WO2012145728A1 - Benzothiazole compounds and their pharmaceutical use - Google Patents
Benzothiazole compounds and their pharmaceutical use Download PDFInfo
- Publication number
- WO2012145728A1 WO2012145728A1 PCT/US2012/034593 US2012034593W WO2012145728A1 WO 2012145728 A1 WO2012145728 A1 WO 2012145728A1 US 2012034593 W US2012034593 W US 2012034593W WO 2012145728 A1 WO2012145728 A1 WO 2012145728A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- heterocycle
- carbocycle
- heteroaryl
- aryl
- Prior art date
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- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 410
- 238000000034 method Methods 0.000 claims abstract description 76
- 150000003839 salts Chemical class 0.000 claims abstract description 73
- 241000124008 Mammalia Species 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 428
- 125000003118 aryl group Chemical group 0.000 claims description 404
- 125000001072 heteroaryl group Chemical group 0.000 claims description 384
- 125000000217 alkyl group Chemical group 0.000 claims description 370
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 224
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 202
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 181
- -1 (C3-C7)carbocycle Chemical group 0.000 claims description 159
- 125000001188 haloalkyl group Chemical group 0.000 claims description 139
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 84
- 125000004429 atom Chemical group 0.000 claims description 71
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 70
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 64
- 125000005843 halogen group Chemical group 0.000 claims description 63
- 239000003112 inhibitor Substances 0.000 claims description 56
- 239000003814 drug Substances 0.000 claims description 47
- 125000004043 oxo group Chemical group O=* 0.000 claims description 45
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 229940124597 therapeutic agent Drugs 0.000 claims description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 24
- 229910003827 NRaRb Inorganic materials 0.000 claims description 19
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
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- 125000002877 alkyl aryl group Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 16
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
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- 125000005025 alkynylaryl group Chemical group 0.000 claims description 13
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- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 10
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
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- 0 *C(*)(C(O)=O)c1c(*)c(*)c2nc(*)[s]c2c1* Chemical compound *C(*)(C(O)=O)c1c(*)c(*)c2nc(*)[s]c2c1* 0.000 description 16
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 16
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
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- NZEUOQMGCPNWKI-CYBMUJFWSA-N [(2s)-2-(7-bromo-3,5-dimethyl-2-oxo-1,3-benzothiazol-6-yl)-2-[(2-methylpropan-2-yl)oxy]ethyl] 2,2-dimethylpropanoate Chemical compound BrC1=C([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)C(C)=CC2=C1SC(=O)N2C NZEUOQMGCPNWKI-CYBMUJFWSA-N 0.000 description 10
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- OGZMTYGAYGHOEL-UHFFFAOYSA-N 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methyl-1,3-benzothiazole Chemical compound COC1=C(C)C=C2N=C(Br)SC2=C1C1=CC=C(Cl)C=C1 OGZMTYGAYGHOEL-UHFFFAOYSA-N 0.000 description 9
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- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 8
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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- ZMEMBOIUHLWVRX-UHFFFAOYSA-N quinolin-7-ylboronic acid Chemical compound C1=CC=NC2=CC(B(O)O)=CC=C21 ZMEMBOIUHLWVRX-UHFFFAOYSA-N 0.000 description 1
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- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000011452 sequencing regimen Methods 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229960003339 sodium phosphate Drugs 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- LFQULJPVXNYWAG-UHFFFAOYSA-N sodium;phenylmethanolate Chemical compound [Na]OCC1=CC=CC=C1 LFQULJPVXNYWAG-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000006223 tetrahydrofuranylmethyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005306 thianaphthenyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003553 thiiranes Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- LWNCDBSQZPDFOG-UHFFFAOYSA-N tributyl(2-methylprop-1-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C(C)C LWNCDBSQZPDFOG-UHFFFAOYSA-N 0.000 description 1
- PUMSLVXNEXVCIC-UHFFFAOYSA-N tributyl(prop-1-en-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C(C)=C PUMSLVXNEXVCIC-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Definitions
- HIV-1 Human immunodeficiency virus
- HIV-1 Human immunodeficiency virus type 1
- reverse transcriptase enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
- drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J Med (1998) 338:853-860;
- the present invention provides compounds and methods for the treatment of an HIV infection. Accordingly, in one embodiment, the invention provides a compound of the invention which is a compound of formula I:
- G 1 is S
- G 2 is N
- the dashed bond connected to G 1 is a single bond
- G 1 is N
- G 2 is S
- the dashed bond connected to G 1 is a double bond
- the dashed bond connected to G is a single bond
- the wavy bond connected to R is a single bond
- G is S
- G is NR
- the dashed bond connected to G is a single bond
- the dashed bond connected to G 2 is a single bond
- R 1 is R la or R lb.
- R 2 is R 2a or R
- R 3 is R 3a or R 3b.
- R 3' is R 3a' or R
- R 4 is R 4a or R 4b.
- R 5 is R 5a or R :
- R 6 is R 6a or R ( 6b.
- R la is selected from:
- each R 11 is independently selected from H, (d-C 6 )alkyl, (C 2 -C )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are
- each R 9 is independently selected from H, (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl
- R is selected from:
- spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups, or wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups;
- Z 4 groups independently substituted with one or more (e.g. 1 , 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more Z'groups;
- aryl heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more Z 1 groups;
- each (C 1 -C 6 )alkyl, as part of a group, is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more Z'groups; and
- R 2a is selected from:
- R 2b is selected from:
- spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups, wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the (C 3 -C 6 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; c) wherein (C 1 -C 6 )alkyl is substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R and R together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are optionally substituted with one or more Z 1 groups;
- R and R together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1, 2
- R 3a is (C r C 6 )alkyl, (C C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
- -0(C I -C 6 )alkyl -heteroaryl of R 3a is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (CrC 6 )alkyl, -0(C ! -C 6 )alkyl, halo, oxo and -CN; and
- R 3a' is H
- R is -(C 3 -C )carbocycle, aryl, heteroaryl, heterocycle, -(C 1 -C 6 )alkylOH, -(d-C 6 )alkyl- 0-(C 1 -C 6 )alkyl-Z 12 , -(C 1 -C 6 )alkyl-0-(C 2 -C 6 )alkenyl-Z 12 , -(C 2 -C 6 )alkyl-0-(C 2 -C 6 )alkynyl-Z 12 , -(C 1 -C 6 )alkyl-S-(Ci-C 6 )alkyl-Z 12 , -(C 1 -C 6 )alkyl-S-(C 2 -C 6 )alkenyl-Z 12 , -(C 2 -C 6 )alkyl-S-(C 2 -C 6 )alkynyl-Z 12 , -(C 1
- R 3b' is H, (d-C 6 )alkyl or -0(d-C 6 )alkyl; or R and R together with the carbon to which they are attached form a heterocycle or (C 3 -C 7 )carbocycle,which heterocycle or (C 3 -C 7 )carbocycle of R 3b and R 3b together with the carbon to which they are attached is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R 4a is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (Q-C ⁇ alkyl, (C2-C 6 )alkenyl, (Ci-C6)haloalkyl, (C 3 -C 7 )cycloalkyl, -(C 1 -C 6 )alkyl-(C 3 -C 7 )cycloalkyl, -OH, -Oid-C ⁇ alkyl, -SH, -S(C r C 6 )alkyl, -NH 2 , -NHid-C ⁇ alkyl and -N((C 1 -C 6 )alkyl) 2 , wherein (Ci-C 6 )alkyl is optionally substituted with hydroxy, -0(Cr)alkyl) 2 , wherein (
- R 4 is selected from;
- (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- aryl, heteroaryl, spiro- heterocycle, fused- heterocycle, or bridged-heterocycle wherein aryl, heteroaryl, spiro- heterocycle, fused- heterocycle and bridged-heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; or
- R 4 and R 3 together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle, wherein any macroheterocycle or macrocarbocycle of R 4 and R 3 together with the atoms to which they are attached may be optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and R 3b> is H or (C r C 6 )alkyl, -0(CrC 6 )alkyl;
- R 5a is selected from:
- R 5b is selected from:
- (C 3 -C 7 )carbocycle, (C2-C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or heteroaryl, either alone or as part of a group is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1 , 2, 3, 4 or 5) Z 1 groups, or wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 - C 7 )carbocycle or heterocycle wherein the (C 3 -C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- -X(C 3 -C 7 )carbocycle wherein -X(C 1 -C 6 )alkyl and -X(C 1 -C 6 )haloalkyl are each independently substituted with one or more Z 3 groups and optionally substituted with one or more Z 1 groups, and wherein -X(C2-C 6 )alkenyl, -X(C 2 -C6)alkynyl and -X(C 3 -C 7 )carbocycle are each
- each (C!-C 6 )alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or S ⁇ groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 6a is selected from:
- each R 11 is independently selected from H, (d-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -C 6 )alkynyl, (d-C 6 )haloalkyl, (C 3 -C )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups
- each R 9 is independently selected from H, (d-C 6 )alkyl and (C 3 -C 7 )cycloalkyl
- R 6b is selected from: a) -(C 1 -C 6 )alkyl-S0 2 -(C 1 -C 6 )alkyl-Z 13 , -C(0)-(C 1 -C 6 )alkyl-Z 13 , -0-(d-C 6 )alkyl-Z 13 , -S-(d-C 6 )alkyl-Z 13 , -S(0)-(C 1 -C 6 )alkyl-Z 13 , -S0 2 -(C 1 -C 6 )alkyl-Z 13 , -(C 1 -C 6 )alkyl-Z 14 , -(d- C 6 )alkyl-C(0)-(C 1 -C 6 )alkyl-Z 13 , -(C 1 -C 6 )alkyl-C(0)-0(C 1 -C 6 )alkyl-Z 13 , -(d-C 6 )alkyl-Z
- any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups, or wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the (C 3 -C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein aryl, heteroaryl and heterocycle, either alone or as part of a group, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- any (d-C 6 )alkyl, as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- each X is independently selected from O, -C(O)-, -C(0)0-, -S-, -S(O)-, -S0 2- , -(d- C 6 )alkylO-, -(d-C 6 )alkylC(0)-, -(C 1 -C 6 )alkylC(0)0-, -(d-C 6 )alkylS-, -(C C 6 )alkylS(0)- and -(C 1 -C 6 )alkylS0 2 -;
- C 7 halocarbocycle, aryl, heteroaryl, heterocycle, -0(C!-C6)alkyl, -0(C 2 -C 6 )alkenyl, -0(C 2 - C 6 )alkynyl, -0(d-C 6 )haloalkyl, -0(C 3 -C 7 )carbocycle, -0(C 3 -C 7 )halocarbocycle, -Oaryl, - Oheteroaryl, -Oheterocycle, -S(d-C 6 )alkyl, -S(C 2 -C 6 )alkenyl, -S(C 2 -C 6 )alkynyl, -S(d- C 6 )haloalkyl, -S(C 3 -C 7 )carbocycle, -S(C 3 -C 7 )halocarbocycle, -Saryl, -She
- each Z is independently selected from -N0 2 , -CN, spiro-heterocycle, bridge-heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NR a S0 2 (C 3 -C 7 )carbocycle, -NR a S0 2 aryl, -NR a S0 2 heteroaryl, -NR a S0 2 NR c R d , -NR a S0 2 0(C 3 -C 7 )carbocycle and -NR a S0 2 Oaryl;
- each Z 5 is independently selected from -N0 2 , -CN, -NR a S0 2 NR c R ⁇ i, -NR a S0 2 0(C 3 - C 7 )carbocycle, -NR a S0 2 Oaryl, -NR a S0 2 (C 1 -C 6 )alkyl, -NR a S0 2 (C 2 -C 6 )alkenyl, -NR a S0 2 (C 2 - C 6 )alkynyl, -NR a S0 2 (C 3 -C 7 )carbocycle, -NR a S0 2 (C 3 -C 7 )halocarbocycle, -NR a S0 2 aryl,
- each Z 6 is independently selected from -N0 2 , -CN, -NR a R a , NR a C(0)R b ,-C(0)NRcR d , (C 3 -C 7 )halocarbocycle, aryl, heteroaryl, heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C 3 -C 7 )halocarbocycle, -0(Ci-C 6 )alkyl, -0(C 3 -C 7 )carbocycle, -Oid-C ⁇ haloalkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C 3 -C
- any aryl, of Z 6 either alone or as part of a group, is otionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -0(Ci-C 6 )alkyl, -CN or -(Ci- C 6 )alkyl;
- each Z is independently selected from -N0 2 or -CN;
- each Z 10 is independently selected from
- halo oxo, thioxo, (C 2 -C 6 )alkenyl, (C 1 -C 6 )haloalkyl, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl-(Ci-C 6 )alkyl-, -OH, -0(d-
- aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl is optionally substituted with halo, (d-C )alkyl or COOH;
- halogen 1, 2, 3, 4 or 5) halogen, -OH, -OR b , -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, - Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0) 2 NR c R d ;
- halogen 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NR a C(0) 2 Rb, - heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or
- each Z 15 is independently selected from aryl, heteroaryl, heterocycle, -Oaryl,
- C 6 )alkyl-heterocycle wherein aryl, heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 16 groups and optionally subsituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups, and wherein any -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C 1 -C )alkyl-heteroaryl or -0(C!-C 6 )alkyl -heterocycle is optionally subsituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- halogen (C 1 -C 6 )alkyl, -OH, -OR b , -CN, -NR a C(0) 2 R b , heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -S(0) 2 NR c R ⁇ i;
- each R a is independently H, (C C )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
- each R b is independently (C],-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C )alkynyl,
- R c and R ⁇ i are each independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl,
- heteroaryl(C 1 -C 6 )alkyl- wherein any (C 1 -C 6 )alkyl, (C 2 -C )alkenyl, (C 2 -C 6 )alkynyl,
- (C 3 -C 7 )carbocycle, heterocycle, aryl, or heteroaryl of R c or R ⁇ j, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, OH or cyano; or R c and Ra together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle of Rc and Rj together with the nitrogen to which they are attached is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, OH or cyano;
- each R e is independently selected from -OR a, (Q-C ⁇ alkyl or (C 3 -C 7 )carbocycle, wherein (C ! -C 6 )alkyl and (C 3 -C 7 )carbocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g.
