JP2014522860A - Ｂｔｋ阻害剤としての４−イミダゾピリダジン−１−イル−ベンズアミドおよび４−イミダゾトリアジン−１−イル−ベンズアミド - Google Patents
Ｂｔｋ阻害剤としての４−イミダゾピリダジン−１−イル−ベンズアミドおよび４−イミダゾトリアジン−１−イル−ベンズアミド Download PDFInfo
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- JP2014522860A JP2014522860A JP2014520607A JP2014520607A JP2014522860A JP 2014522860 A JP2014522860 A JP 2014522860A JP 2014520607 A JP2014520607 A JP 2014520607A JP 2014520607 A JP2014520607 A JP 2014520607A JP 2014522860 A JP2014522860 A JP 2014522860A
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- Prior art keywords
- benzamide
- pyrazin
- methylimidazo
- alkyl
- compound according
- 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.)
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- 229940124291 BTK inhibitor Drugs 0.000 title description 11
- NBOUQRHNEKKMCI-UHFFFAOYSA-N N1(N=CC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 Chemical compound N1(N=CC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 NBOUQRHNEKKMCI-UHFFFAOYSA-N 0.000 title 1
- RFMXXXSWDWZODI-UHFFFAOYSA-N N1(N=NC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 Chemical compound N1(N=NC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 RFMXXXSWDWZODI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 181
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 8
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 8
- -1 pyrazin-1-yl Chemical group 0.000 claims description 129
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 125000004432 carbon atom Chemical group C* 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 7
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- CWJRZDWOLHKIIX-HSDHKRTLSA-N 4-[3-[(2s)-1-[(e)-4-(dimethylamino)but-2-enoyl]piperidin-2-yl]-8-methylimidazo[1,5-a]pyrazin-1-yl]-n-(4-propylpyridin-2-yl)benzamide Chemical compound CCCC1=CC=NC(NC(=O)C=2C=CC(=CC=2)C2=C3C(C)=NC=CN3C([C@H]3N(CCCC3)C(=O)\C=C\CN(C)C)=N2)=C1 CWJRZDWOLHKIIX-HSDHKRTLSA-N 0.000 claims description 3
- XLOGIFFPIIBWGJ-HNNXBMFYSA-N 4-[8-methyl-3-[(1s)-1-(prop-2-enoylamino)ethyl]imidazo[1,5-a]pyrazin-1-yl]-n-[4-(trifluoromethyl)pyridin-2-yl]benzamide Chemical compound C=12C(C)=NC=CN2C([C@@H](NC(=O)C=C)C)=NC=1C(C=C1)=CC=C1C(=O)NC1=CC(C(F)(F)F)=CC=N1 XLOGIFFPIIBWGJ-HNNXBMFYSA-N 0.000 claims description 3
- ZWHKMEXQEXXCRA-DEOSSOPVSA-N 4-[8-methyl-3-[(2s)-1-prop-2-enoylpiperidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-n-(4-propylpyridin-2-yl)benzamide Chemical compound CCCC1=CC=NC(NC(=O)C=2C=CC(=CC=2)C2=C3C(C)=NC=CN3C([C@H]3N(CCCC3)C(=O)C=C)=N2)=C1 ZWHKMEXQEXXCRA-DEOSSOPVSA-N 0.000 claims description 3
- VLEZQOHBDFVKRP-NRFANRHFSA-N 4-[8-methyl-3-[(2s)-1-prop-2-enoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-n-(4-methylpyridin-2-yl)benzamide Chemical compound CC1=CC=NC(NC(=O)C=2C=CC(=CC=2)C2=C3C(C)=NC=CN3C([C@H]3N(CCC3)C(=O)C=C)=N2)=C1 VLEZQOHBDFVKRP-NRFANRHFSA-N 0.000 claims description 3
- UEVJUPPLOHUVON-QHCPKHFHSA-N 4-[8-methyl-3-[(2s)-1-prop-2-enoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-n-(4-propylpyridin-2-yl)benzamide Chemical compound CCCC1=CC=NC(NC(=O)C=2C=CC(=CC=2)C2=C3C(C)=NC=CN3C([C@H]3N(CCC3)C(=O)C=C)=N2)=C1 UEVJUPPLOHUVON-QHCPKHFHSA-N 0.000 claims description 3
- 102220517591 Methyl-CpG-binding domain protein 3-like 2B_R11C_mutation Human genes 0.000 claims description 3
- BOYHADSAXZAUQY-NRFANRHFSA-N n-(4-cyanopyridin-2-yl)-4-[8-methyl-3-[(2s)-1-prop-2-enoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzamide Chemical compound C=12C(C)=NC=CN2C([C@H]2N(CCC2)C(=O)C=C)=NC=1C(C=C1)=CC=C1C(=O)NC1=CC(C#N)=CC=N1 BOYHADSAXZAUQY-NRFANRHFSA-N 0.000 claims description 3
- ZAXOXFZPTLHJQX-QFIPXVFZSA-N n-(4-ethylpyridin-2-yl)-4-[8-methyl-3-[(2s)-1-prop-2-enoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzamide Chemical compound CCC1=CC=NC(NC(=O)C=2C=CC(=CC=2)C2=C3C(C)=NC=CN3C([C@H]3N(CCC3)C(=O)C=C)=N2)=C1 ZAXOXFZPTLHJQX-QFIPXVFZSA-N 0.000 claims description 3
