣球)下在50℃攪拌4小時。過濾混合物並將濾液濃縮。殘留物自甲醇(4毫升)再結晶,以提供標題化合物。母液係藉HPLC分離(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],250x2.54管柱,移動相A:0.1% TFA in H2
O;B:0.1% TFA in CH3
CN;0至100%梯度)以提供額外之標題化合物。MS (DCI/NH3
)m/z 314 (M+H)+
;1
H NMR (400 MHz, DMSO-d6
), δ 1.57-1.63 (m, 2 H), 1.67-1.74 (m, 2 H), 2.33 (t,J
=5.83 Hz, 2 H), 2.45 (t,J
=6.14 Hz, 2 H), 3.14-3.18 (m, 2 H), 3.86-3.90 (m, 2 H), 7.16-7.21 (m, 1 H), 7.34 (dd,J
=11.66, 8.59 Hz, 1 H),
7.93 (dd,J
=7.52, 2.30 Hz, 1 H), 12.89 (s, 1 H)。
標題化合物係依實施例66C之方法製備,以實施例415取代實施例66B。MS (DCI/NH3
)m/z 314 (M+H)+
。
實施例462A(1克,3.2毫莫耳)於7N於甲醇中之氨(5毫升)中之溶液在70℃加熱隔夜,且冷卻至室溫。過濾收集固體,以甲醇洗滌並乾燥,以提供標題化合物。MS (DCI/NH3
)m/z 299 (M+H)+
。
1.5 N KOH水溶液(2毫升)及3克冰之混合物於-10℃以溴(80毫克,0.5毫莫耳)處理10分鐘。添加實施例462(100毫克,0.3毫莫耳)。反應混合物於-10℃攪拌另外10分鐘,隨後使之溫熱至65℃歷經1小時。冷卻後,混合物分溶於乙酸乙酯與鹽水之間。有機相以鹽水洗滌並濃縮至約10毫升。過濾收集固體,以甲醇洗滌並乾燥,以提供標題化合
物。MS (DCI/NH3
)m/z 271 (M+H)+
。
實施例415(1克,3毫莫耳)於無水二甲基甲醯胺(100毫升)中之溶液於室溫以第三丁醇鉀(於四氫呋喃中之1N溶液,3毫升,3毫莫耳)處理30分鐘。隨後添加苄基氧基氯甲烷(0.6克,3.6毫莫耳),混合物於室溫攪拌隔夜。以水中止反應後,反應混合物分溶於乙酸乙酯與鹽水之間。有機層以鹽水洗滌並濃縮。殘留物藉快速層析純化(85%於己烷中之乙酸乙酯)以提供標題化合物。MS (DCI/NH3
)m/z 454 (M+H)+
。
標題化合物係依實施例101之方法製備,以實施例464A取代實施例103。MS (ESI)m/z 459 (M+H)+
。
實施例464B(130毫克,0.28毫莫耳)、5%碳上鉑(25毫
克)、5%碳上Pd(OH)2
(25毫克)、濃HCl水溶液(66毫升)及二甲基甲醯胺(10毫升)之混合物於室溫下在加壓容器中40 psi氫下攪拌48小時。移除揮發物,藉HPLC分離殘留物(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1% TFA/CH3
CN/H2
O)以提供TFA鹽形式之標題產物。MS (ESI)m/z 343 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.57-1.81 (m, 2 H), 2.01-2.18 (m, 2 H), 2.26-2.46 (m, 4 H), 3.17 (m, 2 H), 3.72 (t,J
=6.94 Hz, 2 H), 3.84 (s, 2 H), 6.39 (s, 1 H), 7.16-7.19 (m, 1 H), 7.18-7.25 (m, 1 H), 7.29 (dd,J
=7.54, 1.98 Hz, 1 H), 11.89 (s, 1 H)。
標題化合物係依實施例414之方法製備為TFA鹽形式,以實施例462A取代實施例369。MS (ESI)m/z 318 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
);δ 1.61-1.75 (m, 2 H), 2.34 (t,J
=6.15 Hz, 2 H), 3.17 (m, 2 H), 3.44 (s, 3 H), 3.84 (s, 2 H), 6.39 (s, 1 H), 7.27 (dd,J
=10.91, 8.53 Hz, 1 H), 7.46-7.56 (m, 1 H), 7.76 (dd,J
=7.14, 2.38 Hz, 1 H), 11.84 (s, 1 H)。
標題化合物係依實施例414之方法製備為TFA鹽形式,
以實施例463取代實施例369。MS (ESI)m/z 275 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.62-1.74 (m, 2 H), 2.35 (t,J
=6.27 Hz, 2 H), 3.10-3.23 (m, 2 H), 3.69 (s, 2 H), 4.91 (s, 2 H), 6.25 (s, 1 H), 6.45-6.54 (m, 1 H), 6.64 (dd, J
=8.82, 2.03 Hz, 1 H), 6.92 (dd,J
=11.53, 8.48 Hz, 1 H), 11.93 (s, 1 H)。