- each R f is independently selected from -R g, -ORa , -(C 1 -C 6 )alkyl-Z 6 , -S0 2 R g , -C(0)R g ,
- each R g is independently selected from (C 1 -C 6 )alkyl, (C3-C 7 )carbocycle
- (C ! -C 6 )haloalkyl (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heterocycle and heteroaryl, wherein any (CrC 6 )alkyl, (C 3 -C 7 )carbocycle -(Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heterocycle or heteroaryl of R g is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups;
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the invention also provides a method for treating (e.g. preventing, mediating or inhibiting) the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human), comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the mammal.
- a mammal e.g. a human
- the invention also provides a method of treating an HIV infection in a mammal (e.g. a human) comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the mammal.
- a mammal e.g. a human
- the invention also provides a method for treating an HIV infection in a mammal (e.g. a human) comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in
- HIV protease inhibiting compounds HIV non- nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drug for treating HIV, and combinations thereof.
- additional therapeutic agents selected from the group consisting HIV protease inhibiting compounds, HIV non- nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drug for treating HIV, and combinations thereof.
- the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g. for use in treating (e.g. preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human)).
- the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g. for use in treating (e.g. preventing, mediating or inhibiting) an HIV infection in a mammal (e.g. a human)).
- the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating (e.g. preventing, mediating or inhibiting) the proliferation of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human).
- a mammal e.g. a human
- the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment (e.g. prevention, mediation or inhibiting) of the proliferation of the HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS or ARC symptoms.
- the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV infection in a mammal (e.g. a human).
- the invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV infection in a mammal (e.g. a human).
- the invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.
- Alkyl is hydrocarbon containing normal, secondary or tertiary atoms.
- an alkyl group can have 1 to 20 carbon atoms (i.e, (CrC 20 )alkyl), 1 to 10 carbon atoms (i.e. , (C ⁇ - C 10 )alkyl), 1 to 8 carbon atoms (i.e. , (C 1 -Cg)alkyl)or 1 to 6 carbon atoms (i.e. , (Q-Q alkyl).
- alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1- butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1- pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl
- Alkyl also refers to a saturated, branched or straight chain hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
- an alkyl group can have 1 to 10 carbon atoms (i.e., (Ci-Cio)alkyl), or 1 to 6 carbon atoms (i.e., (Q- C 6 )alkyl) or 1-3 carbon atoms (i.e., (C 1 -C 3 )alkyl).
- Typical alkyl radicals include, but are not limited to, methylene (-CH 2 -), 1, 1 -ethyl (-CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1-propyl
- halo or halogen as used herein refers to fluoro, chloro, bromo and iodo.
- haloalkyl refers to an alkyl as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent.
- a (C 1 -C 6 )haloalkyl is a (C 1 -C 6 )alkyl wherein one or more of the hydrogen atoms have been replaced by a halo substituent.
- Such a range includes one halo substituent on the alkyl group t to complete halogenation of the alkyl group.
- aryl refers to a single aromatic ring or a bicyclic or multicyclic ring.
- an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
- Aryl includes a phenyl radical or an ortho-fused bicyclic or multicyclic radical having about 9 to 14 atoms in which at least one ring is aromatic (e.g. an aryl fused to one or more aryl or carbocycle).
- Such bicyclic or multicyclic rings may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the bicyclic or multicyclic ring.
- aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
- Arylalkyl refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl radical as described herein (i.e., an aryl-alkyl- moiety).
- the alkyl group of the "arylalkyl” is typically 1 to 6 carbon atoms (i.e. aryl(C 1 -C 6 )alkyl).
- Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 1-phenylpropan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl and the like.
- heteroaryl refers to a single aromatic ring or a multiple condensed ring.
- the term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings.
- the sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
- Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
- the term also includes multiple condensed ring systems (e.g. ring systems comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, can be fused with one or more heteroaryls (e.g.
- aryls e.g. indazolyl
- Such multiple condensed rings may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups on the carbocycle portions of the condensed ring. It is to be understood that the point of attachment of a heteroaryl multiple condensed ring, as defined above, can be at any position of the ring including a heteroaryl, aryl or a carbocycle portion of the ring.
- heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.
- heterocyclyl or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring or a multiple condensed ring.
- the term includes single saturated or partially unsaturated ring (e.g. 3, 4, 5, 6 or 7-membered ring) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
- the ring may be substituted with one or more (e.g. 1 , 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
- Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl.
- the term also includes multiple condensed ring systems (e.g. ring systems comprising 2 or 3 rings) wherein a heterocycle group (as defined above) can be connected to two adjacent atoms (fused
- heterocycle with one or more heterocycles (e.g. decahydronapthyridinyl ), heteroaryls (e.g. 1,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g. decahydroquinolyl) or aryls.
- heterocycles e.g. decahydronapthyridinyl
- heteroaryls e.g. 1,2,3,4-tetrahydronaphthyridinyl
- carbocycles e.g. decahydroquinolyl
- aryls e.g. decahydroquinolyl
- heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1,3-benzodioxolyl and 1 ,4-benzodioxanyl.
- bridged-heterocycle refers to a 4, 5, 6, 7 or 8-membered heterocycle as defined herein connected at two non-adjacent atoms of the 4, 5, 6, 7 or 8- membered heterocycle with one or more (e.g. 1 or 2) 3, 4, 5 or 6-membered heterocycles or (C 3 - C 7 )carbocycles as defined herein.
- Such bridged-heterocycles include bicyclic and tricyclic ring systems (e.g. 2-azabicyclo[2.2.1]heptane and 4-azatricyclo[4.3.1.1 ' ] undecane).
- spiro-heterocycle refers to a 3, 4, 5, 6, 7 or 8-membered heterocycle as defined herein connected to one or more (e.g. 1 or 2) single atoms of the 3, 4, 5, 6, 7 or 8-membered heterocycle with one or more (e.g. 1 or 2) 3, 4, 5, 6-membered heterocycles or a (C3-C 7 )carbocycles as defined herein.
- spiro-heterocycles include bicyclic and tricyclic ring systems (e.g. l,4-dioxaspiro[4.5]dec-7-enyl).
- macroheterocycle refers to a saturated or partially unsaturated 8, 9, 10, 11 or 12-membered ring comprising about 5 to 11 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring which may be optionally fused at two adjacent atoms of the macroheterocycle to one or more (e.g. 1, 2 or 3) aryls, carbocycles, heteroaryls or heterocycles.
- the macroheterocycle may be substituted with one or more (e.g. 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
- Heteroarylalkyl refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl radical as described herein (i.e., a heteroaryl-alkyl- moiety).
- the alkyl group of the "heteroarylalkyl” is typically 1 to 6 carbon atoms (i.e. heteroaryl(C 1 -C 6 )alkyl).
- Heteroarylalkyl groups include, but are not limited to heteroaryl-CH 2 -, heteroaryl-CH(CH3)-, heteroaryl-CH 2 CH 2 -, 2-(heteroaryl)ethan-l-yl, and the like, wherein the "heteroaryl" portion includes any of the heteroaryl groups described above.
- the heteroaryl group can be attached to the alkyl portion of the heteroarylalkyl by means of a carbon-carbon bond or a carbon- heteroatom bond, with the proviso that the resulting group is chemically stable.
- heteroarylalkyls include by way of example and not limitation 5 -membered sulfur, oxygen, and/or nitrogen containing heteroaryls such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heteroaryls such pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.
- heteroarylalkyls include by way of example and not limitation 5 -membered sulfur, oxygen, and/or nitrogen containing heteroaryls such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heteroaryls such pyridinylmethyl, pyridizyl
- Heterocyclylalkyl refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl radical as described herein (i.e., a heterocyclyl-alkyl- moiety).
- the alkyl group of the "heterocyclylalkyl” is typically 1 to 6 carbon atoms (i.e. heterocyclyl(C ! -C )alkyl).
- heterocyclylalkyl groups include, but are not limited to heterocyclyl-CH 2 -, heterocyclyl-CH(CH 3 )-, heterocyclyl- CH 2 C3 ⁇ 4-, 2-(heterocyclyl)ethan-l-yl, and the like, wherein the "heterocyclyl" portion includes any of the heterocyclyl groups described above.
- the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
- heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such
- carbocycle refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocycle or a mutlicyclic ring system.
- the carbocycle is a monocycle comprising 3-6 ring carbons (i.e. (C3-C6)carbocycle).
- Carbocycle includes multicyclic carbocyles having 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle provided that the largest single ring of a multicyclic carbocycle is 7 carbon atoms.
- the term "spiro-bicyclic carbocycle” refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to a single carbon atom (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc).
- fused-bicyclic carbocycle refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to two adjacent carbon atoms such as as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane).
- bridged-bicyclic carbocycle refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to two non-adjacent carbon (e.g.
- the "carbocycle” or “carbocyclyl” may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups.
- monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2- enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl and l-cyclohex-3- enyl.
- halocarbocycle refers to a carbocycle as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent.
- (C 3 - C 7 )halocarbocycle is a (C 3 -C 7 )carbocycle wherein one or more of the hydrogen atoms have been replaced by a halo substituent.
- Such a range includes one halo substituent on the carbocycle group to complete halogentation of the carbocycle group.
- microcarbocycle refers to a saturated or partially unsaturated
- 8, 9, 10, 1 1 or 12-membered ring comprising 8 to 12 carbon atoms which may be optionally fused at two adjacent atoms of the macrocarbocycle to one or more (e.g. 1, 2 or 3) aryls, carbocycles, heteroaryls or heterocycles.
- the macrocarbocycle may be substituted with one or more (e.g. 1, 2 or 3) oxo groups.
- Carbocyclylalkyl refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein (i.e., a carbocyclyl-alkyl- moiety).
- the alkyl group of the "carbocyclylalkyl” is typically
- carbocyclyl(C 1 -C 6 )alkyl 1 to 6 carbon atoms (i.e. carbocyclyl(C 1 -C 6 )alkyl).
- Typical carbocyclyl alkyl groups include, but are not limited to carbocyclyl-CH 2 -, carbocyclyl-CH(CH 3 )-, carbocyclyl-CH 2 CH 2 -, 2-
- variable (Q-C ⁇ alkyl when a variable is substituted, for example, as described by the phrase "(C 1 -C 6 )alkyl, either alone or as part of a group, is optionally substituted ", the phrase means that the variable (Q-C ⁇ alkyl can be substituted when it is alone and that it can also be substituted when the variable "(C 1 -C 6 )alkyl" is part of a larger group such as for example an aryl(C 1 -C 6 )alkyl or a -( Ci-C 6 )alkyl-S0 2 -(C 1 -C 6 )alkyl-(C 3 -C 7 )carbocycle group.
- other variables e.g. (d-C6)alkenyl, (CrC 6 )alkynyl, aryl, heteroaryl, heterocycle, etc.
- other variables e.g. (d-C6)alkenyl, (CrC 6 )alkyny
- the -C(0)0- can be oriented as either -C(0)0- or -OC(O)-, relative to the groups it connects.
- the nitrogen that is included in the core of the compound of formula I can be present in an oxidized form.
- the thiazole nitrogen of either G 1 or G of formula I can be an N-oxide. Accordingly, the invention includes a compound of formula
- chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are
- stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
- Diastereomer refers to a stereoisomer with two or more centers or axes of chirality and whose molecules are not mirror images of one another. Diastereomers typically have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
- Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
- Certain compounds of the invention can exist as atropisomers. For example, it has been discovered that atropisomers exist for certain substituents at the R 4 position of formula I as marked by an asterisk in the formula below.
- the invention includes all atropisomers of compounds of the invention including mixtures of atropisomers and well as mixtures that are enriched in an atropisomer as well as single atropisomers, which mixtures or compounds possess the useful properties described herein.
- the compounds of the invention of formula I are greater than 50% a single atropisomer for the R 4 substituent at the asterisk position. In one embodiment, the compounds of the invention of formula I are at least 60% a single atropisomer for the R 4 substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 70% a single atropisomer for the R 4 substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 80% a single atropisomer for the R 4 substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 90% a single atropisomer for the R 4 substituent at the asterisk position.
- the compounds of the invention of formula I are at least 95% a single atropisomer for the R 4 substituent at the asterisk position.
- the stereochemistry for the R 4 substituent at the carbon marked with an asterisk as shown above for Formula I is the (R) stereochemistry.
- the stereochemistry for the R 4 substituent at the carbon marked with an asterisk as shown above for Formula I is the (S) stereochemistry.
- stereochemistry at the carbon marked with an asterisk as shown above for Formula I is the (S) stereochemistry. In another embodiment the stereochemistry at the carbon marked with an asterisk as shown above for Formula I is the (R) stereochemistry.
- the compounds of the invention of formula I are greater than 50% a stereoisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 60% a single stereoisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 70% a single stereoisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 80% a single stereoisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 90% a single steroisomer for the carbon at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 95% a single stereoisomer for the carbon at the asterisk position.
- treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
- d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
- a compound prefixed with (+) or d is dextrorotatory.
- these stereoisomers are identical except that they are mirror images of one another.
- a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
- a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
- racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
- protecting groups include prodrug moieties and chemical protecting groups.
- Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991.
- Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.
- Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
- Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
- Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
- Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group "PG" will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
- protecting groups for -OH groups include “ether- or ester-forming groups”.
- Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.
- some hydroxyl and thio protecting groups are neither ether- nor ester- forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
- the compounds of the invention may have chiral centers, e.g. , chiral carbon or phosphorus atoms.
- the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
- the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
- the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
- racemic mixtures can be separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g. , acids or bases followed by conversion back to the optically active substances.
- optically active adjuncts e.g. , acids or bases followed by conversion back to the optically active substances.
