KR20100137522A - Ｈｉｖ 인테그라제 억제제로서의 가교 헤테로사이클 - Google Patents
Ｈｉｖ 인테그라제 억제제로서의 가교 헤테로사이클 Download PDFInfo
- Publication number
- KR20100137522A KR20100137522A KR1020107023261A KR20107023261A KR20100137522A KR 20100137522 A KR20100137522 A KR 20100137522A KR 1020107023261 A KR1020107023261 A KR 1020107023261A KR 20107023261 A KR20107023261 A KR 20107023261A KR 20100137522 A KR20100137522 A KR 20100137522A
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- mmol
- hydroxy
- methyl
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 229940099797 HIV integrase inhibitor Drugs 0.000 title description 11
- 239000003084 hiv integrase inhibitor Substances 0.000 title description 11
- 125000000623 heterocyclic group Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 257
- 238000000034 method Methods 0.000 claims abstract description 79
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 208000031886 HIV Infections Diseases 0.000 claims abstract description 22
- 208000030507 AIDS Diseases 0.000 claims abstract description 21
- 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 19
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 19
- -1 diphenylalkyl Chemical group 0.000 claims description 360
- 239000000203 mixture Substances 0.000 claims description 242
- 125000000217 alkyl group Chemical group 0.000 claims description 200
- 229910052739 hydrogen Inorganic materials 0.000 claims description 96
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 90
- 125000003545 alkoxy group Chemical group 0.000 claims description 88
- 239000001257 hydrogen Substances 0.000 claims description 84
- 229910052757 nitrogen Inorganic materials 0.000 claims description 84
- 150000002431 hydrogen Chemical class 0.000 claims description 66
- 125000001188 haloalkyl group Chemical group 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 56
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 239000003112 inhibitor Substances 0.000 claims description 39
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 36
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 34
- 239000003795 chemical substances by application Substances 0.000 claims description 32
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 125000001425 triazolyl group Chemical group 0.000 claims description 25
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
- 125000001544 thienyl group Chemical group 0.000 claims description 21
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 19
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000002541 furyl group Chemical group 0.000 claims description 17
- 125000002883 imidazolyl group Chemical group 0.000 claims description 17
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 17
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 17
- 239000002777 nucleoside Substances 0.000 claims description 16
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 15
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 14
- 125000000335 thiazolyl group Chemical group 0.000 claims description 14
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 13
- 125000002971 oxazolyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 13
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 13
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 13
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 12
- 125000002393 azetidinyl group Chemical group 0.000 claims description 12
- 125000002757 morpholinyl group Chemical group 0.000 claims description 12
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 12
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 9
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 9
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 9
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 9
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 9
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 9
- 230000035800 maturation Effects 0.000 claims description 9
- 229940122440 HIV protease inhibitor Drugs 0.000 claims description 8
