TWI457339B - 稠合雜芳香環吡咯啶酮 - Google Patents
稠合雜芳香環吡咯啶酮 Download PDFInfo
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- TWI457339B TWI457339B TW99145627A TW99145627A TWI457339B TW I457339 B TWI457339 B TW I457339B TW 99145627 A TW99145627 A TW 99145627A TW 99145627 A TW99145627 A TW 99145627A TW I457339 B TWI457339 B TW I457339B
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- Taiwan
- Prior art keywords
- pyrrolo
- pyridine
- fluoro
- group
- methyl
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- 125000001072 heteroaryl group Chemical group 0.000 title claims description 44
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 329
- -1 2-amino-cyclohex-1-yl group Chemical group 0.000 claims description 241
- 125000001424 substituent group Chemical group 0.000 claims description 114
- 150000003839 salts Chemical class 0.000 claims description 81
- 229910052736 halogen Inorganic materials 0.000 claims description 79
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 78
- 229920006395 saturated elastomer Polymers 0.000 claims description 75
- 229910052739 hydrogen Inorganic materials 0.000 claims description 69
- 150000002367 halogens Chemical class 0.000 claims description 68
- 239000001257 hydrogen Substances 0.000 claims description 65
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 58
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 238000011282 treatment Methods 0.000 claims description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 34
- 125000005843 halogen group Chemical group 0.000 claims description 32
- 201000010099 disease Diseases 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 150000001412 amines Chemical class 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000002950 monocyclic group Chemical group 0.000 claims description 22
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 16
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- 125000006413 ring segment Chemical group 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 14
- 125000000335 thiazolyl group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 208000024891 symptom Diseases 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 201000009030 Carcinoma Diseases 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 208000011580 syndromic disease Diseases 0.000 claims description 7
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 6
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 6
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- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
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- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 201000009961 allergic asthma Diseases 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
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- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 230000003211 malignant effect Effects 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- BFJMHTOBRRZELQ-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-c]pyridine Chemical compound N1=CC=C2C(I)=NNC2=C1 BFJMHTOBRRZELQ-UHFFFAOYSA-N 0.000 claims description 2
- RLXNNTQQSLSLQA-UHFFFAOYSA-N 7-fluoro-4,6-bis(1-methylpyrazol-4-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one Chemical compound C1=NN(C)C=C1C1=NC(C2=CN(C)N=C2)=C(F)C2=C1C(=O)NC2 RLXNNTQQSLSLQA-UHFFFAOYSA-N 0.000 claims description 2
- 206010066476 Haematological malignancy Diseases 0.000 claims description 2
- 101000604583 Homo sapiens Tyrosine-protein kinase SYK Proteins 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 claims description 2
- 230000007812 deficiency Effects 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 16
- 150000002431 hydrogen Chemical class 0.000 claims 3
- ZNOVTXRBGFNYRX-STQMWFEESA-N (6S)-5-methyltetrahydrofolic acid Chemical compound C([C@@H]1N(C=2C(=O)N=C(N)NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-STQMWFEESA-N 0.000 claims 1
- ROSODFDWJFAKQI-UHFFFAOYSA-N 1,2-dihydropyrrolo[3,4-c]pyridin-3-one Chemical compound C1=NC=C2C(=O)NCC2=C1 ROSODFDWJFAKQI-UHFFFAOYSA-N 0.000 claims 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
- QOEGYIMEVZZRCM-JTQLQIEISA-N 6-[(3s)-3-aminopiperidin-1-yl]-7-fluoro-4-(1-methylpyrazol-4-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one Chemical compound C1=NN(C)C=C1C1=NC(N2C[C@@H](N)CCC2)=C(F)C2=C1C(=O)NC2 QOEGYIMEVZZRCM-JTQLQIEISA-N 0.000 claims 1
- XOTZDLZZONOQJK-QMTHXVAHSA-N 6-[[(1r,2r)-2-amino-3,3-difluorocyclohexyl]amino]-7-fluoro-4-(1-methylpyrazol-4-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one Chemical compound C1=NN(C)C=C1C1=NC(N[C@H]2[C@H](C(F)(F)CCC2)N)=C(F)C2=C1C(=O)NC2 XOTZDLZZONOQJK-QMTHXVAHSA-N 0.000 claims 1
- 208000019838 Blood disease Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 208000014951 hematologic disease Diseases 0.000 claims 1
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- 229960003208 levomefolic acid Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims 1
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- 239000000203 mixture Substances 0.000 description 277