- the desired optical isomer is synthesized by means of
- the compounds of the invention can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
- ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
- Examples of pharmaceutically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C1-C4 alkyl).
- an appropriate base such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C1-C4 alkyl).
- Pharmaceutically acceptable salts of a hydrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids.
- organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
- organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
- Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX (wherein X is independently selected from H or a C t -C 4 alkyl group).
- salts of active ingredients of the compounds of the invention will typically be pharmaceutically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
- salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula I or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
- Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
- metal salts which are prepared in this way are salts containing Li + ,
- a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
- compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
- any of the natural or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
- a basic or acidic group e.g., lysine, arginine or glutamic acid
- a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
- this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( H or D).
- a -CH 3 group may be substituted with -CD 3 .
- a specific group of compounds of formula I are compounds of formula la:
- R is-0(C 1 -C6)alkyl or a salt thereof.
- R J is-0(C 1 -C 6 )alkyl or a salt thereof.
- Another specific group of compounds of formula I are compounds of formula Id:
- R 3 is-0(Ci-C6)alkyl, or a salt thereof.
- R 3 is-0(C 1 -C 6 )alkyl, or a salt thereof.
- R 3 is-0(CrC 6 )alkyl, or a salt thereof.
- R is-0(CrC 6 )alkyl, or a salt thereof.
- G is N, the dashed bond connected to G is a double bond, and the wavy bond connected to R 5 is a single bond;
- G 2 is N, the dashed bond connected to G 2 is a double bond, and the wavy bond connected to R 5 is a single bond;
- G 2 is N, the dashed bond connected to G 2 is a double bond, and the wavy bond connected to R 5 is a single bond;
- G 2 is N, the dashed bond connected to G 2 is a double bond, and the wavy bond connected is a single bond;
- G is S; G is N; the dashed bond connected to G is a single bond and the dashed bond connected to G is a double bond; or
- G is N; G is S; the dashed bond connected to G is a double bond and the dashed bond connected to G is a single bond;
- a specific group of compounds of formula I are compounds wherein at least one of R 1 , R 2 , R 3 , R 3' , R 4 or R 5 is selected from R lb , R 2b , R 3b , R 3b' , R 4b or R 5b .
- Another specific group of compounds of formula I are compounds wherein at least two of R 1 , R 2 , R 3 , R 3' , R 4 or R 5 is selected from R lb , R 2b , R 3b , R 3b' , R 4b or R 5b .
- R 1 , R 2 , R 3 , R 3' , R 4 or R 5 is selected from R lb , R 2b , R 3b , R 3b' , R 4b or R 5b .
- R 1 , R 2 , R 3 , R 3' , R 4 or R 5 is selected from R lb , R 2b , R 3b , R 3b' , R 4b or R 5b .
- R 1 , R 2 , R 3 , R 3' , R 4 or R 5 is selected from R lb , R 2b , R 3b , R 3b' , R 4b or R 5b .
- R 1 , R 2 , R 3 , R 3' , R 4 and R 5 are R lb , R 2b , R 3b , R 3b' , R 4b and R 5b .
- a specific value for R 1 is H.
- R 1 Another specific value for R 1 is H or halo.
- R 1 Another specific value for R 1 is H or F.
- a specific value for R is H.
- R 3b A specific value for R 3 is R 3b .
- R 3b A specific value for R 3b is -OC(CH 3 ) 2 CH 2 OH, -OC(CH 3 ) 2 CH 2 OH,
- R 3b is -(C!-C 6 )alkylOH or -0(Ci-C6)alkyl-0-C(0)-NRcR d .
- R 3a is R 3a .
- R 3a A specific value for R 3a is (C C 6 )alkyl, (C 2 -C 6 )alkenyl or -0(C!-C6)alkyl wherein any (C!-C )alkyl or (C 2 -C 6 )alkenyl of R 3a is optionally substituted with one or more groups selected from -0(C 1 -C 6 )alkyl, halo, oxo and -CN.
- R 3a Another specific value for R 3a is -OC(CH 3 ).
- R 3' A specific value for R 3' is R 3b' .
- R 3b' is (C C 6 )alkyl or -OCQ-C ⁇ alkyl.
- R 3a A specific value for R 3 is R 3a .
- a specific value for R 3a is H.
- R 3 is (C 2 -C 6 )alkenyl or -0(Ci-C 6 )alkyl, wherein any (C]-C 6 )alkyl or (C 2 -C 6 )alkenyl of R 3a is optionally substituted with one or more groups selected from -0(C 1 -C 6 )alkyl, halo, oxo and -CN.
- R 3 is -OC(CH 3 ) 3 .
- a specific group of compounds of fomula I are compounds wherein the compounds of formula I are compounds of formula Ih:
- G is N, the dashed bond connected to G is a double bond, and the wavy bond connected to R 5 is a single bond;
- G is NR , the dashed bond connected to G is a single bond, the wavy bond connected to R 5 is a double bond and R 5 is oxygen.
- a specific group of compounds of fomula I are compounds wherein R and R together with the carbon to which they are attached form a (C 3 -C7)carbocycle or heterocycle; wherein the (C 3 -C 7 )carbocycle or heterocycle is optionally substituted with one or more Z 1 groups.
- Another specific group of compounds of fomula I are compounds wherein R and R together with the carbon to which they are attached form a (C3-C 7 )carbocycle or a 4, 5 or 6- membered heterocycle; wherein the (C 3 -C 6 )carbocycle or the 4, 5 or 6-membered heterocycle is optionally substituted with one or more Z 1 groups.
- Another specific group of compounds of fomula I are compounds wherein R and R together with the carbon to which they are attached form a (C4-C )carbocycle or a 5 or 6- membered heterocycle; wherein the (C 4 -C )carbocycle or the 5 or 6-membered heterocycle is optionally substituted with one or more Z 1 groups.
- Another specific group of compounds of fomula I are compounds wherein R and R together with the carbon to which they are attached form a 5 or 6-membered heterocycle;
- Another specific group of compounds of fomula I are compounds wherein R 3b and R 3b together with the carbon to which they are attached form a tetrahydropyran or tetrahydrofiiran optionally substituted with one or more Z 1 groups.
- Another specific group of compounds of fomula I are compounds wherein R 3b and R 3b together with the carbon to which they are attached form: each of which is optionally substituted with one or more Z groups; and wherein "*" denotes the point of attachment to the carbon of the compound of formula I.
- R 4b A specific value for R 4 is R 4b .
- R 4b is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl; wherein
- (C 1 -C 6 )alkyl, (C2-C 6 )alkenyl or (C 2 -C 6 )alkynyl are each optionally substituted with one or more Z 1 groups.
- R 4b Another specific value for R 4b is:
- R 4b Another specific value for R 4b is (C 3 -C 7 )carbocycle; wherein (C 3 -C 7 )carbocycle is optionally substituted with one or more Z 1 groups; or wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 6 )carbocycle or 5-6-membered heterocycle.
- R 4b is aryl, heterocycle or heteroaryl; wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z groups and optionally substituted with one or more Z 1 groups.
- R 4b Another specific value for R 4b is:
- R 4a Another specific value for R 4 is R 4a .
- R 4a Another specific value for R 4 is:
- R a Another specific value for R a is:
- R a Another specific value for R a is:
- a specific value for R is selected from:
- aryl, heterocycle and heteroaryl wherein any aryl, heterocycle and heteroaryl of R 4 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (d-C ⁇ haloalkyl, (C 3 -C 7 )cycloalkyl,
- aryl, heteroaryl, spiro-, fused-, or bridged-heterocycle wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- R 4 is selected from: a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R 4 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C ⁇ haloalkyl, (C 3 -C 7 )cycloalkyl,
- aryl and heteroaryl are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- R 4 is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R 4 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (Ci-C6)alkyl, (C 2 -C6)alkenyl, (d-C ⁇ haloalkyl, (C 3 -C 7 )cycloalkyl, -(C 1 -C 6 )alkyl-(C 3 -C 7 )cycloalkyl, -OH, - ⁇ (d-C ⁇ alkyl, -SH, -S Q-QOalkyl, - NH 2 , -NHiQ-Ce alkyl and -N ⁇ Q ⁇ alkyl) ⁇ wherein (d ⁇ alkyl is optionally substituted with hydroxy, -0(C 1 -C 6 )alkyl, cyano or oxo.
- groups each independently selected from halo,
- R 4 Another specific value for R 4 is:
- a specific group of compounds of formula I are compounds wherein R 4 and R 3 together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R 4 and R 3 together with the atoms to which they are attached may be optionally substituted with one or more Z groups; and R is H, (C 1 -C 6 )alkyl or -0(C C 6 )alkyl.
- Another specific group of compounds of formula I are compounds wherein R 4 and R 3 together with the atoms to which they are attached form a macroheterocycle or a
- any macroheterocycle or macrocarbocycle of R 4 and R 3 together with the atoms to which they are attached may be optionally substituted with one or more Z 1 groups; and R 3' is H.
- Another specific group of compounds of formula I are compounds wherein R 4 and R 3 together with the atoms to which they are attached form the macroheterocycle or a
- Z is aryl, heteroaryl or (C 3 -C 6 )carbocycle
- n3 is 2, 3 or 4;
- W 1 and W z are each independently O, NH or CH 2 ;
- R 2b A specific value for R 2 is R 2b .
- R 2 is R 2a .
- R 2a is H, halo or -CH 3 .
- R 2a Another specific value for R 2a is CI.
- R is halo, H or (C 1 -C )alkyl.
- R is halo, H or -CH 3 .
- R is H or -CH 3 .
- R 2 is H or (C 1 -C 6 )alkyl.
- R 2 Another specific value for R 2 is (Q-C ⁇ alkyl.
- R 2 Another specific value for R 2 is -CH 3 .
- R 5a Another specific value for R 5 is R 5a .
- R 5a Another specific value for R 5a is H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl or -(C 1 -C 6 )alkyl-R 11 .
- R n is aryl
- R 11 is carbocycle or aryl.
- R 11 Another specific value for R 11 is carbocycle.
- R 5a Another specific value for R 5a is -N(R 9 )R 10 .
- R 9 is H or (Q-C ⁇ alkyl.
- a specific value for R 10 is H or ⁇ ⁇ -C ⁇ )a ky ⁇ .
- a value for Z 9 is "each Z 9 is independently selected from -(C 1 -C 6 )alkyl, -0(C 1 -C 6 )alkyl".
- a specific value for R 5a is:
- R 5a Another specific value for R 5a is:
- R 5 A specific value for R 5 is R 5 b
- R 5 is-(C2-C 6 )alkynyl-(C3-C 7 )carbocycle.
- R 5b Another specific value for R 5b is:
- R 5 A specific value for R 5 is:
- a specific value for R 5 is selected from:
- each R 11 is independently selected from H, (CrC 6 )alkyl, (C2-C 6 )alkenyl, (C2-C 6 )alkynyl, (CrC 6 )haloalkyl, (C3-C 7 )carbocycle, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or
- each (C 1 -C 6 )alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
- R 5 Another specific value for R 5 is selected from:
- R 5 Another specific value for R 5 is selected from:
- R 5 Another specific value for R 5 is selected from:
- heterocycle is optionally substituted with one or more (e.g. 1, 2 or 3) Z n groups and wherein each R 11 is independently selected from H, (C ! -C )alkyl, (C 2 - C 6 )alkenyl, (C2-C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )carbocycle, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1 , 2 or 3) Z 11 groups;
- R 5 Another specific value for R 5 is selected from:
- a specifc group of compounds of formula I are compounds wherein R is oxo and R 6 is selected from R 11 and -(CrC ⁇ alkyl-R 11 , wherein each R n is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups.
- R 5 is oxo and R 6 is selected from:
- a specific group of compounds of formula I are compounds wherein R is selected from; a) (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl, wherein any (C 1 -C 6 )alkyl, (C 2 -C )alkenyl or (C 2 -C 6 )alkynyl is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- the invention provides a compound of the invention which is a compound of formula I:
- G is S; G is N; the dashed bond connected to G is a single bond and the dashed bond connected to G 2 is a double bond; or
- R 1 is R la or R lb ;
- R 2 is R 2a or R 2b ;
- R 3 is R 3a or R 3b ;
- R 3 is R 3a or R 3b ;
- R 4 is R 4a or R 4b ;
- R 5 is R 5a or R 5b ;
- R la is selected from:
- each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C )alkynyl, (d-C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one
- R lb is selected from:
- (d-C 6 )alkyl, (d-C 6 )haloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g.
- Z 1 groups wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- (d-C6)alkyl wherein (d-C 6 )alkyl is substituted with one or more Z 2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z ⁇ oups;
- (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more Z ! groups;
- (d-C 6 )haloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more Z'groups;
- each (d-C 6 )alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more Z ⁇ oups; and h) nitro and cyano
- R 2a is selected from:
- each R 11 is independently selected from H, (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl and heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optional
- each R 9 is independently selected from H, (d-C 6 )alkyl and (C 3 - C 7 )cycloalkyl;
- C 6 )alkyl (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C6)haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl;
- R is selected from:
- -(d-C 6 )alkyl-Z 14 -(d-C6)alkyl-C(0)-(d-C 6 )alkyl-Z 13 , -(d-C 6 )alkyl-C(0)-0(d-C 6 )alkyl-Z 13 , -(C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkyl-Z 13 , -(d-C 6 )aH yl-S-(d-C6)alkyl-Z 13 , -(C 3 -C 7 )halocarbocycle,- NR a S0 2 NR c R d , -NR a S0 2 0(C 3 -C 7 )carbocycle, -NR a S0 2 Oaryl,
- spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C3-C 7 )carbocycle or heterocycle wherein the (C 3 -C )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- aryl heteroaryl and heterocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- (C 1 -C 6 )haloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C )alkenyl and (C 2 -C 6 )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z ⁇ roups;
- each (d-C 6 )alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups; and
- R 3a is (C C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
- (d-C 6 )haloalkyl (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -(d-C 6 )alkyl-(C 3 -C 7 )cycloalkyl,
- -0(C 1 -C 6 )alkyl -heteroaryl of R 3a is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (C 1 -C 6 )alkyl, -0(d-C 6 )alkyl, halo, oxo and -CN; and
- R 3a' is H ;
- R 3b is -(C 3 -C 7 )carbocycle, aryl, heteroaryl, heterocycle, -(d-C 6 )alkylOH, -(C 1 -C 6 )alkyl- 0-(d-C 6 )alkyl-Z 12 , -(C 1 -C 6 )alkyl-0-(C 2 -C 6 )alkenyl-Z 12 , -(C 2 -C 6 )alkyl-0-(C 2 -C 6 )alkynyl-Z 12 , - (d-C 6 )alkyl-S-(d-C 6 )alkyl-Z 12 , -(C !