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 8
- 230000035784 germination Effects 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000005359 phenoxyalkyl group Chemical group 0.000 claims description 4
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 239000002850 integrase inhibitor Substances 0.000 claims description 3
- 229940124524 integrase inhibitor Drugs 0.000 claims description 3
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 3
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 22
- 125000001475 halogen functional group Chemical group 0.000 claims 19
- 150000003018 phosphorus compounds Chemical class 0.000 claims 1
- 230000003612 virological effect Effects 0.000 abstract description 10
- 108010002459 HIV Integrase Proteins 0.000 abstract description 8
- 230000010354 integration Effects 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 230000009471 action Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 444
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 286
- 239000000543 intermediate Substances 0.000 description 232
- 239000007787 solid Substances 0.000 description 221
- 239000000243 solution Substances 0.000 description 180
- 235000019439 ethyl acetate Nutrition 0.000 description 148
- 229940093499 ethyl acetate Drugs 0.000 description 147
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 140
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
- 239000011541 reaction mixture Substances 0.000 description 113
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 112
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 107
- 239000011734 sodium Substances 0.000 description 100
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
- 239000003921 oil Substances 0.000 description 82
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 74
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 73
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 70
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 68
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 66
- 239000012267 brine Substances 0.000 description 59
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 53
- 238000006243 chemical reaction Methods 0.000 description 50
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 238000003818 flash chromatography Methods 0.000 description 48
- 239000002904 solvent Substances 0.000 description 46
- 238000002953 preparative HPLC Methods 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 38
- JVANDLOBMHTTNX-UHFFFAOYSA-N 1h-azepine-2-carboxamide Chemical compound NC(=O)C1=CC=CC=CN1 JVANDLOBMHTTNX-UHFFFAOYSA-N 0.000 description 36
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 239000010410 layer Substances 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 26
- 241000725303 Human immunodeficiency virus Species 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 239000013058 crude material Substances 0.000 description 20
- 125000005843 halogen group Chemical group 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 17
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 16
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 15
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- 239000006260 foam Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 14
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 13
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 239000008096 xylene Substances 0.000 description 13
- DTRBIIDYMYVRNE-UHFFFAOYSA-N 1h-azepine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC=CN1 DTRBIIDYMYVRNE-UHFFFAOYSA-N 0.000 description 12
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 11
- 125000004494 ethyl ester group Chemical group 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 241000700605 Viruses Species 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical class NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 9
- SOSFYCQTXQIGFF-UHFFFAOYSA-N 2,6-diazatricyclo[6.2.2.02,7]dodeca-1(10),4,6,8-tetraene-5-carboxamide Chemical compound C1=C(CC2)C3=NC(C(=O)N)=CCN3C2=C1 SOSFYCQTXQIGFF-UHFFFAOYSA-N 0.000 description 9
