CN106986867B - 作为pi3k抑制剂的杂环基胺 - Google Patents
作为pi3k抑制剂的杂环基胺 Download PDFInfo
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- CN106986867B CN106986867B CN201610946568.1A CN201610946568A CN106986867B CN 106986867 B CN106986867 B CN 106986867B CN 201610946568 A CN201610946568 A CN 201610946568A CN 106986867 B CN106986867 B CN 106986867B
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- alkyl
- compound
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- base
- halogenated
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- -1 Heterocycle amine Chemical class 0.000 title claims description 189
- 239000012828 PI3K inhibitor Substances 0.000 title description 5
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 title description 5
- 108091007960 PI3Ks Proteins 0.000 claims abstract description 131
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 74
- 201000010099 disease Diseases 0.000 claims abstract description 70
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 201000011510 cancer Diseases 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 329
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 194
- 150000003839 salts Chemical class 0.000 claims description 130
- 102000038030 PI3Ks Human genes 0.000 claims description 128
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 111
- VQXHGXDVBHJJJU-UHFFFAOYSA-N 3-methyl-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C(N)C2=C(C)NN=C21 VQXHGXDVBHJJJU-UHFFFAOYSA-N 0.000 claims description 96
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 125000001072 heteroaryl group Chemical group 0.000 claims description 74
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 64
- 229910052799 carbon Inorganic materials 0.000 claims description 62
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 49
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 45
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 43
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 25
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- 125000001424 substituent group Chemical group 0.000 claims description 22
- 108091000080 Phosphotransferase Proteins 0.000 claims description 21
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- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
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- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 13
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000006603 (C1-C3) alkylaminosulfonyl group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
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- 125000006599 (C1-C3) alkylaminocarbonylamino group Chemical group 0.000 claims description 4
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- 206010060862 Prostate cancer Diseases 0.000 claims description 3
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- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000007815 allergy Effects 0.000 claims description 3
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
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- 201000003914 endometrial carcinoma Diseases 0.000 claims description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims description 3
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- 208000009928 nephrosis Diseases 0.000 claims description 3
- 231100001027 nephrosis Toxicity 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
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- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
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- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
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- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 4
- 210000000988 bone and bone Anatomy 0.000 claims 1
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- 208000025113 myeloid leukemia Diseases 0.000 claims 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 abstract description 115
- 150000001412 amines Chemical class 0.000 abstract description 26
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 11
- 230000004968 inflammatory condition Effects 0.000 abstract description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 abstract 3
- 239000002585 base Substances 0.000 description 350
- 239000000203 mixture Substances 0.000 description 215
- 229910001868 water Inorganic materials 0.000 description 149
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 145
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 141
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
- 239000000047 product Substances 0.000 description 112
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 111
- 229910052757 nitrogen Inorganic materials 0.000 description 111
- 238000002474 experimental method Methods 0.000 description 94
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 77
- 239000000243 solution Substances 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 66
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 235000019439 ethyl acetate Nutrition 0.000 description 55
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 48
- 239000003513 alkali Substances 0.000 description 46
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 45
- 150000001721 carbon Chemical group 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 239000000460 chlorine Substances 0.000 description 44
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 42
- 238000000034 method Methods 0.000 description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 41
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical group [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 34
- 239000003054 catalyst Substances 0.000 description 34
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 33
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
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- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 27
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
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- 238000004007 reversed phase HPLC Methods 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
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Classifications
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- 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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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- 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]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