- R 3b' is H, (d-C 6 )alkyl or -0(d-C 6 )alkyl; or
- R and R together with the carbon to which they are attached form a heterocycle or (C3-C 7 )carbocycle which heterocycle or (C 3 -C 7 )carbocycle of R and R together with the carbon to which they are attached is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R 4a is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (d-C ⁇ haloalkyl, (C3-C 7 )cycloalkyl, -(d-C 6 )alkyl-(C 3 -C 7 )cycloalkyl, -OH, -0(d-C 6 )alkyl, -SH, -S(d-C 6 )alkyl, -NH 2 , - H(Cj-C 6 )alkyl and -N((C 1 -C 6 )alkyl) 2 ; wherein (d-C ⁇ alkyl is optionally substituted with hydroxy, -0(d- C 6 )alkyl, cyan
- R 4b is selected from;
- (C 2 -C 6 )alkenyl or (C 2 -C )alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- aryl, heteroaryl, spiro-, fused-, or bridged-heterocycle wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; or
- R 4 and R 3 together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R 4 and R 3 together with the atoms to which they are attached may be optionally substituted with one or more (e.g. 1 , 2, 3, 4 or 5) Z 1 groups; and R 3b' is H or (d-C 6 )alkyl, -0(d-C 6 )alkyl.
- R 5a is selected from:
- each R 9 is independently selected from H, (d-C )alkyl and (C 3 - C 7 )cycloalkyl
- each R 11 is independently selected from H, (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl
- R 5b is selected from:
- (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or heteroaryl are each optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 - C7)carbocycle or heterocycle wherein the (C 3 -C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- (Ci-Ce ⁇ aloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- each (d-C 6 )alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
- R 1 and R 2 together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1,
- X is independently selected from O, -C(O)-, -C(0)0-, -S-, -S(O)-, -S0 2- , -(Cr
- C 7 halocarbocycle, -aryl, -heteroaryl, -heterocycle, -0(C C 6 )alkyl, -0(C 2 -C 6 )alkenyl, -0(C 2 - C 6 )alkynyl, -0(C 1 -C 6 )haloalkyl, -0(C 3 -C 7 )carbocycle, -0(C 3 -C 7 )halocarbocycle, -Oaryl, - Oheteroaryl, -Oheterocycle, -S(C !
- halogen 1, 2, 3, 4 or 5) halogen, -OH, -OR b , -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0) 2 NRcR ⁇ i;
- each Z 5 is independently selected from -N0 2 , -CN, -NR a SO ⁇ R c R d , -NR a S0 2 0(C 3 - C 7 )carbocycle, -NR a S0 2 Oaryl, -NR a S0 2 (Ci-C 6 )alkyl, -NR a S0 2 (C 2 -C 6 )alkenyl, -NR a S0 2 (C 2 - C 6 )alkynyl, -NR a S0 2 (C 3 -C 7 )carbocycle, -NR a S0 2 (C 3 -C 7 )halocarbocycle, -NR a S0 2 aryl,
- each Z 6 is independently selected from -N0 2 , -CN, -NRJ ⁇ , NR a C(0)R b ,-C(0)NR c R d , -(C 3 -C 7 )halocarbocycle, -aryl, -heteroaryl, -heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C 3 -C 7 )halocarbocycle, -0(C!-C 6 )alkyl, -0(C 3 -C 7 )carbocycle, -Ohalo(C 1 -C 6 )alkyl, -Saryl, -Sheteroaryl, -Sheteroaryl, -Sheter
- any (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 7 )carbocycle, (C 3 -C 7 )halocarbocycle, aryl, heteroaryl or heterocycle of Z 7 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN,
- each Z is independently selected from -N0 2 or -CN;
- each Z 9 is independently selected from -(d-C 6 )alkyl, -0(d-C )alkyl;
- each Z 10 is independently selected from
- aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl is optionally substituted with halo, (d-C 6 )alkyl or COOH;
- C 7 )halocarbocycle, (C3-C 7 )carbocycle, (C3-C 7 )halocarbocycle, aryl, heteroaryl or heterocycle of Z is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(0) 2 NRcR d ;
- any -(C 3 -C 7 )halocarbocycle of Z 14 is optionally substituted with one or more (e.g.
- halogen -OH, -OR b , -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0) 2 NR c R ⁇ 1 ;
- each R a is independently H, (Ci-C6)alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
- each 3 ⁇ 4 is independently -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, (C3-C 7 )carbocycle, heterocycle, aryl, or heteroaryl of R a is optionally substituted by halogen, OH and cyano; each 3 ⁇ 4 is independently -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, (C3-C 7 )carbocycle, heterocycle, aryl, aryl(C 1 -C 6 )alkyl-, heteroaryl or heteroaryl(C 1 -C 6 )alkyl-;
- R c and Ra are each independently selected from H, (Ci-C ⁇ alkyl, (C 2 -C 6 )alkenyl,
- (C3-C 7 )carbocycle, heterocycle, aryl, or heteroaryl of R c or Ra is optionally substituted by halogen, OH and cyano; or c and Ra together with the nitrogen to which they are attached form a heterocycle; wherein any hetereocycle of Rc and R together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano;
- each R e is independently selected from -OR a, (C 1 -C 6 )alkyl or (C 3 -C 7 )carbocycle wherein (Ci-Ce ⁇ lkyl or (C 3 -C 7 )carbocycle is substituted by one or more Z 6 and optionally substituted with one or more Z ⁇ -(C 2 -C6)haloalkyl, -(C 2 -C 6 )alkenyl, or -(C 2 -C 6 )alkynyl wherein any haloalkyl, alkenyl or alkynyl is optionally substituted with one or more Z ⁇ aryl, heterocycle or heteroaryl wherein aryl, heterocycle or heteroaryl is substituted by one or more Z 5 ;
- each R f is independently selected from -R & -OR ⁇ -(C 1 -C 6 )alkyl-Z 6 , -S0 2 R g , -C(0)R g , C(0)OR g , or -C(0)NR e R g ; and
- each R g is independently selected from (d-C ⁇ alkyl, (C 3 -C 7 )carbocycle
- the compounds of formula I are selected from:
- the compounds of formula I are selected from:
- Schemes 1, 2, 3, 4, 5, 6 and 7 are provided as further embodiments of the invention and illustrate general methods which were used to prepare compounds of formula I and which can be used to prepare additional compounds of formula I.
- the benzothiazole intermediate 2B can be converted to the final compound 2C by the methods used to convert 1C to 1M as outlined in Scheme 1.
- the benzothiazole intermediate 3E can be converted to the final compound 2C by the methods used to convert 1C to ID and IF to 1M as outlined in Scheme 1.
- the benzothiazole intermediate 4A can be converted to the final compound 4B by the methods used to convert 1C to ID and IF to 1M as outlined in Scheme 1 wherein HNRR represents an HNR 9 R 10 , HNR e R f or a heterocycle (when R and R taken together with the nitrogen to which they are attached form a ring).
- the benzothiazoline intermediate 4V can be converted to the final compound 4W by the methods used to convert 1C to 1M as outlined in Scheme 1.
- a specific value for R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 3 is H.
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z n groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z ! groups;
- R 3 is H; R 1 is H; and
- R 2 is H or (Ci-Qdalkyl.
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 3' is H; R 1 is H;
- R 2 is H or (Ci-C 6 )alkyl
- R 3 is -0(d-C 6 )alkyl.
- a specific value for R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- R 5 is selected from: a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 3' is H.
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 3' is H; R 1 is H; and
- R 2 is H or (C 1 -C 6 )alkyl.
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 3' is H; R 1 is H;
- R 2 is H or (C!-C6)alkyl
- R 3 is -0(C 1 -C 6 )alkyl.
- R 5 is aryl, heteroaryl, heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 5 is selected from aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z J groups; and
- R 3' is H.
- R 5 is selected from aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 3 is H; R 1 is H; and
- R 2 is H or (d-C 6 )alkyl.
- R 5 is selected from aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
- R 3' is H; R 1 is H;
- R 2 is H or (C C 6 )alkyl
- R 3 is -Oid-C ⁇ alkyl.
- R 5 Another specific value for R 5 is selected from:
- aryl wherein aryl is optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
- R 5 is selected from:
- aryl wherein aryl is optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z ! groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 3' is H.
- R 5 is selected from: a) aryl, wherein aryl is optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 3' is H; R 1 is H; and
- R 2 is H or (C,-C 6 )alkyl.
- R 5 is selected from:
- aryl wherein aryl is optionally substituted with one or more (e.g. 1 , 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z ⁇ oups;
- R 3 is H; R 1 is H;
- R 2 is H or (C 1 -C 6 )alkyl
- R 3 is -0(C 1 -C 6 )alkyl.
- R 5 Another specific value for R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z ⁇ oups;
- each Z 10 is independently selected from: i) halo, oxo, thioxo, (C 2 -C 6 )alkenyl, (C 1 -C6)haloalkyl, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl-(Ci-C6)alk l-, -OH, -0(C
- aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl is optionally substituted with halo, (d-C6)alkyl or COOH;
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1 , 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 3' is H
- each Z 10 is independently selected from:
- aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C 1 -C6)alkyl or COOH;
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z ⁇ oups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 3' is H; R 1 is H;
- R 2 is H or (C 1 -C 6 )alkyl
- each Z 10 is independently selected from:
- halo oxo, thioxo, (C2-C 6 )alkenyl, (d-Ce ⁇ aloalkyl, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl-(C ] -C 6 )alkyl-, -OH, -0(C,- C 6 )alkyl, -(Xd-Cgihaloalkyl, -SH, -S(d-C 6 )alkyl, -SO(C r
- aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C 1 -C 6 )alkyl or COOH;
- R 5 is selected from:
- aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl are heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups; and
- aryl, heteroaryl and heterocycle wherein aryl, heteroaryl and heterocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 15 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z'groups;
- R 3' is H; R 1 is H;
- R 2 is H or(d-C 6 )alkyl;
- R 3 is -0(d-C 6 )alkyl;
- each Z 10 is independently selected from:
- C 6 )alkyl -0(d-C 6 )haloalkyl, -SH, -S(d-C 6 )alkyl, -SO(d- C 6 )alkyl, -S0 2 (C 1 -C 6 )alkyl, -NH 2 , -NH(d-C 6 )alkyl and
- aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl optionally substituted with halo, (d-C )alkyl or COOH;
- the compound of formula I is selected from a compound of formulas Ial00-Ial45 (e.g. compounds IalOO, IalOl, lal 02, Ial03, Ial04, Ial05, lal 06, lal 07, lal 08, lal 09, lal 10, lal 11, lal 12, lal 13, lal 14, lal 15, lal 16, lal 17, lal 18, lal 19, Ial20, Ial21, Ial22, Ial23, Ial24, Ial25, Ial26, Ial27, Ial28, Ial29, Ial30, Ial31, Ial32, Ial33, Ial34, Ial35, Ial36, Ial37, Ial38, Ial39, Ial40, lal 41, Ial42, Ial43, Ial44, Ial45):
- the compounds of formula I are selected from the compounds of formulas Ial00-Ial45 wherein:
- R 1 is H; R 2 is methyl, R 3' is H; R 3 is -OtBu; and
- R 4 is:
- the compounds of formula I are selected from the compounds of formulas Ial 00-Ial 45 wherein:
- R 1 is H; R 2 is methyl, R 3' is H; R 3 is -OtBu; and 4 is:
- the compounds of formula I are selected from the compounds of formulas Ial00-Ial45 wherein:
- R 1 is H; R 2 is methyl, R 3' is H; R 3 is -OtBu; and
- R 4 is:
- the compounds of formula I are selected from the compounds of formulas Ial00-Ial45 wherein:
- R 1 is H; R 2 is methyl, R 3' is H; R 3 is -OtBu; and
- R 4 is:
- the compounds of formula I are selected from the compounds of formulas Ial00-Ial45 wherein R 3 is H; R 3 is -0(Ci-C6)alkyl and the
- the compounds of formula I are selected from the compounds of formulas Ial00-Ial45 wherein R is H; R is -0(C C 6 )alkyl and the stereochemistry of the carbon bearing the R (-0(C 1 -C6)alkyl) group is (R).
- the compounds of formula I are selected from:
- the invention provides for a prodrug of a compound of the invention.
- prodrug refers to any compound that when administered to a biological system generates a compound of the invention that inhibits the replication of HIV ("the active inhibitory compound").
- the compound may be formed from the prodrug as a result of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzed chemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemical reaction(s).
- Prodrug moiety refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191).
- Enzymes which are capable of an enzymatic activation mechanism with the prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
- Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
- a prodrug moiety may include an active metabolite or drug itself.
- the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J Pharm. Sci. 72: 24; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756.
- acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
- a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
- Aryl esters of phosphorus groups are reported to enhance oral bioavailability (De Lombaert et al. (1994) J Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to a phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate parent phosphonic acids. In some cases, substituents at the ortho- or para- position may accelerate the hydrolysis.
- Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-0 bond to generate phosphoric acid and a quinone methide intermediate.
- enzymes e.g., esterases, oxidases, etc.
- prodrugs examples include Mitchell et al. (1992) J Chem. Soc. Per kin Trans. 7/2345; Glazier WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide.