- 229910004298 SiO 2 Inorganic materials 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 239000010779 crude oil Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- 125000003368 amide group Chemical group 0.000 description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 8
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- IFYDWYVPVAMGRO-UHFFFAOYSA-N n-[3-(dimethylamino)propyl]tetradecanamide Chemical compound CCCCCCCCCCCCCC(=O)NCCCN(C)C IFYDWYVPVAMGRO-UHFFFAOYSA-N 0.000 description 8
- YKFGLGXRUVEMNF-UHFFFAOYSA-N 2-(dimethylamino)-2-oxoacetic acid Chemical compound CN(C)C(=O)C(O)=O YKFGLGXRUVEMNF-UHFFFAOYSA-N 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- STRNXFOUBFLVIN-UHFFFAOYSA-N diethyl but-2-ynedioate Chemical compound CCOC(=O)C#CC(=O)OCC STRNXFOUBFLVIN-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 7
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 6
- 239000012346 acetyl chloride Substances 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 description 6
- 150000007942 carboxylates Chemical class 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 6
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 6
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 6
- 229960001693 terazosin Drugs 0.000 description 6
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- PSADNECHGXKQOE-UHFFFAOYSA-N ethyl 11-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-7,8,10,11-tetrahydro-4 h,6h-8,11-methanopyrimido[2,1-d][1,5]oxazocine-2-carboxylate Chemical compound O=C1C(O)=C(C(=O)OCC)N=C2N1CCC(OC1)CC21NC(=O)OCC1=CC=CC=C1 PSADNECHGXKQOE-UHFFFAOYSA-N 0.000 description 1
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- JYWNRMLNNCPYNG-UHFFFAOYSA-N ethyl 2-[3-(chloromethyl)-1-(phenylmethoxycarbonylamino)cyclohexyl]-5-hydroxy-4-oxo-1h-pyrimidine-6-carboxylate Chemical compound N1C(=O)C(O)=C(C(=O)OCC)N=C1C1(NC(=O)OCC=2C=CC=CC=2)CC(CCl)CCC1 JYWNRMLNNCPYNG-UHFFFAOYSA-N 0.000 description 1
- ODMUVMKOFCNYPA-UHFFFAOYSA-N ethyl 2-[4-(hydroxymethyl)piperidin-1-yl]-4-oxo-5-phenylmethoxy-1h-pyrimidine-6-carboxylate Chemical compound CCOC(=O)C=1N=C(N2CCC(CO)CC2)NC(=O)C=1OCC1=CC=CC=C1 ODMUVMKOFCNYPA-UHFFFAOYSA-N 0.000 description 1
- TZKNKEVYMAACRD-UHFFFAOYSA-N ethyl 2-methylsulfonyl-5-phenylmethoxy-6-prop-2-enoxypyrimidine-4-carboxylate Chemical compound CCOC(=O)C1=NC(S(C)(=O)=O)=NC(OCC=C)=C1OCC1=CC=CC=C1 TZKNKEVYMAACRD-UHFFFAOYSA-N 0.000 description 1
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- BMPSHOYVCUTFLJ-UHFFFAOYSA-N ethyl 5-benzoyloxy-2-[1-(2-benzoyloxyethoxy)-4-(methylsulfonyloxymethyl)cyclohexyl]-4-oxo-1h-pyrimidine-6-carboxylate Chemical compound CCOC(=O)C=1N=C(C2(CCC(COS(C)(=O)=O)CC2)OCCOC(=O)C=2C=CC=CC=2)NC(=O)C=1OC(=O)C1=CC=CC=C1 BMPSHOYVCUTFLJ-UHFFFAOYSA-N 0.000 description 1
- LXPMAERUBIBWAZ-UHFFFAOYSA-N ethyl 5-hydroxy-2-[4-hydroxy-1-(phenylmethoxycarbonylamino)cyclohexyl]-1,4-dihydropyrimidine-6-carboxylate Chemical compound CCOC(=O)C1=C(O)CNC(C2(CCC(O)CC2)NC(=O)OCC=2C=CC=CC=2)=N1 LXPMAERUBIBWAZ-UHFFFAOYSA-N 0.000 description 1
- SKOUKFXHFXAAAT-UHFFFAOYSA-N ethyl 5-hydroxy-2-[[3-(hydroxymethyl)cyclopentyl]-[methyl(phenylmethoxycarbonyl)amino]methyl]-4-oxo-1h-pyrimidine-6-carboxylate Chemical compound N1C(=O)C(O)=C(C(=O)OCC)N=C1C(N(C)C(=O)OCC=1C=CC=CC=1)C1CC(CO)CC1 SKOUKFXHFXAAAT-UHFFFAOYSA-N 0.000 description 1
- ISLNJBVOESYBTI-UHFFFAOYSA-N ethyl 5-hydroxy-4-oxo-2-[4-oxo-1-(phenylmethoxycarbonylamino)cyclohexyl]-1h-pyrimidine-6-carboxylate Chemical compound N1C(=O)C(O)=C(C(=O)OCC)N=C1C1(NC(=O)OCC=2C=CC=CC=2)CCC(=O)CC1 ISLNJBVOESYBTI-UHFFFAOYSA-N 0.000 description 1
- PRSPNDJYSZQEFV-UHFFFAOYSA-N ethyl 5-hydroxy-4-oxo-2-[8-(phenylmethoxycarbonylamino)-1,4-dioxaspiro[4.5]decan-8-yl]-1h-pyrimidine-6-carboxylate Chemical compound N1C(=O)C(O)=C(C(=O)OCC)N=C1C1(NC(=O)OCC=2C=CC=CC=2)CCC2(OCCO2)CC1 PRSPNDJYSZQEFV-UHFFFAOYSA-N 0.000 description 1
