AU2015315174B2 - Smyd inhibitors - Google Patents
Smyd inhibitors Download PDFInfo
- Publication number
- AU2015315174B2 AU2015315174B2 AU2015315174A AU2015315174A AU2015315174B2 AU 2015315174 B2 AU2015315174 B2 AU 2015315174B2 AU 2015315174 A AU2015315174 A AU 2015315174A AU 2015315174 A AU2015315174 A AU 2015315174A AU 2015315174 B2 AU2015315174 B2 AU 2015315174B2
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- optionally substituted
- group
- optionally
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 239000003112 inhibitor Substances 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 150000003839 salts Chemical class 0.000 claims abstract description 86
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 51
- 201000011510 cancer Diseases 0.000 claims abstract description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 469
- -1 1-imidazolyl Chemical group 0.000 claims description 337
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 108
- 125000001072 heteroaryl group Chemical group 0.000 claims description 105
- 125000003282 alkyl amino group Chemical group 0.000 claims description 71
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 71
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 69
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 66
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 125000005518 carboxamido group Chemical group 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims description 21
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 14
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 12
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 12
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 125000005466 alkylenyl group Chemical group 0.000 claims description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 6
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 6
- 125000005605 benzo group Chemical group 0.000 claims description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 5
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 4
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 4
- NPUKKLNOJTXUGO-UHFFFAOYSA-N n-[1-(4-acetamidophenyl)sulfonylpiperidin-4-yl]benzamide Chemical compound C1=CC(NC(=O)C)=CC=C1S(=O)(=O)N1CCC(NC(=O)C=2C=CC=CC=2)CC1 NPUKKLNOJTXUGO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- KOFIDSXHWGFEMO-UHFFFAOYSA-N 1-(2-methylpropyl)pyrrolidine Chemical compound CC(C)CN1CCCC1 KOFIDSXHWGFEMO-UHFFFAOYSA-N 0.000 claims description 3
- MCMFEZDRQOJKMN-UHFFFAOYSA-N 1-butylimidazole Chemical compound CCCCN1C=CN=C1 MCMFEZDRQOJKMN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- INSSHDIMRIMVLZ-UHFFFAOYSA-N butan-2-ylcyclopropane Chemical compound CCC(C)C1CC1 INSSHDIMRIMVLZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 56
- 102100032804 Histone-lysine N-methyltransferase SMYD3 Human genes 0.000 abstract description 44
- 101000708574 Homo sapiens Histone-lysine N-methyltransferase SMYD3 Proteins 0.000 abstract description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 42
- 102100032806 N-lysine methyltransferase SMYD2 Human genes 0.000 abstract description 40
- 108090000623 proteins and genes Proteins 0.000 abstract description 38
- 102000004169 proteins and genes Human genes 0.000 abstract description 36
- 150000003857 carboxamides Chemical class 0.000 abstract description 3
- 229940124530 sulfonamide Drugs 0.000 abstract description 3
- 150000003456 sulfonamides Chemical class 0.000 abstract description 2
- 101000708645 Homo sapiens N-lysine methyltransferase SMYD2 Proteins 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 226
- 239000000243 solution Substances 0.000 description 153
- 238000003786 synthesis reaction Methods 0.000 description 150
- 230000015572 biosynthetic process Effects 0.000 description 149
- 239000000203 mixture Substances 0.000 description 144
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 142
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 125
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 111
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 106
- 239000007787 solid Substances 0.000 description 88
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 88
- 238000000034 method Methods 0.000 description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 84
- 229910001868 water Inorganic materials 0.000 description 84
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 70
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 69
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 62
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 57
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 52
- 235000019439 ethyl acetate Nutrition 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- 238000005481 NMR spectroscopy Methods 0.000 description 45
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 43
- 239000012044 organic layer Substances 0.000 description 43
- 101710131374 N-lysine methyltransferase SMYD2 Proteins 0.000 description 39
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 150000004677 hydrates Chemical class 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 38
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 33
- 235000018102 proteins Nutrition 0.000 description 33
- 239000012071 phase Substances 0.000 description 31
- 125000003107 substituted aryl group Chemical group 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 201000010099 disease Diseases 0.000 description 23
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 22
- 238000004809 thin layer chromatography Methods 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 21
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- 229960001866 silicon dioxide Drugs 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- 230000005764 inhibitory process Effects 0.000 description 20
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 20
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 19
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 14
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 14
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 13
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- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 13
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- SATOBHVAZUERBJ-UHFFFAOYSA-N 2,3-dihydro-1h-indole-5-carboxamide Chemical compound NC(=O)C1=CC=C2NCCC2=C1 SATOBHVAZUERBJ-UHFFFAOYSA-N 0.000 description 12
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- 125000005129 aryl carbonyl group Chemical group 0.000 description 12
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 12
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- 239000007858 starting material Substances 0.000 description 12
- 125000000547 substituted alkyl group Chemical group 0.000 description 12
- OSKSVLBJJXQUPI-UHFFFAOYSA-N 2h-triazole-4-carboxamide Chemical compound NC(=O)C1=CNN=N1 OSKSVLBJJXQUPI-UHFFFAOYSA-N 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
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- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 10
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- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 8
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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| US8563573B2 (en) | 2007-11-02 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
| US8802868B2 (en) | 2010-03-25 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide |
| RU2569678C2 (ru) | 2010-04-22 | 2015-11-27 | Вертекс Фармасьютикалз Инкорпорейтед | Способ получения циклоалкилкарбоксамидо-индольных соединений |
| PT3131582T (pt) | 2014-04-15 | 2018-10-08 | Vertex Pharma | Composições farmacêuticas para o tratamento de doenças mediadas pelo regulador de condutância transmembranar da fibrose quística |
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| US10266526B2 (en) | 2019-04-23 |
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| CN107072205A (zh) | 2017-08-18 |
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| SG10201901192TA (en) | 2019-03-28 |
| BR112017004612A2 (pt) | 2018-01-30 |
| KR20230026515A (ko) | 2023-02-24 |
| US20190322660A1 (en) | 2019-10-24 |
| US20210198252A1 (en) | 2021-07-01 |
| KR102496364B1 (ko) | 2023-02-06 |
| MX2017002985A (es) | 2017-11-17 |
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