- the invention provides for a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
- the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in
- the therapeutic agent used in combination with the compound of the present invention can be any anti-HIV agent.
- the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in
- HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drug for treating HIV, and combinations thereof, and a pharmaceutically acceptable carrier.
- the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent selected from the group consisting of:
- HIV protease inhibiting compounds selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, K I-272, DPC-681, DPC-684, GW640385X, DG17, PPL- 100, DG35, and AG 1859;
- HIV non-nucleoside inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, rilpivirene, BILR 355 BS, VRX 840773, UK-453061, and RDEA806;
- HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ⁇ -FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), ;
- HIV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, GS-7340 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix)
- HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011 and dolutegravir;
- gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide,
- CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer), and CCR5mAb004;
- the invention provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with two, three, four or more additional therapeutic agents.
- a compound of the present invention, or a pharmaceutically acceptable salt, thereof is combined with two, three, four or more additional therapeutic agents selected from the classes of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors and other drug for treating HIV.
- the two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents.
- the invention provides for a combination pharmaceutical agent comprising:
- a compound of the invention e.g. a compound of Formula I
- a compound of Formula I e.g. a compound of Formula I
- the invention provides a combination pharmaceutical agent comprising:
- a compound of the invention e.g. a compound of Formula I
- a compound of Formula I e.g. a compound of Formula I
- HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors and other drug for treating HIV.
- any compound of the invention with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
- the combination therapy may be administered as a simultaneous or sequential regimen.
- the combination When administered sequentially, the combination may be administered in two or more adininistrations.
- Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
- Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
- a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
- a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
- the combination therapy may provide "synergy” and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
- a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
- a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes.
- an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
- the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non- nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drug for treating HI V .
- additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non- nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors
- the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of:
- HIV protease inhibiting compounds selected from the group consisting of
- amprenavir atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147
- HIV non-nucleoside inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, rilpivirene, BILR 355 BS, VRX 840773, UK-453061, and RDEA806;
- HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ⁇ -FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), ; (4) HIV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, GS-7340 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chi
- HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of
- 3,5-dicaffeoylquinic acid 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011 and dolutegravir;
- gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide,
- CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer), and CCR5mAb004;
- the compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the
- Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin,
- hydroxyalkylcellulose hydroxyalkylmethylcellulose, stearic acid and the like.
- the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
- the formulations both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
- the formulations include those suitable for the foregoing administration routes.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
- Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be administered as a bolus, electuary or paste.
- a tablet is made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
- the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
- the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
- the active ingredients may be formulated in a cream with an oil- in-water cream base.
- the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
- the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
- the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
- the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
- the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
- Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
- the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
- the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
- Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
- compositions according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
- Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
- Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
- excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
- inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
- granulating and disintegrating agents such as maize starch, or alginic acid
- binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia
- lubricating agents such as magnesium stearate, stearic acid or talc.
- Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
- Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example calcium phosphate or kaolin
- an oil medium such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. , polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g.,
- heptadecaethyleneoxycetanol a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
- the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p- hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
- Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
- These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
- Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
- a dispersing or wetting agent e.g., sodium tartrate
- suspending agent e.g., sodium EDTA
- preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
- the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
- the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
- Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
- the emulsion may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
- sweetening agents such as glycerol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
- compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
- a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile fixed oils may conventionally be employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic
- a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
- the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
- an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
- Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
- the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
- Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
- Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
- Suitable formulations include aqueous or oily solutions of the active ingredient.
- Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
- sterile liquid carrier for example water for injection
- Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
- Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
- formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
- the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier.
- Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
- Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provides compositions comprising one or more compounds of the invention formulated for sustained or controlled release.
- Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
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Abstract
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Priority Applications (22)
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AP2013007249A AP2013007249A0 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
BR112013027096A BR112013027096A2 (en) | 2011-04-21 | 2012-04-20 | benzothiazole compounds and their pharmaceutical use |
EA201391395A EA024952B1 (en) | 2011-04-21 | 2012-04-20 | Benzothiazoles and their use for treating an hiv infection |
AU2012245187A AU2012245187B2 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
JP2014506609A JP5918848B2 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
ES12719182.3T ES2615734T3 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
KR1020137030857A KR20140027295A (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
MX2013012266A MX2013012266A (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use. |
CA2833377A CA2833377C (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
US14/112,473 US9006229B2 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
UAA201312204A UA111841C2 (en) | 2011-04-21 | 2012-04-20 | BENZOTHIAZOL COMPOUNDS AND THEIR PHARMACEUTICAL APPLICATION |
SG2013077110A SG194512A1 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
CN201280029211.7A CN103797001B (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compound and application pharmaceutically thereof |
NZ617996A NZ617996B2 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
EP12719182.3A EP2699558B1 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
EP16196723.7A EP3181555B1 (en) | 2011-04-21 | 2012-04-20 | Benzothiazole compounds and their pharmaceutical use |
IL228925A IL228925A0 (en) | 2011-04-21 | 2013-10-17 | Benzothiazole compounds and their pharmaceutical use |
MA36432A MA35804B1 (en) | 2011-04-21 | 2013-11-14 | Modulation of the expression of the hepatitis b virus (vhb) |
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---|---|---|---|---|
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WO2014119636A1 (en) | 2013-01-31 | 2014-08-07 | 塩野義製薬株式会社 | Hiv replication inhibitor |
WO2014134566A2 (en) | 2013-03-01 | 2014-09-04 | Gilead Sciences, Inc. | Therapeutic compounds |
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WO2015006733A1 (en) | 2013-07-12 | 2015-01-15 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their use for the treatment of hiv infections |
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US9006229B2 (en) | 2011-04-21 | 2015-04-14 | Gilead Sciences, Inc. | Benzothiazole compounds and their pharmaceutical use |
US9102614B2 (en) | 2010-07-02 | 2015-08-11 | Gilead Sciences, Inc. | Naphth-2-ylacetic acid derivatives to treat AIDS |
WO2015123230A1 (en) | 2014-02-12 | 2015-08-20 | Bristol-Myers Squibb Company | Benzothiazole macrocycles as inhibitors of human immunodeficiency virus replication |
WO2016007765A1 (en) | 2014-07-11 | 2016-01-14 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of hiv |
WO2016036759A1 (en) | 2014-09-04 | 2016-03-10 | Gilead Sciences, Inc. | Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir |
US9284323B2 (en) | 2012-01-04 | 2016-03-15 | Gilead Sciences, Inc. | Naphthalene acetic acid derivatives against HIV infection |
US9290468B2 (en) | 2012-01-17 | 2016-03-22 | Shanghai Kechow Pharma, Inc. | Benzoheterocyclic compounds and use thereof |
US9296758B2 (en) | 2010-07-02 | 2016-03-29 | Gilead Sciences, Inc. | 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds |
US9376392B2 (en) | 2012-01-04 | 2016-06-28 | Gilead Sciences, Inc. | 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS |
WO2016106237A1 (en) | 2014-12-23 | 2016-06-30 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
WO2016105532A1 (en) | 2014-12-24 | 2016-06-30 | Gilead Sciences, Inc. | Fused pyrimidine compounds for the treatment of hiv |
WO2016105564A1 (en) | 2014-12-24 | 2016-06-30 | Gilead Sciences, Inc. | Quinazoline derivatives used to treat hiv |
WO2016105534A1 (en) | 2014-12-24 | 2016-06-30 | Gilead Sciences, Inc. | Isoquinoline compounds for the treatment of hiv |
WO2016141092A1 (en) | 2015-03-04 | 2016-09-09 | Gilead Sciences, Inc. | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds |
WO2016161382A1 (en) | 2015-04-02 | 2016-10-06 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
WO2017035230A1 (en) | 2015-08-26 | 2017-03-02 | Gilead Sciences, Inc. | Deuterated toll-like receptor modulators |
WO2017059120A1 (en) | 2015-09-30 | 2017-04-06 | Gilead Sciences, Inc. | Compounds and combinations for the treatment of hiv |
WO2017106346A2 (en) | 2015-12-15 | 2017-06-22 | Gilead Sciences, Inc. | Human immunodeficiency virus neutralizing antibodies |
WO2018035359A1 (en) | 2016-08-19 | 2018-02-22 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
WO2018045144A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
WO2018042331A1 (en) | 2016-08-31 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Combinations and uses and treatments thereof |
WO2018042332A1 (en) | 2016-08-31 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Combinations and uses and treatments thereof |
WO2018045150A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators |
WO2018051250A1 (en) | 2016-09-14 | 2018-03-22 | Viiv Healthcare Company | Combination comprising tenofovir alafenamide, bictegravir and 3tc |
