CA2961525A1 - Histone demethylase inhibitors - Google Patents
Histone demethylase inhibitors Download PDFInfo
- Publication number
- CA2961525A1 CA2961525A1 CA2961525A CA2961525A CA2961525A1 CA 2961525 A1 CA2961525 A1 CA 2961525A1 CA 2961525 A CA2961525 A CA 2961525A CA 2961525 A CA2961525 A CA 2961525A CA 2961525 A1 CA2961525 A1 CA 2961525A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- pyridine
- aryl
- 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.)
- Abandoned
Links
- 108010074870 Histone Demethylases Proteins 0.000 title claims abstract description 20
- 102000008157 Histone Demethylases Human genes 0.000 title claims abstract description 20
- 239000003112 inhibitor Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 290
- -1 imidazole-pyridine derivative compounds Chemical class 0.000 claims abstract description 169
- 238000000034 method Methods 0.000 claims abstract description 86
- 239000000203 mixture Substances 0.000 claims abstract description 62
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims description 165
- 125000003118 aryl group Chemical group 0.000 claims description 111
- 125000000217 alkyl group Chemical group 0.000 claims description 94
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 76
- 125000000623 heterocyclic group Chemical group 0.000 claims description 73
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 71
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 60
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 56
- 125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 56
- 125000001072 heteroaryl group Chemical group 0.000 claims description 54
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 54
- 229910052736 halogen Inorganic materials 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 50
- 150000002367 halogens Chemical group 0.000 claims description 48
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 5
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 4
- 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 4
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 3
- 230000000063 preceeding effect Effects 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
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- 206010060862 Prostate cancer Diseases 0.000 abstract description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 abstract description 4
- 206010017758 gastric cancer Diseases 0.000 abstract description 4
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- 230000001613 neoplastic effect Effects 0.000 abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 253
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 126
- 238000002360 preparation method Methods 0.000 description 89
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 55
- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- 125000002947 alkylene group Chemical group 0.000 description 54
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 125000004432 carbon atom Chemical group C* 0.000 description 32
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 101710105678 Lysine-specific demethylase 2A Proteins 0.000 description 22
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
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- 101000614013 Homo sapiens Lysine-specific demethylase 2B Proteins 0.000 description 13
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- 125000003709 fluoroalkyl group Chemical group 0.000 description 13
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- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 12
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- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 12
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 12
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- 229910002027 silica gel Inorganic materials 0.000 description 12
- NZHDJNMKYDTLEC-UHFFFAOYSA-N 2-(1h-imidazol-5-yl)pyridine-4-carboxamide Chemical compound NC(=O)C1=CC=NC(C=2N=CNC=2)=C1 NZHDJNMKYDTLEC-UHFFFAOYSA-N 0.000 description 11
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- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- 239000007995 HEPES buffer Substances 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
- A61K31/4192—1,2,3-Triazoles
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| US201462051268P | 2014-09-16 | 2014-09-16 | |
| US62/051,268 | 2014-09-16 | ||
| PCT/US2015/050289 WO2016044342A1 (en) | 2014-09-16 | 2015-09-15 | Histone demethylase inhibitors |