標題化合物係依實施例288之方法製備,以實施例465取代實施例266。MS (ESI)m/z 304 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.61-1.77 (m, 2 H), 2.34 (t,J
=6.10 Hz, 2 H), 3.06-3.25 (m, 2 H), 3.84 (s, 2 H), 6.36 (s, 1 H), 7.22 (dd,J
=10.85, 8.48 Hz, 1 H), 7.39-7.52 (m, 1 H), 7.73 (dd,J
=7.12, 2.37 Hz, 1 H), 11.82 (s, 1 H), 13.19 (s, 1 H)。
標題化合物係以實施例48之方法製備為TFA鹽形式,以實施例468取代實施例48C且以乙基胺取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 331 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.09 (t,J
=7.14 Hz, 3 H), 1.58-1.74 (m, 2 H), 2.34 (t,J
=6.15 Hz, 2 H), 3.12-3.20 (m, 2 H), 3.20-3.29 (m, 2 H), 3.82 (s, 2 H), 6.39 (s, 1 H), 7.19
(dd,J
=10.31, 8.33 Hz, 1 H), 7.30-7.38 (m, 1 H), 7.47 (dd,J
=6.74, 2.38 Hz, 1 H), 8.17-8.29 (m, 1 H), 11.88 (s, 1 H)。
標題化合物係以實施例48之方法製備為TFA鹽形式,以實施例468取代實施例48C且以環丁胺取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 357 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.56-1.77 (m, 4 H), 1.90-2.10 (m, 2 H), 2.12-2.28 (m, 2 H), 2.33 (t,J
=6.35 Hz, 2 H), 3.05-3.25 (m, 2 H), 3.81 (s, 2 H), 4.27-4.45 (m, 1 H), 6.35 (s, 1 H), 7.18 (dd,J
=10.31, 8.33 Hz, 1 H), 7.26-7.37 (m, 1 H), 7.42 (dd,J
=6.74, 2.38 Hz, 1 H), 8.49 (d,J
=7.54 Hz, 1 H), 11.84 (s, 1 H)。
標題化合物係以實施例48之方法製備為TFA鹽形式,以實施例468取代實施例48C且以2-(吡咯啶-1-基)乙胺取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 400 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.63-1.76 (m, 2 H), 1.76-1.93 (m, 2 H), 1.93-2.10 (m, 2 H), 2.34 (t,J
=6.10 Hz, 2 H), 2.61-2.76 (m, 2 H), 2.96-3.12 (m, 2 H), 3.12-3.22 (m, 2 H), 3.25-3.40 (m, 2 H), 3.52-3.68 (m, 2 H),
3.84 (s, 2 H), 6.35 (s, 1 H), 7.25 (dd,J
=10.85, 8.48 Hz, 1 H), 7.33-7.49 (m, 1 H), 7.57 (dd,J
=7.12, 2.37 Hz, 1 H), 8.31-8.50 (m, 1 H), 11.84 (s, 1 H)。
標題化合物係以實施例48之方法製備為TFA鹽形式,以實施例468取代實施例48C且以嗎啉(哌嗪-1-基)甲酮取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 485 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.60-1.78 (m, 2 H), 2.35 (t,J
=6.15 Hz, 2 H), 3.05-3.28 (m, 12 H), 3.51-3.58 (m, 4 H), 3.60-3.70 (m, 2 H), 3.82 (s, 2 H), 6.41 (s, 1 H), 7.16-7.29 (m, 2 H), 7.29-7.37 (m, 1 H), 11.92 (s, 1 H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例467取代實施例89且以5-側氧基-5-(苯基胺基)戊酸取代1-甲基環丙烷甲酸。MS (ESI)m/z 464 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.62-1.75 (m, 2 H), 1.81-1.96 (m, 2 H), 2.34 (t,J
=7.12 Hz, 4 H), 2.42 (t,J
=8.14 Hz, 2 H), 3.09-3.22 (m, 2 H), 3.77 (s, 2 H), 6.30 (s, 1 H), 6.93-7.07 (m, 1 H), 7.14 (dd,J