WO2018064080A1 (en) | 2016-09-28 | 2018-04-05 | Gilead Sciences, Inc. | Benzothiazol-6-yl acetic acid derivatives and their use for treating hiv infection |
WO2018081292A1 (en) | 2016-10-27 | 2018-05-03 | Gilead Sciences, Inc. | Crystalline forms of darunavir free base, hydrate, solvates and salts |
EP3321270A1 (en) | 2014-06-20 | 2018-05-16 | Gilead Sciences, Inc. | Sodium (2r, 5s, 13ar) -7, 9-dioxo-10- ( (2,4,6-trifluorobenzyl) carbamoyl) -2, 3, 4, 5, 7, 9, 13, 13a-octahydro-2, 5-methanopyrido [1',2' : 4.5] pyrazino [2, 1-b] oxazepin-8-olate |
US9975906B2 (en) | 2014-05-16 | 2018-05-22 | Shionogi & Co., Ltd. | Tricyclic heterocycle derivatives having HIV replication inhibitory effect |
WO2018127801A1 (en) | 2017-01-03 | 2018-07-12 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
WO2018127800A1 (en) | 2017-01-03 | 2018-07-12 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
WO2018145021A1 (en) | 2017-02-06 | 2018-08-09 | Gilead Sciences, Inc. | Atazanavir (atv) analogues for treating hiv infections |
WO2018144390A1 (en) | 2017-01-31 | 2018-08-09 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
WO2018237148A1 (en) | 2017-06-21 | 2018-12-27 | Gilead Sciences, Inc. | Multispecific antibodies that target hiv gp120 and cd3 |
WO2019027920A1 (en) | 2017-08-01 | 2019-02-07 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections |
US10202353B2 (en) | 2014-02-28 | 2019-02-12 | Gilead Sciences, Inc. | Therapeutic compounds |
WO2019035904A1 (en) | 2017-08-17 | 2019-02-21 | Gilead Sciences, Inc. | Solid forms of an hiv capsid inhibitor |
WO2019035973A1 (en) | 2017-08-17 | 2019-02-21 | Gilead Sciences, Inc | Choline salt forms of an hiv capsid inhibitor |
WO2019040102A1 (en) | 2017-08-22 | 2019-02-28 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
WO2019075291A1 (en) | 2017-10-13 | 2019-04-18 | Gilead Sciences, Inc. | 1-benzyl-2-imino-4-phenyl-5-oxoimidazolidine derivatives as hiv protease inhibitors |
WO2019084020A1 (en) | 2017-10-24 | 2019-05-02 | Gilead Sciences, Inc. | Methods of treating patients co-infected with a virus and tuberculosis |
WO2019113462A1 (en) | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
WO2019144015A1 (en) | 2018-01-19 | 2019-07-25 | Gilead Sciences, Inc. | Metabolites of bictegravir |
US10370358B2 (en) | 2011-07-06 | 2019-08-06 | Gilead Sciences, Inc. | Compounds for the treatment of HIV |
WO2019161017A1 (en) | 2018-02-15 | 2019-08-22 | Gilead Sciences, Inc. | Pyridine derivatives and their use for treating hiv infection |
WO2019193533A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'2'-cyclic dinucleotides |
WO2019193542A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides |
WO2019193543A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides |
EP3564244A1 (en) | 2014-06-20 | 2019-11-06 | 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 |
WO2019211799A1 (en) | 2018-05-03 | 2019-11-07 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide |
US10494380B2 (en) | 2015-05-29 | 2019-12-03 | Shionogi & Co., Ltd. | Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity |
US10508117B2 (en) | 2014-09-16 | 2019-12-17 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020010107A1 (en) | 2018-07-03 | 2020-01-09 | Gilead Sciences, Inc. | Antibodies that target hiv gp120 and methods of use |
WO2020010223A1 (en) | 2018-07-06 | 2020-01-09 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
WO2020010200A1 (en) | 2018-07-06 | 2020-01-09 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
WO2020018459A1 (en) | 2018-07-16 | 2020-01-23 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of hiv |
WO2020028272A1 (en) | 2018-07-30 | 2020-02-06 | Gilead Sciences, Inc. | Anti-hiv compounds |
WO2020061163A1 (en) | 2018-09-19 | 2020-03-26 | Gilead Sciences, Inc. | Integrase inhibitors for the prevention of hiv |
WO2020072656A1 (en) | 2018-10-03 | 2020-04-09 | Gilead Sciences, Inc. | Imidozopyrimidine derivatives |
WO2020092528A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
WO2020092621A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
US10696657B2 (en) | 2018-02-16 | 2020-06-30 | Gilead Sciences, Inc. | Methods and intermediates for preparing therapeutic compounds |
WO2020176510A1 (en) | 2019-02-25 | 2020-09-03 | Gilead Sciences, Inc. | Protein kinase c agonists |
WO2020176505A1 (en) | 2019-02-25 | 2020-09-03 | Gilead Sciences, Inc. | Protein kinase c agonists |
WO2020178768A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
WO2020178770A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides and prodrugs thereof |
WO2020178769A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides and prodrugs thereof |
WO2020197991A1 (en) | 2019-03-22 | 2020-10-01 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use |
WO2020214716A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | 2-imino-5-oxo-imidazolidine inhibitors of hiv protease |
WO2020214652A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020214663A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020214647A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of an hiv protease inhibitor |
WO2020237025A1 (en) | 2019-05-23 | 2020-11-26 | Gilead Sciences, Inc. | Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors |
WO2020236753A1 (en) | 2019-05-21 | 2020-11-26 | Gilead Sciences, Inc. | Methods of identifying hiv patients sensitive to therapy with gp120 v3 glycan-directed antibodies |
WO2020246910A1 (en) | 2019-06-03 | 2020-12-10 | Александл Васильевич ИВАЩЕНКО | ANNELATED 9-HYDROXY-1,8-DIOXO-1,3,4,8-TETRAHYDRO-2Н-PYRIDO[1,2-α]PYRAZINE-7-CARBOXAMIDES AS HIV INTEGRASE INHIBITORS |
WO2020255038A1 (en) | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and pyridopyrimidine derivatives |
WO2020263830A1 (en) | 2019-06-25 | 2020-12-30 | Gilead Sciences, Inc. | Flt3l-fc fusion proteins and methods of use |
WO2021011544A1 (en) | 2019-07-16 | 2021-01-21 | Gilead Sciences, Inc. | Hiv vaccines and methods of making and using |
WO2021011891A1 (en) | 2019-07-18 | 2021-01-21 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
US10966999B2 (en) | 2017-12-20 | 2021-04-06 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
WO2021108544A1 (en) | 2019-11-26 | 2021-06-03 | Gilead Sciences, Inc. | Capsid inhibitors for the prevention of hiv |
WO2021130638A1 (en) | 2019-12-24 | 2021-07-01 | Carna Biosciences, Inc. | Diacylglycerol kinase modulating compounds |
WO2021173522A1 (en) | 2020-02-24 | 2021-09-02 | Gilead Sciences, Inc. | Tetracyclic compounds for treating hiv infection |
US11110091B2 (en) | 2008-12-09 | 2021-09-07 | Gilead Sciences, Inc. | Modulators of toll-like receptors |
WO2021188959A1 (en) | 2020-03-20 | 2021-09-23 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
WO2021236944A1 (en) | 2020-05-21 | 2021-11-25 | Gilead Sciences, Inc. | Pharmaceutical compositions comprising bictegravir |
US11203610B2 (en) | 2017-12-20 | 2021-12-21 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
WO2021262990A1 (en) | 2020-06-25 | 2021-12-30 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of hiv |
WO2022031894A1 (en) | 2020-08-07 | 2022-02-10 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
WO2022072520A1 (en) | 2020-09-30 | 2022-04-07 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and uses thereof |
WO2022087149A2 (en) | 2020-10-22 | 2022-04-28 | Gilead Sciences, Inc. | Interleukin-2-fc fusion proteins and methods of use |
WO2022103758A1 (en) | 2020-11-11 | 2022-05-19 | Gilead Sciences, Inc. | METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH gp120 CD4 BINDING SITE-DIRECTED ANTIBODIES |
WO2022159387A1 (en) | 2021-01-19 | 2022-07-28 | Gilead Sciences, Inc. | Substituted pyridotriazine compounds and uses thereof |
WO2022245671A1 (en) | 2021-05-18 | 2022-11-24 | Gilead Sciences, Inc. | Methods of using flt3l-fc fusion proteins |
WO2022271659A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271650A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271677A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271684A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
US11548901B2 (en) | 2012-12-21 | 2023-01-10 | Gilead Sciences, Inc. | Substituted 1,4-methanopyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidines for treating viral infections |
US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
WO2023102523A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
WO2023102239A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
WO2023102529A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
WO2023196875A1 (en) | 2022-04-06 | 2023-10-12 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and uses thereof |
WO2024006982A1 (en) | 2022-07-01 | 2024-01-04 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
WO2024015741A1 (en) | 2022-07-12 | 2024-01-18 | Gilead Sciences, Inc. | Hiv immunogenic polypeptides and vaccines and uses thereof |
WO2024044477A1 (en) | 2022-08-26 | 2024-02-29 | Gilead Sciences, Inc. | Dosing and scheduling regimen for broadly neutralizing antibodies |
WO2024076915A1 (en) | 2022-10-04 | 2024-04-11 | Gilead Sciences, Inc. | 4'-thionucleoside analogues and their pharmaceutical use |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2958591A1 (en) * | 2014-08-27 | 2016-03-03 | VIIV Healthcare UK (No.5) Limited | Inhibitors of human immunodeficiency virus replication |
CA2997955A1 (en) | 2015-09-15 | 2017-03-23 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of hiv |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2403682A1 (en) * | 1973-01-23 | 1974-07-25 | Tokyo Tanabe Co | 3-METHYL-2-PHENYL-5-BENZOTHIAZOLIC ACID COMPOUNDS AND METHOD FOR THEIR PRODUCTION |
US3895028A (en) * | 1972-09-12 | 1975-07-15 | Tokyo Tanabe Co | Alpha-(2-phenylbenzothiazol-5-yl)propionic acid |
EP0017543A1 (en) * | 1979-04-03 | 1980-10-15 | Albert ROLLAND S.A. Société dite | Benzothiazole derivatives, process for their preparation and their therapeutical uses |
GB2154583A (en) * | 1984-02-13 | 1985-09-11 | Roussel Lab Ltd | pyrimidobenzthiazoles |
US4816570A (en) | 1982-11-30 | 1989-03-28 | The Board Of Regents Of The University Of Texas System | Biologically reversible phosphate and phosphonate protective groups |
US4968788A (en) | 1986-04-04 | 1990-11-06 | Board Of Regents, The University Of Texas System | Biologically reversible phosphate and phosphonate protective gruops |
WO1991019721A1 (en) | 1990-06-13 | 1991-12-26 | Arnold Glazier | Phosphorous produgs |
US5663159A (en) | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
WO1999052850A1 (en) | 1998-04-09 | 1999-10-21 | Merck & Co., Inc. | Oxidation process using periodic acid |
WO2004014371A1 (en) * | 2002-08-02 | 2004-02-19 | Tibotec Pharmaceuticals Ltd. | Broadspectrum 2-amino-benzothiazole sulfonamide hiv protease inhibitors |
WO2005120508A1 (en) * | 2004-06-03 | 2005-12-22 | Bristol-Myers Squibb Company | Benzothiazole antiviral agents |
WO2007016392A2 (en) * | 2005-08-01 | 2007-02-08 | Bristol-Myers Squibb Company | Benzothiazole and azabenzothiazole compounds useful as kinase inhibitors |
WO2007147884A1 (en) * | 2006-06-23 | 2007-12-27 | Tibotec Pharmaceuticals Ltd. | 2-(substituted-amino)-benzothiazole sulfonamide hiv protease inhibitors |
Family Cites Families (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03287558A (en) | 1990-04-05 | 1991-12-18 | Teijin Ltd | Enzyme inhibitor |
US5733906A (en) | 1993-10-12 | 1998-03-31 | Eli Lilly And Company | Inhibitors of HIV Protease useful for the treatment of Aids |
MX9308016A (en) | 1992-12-22 | 1994-08-31 | Lilly Co Eli | HUMAN IMMUNODEFICIENCY VIRUS PROTEASE INHIBITING COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL FORMULATION CONTAINING THEM. |
EP0693126B9 (en) | 1993-04-02 | 2007-09-12 | Rigel Pharmaceuticals, Inc. | Method for selective inactivation of viral replication |
JP3287558B2 (en) | 1993-07-27 | 2002-06-04 | 株式会社半導体エネルギー研究所 | Method for manufacturing semiconductor device |
US5434188A (en) | 1994-03-07 | 1995-07-18 | Warner-Lambert Company | 1-ether and 1-thioether-naphthalene-2-carboxamides as inhibitors of cell adhesion and as inhibitors of the activation of HIV |
DE4428932A1 (en) | 1994-08-16 | 1996-02-22 | Hoechst Ag | Substituted quinoline derivatives, process for their preparation and their use |
WO2000063152A1 (en) | 1999-02-22 | 2000-10-26 | The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Acetylated and related analogues of chicoric acid as hiv integrase inhibitors |
US20020052323A1 (en) | 2000-08-30 | 2002-05-02 | Jinhai Wang | Quinoline-(C=O)-(multiple amino acids)-leaving group compounds for pharmaceutical compositions and reagents |
WO2002042773A2 (en) | 2000-11-21 | 2002-05-30 | Sunesis Pharmaceuticals, Inc. | An extended tethering approach for rapid identification of ligands |
FR2819507B1 (en) | 2001-01-17 | 2007-09-28 | Inst Rech Developpement Ird | SUBSTITUTED QUINOLINES FOR THE TREATMENT OF PROTOZOAN AND RETROVIRUS CO-INFECTIONS |
FR2839646B1 (en) | 2002-05-17 | 2008-04-11 | Bioalliance Pharma | USE OF QUINOLINE DERIVATIVES WITH ANTI-INTEGRASE EFFECT AND APPLICATIONS THEREOF |
OA12893A (en) * | 2002-08-02 | 2006-10-13 | Tibotec Pharm Ltd | Broadspectrum 2-Amino-Benzothiazole Sulfonamide HIV Protease Inhibitors. |
JP3908248B2 (en) | 2002-08-13 | 2007-04-25 | 塩野義製薬株式会社 | Heterocyclic compounds having HIV integrase inhibitory activity |
EP2371955A1 (en) | 2002-09-26 | 2011-10-05 | K.U. Leuven Research & Development | Integrase cofactor |
EP1564210B9 (en) | 2002-11-20 | 2010-03-31 | Japan Tobacco Inc. | 4-oxoquinoline compounds and utilization thereof as hiv integrase inhibitors |
UA80571C2 (en) | 2002-11-22 | 2007-10-10 | Lilly Co Eli | Quinolinyl-pyrrolopyrazoles |
CA2520124A1 (en) | 2003-03-28 | 2004-10-14 | Chiron Corporation | Use of benzazole compounds for immunopotentiation |
CN1956975A (en) | 2004-05-21 | 2007-05-02 | 默克公司 | Amino cyclopentyl heterocyclic and carbocyclic modulators of chemokine receptor activity |