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- Organic Chemistry (AREA)
- Public Health (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Urology & Nephrology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (7)
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| US201161530866P | 2011-09-02 | 2011-09-02 | |
| US61/530,866 | 2011-09-02 | ||
| US201261594882P | 2012-02-03 | 2012-02-03 | |
| US61/594,882 | 2012-02-03 | ||
| US201261677445P | 2012-07-30 | 2012-07-30 | |
| US61/677,445 | 2012-07-30 | ||
| CN201280052912.2A CN104024253B (zh) | 2011-09-02 | 2012-08-31 | 作为pi3k抑制剂的杂环基胺 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201280052912.2A Division CN104024253B (zh) | 2011-09-02 | 2012-08-31 | 作为pi3k抑制剂的杂环基胺 |
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| CN106986867A CN106986867A (zh) | 2017-07-28 |
| CN106986867B true CN106986867B (zh) | 2019-06-28 |
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| CN201610946568.1A Active CN106986867B (zh) | 2011-09-02 | 2012-08-31 | 作为pi3k抑制剂的杂环基胺 |
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| PL2448938T3 (pl) | 2009-06-29 | 2014-11-28 | Incyte Holdings Corp | Pirymidynony jako inhibitory PI3K |
| TW201130842A (en) * | 2009-12-18 | 2011-09-16 | Incyte Corp | Substituted fused aryl and heteroaryl derivatives as PI3K inhibitors |
| WO2011075643A1 (en) | 2009-12-18 | 2011-06-23 | Incyte Corporation | Substituted heteroaryl fused derivatives as pi3k inhibitors |
| CA2796311A1 (en) | 2010-04-14 | 2011-10-20 | Incyte Corporation | Fused derivatives as pi3k.delta. inhibitors |
| US9062055B2 (en) | 2010-06-21 | 2015-06-23 | Incyte Corporation | Fused pyrrole derivatives as PI3K inhibitors |
| CA2822070C (en) | 2010-12-20 | 2019-09-17 | Incyte Corporation | N-(1-(substituted-phenyl)ethyl)-9h-purin-6-amines as pi3k inhibitors |
| WO2012125629A1 (en) | 2011-03-14 | 2012-09-20 | Incyte Corporation | Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors |
| WO2012135009A1 (en) | 2011-03-25 | 2012-10-04 | Incyte Corporation | Pyrimidine-4,6-diamine derivatives as pi3k inhibitors |
| PH12021552978A1 (en) | 2011-09-02 | 2022-08-22 | Incyte Holdings Corp | Heterocyclylamines as pi3k inhibitors |
| AR090548A1 (es) | 2012-04-02 | 2014-11-19 | Incyte Corp | Azaheterociclobencilaminas biciclicas como inhibidores de pi3k |
| KR20230170108A (ko) | 2012-06-04 | 2023-12-18 | 파마싸이클릭스 엘엘씨 | 브루톤 타이로신 키나아제 저해제의 결정 형태 |
| KR20150079745A (ko) | 2012-11-08 | 2015-07-08 | 리젠 파마슈티컬스 소시에떼 아노님 | Pde4 억제제 및 pi3 델타 또는 이중 pi3 델타-감마 키나아제 억제제를 함유하는 약제학적 조성물 |
| WO2014110574A1 (en) | 2013-01-14 | 2014-07-17 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors |
| UA121098C2 (uk) | 2013-01-15 | 2020-04-10 | Інсайт Холдинґс Корпорейшн | Тіазолкарбоксаміди і піридинкарбоксаміди, які використовуються як інгібітори рім-кінази |
| TW202214254A (zh) * | 2013-03-01 | 2022-04-16 | 美商英塞特控股公司 | 吡唑并嘧啶衍生物治療PI3Kδ相關病症之用途 |
| WO2015027124A1 (en) | 2013-08-23 | 2015-02-26 | Incyte Corporation | Furo- and thieno-pyridine carboxamide compounds useful as pim kinase inhibitors |
| EP3102195B1 (en) | 2014-02-03 | 2021-10-06 | Quadriga Biosciences, Inc. | Beta-substituted beta-amino acids and analogs as chemotherapeutic agents |
| JP6271766B2 (ja) * | 2014-02-03 | 2018-01-31 | クワドリガ バイオサイエンシーズ， インコーポレイテッド | 化学療法剤としてのβ置換γアミノ酸および類似体 |
| NZ763326A (en) * | 2014-04-08 | 2023-04-28 | Incyte Holdings Corp | Treatment of b-cell malignancies by a combination jak and pi3k inhibitor |
| US10077277B2 (en) | 2014-06-11 | 2018-09-18 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors |
| US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
| WO2016010897A1 (en) | 2014-07-14 | 2016-01-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as pim kinase inhibitors |
| WO2016130501A1 (en) | 2015-02-09 | 2016-08-18 | Incyte Corporation | Aza-heteroaryl compounds as pi3k-gamma inhibitors |
| LT3262046T (lt) * | 2015-02-27 | 2021-01-11 | Incyte Corporation | Pi3k inhibitoriaus druskos ir jų gamybos būdai |
| IL315294A (en) | 2015-03-03 | 2024-10-01 | Pharmacyclics Llc | Pharmaceutical formulations of bruton's tyrosine kinase inhibitor |
| JP6793401B2 (ja) * | 2015-03-11 | 2020-12-02 | 国立研究開発法人理化学研究所 | 難治性白血病治療薬 |
| WO2016183071A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Hetero-tricyclic compounds and their use for the treatment of cancer |
| WO2016183060A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Process for the synthesis of a phosphoinositide 3-kinase inhibitor |
| US9988401B2 (en) | 2015-05-11 | 2018-06-05 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
| WO2016196244A1 (en) | 2015-05-29 | 2016-12-08 | Incyte Corporation | Pyridineamine compounds useful as pim kinase inhibitors |
| AU2016302243B2 (en) | 2015-08-03 | 2019-07-11 | Quadriga Biosciences, Inc. | Beta-substituted Beta-amino acids and analogs as chemotherapeutic agents and uses thereof |
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| US10053465B2 (en) | 2015-08-26 | 2018-08-21 | Incyte Corporation | Pyrrolopyrimidine derivatives as TAM inhibitors |
| TWI734699B (zh) | 2015-09-09 | 2021-08-01 | 美商英塞特公司 | Ｐｉｍ激酶抑制劑之鹽 |
| WO2017059251A1 (en) | 2015-10-02 | 2017-04-06 | Incyte Corporation | Heterocyclic compounds useful as pim kinase inhibitors |
| PT3371190T (pt) | 2015-11-06 | 2022-07-08 | Incyte Corp | Compostos heterocíclicos como inibidores de pi3k-gamma |
| US20170190689A1 (en) | 2016-01-05 | 2017-07-06 | Incyte Corporation | Pyridine and pyridimine compounds as pi3k-gamma inhibitors |
| KR102744951B1 (ko) | 2016-03-28 | 2024-12-23 | 인사이트 코포레이션 | Tam 억제제로서 피롤로트리아진 화합물 |
| TW201803871A (zh) | 2016-06-24 | 2018-02-01 | 英塞特公司 | 作為ＰＩ３Ｋ-γ抑制劑之雜環化合物 |
| AU2018342471B2 (en) | 2017-09-27 | 2023-08-24 | Incyte Corporation | Salts of pyrrolotriazine derivatives useful as TAM inhibitors |
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| AR113922A1 (es) | 2017-12-08 | 2020-07-01 | Incyte Corp | Terapia de combinación de dosis baja para el tratamiento de neoplasias mieloproliferativas |
| PE20251292A1 (es) | 2018-03-08 | 2025-05-14 | Incyte Corp | Compuestos diolicos de aminopirazina como inhibidores de pi3k-gamma |
| CA3101323A1 (en) | 2018-06-01 | 2019-12-05 | Incyte Corporation | Dosing regimen for the treatment of pi3k related disorders |
| ES3031110T3 (en) | 2018-06-29 | 2025-07-04 | Incyte Corp | Formulations of an axl/mer inhibitor |
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