- CURFWWLOAFODIF-UHFFFAOYSA-N ethyl 5-methylsulfonyloxy-2-[4-methylsulfonyloxy-1-(phenylmethoxycarbonylamino)cyclohexyl]-1,4-dihydropyrimidine-6-carboxylate Chemical compound CCOC(=O)C1=C(OS(C)(=O)=O)CNC(C2(CCC(CC2)OS(C)(=O)=O)NC(=O)OCC=2C=CC=CC=2)=N1 CURFWWLOAFODIF-UHFFFAOYSA-N 0.000 description 1
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- 230000001629 suppression Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 1
- VHKIEYIESYMHPT-UHFFFAOYSA-N triethyl(methoxycarbonylsulfamoyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC VHKIEYIESYMHPT-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- UOCLRXFKRLRMKV-UHFFFAOYSA-N trolnitrate phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.[O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O UOCLRXFKRLRMKV-UHFFFAOYSA-N 0.000 description 1
- 230000036967 uncompetitive effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3772908P | 2008-03-19 | 2008-03-19 | |
| US61/037,729 | 2008-03-19 | ||
| US12/406,268 US8129398B2 (en) | 2008-03-19 | 2009-03-18 | HIV integrase inhibitors |
| US12/406,268 | 2009-03-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20100137522A true KR20100137522A (ko) | 2010-12-30 |
Family
ID=40863725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020107023261A Withdrawn KR20100137522A (ko) | 2008-03-19 | 2009-03-19 | Ｈｉｖ 인테그라제 억제제로서의 가교 헤테로사이클 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US8129398B2 (https=) |
| EP (1) | EP2280981B8 (https=) |
| JP (1) | JP2011515412A (https=) |
| KR (1) | KR20100137522A (https=) |
| CN (1) | CN102036996A (https=) |
| AU (1) | AU2009225577A1 (https=) |
| BR (1) | BRPI0910307A2 (https=) |
| CA (1) | CA2718950A1 (https=) |
| CO (1) | CO6331439A2 (https=) |
| EA (1) | EA201001508A1 (https=) |
| IL (1) | IL208068A0 (https=) |
| MX (1) | MX2010009995A (https=) |
| NZ (1) | NZ588031A (https=) |
| WO (1) | WO2009117540A1 (https=) |
| ZA (1) | ZA201006589B (https=) |
Families Citing this family (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012516333A (ja) * | 2009-01-28 | 2012-07-19 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｈｉｖインテグラーゼ阻害剤としての架橋化合物 |
| US8143244B2 (en) * | 2009-02-26 | 2012-03-27 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
| US8383639B2 (en) | 2009-10-15 | 2013-02-26 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US8283366B2 (en) | 2010-01-22 | 2012-10-09 | Ambrilia Biopharma, Inc. | Derivatives of pyridoxine for inhibiting HIV integrase |
| RS60310B1 (sr) | 2010-08-10 | 2020-07-31 | Rempex Pharmaceuticals Inc | Ciklični derivati estra boronske kiseline, postupak za pripremu injihove terapeutske upotrebe |
| WO2012077221A1 (ja) * | 2010-12-10 | 2012-06-14 | アグロカネショウ株式会社 | ３-アミノオキサリルアミノベンズアミド誘導体及びこれを有効成分とする殺虫、殺ダニ剤 |
| US8846659B2 (en) | 2010-12-10 | 2014-09-30 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US8835411B2 (en) * | 2010-12-10 | 2014-09-16 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| CN102675305B (zh) * | 2011-03-08 | 2014-11-12 | 中国科学院上海药物研究所 | 一类咪唑并吡啶类化合物及其制备方法和用途 |
| US9012491B2 (en) | 2011-08-31 | 2015-04-21 | Rempex Pharmaceuticals, Inc. | Heterocyclic boronic acid ester derivatives and therapeutic uses thereof |
| US9156858B2 (en) | 2012-05-23 | 2015-10-13 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US10561675B2 (en) | 2012-06-06 | 2020-02-18 | Rempex Pharmaceuticals, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| WO2014008636A1 (en) * | 2012-07-11 | 2014-01-16 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as hiv integrase inhibitors |
| US8906929B2 (en) * | 2012-08-16 | 2014-12-09 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
| EA030003B1 (ru) | 2012-12-21 | 2018-06-29 | Джилид Сайэнс, Инк. | Полициклическое карбамоилпиридоновое соединение и его фармацевтическое применение для лечения вич-инфекции |
| KR20150103270A (ko) | 2013-01-04 | 2015-09-09 | 렘펙스 파머수티클스 인코퍼레이티드 | 보론산 유도체 및 그의 치료적 용도 |
| US9101638B2 (en) | 2013-01-04 | 2015-08-11 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US9241947B2 (en) | 2013-01-04 | 2016-01-26 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| KR20150103269A (ko) | 2013-01-04 | 2015-09-09 | 렘펙스 파머수티클스 인코퍼레이티드 | 보론산 유도체 및 그의 치료적 용도 |