RU2352555C2 (en) | 2004-06-22 | 2009-04-20 | Смитклайн Бичем Корпорейшн | CHEMICAL COMPOUNDS, PHARMACEUTICAL CMPOSITION, CONTAINING THEM, THEIR APPLICATION (VERSIONS) AND METHOD OF BINDING ERα AND ERβ -ESTROGEN RECEPTORS |
TWI306401B (en) | 2004-08-13 | 2009-02-21 | Nat Health Research Institutes | Benzothiazolium compounds |
US20060094755A1 (en) | 2004-10-28 | 2006-05-04 | Bioflexis, Llc | Novel quinoline-based metal chelators as antiviral agents |
TWI370820B (en) | 2005-04-27 | 2012-08-21 | Takeda Pharmaceutical | Fused heterocyclic compounds |
WO2006124780A2 (en) | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Ih-benzo [d] imidazole compounds as inhibitors of b-raf kinase |
US7939545B2 (en) | 2006-05-16 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
JP2009538899A (en) | 2006-05-30 | 2009-11-12 | ファイザー・プロダクツ・インク | Triazolopyridazine derivatives |
US8435774B2 (en) | 2006-06-28 | 2013-05-07 | Qiagen Gmbh | Enhancing reactivation of thermostable reversibly inactivated enzymes |
WO2008053478A2 (en) | 2006-10-30 | 2008-05-08 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions and methods for inhibiting hiv-1 replication and integrase activity |
RU2469032C2 (en) | 2006-12-13 | 2012-12-10 | Ф.Хоффманн-Ля Рош Аг | 2-(piperidin-4-yl)-4-phenoxy- or phenylaminopyrimidine derivatives as non nucleoside reverse transcriptase inhibitors |
US7956068B2 (en) * | 2007-11-15 | 2011-06-07 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
JP5269086B2 (en) | 2007-11-15 | 2013-08-21 | ギリアード サイエンシス インコーポレーテッド | Human immunodeficiency virus replication inhibitor |
WO2009062308A1 (en) | 2007-11-16 | 2009-05-22 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
WO2009062285A1 (en) | 2007-11-16 | 2009-05-22 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
GB0801940D0 (en) | 2008-02-01 | 2008-03-12 | Univ Leuven Kath | Inhibitors of lentiviral replication |
WO2009099982A1 (en) | 2008-02-04 | 2009-08-13 | Osi Pharmaceuticals, Inc. | 2-aminopyridine kinase inhibitors |
WO2010059658A1 (en) | 2008-11-20 | 2010-05-27 | Glaxosmithkline Llc | Chemical compounds |
GB0908394D0 (en) | 2009-05-15 | 2009-06-24 | Univ Leuven Kath | Novel viral replication inhibitors |
US8338441B2 (en) | 2009-05-15 | 2012-12-25 | Gilead Sciences, Inc. | Inhibitors of human immunodeficiency virus replication |
JP2012532102A (en) | 2009-06-30 | 2012-12-13 | シガ・テクノロジーズ・インコーポレーテッド | Treatment and prevention of dengue virus infection |
GB0913636D0 (en) | 2009-08-05 | 2009-09-16 | Univ Leuven Kath | Novel viral replication inhibitors |
US9095596B2 (en) | 2009-10-15 | 2015-08-04 | Southern Research Institute | Treatment of neurodegenerative diseases, causation of memory enhancement, and assay for screening compounds for such |
PT2516008E (en) | 2009-12-23 | 2014-07-16 | Univ Leuven Kath | Novel antiviral compounds |
US20110223131A1 (en) | 2010-02-24 | 2011-09-15 | Gilead Sciences, Inc. | Antiviral compounds |
EP2576549A4 (en) | 2010-05-24 | 2013-12-18 | Univ Rochester | Bicyclic heteroaryl kinase inhibitors and methods of use |
JP5984218B2 (en) | 2010-07-02 | 2016-09-06 | ギリアード サイエンシーズ, インコーポレイテッド | Naphtho-2-ylacetic acid derivatives for treating AIDS |
WO2012003498A1 (en) | 2010-07-02 | 2012-01-05 | Gilead Sciences, Inc. | 2 -quinolinyl- acetic acid derivatives as hiv antiviral compounds |
US8633200B2 (en) | 2010-09-08 | 2014-01-21 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
WO2012065963A2 (en) | 2010-11-15 | 2012-05-24 | Katholieke Universiteit Leuven | Novel antiviral compounds |
BR112013011991A2 (en) | 2010-11-15 | 2016-08-30 | Viiv Healthcare Uk Ltd | compound, pharmaceutical composition, use of a compound, treatment method, product, and kit. |
AR084457A1 (en) | 2010-12-22 | 2013-05-15 | Lundbeck & Co As H | BICYCLE DERIVATIVES [3,2,1] OCTILAMIDE |
US9029391B2 (en) | 2011-01-24 | 2015-05-12 | Viiv Healthcare Uk Limited | Isoquinoline compounds and methods for treating HIV |
JP2014510139A (en) | 2011-04-04 | 2014-04-24 | ギリアード サイエンシーズ, インコーポレイテッド | HIV inhibitor in solid form |
AU2012240314A1 (en) | 2011-04-04 | 2013-05-02 | Gilead Sciences, Inc. | Process for the preparation of an HIV integrase inhibitor |
EP2508511A1 (en) | 2011-04-07 | 2012-10-10 | Laboratoire Biodim | Inhibitors of viral replication, their process of preparation and their therapeutical uses |
EP2511273B8 (en) | 2011-04-15 | 2019-06-26 | Hivih | Inhibitors of viral replication, their process of preparation and their therapeutical uses |
DK2699575T3 (en) | 2011-04-21 | 2015-06-22 | Bayer Ip Gmbh | TRIAZOLOPYRIDINES |
US9499535B2 (en) | 2011-04-21 | 2016-11-22 | Origenis Gmbh | Kinase inhibitors |
KR20140027295A (en) | 2011-04-21 | 2014-03-06 | 길리애드 사이언시즈, 인코포레이티드 | Benzothiazole compounds and their pharmaceutical use |
MX363696B (en) | 2011-04-21 | 2019-03-28 | Origenis Gmbh | Pyrazolo [4, 3-d] pyrimidines useful as kinase inhibitors. |
WO2013002357A1 (en) | 2011-06-30 | 2013-01-03 | 塩野義製薬株式会社 | Hiv replication inhibitor |
US8791108B2 (en) | 2011-08-18 | 2014-07-29 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
EP2757887B1 (en) | 2011-09-22 | 2017-04-26 | VIIV Healthcare UK Limited | Pyrrolopyridinone compounds and methods for treating hiv |
WO2013058448A1 (en) | 2011-10-20 | 2013-04-25 | 한국해양연구원 | Marine medaka genes responding to the exposure of endocrine-disrupting chemicals, and method for diagnosing an aquatic eco-system contamination using same |
JP6099149B2 (en) | 2011-10-25 | 2017-03-22 | 塩野義製薬株式会社 | HIV replication inhibitor |
US8332160B1 (en) * | 2011-11-17 | 2012-12-11 | Amyris Biotechnologies, Inc. | Systems and methods for engineering nucleic acid constructs using scoring techniques |
US9284323B2 (en) | 2012-01-04 | 2016-03-15 | Gilead Sciences, Inc. | Naphthalene acetic acid derivatives against HIV infection |
WO2013103724A1 (en) | 2012-01-04 | 2013-07-11 | Gilead Sciences, Inc. | 2- (tert - butoxy) -2- (7 -methylquinolin- 6 - yl) acetic acid derivatives for treating aids |
EP3608317A1 (en) | 2012-01-12 | 2020-02-12 | Yale University | Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase |
US8629276B2 (en) | 2012-02-15 | 2014-01-14 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
US9034882B2 (en) | 2012-03-05 | 2015-05-19 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
US9006235B2 (en) | 2012-03-06 | 2015-04-14 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
WO2013157622A1 (en) | 2012-04-19 | 2013-10-24 | 塩野義製薬株式会社 | Hiv replication inhibitor |
PE20141558A1 (en) | 2012-04-20 | 2014-11-06 | Gilead Sciences Inc | DERIVATIVES OF BENZOTHIAZOLE-6-IL ACETIC ACID AND THEIR USE TO TREAT HIV INFECTION |
CA2876370A1 (en) | 2012-07-12 | 2014-01-16 | Viiv Healthcare Uk Limited | Compounds and methods for treating hiv |
US8906929B2 (en) | 2012-08-16 | 2014-12-09 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
US20140094485A1 (en) | 2012-10-03 | 2014-04-03 | Gilead Sciences, Inc. | Solid state forms of hiv inhibitor |
US20140094609A1 (en) | 2012-10-03 | 2014-04-03 | Gilead Sciences, Inc. | Process for the preparation of an hiv integrase inhibitor |
-
2012
- 2012-04-20 KR KR1020137030857A patent/KR20140027295A/en not_active Application Discontinuation
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Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3895028A (en) * | 1972-09-12 | 1975-07-15 | Tokyo Tanabe Co | Alpha-(2-phenylbenzothiazol-5-yl)propionic acid |
DE2403682A1 (en) * | 1973-01-23 | 1974-07-25 | Tokyo Tanabe Co | 3-METHYL-2-PHENYL-5-BENZOTHIAZOLIC ACID COMPOUNDS AND METHOD FOR THEIR PRODUCTION |
EP0017543A1 (en) * | 1979-04-03 | 1980-10-15 | Albert ROLLAND S.A. Société dite | Benzothiazole derivatives, process for their preparation and their therapeutical uses |
US4816570A (en) | 1982-11-30 | 1989-03-28 | The Board Of Regents Of The University Of Texas System | Biologically reversible phosphate and phosphonate protective groups |
GB2154583A (en) * | 1984-02-13 | 1985-09-11 | Roussel Lab Ltd | pyrimidobenzthiazoles |
US4968788A (en) | 1986-04-04 | 1990-11-06 | Board Of Regents, The University Of Texas System | Biologically reversible phosphate and phosphonate protective gruops |
WO1991019721A1 (en) | 1990-06-13 | 1991-12-26 | Arnold Glazier | Phosphorous produgs |
US5663159A (en) | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
US5792756A (en) | 1990-09-14 | 1998-08-11 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
WO1999052850A1 (en) | 1998-04-09 | 1999-10-21 | Merck & Co., Inc. | Oxidation process using periodic acid |
WO2004014371A1 (en) * | 2002-08-02 | 2004-02-19 | Tibotec Pharmaceuticals Ltd. | Broadspectrum 2-amino-benzothiazole sulfonamide hiv protease inhibitors |
WO2005120508A1 (en) * | 2004-06-03 | 2005-12-22 | Bristol-Myers Squibb Company | Benzothiazole antiviral agents |
WO2007016392A2 (en) * | 2005-08-01 | 2007-02-08 | Bristol-Myers Squibb Company | Benzothiazole and azabenzothiazole compounds useful as kinase inhibitors |
WO2007147884A1 (en) * | 2006-06-23 | 2007-12-27 | Tibotec Pharmaceuticals Ltd. | 2-(substituted-amino)-benzothiazole sulfonamide hiv protease inhibitors |
Non-Patent Citations (21)
Title |
---|
"Carbonyl Protecting Groups", pages: 155 - 184 |
"Carboxyl Protecting Groups", pages: 118 - 154 |
"Diol Protecting Groups", pages: 95 - 117 |
"Handbook of Pharmaceutical Excipients", 1986 |
"Hydroxyl Protecting Groups", pages: 21 - 94 |
"McGraw-Hill Dictionary of Chemical Terms", 1984, MCGRAW-HILL BOOK COMPANY |
"Protecting Groups: An Overview", pages: 1 - 20 |
"Remington's Pharmaceutical Sciences", MACK PUBLISHING CO. |
BENZARIA ET AL., J. MED CHEM., vol. 39, 1996, pages 4958 |
BUNDGAARD, HANS: "A Textbook of Drug Design and Development", 1991, HARWOOD ACADEMIC PUBLISHERS, article "Design and Application of Prodrugs", pages: 113 - 191 |
DE LOMBAERT ET AL., J. MED. CHEM., vol. 37, 1994, pages 498 |
ELIEL, E.; WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC. |
FARQUHAR ET AL., J. PHARM. SCI., vol. 72, 1983, pages 24 |
KHAMNEI; TORRENCE, J. MED. CHEM., vol. 39, 1996, pages 4109 - 4115 |
KOCIENSKI, PHILIP J.: "Protecting Groups", 1994, GEORG THIEME VERLAG |
MITCHELL ET AL., J. CHEM. SOC. PERKIN TRANS., 1992, pages 112345 |
PALELLA ET AL., N ENGL. .I MED, vol. 338, 1998, pages 853 - 860 |
PUECH ET AL., ANTIVIRAL RES., vol. 22, 1993, pages 155 - 174 |
RICHMAN, D. D., NATURE, vol. 410, 2001, pages 995 - 1001 |
THEODORA W. GREENE: "Protective Groups in Organic Chemistry", 1991, JOHN WILEY & SONS, INC. |
THEODORA W. GREENE: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC. |
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US11116774B2 (en) | 2014-07-11 | 2021-09-14 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of HIV |
WO2016007765A1 (en) | 2014-07-11 | 2016-01-14 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of hiv |
EP4140485A1 (en) | 2014-07-11 | 2023-03-01 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of hiv |
WO2016036759A1 (en) | 2014-09-04 | 2016-03-10 | Gilead Sciences, Inc. | Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir |
US10508117B2 (en) | 2014-09-16 | 2019-12-17 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
US11072615B2 (en) | 2014-09-16 | 2021-07-27 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
US11773098B2 (en) | 2014-09-16 | 2023-10-03 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
EP3388431A1 (en) | 2014-12-23 | 2018-10-17 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
WO2016106237A1 (en) | 2014-12-23 | 2016-06-30 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
US9701677B2 (en) | 2014-12-24 | 2017-07-11 | Gilead Sciences, Inc. | Fused pyrimidine compounds |
WO2016105532A1 (en) | 2014-12-24 | 2016-06-30 | Gilead Sciences, Inc. | Fused pyrimidine compounds for the treatment of hiv |
WO2016105564A1 (en) | 2014-12-24 | 2016-06-30 | Gilead Sciences, Inc. | Quinazoline derivatives used to treat hiv |
US9730936B2 (en) | 2014-12-24 | 2017-08-15 | Gilead Sciences, Inc. | Quinazoline compounds |
WO2016105534A1 (en) | 2014-12-24 | 2016-06-30 | Gilead Sciences, Inc. | Isoquinoline compounds for the treatment of hiv |
US9624195B2 (en) | 2014-12-24 | 2017-04-18 | Gilead Sciences, Inc. | Isoquinoline compounds |
EP4302830A2 (en) | 2014-12-24 | 2024-01-10 | Gilead Sciences, Inc. | Quinazoline derivatives used to treat hiv |
EP3960735A1 (en) | 2014-12-24 | 2022-03-02 | Gilead Sciences, Inc. | Quinazoline derivatives used to treat hiv |
EP3521282A1 (en) | 2014-12-24 | 2019-08-07 | Gilead Sciences, Inc. | Quinazoline derivatives used to treat hiv |
US10548898B2 (en) | 2014-12-24 | 2020-02-04 | Gilead Sciences Inc. | Quinazoline compounds |
US11304948B2 (en) | 2014-12-24 | 2022-04-19 | Gilead Sciences, Inc. | Quinazoline compounds |
US10206926B2 (en) | 2014-12-24 | 2019-02-19 | Gilead Sciences, Inc. | Quinazoline compounds |
US11628181B2 (en) | 2014-12-26 | 2023-04-18 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
WO2016141092A1 (en) | 2015-03-04 | 2016-09-09 | Gilead Sciences, Inc. | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds |
EP3722297A1 (en) | 2015-03-04 | 2020-10-14 | Gilead Sciences, Inc. | Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds |
EP3321265A1 (en) | 2015-03-04 | 2018-05-16 | Gilead Sciences, Inc. | 4,6-diamino-pyrido[3,2-d]pyrimidine compounds and their utilisation as modulators of toll-like receptors |
WO2016161382A1 (en) | 2015-04-02 | 2016-10-06 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
EP3736274A1 (en) | 2015-04-02 | 2020-11-11 | Gilead Sciences, Inc. | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
US10494380B2 (en) | 2015-05-29 | 2019-12-03 | Shionogi & Co., Ltd. | Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity |
US10870661B2 (en) | 2015-05-29 | 2020-12-22 | Shionogi & Co., Ltd. | Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity |
WO2017035230A1 (en) | 2015-08-26 | 2017-03-02 | Gilead Sciences, Inc. | Deuterated toll-like receptor modulators |
WO2017059120A1 (en) | 2015-09-30 | 2017-04-06 | Gilead Sciences, Inc. | Compounds and combinations for the treatment of hiv |