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| CA2961525A1 true CA2961525A1 (en) | 2016-03-24 |
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| ES2731773T3 (es) | 2013-03-14 | 2019-11-19 | Celgene Quanticel Res Inc | Inhibidores de la histona desmetilasa |
| US9896436B2 (en) | 2014-09-16 | 2018-02-20 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
| MX2017003464A (es) * | 2014-09-16 | 2017-07-13 | Celgene Quanticel Res Inc | Inhibidores de histona desmetilasa. |
| WO2016130501A1 (en) | 2015-02-09 | 2016-08-18 | Incyte Corporation | Aza-heteroaryl compounds as pi3k-gamma inhibitors |
| SI3371190T1 (sl) | 2015-11-06 | 2022-08-31 | Incyte Corporation | Heterociklične spojine kot inhibitorji PI3K gama |
| WO2017120194A1 (en) * | 2016-01-05 | 2017-07-13 | Incyte Corporation | Pyridine and pyridimine compounds as pi3k-gamma inhibitors |
| WO2017161033A1 (en) * | 2016-03-15 | 2017-09-21 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
| US10150754B2 (en) * | 2016-04-19 | 2018-12-11 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
| WO2017223414A1 (en) | 2016-06-24 | 2017-12-28 | Incyte Corporation | HETEROCYCLIC COMPOUNDS AS PI3K-γ INHIBITORS |
| SI3697789T1 (sl) | 2017-10-18 | 2022-04-29 | Incyte Corporation | Kondenzirani imidazolni derivati, substituirani s terciarnimi hidroksi skupinami, kot zaviralci PI3K-gama |
| CR20250050A (es) | 2018-09-05 | 2025-03-19 | Incyte Corp | Formas cristalinas de un inhibidor de fosfoinositida 3–quinasa (pi3k) (divisional 2021-0165) |
| CN111116571B (zh) * | 2019-12-27 | 2022-07-12 | 吉首大学 | 含恶唑及三唑双杂环的化合物及其制备与应用方法 |
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| EP1058549A4 (en) | 1998-12-23 | 2003-11-12 | Bristol Myers Squibb Pharma Co | FACTOR Xa OR THROMBIN INHIBITORS |
| MXPA03003599A (es) | 2000-10-26 | 2003-08-01 | Tularik Inc | Agentes antiinflamatorios. |
| GB0217780D0 (en) | 2002-07-31 | 2002-09-11 | Glaxo Group Ltd | Compounds |
| US20040127733A1 (en) | 2002-10-31 | 2004-07-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New beta-agonists, processes for preparing them and their use as pharmaceutical compositions |
| DE102004021779A1 (de) | 2004-04-30 | 2005-11-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Beta-Agonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
| CA2632444A1 (en) | 2005-12-19 | 2007-06-28 | Boehringer Ingelheim International Gmbh | Use of aminoalcohol derivatives for the treatment of overactive bladder |
| CA2701124A1 (en) | 2007-10-03 | 2009-04-09 | Vertex Pharmaceuticals Incorporated | C-met protein kinase inhibitors |
| DE102009019962A1 (de) | 2009-05-05 | 2010-11-11 | Merck Patent Gmbh | 3-([1,2,3]Triazol-4-yl)-pyrrolo[2,3-b]pyridinderivate |
| CA2778886C (en) | 2009-11-10 | 2014-01-07 | Pfizer Inc. | N1-pyrazolospiroketone acetyl-coa carboxylase inhibitors |
| WO2011088181A1 (en) | 2010-01-13 | 2011-07-21 | Tempero Pharmaceuticals, Inc. | Compounds and methods |
| EP3763367A1 (en) * | 2012-12-06 | 2021-01-13 | Celgene Quanticel Research, Inc. | Pyridine-pyrazole derivatives as histone demethylase inhibitors |
| ES2731773T3 (es) * | 2013-03-14 | 2019-11-19 | Celgene Quanticel Res Inc | Inhibidores de la histona desmetilasa |
| WO2016007722A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Triazolopyridines and triazolopyrazines as lsd1 inhibitors |
| US9896436B2 (en) * | 2014-09-16 | 2018-02-20 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
| MX2017003464A (es) | 2014-09-16 | 2017-07-13 | Celgene Quanticel Res Inc | Inhibidores de histona desmetilasa. |
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| IL251103A0 (en) | 2017-04-30 |
| AU2015317904A1 (en) | 2017-04-06 |
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| EP3193881A4 (en) | 2018-02-21 |
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| KR20170048590A (ko) | 2017-05-08 |
| US20160108033A1 (en) | 2016-04-21 |
| SG11201702108PA (en) | 2017-04-27 |
| WO2016044342A1 (en) | 2016-03-24 |
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| US10071984B2 (en) | 2018-09-11 |
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| US9676770B2 (en) | 2017-06-13 |
| CL2017000643A1 (es) | 2017-12-01 |
| US20170240529A1 (en) | 2017-08-24 |
| JP2017527590A (ja) | 2017-09-21 |
| EP3193881B1 (en) | 2022-02-09 |
| ES2911292T3 (es) | 2022-05-18 |
| ECSP17020172A (es) | 2017-05-31 |
| CN107073006A (zh) | 2017-08-18 |
| MX2017003464A (es) | 2017-07-13 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |
Effective date: 20200916 |