- 235000019439 ethyl acetate Nutrition 0.000 description 232
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 160
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- 238000005481 NMR spectroscopy Methods 0.000 description 97
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 88
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- 239000000243 solution Substances 0.000 description 79
- 239000012267 brine Substances 0.000 description 69
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 67
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- 239000011734 sodium Substances 0.000 description 59
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 55
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- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 38
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 31
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- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 26
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
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- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- JJYPMNFTHPTTDI-UHFFFAOYSA-N meta-toluidine Natural products CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 14
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- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
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Classifications
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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
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
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| SG181857A1 (en) * | 2009-12-23 | 2012-07-30 | Takeda Pharmaceutical | Fused heteroaromatic pyrrolidinones as syk inhibitors |
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| US20140377258A1 (en) | 2013-05-30 | 2014-12-25 | Infinity Pharmaceuticals, Inc. | Treatment Of Cancers Using PI3 Kinase Isoform Modulators |
| AU2014296184B2 (en) | 2013-07-31 | 2017-04-27 | Gilead Sciences, Inc. | Syk inhibitors |
| PE20160685A1 (es) | 2013-10-04 | 2016-07-23 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos y usos de los mismos |
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| US20160244452A1 (en) | 2013-10-21 | 2016-08-25 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| TWI735853B (zh) | 2013-12-23 | 2021-08-11 | 美商克洛諾斯生技有限公司 | 脾酪胺酸激酶抑制劑 |
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| CN113620958A (zh) | 2014-03-19 | 2021-11-09 | 无限药品股份有限公司 | 用于治疗PI3K-γ介导的障碍的杂环化合物 |
| US10245262B2 (en) | 2014-04-01 | 2019-04-02 | The University Of Queensland | Immunological reagents and uses therefor |
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| US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
| KR20170090476A (ko) * | 2014-12-05 | 2017-08-07 | 어레이 바이오파마 인크. | 야누스 키나제 저해제로서의 4,6-치환된-피라졸로[1,5-a]피라진 |
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| ES2930585T3 (es) | 2015-02-27 | 2022-12-19 | Nimbus Lakshmi Inc | Inhibidores de TYK2 y usos de los mismos |
| US10023571B2 (en) * | 2015-09-02 | 2018-07-17 | Nimbus Lakshimi, Inc. | TYK2 inhibitors and uses thereof |
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| WO2017205801A1 (en) * | 2016-05-27 | 2017-11-30 | Takeda Pharmaceutical Company Limited | Combination of immunotherapy agents and spleen tyrosine kinase inhibitors |
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| PE20190971A1 (es) | 2016-06-13 | 2019-07-09 | Glaxosmithkline Ip Dev Ltd | Compuestos quimicos |
| RU2754507C2 (ru) | 2016-06-24 | 2021-09-02 | Инфинити Фармасьютикалз, Инк. | Комбинированная терапия |
| JP2019520419A (ja) * | 2016-07-13 | 2019-07-18 | 武田薬品工業株式会社 | 脾臓チロシンキナーゼ阻害剤と他の治療薬の併用 |
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| CA3036384A1 (en) | 2016-09-14 | 2018-03-22 | Gilead Sciences, Inc. | Syk inhibitors |
| WO2018195471A1 (en) | 2017-04-21 | 2018-10-25 | Gilead Sciences, Inc. | Syk inhibitors in combination with hypomethylating agents |
| ES2906205T3 (es) * | 2017-06-14 | 2022-04-13 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Inhibidor de Syk y método de uso para el mismo |
| TWI782056B (zh) * | 2017-07-14 | 2022-11-01 | 日商鹽野義製藥股份有限公司 | 具有mgat2抑制活性的縮合環衍生物 |
| US11174254B2 (en) | 2017-09-28 | 2021-11-16 | Yangtze River Pharmaceutical Group Co., Ltd. | Aniline-substituted 1,2-dihydropyrrol[3,4-C]pyridin/pyrimidin-3-one derivative and use thereof |
| JOP20180094A1 (ar) | 2017-10-18 | 2019-04-18 | Hk Inno N Corp | مركب حلقي غير متجانس كمثبط بروتين كيناز |
| SG11202002475TA (en) * | 2017-10-19 | 2020-04-29 | Bayer Animal Health Gmbh | Use of fused heteroaromatic pyrrolidones for treatment and prevention of diseases in animals |
| WO2019088039A1 (en) | 2017-10-30 | 2019-05-09 | Takeda Pharmaceutical Company Limited | Treatment of acute myeloid leukemia |
| CN111295384B (zh) * | 2018-10-10 | 2022-08-12 | 江苏豪森药业集团有限公司 | 双环类衍生物抑制剂、其制备方法和应用 |
| KR102195348B1 (ko) | 2018-11-15 | 2020-12-24 | 에이치케이이노엔 주식회사 | 단백질 키나제 억제제로서의 신규 화합물 및 이를 포함하는 약제학적 조성물 |
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