EP3992206A1 (en) | 2015-12-15 | 2022-05-04 | Gilead Sciences, Inc. | Human immunodeficiency virus neutralizing antibodies |
WO2017106346A2 (en) | 2015-12-15 | 2017-06-22 | Gilead Sciences, Inc. | Human immunodeficiency virus neutralizing antibodies |
EP3597646A1 (en) | 2016-08-19 | 2020-01-22 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
US11993583B2 (en) | 2016-08-19 | 2024-05-28 | Gilead Sciences, Inc. | Therapeutic compounds |
WO2018035359A1 (en) | 2016-08-19 | 2018-02-22 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
US10071985B2 (en) | 2016-08-19 | 2018-09-11 | Gilead Sciences, Inc. | Therapeutic compounds |
US10654827B2 (en) | 2016-08-19 | 2020-05-19 | Gilead Sciences, Inc. | Therapeutic compounds |
EP4265299A2 (en) | 2016-08-19 | 2023-10-25 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
WO2018042331A1 (en) | 2016-08-31 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Combinations and uses and treatments thereof |
WO2018042332A1 (en) | 2016-08-31 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Combinations and uses and treatments thereof |
WO2018045144A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
WO2018045150A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators |
WO2018051250A1 (en) | 2016-09-14 | 2018-03-22 | Viiv Healthcare Company | Combination comprising tenofovir alafenamide, bictegravir and 3tc |
WO2018064080A1 (en) | 2016-09-28 | 2018-04-05 | Gilead Sciences, Inc. | Benzothiazol-6-yl acetic acid derivatives and their use for treating hiv infection |
WO2018081292A1 (en) | 2016-10-27 | 2018-05-03 | Gilead Sciences, Inc. | Crystalline forms of darunavir free base, hydrate, solvates and salts |
WO2018127801A1 (en) | 2017-01-03 | 2018-07-12 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
WO2018127800A1 (en) | 2017-01-03 | 2018-07-12 | VIIV Healthcare UK (No.5) Limited | Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication |
WO2018144390A1 (en) | 2017-01-31 | 2018-08-09 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
EP4424374A2 (en) | 2017-01-31 | 2024-09-04 | Gilead Sciences, Inc. | Crystalline forms of tenofovir alafenamide |
US11078208B1 (en) | 2017-02-06 | 2021-08-03 | Gilead Sciences, Inc. | HIV inhibitor compounds |
EP3909949A1 (en) | 2017-02-06 | 2021-11-17 | Gilead Sciences, Inc. | Atazanavir (atv) analogues for treating hiv infections |
US12084455B2 (en) | 2017-02-06 | 2024-09-10 | Gilead Sciences, Inc. | HIV inhibitor compounds |
WO2018145021A1 (en) | 2017-02-06 | 2018-08-09 | Gilead Sciences, Inc. | Atazanavir (atv) analogues for treating hiv infections |
US10752636B2 (en) | 2017-02-06 | 2020-08-25 | Gilead Sciences, Inc. | HIV inhibitor compounds |
WO2018237148A1 (en) | 2017-06-21 | 2018-12-27 | Gilead Sciences, Inc. | Multispecific antibodies that target hiv gp120 and cd3 |
WO2019027920A1 (en) | 2017-08-01 | 2019-02-07 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections |
EP3960740A1 (en) | 2017-08-01 | 2022-03-02 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) vanillate for treating viral infections |
US10851125B2 (en) | 2017-08-01 | 2020-12-01 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate |
US11833143B2 (en) | 2017-08-17 | 2023-12-05 | Gilead Sciences, Inc. | Choline salt forms of an HIV capsid inhibitor |
US10849892B2 (en) | 2017-08-17 | 2020-12-01 | Gilead Sciences, Inc. | Choline salt forms of an HIV capsid inhibitor |
WO2019035904A1 (en) | 2017-08-17 | 2019-02-21 | Gilead Sciences, Inc. | Solid forms of an hiv capsid inhibitor |
US11266638B2 (en) | 2017-08-17 | 2022-03-08 | Gilead Sciences, Inc. | Choline salt forms of an HIV capsid inhibitor |
EP4382105A2 (en) | 2017-08-17 | 2024-06-12 | Gilead Sciences, Inc. | Choline salt forms of an hiv capsid inhibitor |
EP4046994A1 (en) | 2017-08-17 | 2022-08-24 | Gilead Sciences, Inc. | Choline salt forms of an hiv capsid inhibitor |
EP4092020A1 (en) | 2017-08-17 | 2022-11-23 | Gilead Sciences, Inc. | Solid forms of an hiv capsid inhibitor |
US11845739B2 (en) | 2017-08-17 | 2023-12-19 | Gilead Sciences, Inc. | Solid forms of an HIV capsid inhibitor |
WO2019035973A1 (en) | 2017-08-17 | 2019-02-21 | Gilead Sciences, Inc | Choline salt forms of an hiv capsid inhibitor |
US11267799B2 (en) | 2017-08-17 | 2022-03-08 | Gilead Sciences, Inc. | Solid forms of an HIV capsid inhibitor |
WO2019040102A1 (en) | 2017-08-22 | 2019-02-28 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
WO2019075291A1 (en) | 2017-10-13 | 2019-04-18 | Gilead Sciences, Inc. | 1-benzyl-2-imino-4-phenyl-5-oxoimidazolidine derivatives as hiv protease inhibitors |
WO2019084020A1 (en) | 2017-10-24 | 2019-05-02 | Gilead Sciences, Inc. | Methods of treating patients co-infected with a virus and tuberculosis |
WO2019113462A1 (en) | 2017-12-07 | 2019-06-13 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11331331B2 (en) | 2017-12-07 | 2022-05-17 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11903959B2 (en) | 2017-12-07 | 2024-02-20 | Emory University | N4-hydroxycytidine and derivatives and anti-viral uses related thereto |
US11203610B2 (en) | 2017-12-20 | 2021-12-21 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
US10966999B2 (en) | 2017-12-20 | 2021-04-06 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
WO2019144015A1 (en) | 2018-01-19 | 2019-07-25 | Gilead Sciences, Inc. | Metabolites of bictegravir |
US11253524B2 (en) | 2018-01-19 | 2022-02-22 | Gilead Sciences, Inc. | Metabolites of bictegravir |
US11267801B2 (en) | 2018-02-15 | 2022-03-08 | Gilead Sciences, Inc. | Therapeutic compounds |
WO2019161017A1 (en) | 2018-02-15 | 2019-08-22 | Gilead Sciences, Inc. | Pyridine derivatives and their use for treating hiv infection |
US11753399B2 (en) | 2018-02-15 | 2023-09-12 | Gilead Sciences, Inc. | Therapeutic compounds |
US10836746B2 (en) | 2018-02-15 | 2020-11-17 | Gilead Sciences, Inc. | Therapeutic compounds |
US11760746B2 (en) | 2018-02-16 | 2023-09-19 | Gilead Sciences, Inc. | Methods and intermediates for preparing therapeutic compounds |
US11117886B2 (en) | 2018-02-16 | 2021-09-14 | Gilead Sciences, Inc. | Methods and intermediates for preparing therapeutic compounds |
US10696657B2 (en) | 2018-02-16 | 2020-06-30 | Gilead Sciences, Inc. | Methods and intermediates for preparing therapeutic compounds |
US11149052B2 (en) | 2018-04-06 | 2021-10-19 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2′3′-cyclic dinucleotides |
WO2019193533A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'2'-cyclic dinucleotides |
WO2019193542A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides |
WO2019193543A1 (en) | 2018-04-06 | 2019-10-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides |
US11292812B2 (en) | 2018-04-06 | 2022-04-05 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′-cyclic dinucleotides |
WO2019211799A1 (en) | 2018-05-03 | 2019-11-07 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide |
EP4257600A2 (en) | 2018-07-03 | 2023-10-11 | Gilead Sciences, Inc. | Antibodies that target hiv gp120 and methods of use |
WO2020010107A1 (en) | 2018-07-03 | 2020-01-09 | Gilead Sciences, Inc. | Antibodies that target hiv gp120 and methods of use |
WO2020010223A1 (en) | 2018-07-06 | 2020-01-09 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
US11186579B2 (en) | 2018-07-06 | 2021-11-30 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
WO2020010200A1 (en) | 2018-07-06 | 2020-01-09 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
US11098027B2 (en) | 2018-07-06 | 2021-08-24 | Gilead Sciences, Inc. | Therapeutic heterocyclic compounds |
WO2020018459A1 (en) | 2018-07-16 | 2020-01-23 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of hiv |
US11944611B2 (en) | 2018-07-16 | 2024-04-02 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of HIV |
US11052087B2 (en) | 2018-07-30 | 2021-07-06 | Gilead Sciences, Inc. | Anti-HIV compounds |
WO2020028272A1 (en) | 2018-07-30 | 2020-02-06 | Gilead Sciences, Inc. | Anti-hiv compounds |
WO2020061163A1 (en) | 2018-09-19 | 2020-03-26 | Gilead Sciences, Inc. | Integrase inhibitors for the prevention of hiv |
WO2020072656A1 (en) | 2018-10-03 | 2020-04-09 | Gilead Sciences, Inc. | Imidozopyrimidine derivatives |
WO2020092621A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
WO2020092528A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
EP4371987A1 (en) | 2018-10-31 | 2024-05-22 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
WO2020176510A1 (en) | 2019-02-25 | 2020-09-03 | Gilead Sciences, Inc. | Protein kinase c agonists |
WO2020176505A1 (en) | 2019-02-25 | 2020-09-03 | Gilead Sciences, Inc. | Protein kinase c agonists |
WO2020178768A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
WO2020178770A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides and prodrugs thereof |
US11766447B2 (en) | 2019-03-07 | 2023-09-26 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
WO2020178769A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides and prodrugs thereof |
WO2020197991A1 (en) | 2019-03-22 | 2020-10-01 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use |
EP4122537A1 (en) | 2019-03-22 | 2023-01-25 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use |
WO2020214652A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020214647A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of an hiv protease inhibitor |
WO2020214663A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | Solid forms of a toll-like receptor modulator |
WO2020214716A1 (en) | 2019-04-17 | 2020-10-22 | Gilead Sciences, Inc. | 2-imino-5-oxo-imidazolidine inhibitors of hiv protease |
WO2020236753A1 (en) | 2019-05-21 | 2020-11-26 | Gilead Sciences, Inc. | Methods of identifying hiv patients sensitive to therapy with gp120 v3 glycan-directed antibodies |
WO2020237025A1 (en) | 2019-05-23 | 2020-11-26 | Gilead Sciences, Inc. | Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors |
WO2020246910A1 (en) | 2019-06-03 | 2020-12-10 | Александл Васильевич ИВАЩЕНКО | ANNELATED 9-HYDROXY-1,8-DIOXO-1,3,4,8-TETRAHYDRO-2Н-PYRIDO[1,2-α]PYRAZINE-7-CARBOXAMIDES AS HIV INTEGRASE INHIBITORS |
WO2020255038A1 (en) | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and pyridopyrimidine derivatives |
WO2020263830A1 (en) | 2019-06-25 | 2020-12-30 | Gilead Sciences, Inc. | Flt3l-fc fusion proteins and methods of use |
WO2021011544A1 (en) | 2019-07-16 | 2021-01-21 | Gilead Sciences, Inc. | Hiv vaccines and methods of making and using |
WO2021011891A1 (en) | 2019-07-18 | 2021-01-21 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
US11807625B2 (en) | 2019-11-26 | 2023-11-07 | Gilead Sciences, Inc. | Capsid inhibitors for the prevention of HIV |
WO2021108544A1 (en) | 2019-11-26 | 2021-06-03 | Gilead Sciences, Inc. | Capsid inhibitors for the prevention of hiv |
WO2021130638A1 (en) | 2019-12-24 | 2021-07-01 | Carna Biosciences, Inc. | Diacylglycerol kinase modulating compounds |
WO2021173522A1 (en) | 2020-02-24 | 2021-09-02 | Gilead Sciences, Inc. | Tetracyclic compounds for treating hiv infection |
WO2021188959A1 (en) | 2020-03-20 | 2021-09-23 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
WO2021236944A1 (en) | 2020-05-21 | 2021-11-25 | Gilead Sciences, Inc. | Pharmaceutical compositions comprising bictegravir |
US11680064B2 (en) | 2020-06-25 | 2023-06-20 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of HIV |
US12077537B2 (en) | 2020-06-25 | 2024-09-03 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of HIV |
WO2021262990A1 (en) | 2020-06-25 | 2021-12-30 | Gilead Sciences, Inc. | Capsid inhibitors for the treatment of hiv |
WO2022031894A1 (en) | 2020-08-07 | 2022-02-10 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
WO2022072520A1 (en) | 2020-09-30 | 2022-04-07 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and uses thereof |
WO2022087149A2 (en) | 2020-10-22 | 2022-04-28 | Gilead Sciences, Inc. | Interleukin-2-fc fusion proteins and methods of use |
WO2022103758A1 (en) | 2020-11-11 | 2022-05-19 | Gilead Sciences, Inc. | METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH gp120 CD4 BINDING SITE-DIRECTED ANTIBODIES |
WO2022159387A1 (en) | 2021-01-19 | 2022-07-28 | Gilead Sciences, Inc. | Substituted pyridotriazine compounds and uses thereof |
EP4321217A2 (en) | 2021-01-19 | 2024-02-14 | Gilead Sciences, Inc. | Substituted pyridotriazine compounds and uses thereof |
WO2022245671A1 (en) | 2021-05-18 | 2022-11-24 | Gilead Sciences, Inc. | Methods of using flt3l-fc fusion proteins |
WO2022271684A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271677A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271650A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2022271659A1 (en) | 2021-06-23 | 2022-12-29 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
WO2023102523A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
WO2023102529A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
WO2023102239A1 (en) | 2021-12-03 | 2023-06-08 | Gilead Sciences, Inc. | Therapeutic compounds for hiv virus infection |
US11787825B2 (en) | 2021-12-03 | 2023-10-17 | Gilead Sciences, Inc. | Therapeutic compounds for HIV virus infection |
US12084467B2 (en) | 2021-12-03 | 2024-09-10 | Gilead Sciences, Inc. | Therapeutic compounds for HIV virus infection |
WO2023196875A1 (en) | 2022-04-06 | 2023-10-12 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and uses thereof |
EP4310087A1 (en) | 2022-04-06 | 2024-01-24 | Gilead Sciences, Inc. | Bridged tricyclic carbamoylpyridone compounds and uses thereof |
WO2024006982A1 (en) | 2022-07-01 | 2024-01-04 | Gilead Sciences, Inc. | Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection |
WO2024015741A1 (en) | 2022-07-12 | 2024-01-18 | Gilead Sciences, Inc. | Hiv immunogenic polypeptides and vaccines and uses thereof |
WO2024044477A1 (en) | 2022-08-26 | 2024-02-29 | Gilead Sciences, Inc. | Dosing and scheduling regimen for broadly neutralizing antibodies |
WO2024076915A1 (en) | 2022-10-04 | 2024-04-11 | Gilead Sciences, Inc. | 4'-thionucleoside analogues and their pharmaceutical use |
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