| ES2753386T3 (es) | 2013-03-13 | 2020-04-08 | Forma Therapeutics Inc | Derivados de 2-hidroxi-1-{4-[(4-fenil)fenil]carbonil}piperazin-1-il}etano-1-ona y compuestos relacionados como inhibidores de sintasa de ácido graso (FASN) para el tratamiento del cáncer |
| CN105008369B (zh) * | 2013-03-14 | 2017-07-11 | 百时美施贵宝公司 | 人类免疫缺陷病毒复制抑制剂 |
| NO2865735T3 (https=) | 2013-07-12 | 2018-07-21 | ||
| ES2859102T3 (es) | 2013-07-12 | 2021-10-01 | Gilead Sciences Inc | Compuestos de carbamoilpiridona policíclica y su uso para el tratamiento de infecciones por VIH |
| CN103601613B (zh) * | 2013-11-19 | 2015-07-08 | 浙江林江化工股份有限公司 | 一种3,4,5-三氟溴苯的制备方法 |
| WO2015096651A1 (en) | 2013-12-23 | 2015-07-02 | Merck Sharp & Dohme Corp. | Pyrimidone carboxamide compounds as pde2 inhibitors |
| EP3139930B1 (en) | 2014-05-05 | 2024-08-14 | Melinta Therapeutics, Inc. | Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof |
| SI3140310T1 (sl) | 2014-05-05 | 2020-01-31 | Rempex Pharmaceuticals, Inc. | Sinteza boronatnih soli in njihova uporaba |
| WO2015179308A1 (en) | 2014-05-19 | 2015-11-26 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| TWI677489B (zh) | 2014-06-20 | 2019-11-21 | 美商基利科學股份有限公司 | 多環型胺甲醯基吡啶酮化合物之合成 |
| TW201613936A (en) | 2014-06-20 | 2016-04-16 | Gilead Sciences Inc | Crystalline forms of(2R,5S,13aR)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide |
| NO2717902T3 (https=) | 2014-06-20 | 2018-06-23 | ||
| EA201692301A1 (ru) | 2014-07-01 | 2017-06-30 | Ремпекс Фармасьютикалз, Инк. | Производные бороновой кислоты и их терапевтическое применение |
| WO2016081297A1 (en) | 2014-11-18 | 2016-05-26 | Rempex Pharmaceuticals, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
| TWI695003B (zh) | 2014-12-23 | 2020-06-01 | 美商基利科學股份有限公司 | 多環胺甲醯基吡啶酮化合物及其醫藥用途 |
| WO2016145614A1 (en) | 2015-03-17 | 2016-09-22 | Merck Sharp & Dohme Corp. | Triazolyl pyrimidinone compounds as pde2 inhibitors |
| US20180051041A1 (en) | 2015-03-17 | 2018-02-22 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| WO2016154081A1 (en) | 2015-03-26 | 2016-09-29 | Merck Sharp & Dohme Corp. | Pyrazolyl pyrimidinone compounds as pde2 inhibitors |
| KR20190057158A (ko) | 2015-04-02 | 2019-05-27 | 길리애드 사이언시즈, 인코포레이티드 | 폴리시클릭-카르바모일피리돈 화합물 및 그의 제약 용도 |
| WO2016183741A1 (en) | 2015-05-15 | 2016-11-24 | Merck Sharp & Dohme Corp. | Pyrimidinone amide compounds as pde2 inhibitors |
| US10647727B2 (en) | 2015-06-25 | 2020-05-12 | Merck Sharp & Dohme Corp. | Substituted pyrazolo/imidazolo bicyclic compounds as PDE2 inhibitors |
| WO2017000277A1 (en) | 2015-07-01 | 2017-01-05 | Merck Sharp & Dohme Corp. | Substituted triazolo bicycliccompounds as pde2 inhibitors |
| AU2016330895A1 (en) * | 2015-09-30 | 2018-05-10 | Gilead Sciences, Inc. | Compounds and combinations for the treatment of HIV |
| ES2894251T3 (es) | 2016-06-30 | 2022-02-14 | Qpex Biopharma Inc | Derivados de ácido borónico y usos terapéuticos de los mismos |
| MX2020003495A (es) | 2017-10-11 | 2020-09-18 | Qpex Biopharma Inc | Derivados de acido boronico y sintesis de los mismos. |
| US12016868B2 (en) | 2018-04-20 | 2024-06-25 | Qpex Biopharma, Inc. | Boronic acid derivatives and therapeutic uses thereof |
| US10793554B2 (en) | 2018-10-29 | 2020-10-06 | Forma Therapeutics, Inc. | Solid forms of 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone |
| MY201239A (en) | 2019-03-22 | 2024-02-13 | Gilead Sciences Inc | Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use |
| PE20221569A1 (es) | 2020-02-24 | 2022-10-06 | Gilead Sciences Inc | Compuestos tetraciclicos para el tratamiento de infecciones por vih |
| BR112022022367A2 (pt) | 2020-05-05 | 2023-01-10 | Qpex Biopharma Inc | Derivados e síntese de ácido borônico, formas polimórficas e usos terapêuticos dos mesmos |
| ES3064867T3 (en) | 2020-09-30 | 2026-04-29 | Gilead Sciences Inc | Bridged tricyclic carbamoylpyridone compounds for a use in the treatment of hiv |
| US11613546B2 (en) | 2021-01-19 | 2023-03-28 | Gilead Sciences, Inc. | Substituted pyridotriazine compounds and uses thereof |