- OPELHLHHRKSOEG-NRFANRHFSA-N n-(4-methoxypyridin-2-yl)-4-[8-methyl-3-[(2s)-1-prop-2-enoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]benzamide Chemical compound COC1=CC=NC(NC(=O)C=2C=CC(=CC=2)C2=C3C(C)=NC=CN3C([C@H]3N(CCC3)C(=O)C=C)=N2)=C1 OPELHLHHRKSOEG-NRFANRHFSA-N 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- LCRSPYXMSMVXJE-BDUNBXCCSA-N 4-[3-[(1s)-1-[[(e)-4-methoxybut-2-enoyl]amino]ethyl]-8-methylimidazo[1,5-a]pyrazin-1-yl]-n-[4-(trifluoromethyl)pyridin-2-yl]benzamide Chemical compound C=12C(C)=NC=CN2C([C@H](C)NC(=O)/C=C/COC)=NC=1C(C=C1)=CC=C1C(=O)NC1=CC(C(F)(F)F)=CC=N1 LCRSPYXMSMVXJE-BDUNBXCCSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- ACJIPXJQUWPIFD-UHFFFAOYSA-N n-(4-propylpyridin-2-yl)benzamide Chemical compound CCCC1=CC=NC(NC(=O)C=2C=CC=CC=2)=C1 ACJIPXJQUWPIFD-UHFFFAOYSA-N 0.000 claims description 2
- 102200080066 rs122460151 Human genes 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- BETCAYZPULVFFU-UHFFFAOYSA-N n-[4-(trifluoromethyl)pyridin-2-yl]benzamide Chemical compound FC(F)(F)C1=CC=NC(NC(=O)C=2C=CC=CC=2)=C1 BETCAYZPULVFFU-UHFFFAOYSA-N 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 54
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- 238000003556 assay Methods 0.000 description 43
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
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Classifications
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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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
- A61K31/495—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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161509376P | 2011-07-19 | 2011-07-19 | |
| EP11174582 | 2011-07-19 | ||
| EP11174582.4 | 2011-07-19 | ||
| US61/509,376 | 2011-07-19 | ||
| PCT/EP2012/063556 WO2013010869A1 (en) | 2011-07-19 | 2012-07-11 | 4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides btk-inhibitors |
Publications (2)
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| JP2014522860A true JP2014522860A (ja) | 2014-09-08 |
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| AU (1) | AU2012285988B2 (OSRAM) |
| CA (1) | CA2841887A1 (OSRAM) |
| WO (1) | WO2013010869A1 (OSRAM) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020511547A (ja) * | 2017-03-22 | 2020-04-16 | スジョウ・バイジブゴン・ファーマスーティカル・テクノロジー・カンパニー・リミテッドSuzhou Baijibugong Pharmaceutical Technology Co. Ltd. | ブルトン型チロシンキナーゼ阻害剤 |
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| AR110998A1 (es) | 2017-02-24 | 2019-05-22 | Gilead Sciences Inc | Inhibidores de la tirosina cinasa de bruton |
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| WO2019090269A1 (en) * | 2017-11-06 | 2019-05-09 | Peng Wang | Processes to produce acalabrutinib |
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| DK4426434T3 (da) | 2021-11-02 | 2025-11-10 | Flare Therapeutics Inc | Pparg inverse agonists and uses thereof |
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- 2012-07-11 CA CA2841887A patent/CA2841887A1/en not_active Abandoned
- 2012-07-11 WO PCT/EP2012/063556 patent/WO2013010869A1/en not_active Ceased
- 2012-07-11 AU AU2012285988A patent/AU2012285988B2/en not_active Expired - Fee Related
- 2012-07-11 EP EP12735138.5A patent/EP2734523A1/en not_active Withdrawn
- 2012-07-11 US US14/233,429 patent/US20140155406A1/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020511547A (ja) * | 2017-03-22 | 2020-04-16 | スジョウ・バイジブゴン・ファーマスーティカル・テクノロジー・カンパニー・リミテッドSuzhou Baijibugong Pharmaceutical Technology Co. Ltd. | ブルトン型チロシンキナーゼ阻害剤 |
| JP7219902B2 (ja) | 2017-03-22 | 2023-02-09 | スジョウ・バイジブゴン・ファーマスーティカル・テクノロジー・カンパニー・リミテッド | ブルトン型チロシンキナーゼ阻害剤 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20140155406A1 (en) | 2014-06-05 |
| WO2013010869A1 (en) | 2013-01-24 |
| AU2012285988A1 (en) | 2014-01-30 |
| CA2841887A1 (en) | 2013-01-24 |
| EP2734523A1 (en) | 2014-05-28 |
| AU2012285988B2 (en) | 2017-05-25 |
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