=10.85, 8.48 Hz, 1 H), 7.22-7.34
(m, 3 H), 7.59 (d,J
=7.80 Hz, 2 H), 7.68-7.77 (m, 1 H), 9.62 (s, 1 H), 9.87 (s, 1 H), 11.82 (s, 1 H)。
標題化合物係依實施例3之方法製備,以實施例463取代實施例2。MS (ESI)m/z 371 (M+H)+
。
標題化合物係依實施例4之方法製備,以實施例475A取代實施例3。MS (ESI)m/z 353 (M+H)+
。
標題化合物係依實施例414之方法製備,以實施例475B取代實施例369。MS (ESI)m/z 357 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.58-1.78 (m, 2 H), 2.33 (t,J
=6.27 Hz, 2 H), 2.72-2.90 (m, 4 H), 3.07-3.23 (m, 2 H), 3.84 (s, 2 H), 6.34 (s, 1 H), 7.13 (dd,J
=6.95, 2.20 Hz, 1 H), 7.27-7.37 (m, 1 H), 7.37-7.43 (m, 1 H), 11.83 (s, 1 H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例467取代實施例89且以3-甲氧丙酸取代1-甲基環丙烷甲酸。MS (ESI)m/z 361 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.63-1.74 (m, 2 H), 2.33 (t,J
=6.15 Hz, 2 H), 2.60 (t,J
=6.15 Hz, 2 H), 3.09-3.21 (m, 2 H), 3.24 (s, 3 H), 3.59 (t,J
=6.15 Hz, 2 H), 3.77 (s, 2 H), 6.33 (s, 1 H), 6.93-7.05 (m, 1 H), 7.14 (dd,J
=10.91, 8.53 Hz, 1 H), 7.69-7.80 (m, 1 H), 9.63 (s, 1 H), 11.85 (s, 1 H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例467取代實施例89且以5-側氧基己酸取代1-甲基環丙烷甲酸。MS (ESI)m/z 387 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.64-1.80 (m, 4 H), 2.08 (s, 3 H), 2.27-2.39 (m, 4 H), 2.42-2.50 (m, 2 H), 3.10-3.23 (m, 2 H), 3.74 (s, 2 H), 6.34 (s, 1 H), 6.94-7.04 (m, 1 H), 7.13 (dd,J
=10.85, 8.48 Hz, 1 H), 7.66-7.71 (m, 1 H), 9.58 (s, 1 H), 11.86 (s, 1 H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例467取代實施例89且以3-苯氧基丙酸取代1-甲基環丙烷甲酸。MS (ESI)m/z 423 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.55-1.74 (m, 2 H), 2.33 (t,J
=6.15 Hz, 2 H), 2.84 (t,J
=6.15 Hz, 2 H), 3.08-3.21 (m, 2 H), 3.78 (s, 2 H), 4.24 (t,J
=6.15 Hz, 2 H), 6.36 (s, 1 H), 6.88-6.96 (m, 3 H), 6.97-7.05 (m, 1 H), 7.16 (dd,J
=10.91, 8.53 Hz, 1 H), 7.25-7.31 (m, 2 H), 7.77 (dd,J
=7.54, 1.98 Hz, 1 H), 9.79 (s, 1 H), 11.89 (s, 1 H)。
標題化合物係依實施例136之方法製備,以實施例467取代實施例89且以4-側氧基-4-苯基丁酸取代1-甲基環丙烷甲酸。MS (ESI)m/z 435 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.63-1.73 (m, 2 H), 2.32 (t,J
=5.95 Hz, 2 H), 2.75-2.79 (m, 2 H), 3.08-3.19 (m, 2 H), 3.27-3.36 (m, 2 H), 3.75 (s, 2 H), 6.27 (s, 1 H), 6.91-7.04 (m, 1 H), 7.14 (dd,J
=10.91, 8.53 Hz, 1 H), 7.54 (t,J