| TW202446773A (zh) | 2022-04-06 | 2024-12-01 | 美商基利科學股份有限公司 | 橋聯三環胺甲醯基吡啶酮化合物及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ540729A (en) * | 2002-12-27 | 2008-03-28 | Angeletti P Ist Richerche Bio | Tetrahydro-4H-pyrido[1,2-a]pyrimidines and related compounds useful as HIV integrase inhibitors |
| AR046938A1 (es) | 2003-12-12 | 2006-01-04 | Merck & Co Inc | Procedimiento para preparar hexahidropirimido[1,2-a]azepin-2-carboxilatos y compuetos similares |
| TW200526635A (en) | 2003-12-22 | 2005-08-16 | Shionogi & Co | Hydroxypyrimidinone derivative having HIV integrase inhibitory activity |
| US7273859B2 (en) * | 2004-05-12 | 2007-09-25 | Bristol-Myers Squibb Company | HIV integrase inhibitors: cyclic pyrimidinone compounds |
| US7192948B2 (en) * | 2004-05-28 | 2007-03-20 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| US7157447B2 (en) * | 2004-05-28 | 2007-01-02 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| US7176196B2 (en) * | 2004-05-28 | 2007-02-13 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| US7173022B2 (en) * | 2004-05-28 | 2007-02-06 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
| CA2600832C (en) | 2005-03-31 | 2011-12-13 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Hiv integrase inhibitors |
| WO2006121831A2 (en) | 2005-05-10 | 2006-11-16 | Merck & Co., Inc. | Hiv integrase inhibitors |
| US7494984B2 (en) * | 2005-08-31 | 2009-02-24 | Bristol-Myers Squibb Company | Substituted imidazo[1,2-a]pyrimidines as HIV viral DNA integrase inhibitors |
| US7897592B2 (en) * | 2005-11-15 | 2011-03-01 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US8039458B2 (en) * | 2005-11-17 | 2011-10-18 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| WO2007143446A1 (en) * | 2006-05-30 | 2007-12-13 | Bristol-Myers Squibb Company | Spiro-condensed heterotricyclic compounds as hiv integrase inhibitors |
| US7893055B2 (en) * | 2006-06-28 | 2011-02-22 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| US7763630B2 (en) * | 2007-06-06 | 2010-07-27 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
| JP2012516333A (ja) * | 2009-01-28 | 2012-07-19 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｈｉｖインテグラーゼ阻害剤としての架橋化合物 |
-
2009
- 2009-03-18 US US12/406,268 patent/US8129398B2/en active Active
- 2009-03-19 WO PCT/US2009/037596 patent/WO2009117540A1/en not_active Ceased
- 2009-03-19 CN CN2009801183261A patent/CN102036996A/zh active Pending
- 2009-03-19 JP JP2011500942A patent/JP2011515412A/ja active Pending
- 2009-03-19 BR BRPI0910307A patent/BRPI0910307A2/pt not_active IP Right Cessation
- 2009-03-19 MX MX2010009995A patent/MX2010009995A/es not_active Application Discontinuation
- 2009-03-19 EP EP09722517.1A patent/EP2280981B8/en not_active Not-in-force
- 2009-03-19 AU AU2009225577A patent/AU2009225577A1/en not_active Abandoned
- 2009-03-19 EA EA201001508A patent/EA201001508A1/ru unknown
- 2009-03-19 NZ NZ588031A patent/NZ588031A/en not_active IP Right Cessation
- 2009-03-19 CA CA2718950A patent/CA2718950A1/en not_active Abandoned
- 2009-03-19 KR KR1020107023261A patent/KR20100137522A/ko not_active Withdrawn
-
2010
- 2010-09-07 IL IL208068A patent/IL208068A0/en unknown
- 2010-09-14 ZA ZA2010/06589A patent/ZA201006589B/en unknown
- 2010-09-16 CO CO10115016A patent/CO6331439A2/es not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| US20090253677A1 (en) | 2009-10-08 |
| CO6331439A2 (es) | 2011-10-20 |
| EP2280981A1 (en) | 2011-02-09 |
| MX2010009995A (es) | 2010-09-30 |
| WO2009117540A1 (en) | 2009-09-24 |
| CA2718950A1 (en) | 2009-09-24 |
| CN102036996A (zh) | 2011-04-27 |
| ZA201006589B (en) | 2012-02-29 |
| AU2009225577A1 (en) | 2009-09-24 |
| EA201001508A1 (ru) | 2011-04-29 |
| JP2011515412A (ja) | 2011-05-19 |
| IL208068A0 (en) | 2010-12-30 |
| NZ588031A (en) | 2011-12-22 |
| EP2280981B1 (en) | 2014-04-23 |
| US8129398B2 (en) | 2012-03-06 |
| EP2280981B8 (en) | 2014-09-17 |
| BRPI0910307A2 (pt) | 2019-09-24 |
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