=7.54 Hz, 2 H), 7.59-7.69 (m, 1 H), 7.70-7.77 (m, 1 H), 7.94-8.03 (m, 2 H), 9.74 (s, 1 H), 11.78 (s, 1 H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例467取代實施例89且以2-(4-(苄基氧基)苯氧基)乙酸取代1-甲基環丙烷甲酸。MS (ESI)m/z 515 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.53-1.81 (m, 2 H), 2.22-2.39 (m, 2 H), 3.07-3.21 (m, 2 H), 3.78 (s, 2 H), 4.66 (s, 2 H), 5.04 (s, 2 H), 6.34 (s, 1 H), 6.83-6.99 (m, 4 H), 7.02-7.10 (m, 1 H), 7.14-7.23 (m, 1 H), 7.30-7.37 (m, 2 H), 7.37-7.46 (m, 3 H), 7.65 (dd,J
=7.54, 1.98 Hz, 1 H), 9.77 (s, 1 H), 11.84 (s, 1 H)。
標題化合物係依實施例136之方法製備為TFA鹽形式,以實施例467取代實施例89且以2-(4-甲氧苯氧基)乙酸取代1-甲基環丙烷甲酸。MS (ESI)m/z 438 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.63-1.75 (m, 2 H), 2.33 (t,J
=6.27 Hz, 2 H), 3.08-3.24 (m, 2 H), 3.70 (s, 3 H), 3.79 (s, 2 H), 4.66 (s, 2 H), 6.35 (s, 1 H), 6.84-6.96 (m, 4 H), 7.01-7.11 (m, 1 H), 7.18 (dd,J
=10.85, 8.48 Hz, 1 H), 7.66 (dd,J
=7.63, 2.20 Hz, 1 H), 9.73 (s, 1 H), 11.85 (s, 1 H)。
標題化合物係以實施例48之方法製備為TFA鹽形式,以實施例468取代實施例48C且以環丙胺取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 343 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):0.44-0.59 (m, 2 H), 0.63-0.76 (m, 2 H), 1.60-1.78 (m, 2 H), 2.34 (t,J
=6.35 Hz, 2 H), 2.74-2.90 (m, 1 H), 3.09-3.22 (m, 2 H), 3.81 (s, 2 H), 6.39 (s, 1 H), 7.03-7.25 (m, 1 H), 7.25-7.37 (m, 1 H), 7.42 (dd,J
=6.74, 2.38 Hz, 1 H), 8.33 (d,J
=3.97 Hz, 1 H), 11.89 (s, 1 H)。
標題化合物係以實施例48之方法製備為TFA鹽形式,以實施例468取代實施例48C且以1-(2-乙氧乙基)哌嗪取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 444 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.09 (t,J
=9.0 Hz, 3 H), 1.61-1.76 (m, 2 H), 2.56-2.69 (m, 2 H), 3.01-3.11 (m, 2 H), 3.11-3.24 (m, 4 H), 3.35-3.43 (m, 4 H), 3.43-3.61 (m, 4 H), 3.82 (s, 2 H), 6.35 (s, 1 H), 7.18-7.26 (m, 1 H), 7.28-7.34 (m, 1 H), 7.34-7.41 (m, 1 H), 11.84 (s, 1 H)。
標題化合物係依實施例48之方法製備,以實施例468取代實施例48C且以2-(哌啶-1-基)乙胺取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 414 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.33-1.49 (m, 2 H), 1.50-1.64 (m, 4 H), 1.62-1.75 (m, 2 H), 2.33 (t,J
=6.35 Hz, 2 H), 2.54-2.82 (m, 4 H), 3.10-3.20 (m, 2 H), 3.20-3.35 (m, 2 H), 3.37-3.55 (m, 2 H), 3.82 (s, 2 H), 6.35 (s, 1 H), 7.20 (dd,J
=10.51, 8.53 Hz, 1 H), 7.33-7.44 (m, 1 H), 7.53 (dd,J
=7.14, 2.38 Hz, 1 H), 8.51 (dd,J
=4.36, 1.59 Hz, 1 H,)11.83 (s, 1 H)。
標題化合物係依實施例48之方法製備,以實施例468取代實施例48C且以2-胺基-1-(哌啶-1-基)乙酮取代1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺。MS (ESI)m/z 428 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):1.44 (m, 2 H), 1.48-1.65 (m, 4 H), 1.65-1.79 (m, 2 H), 2.33 (t,J
=6.27 Hz, 2 H), 3.10-3.24 (m, 2 H), 3.34-3.42 (m, 2 H), 3.41-3.50 (m, 2 H), 3.84 (s, 2 H), 4.13 (d,J
=5.09 Hz, 2 H), 6.00-6.50 (m, 1 H), 7.05-7.28 (m, 1 H), 7.32-7.53 (m, 1 H), 7.63 (dd,J
=7.12, 2.37 Hz, 1 H), 8.17 (q,J
=5.09 Hz, 1 H), 11.82 (s, 1 H)。
實施例1(100毫克,0.33毫莫耳)於二甲基乙醯胺(5毫升)中之溶液中添加六氟磷酸2-(1H-7-氮雜苯并三唑-1-基)-1,1,3,3-四甲基脲鎓三甲銨乙內酯(HATU)(126毫克,0.33毫莫耳)及三乙基胺(92微升,0.66毫莫耳)並於室溫攪拌20分鐘。隨後添加(哌嗪-1-基)嘧啶二鹽酸鹽(78毫克,0.33毫莫耳),反應混合物於室溫攪拌16小時。濃縮後,殘留油藉HPLC純化(Zorbax® C-18 ODS充填材料[Agilent Technologies, Santa Clara, CA],0.1% TFA/CH3
CN/H2
O)以提供標題產物。MS (DCI/NH3
)m/z 449 (M+H)+
;1
H NMR (300 MHz, DMSO-d 6
):δ 1.53-1.71 (m, 4H), 2.32-2.44 (m, 4H), 3.24-3.39 (m, 2H), 3.67-3.78 (m, 4H), 3.79-3.88 (m, 2H), 3.93 (s, 2H), 6.67 (t,J
=4.75 Hz, 1H), 7.21-7.23 (m, 1H), 7.24-7.28 (m, 1H), 7.30-7.35 (m, 1H), 8.39 (d,J
=4.75 Hz, 2H), 12.62 (br s, 1H)。
標題化合物係依實施例461之方法製備,以2-吡咯啶酮取代實施例461B中之2-吖丁啶酮。MS (DCI/NH3
)m/z 328 (M+H)+
;1
H NMR (400 MHz, CD3
OD):δ 1.73-1.79 (m, 2 H), 1.83-1.90 (m, 2 H), 2.22-2.29 (m, 2 H), 2.55-2.60 (m, 4 H), 2.69 (t,J
=5.83 Hz, 2 H), 3.91 (t,J
=7.06 Hz, 2 H), 7.35-
7.41 (m, 1 H), 7.48-7.52 (m, 1 H), 7.60-7.64 (m, 1 H)。
以上係用以說明本發明,而非表示將其限制於所揭示之具體實施態樣。熟習此技術者顯而易見之變化及改變係涵蓋於所附申請專利範圍所定義之發明範圍及性質內。
Claims (9)
- 一種具有式(Ik)之化合物,
- 如請求項1之化合物,其中R11 係為吡咯啶基,或其醫藥上可接受之鹽。
- 如請求項1之化合物,其係選自:1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡咯啶-2,5-二酮;4-(4-氟-3-(2-側氧基吡咯啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基-1,3-噁唑啶-3-基)苄基)-5,6,7,8-四氫 二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基氮-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)哌啶-2,6-二酮;4-(4-氟-3-(2-側氧基咪唑啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;4-(4-氟-3-(2-側氧基哌啶-1-基)苄基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;及4-(4-氟-3-(2-側氧基吡咯啶-1-基)苯基)-5,6,7,8-四氫二氮雜萘-1(2H)-酮;或其醫藥上可接受之鹽。
- 一種化合物,其係為1-(2-氟-5-((4-側氧基-3,4,5,6,7,8-六氫二氮雜萘-1-基)甲基)苯基)吡咯啶-2,5-二酮,或其醫藥上可接受之鹽。
- 一種具有聚(ADP-核糖)聚合酶(PARP)抑制活性之醫藥組合物,其包含如請求項1之化合物及醫藥上可接受之賦形劑。
- 一種如請求項1之化合物之用途,其係用以製造治療哺乳類癌症之藥劑。
- 一種如請求項1之化合物之用途,其係用以製造縮減哺乳類腫瘤體積之藥劑。
- 如請求項6之用途,其中該藥劑係連同放射線療法一起使用。
- 如請求項6之用途,其中該藥劑係連同選自替莫唑胺(temozolomide)、達卡巴嗪(dacarbazine)、環磷醯胺(cyclophosphamide)、卡氮芥(carmustine)、美法侖(melphalan)、洛莫司汀(lomustine)、卡鉑(carboplatin)、順鉑、5-FU+/-白葉素(leucovorin)、吉西他賓(gemcitabine)、甲胺喋呤(methotrexate)、平陽黴素(bleomycin)、依利替康(irinotecan)、喜樹鹼及托泊替康(topotecan)之化學療劑一起使用。
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