CA2899948C - Pyridinyl and fused pyridinyl triazolone derivatives - Google Patents
Pyridinyl and fused pyridinyl triazolone derivatives Download PDFInfo
- Publication number
- CA2899948C CA2899948C CA2899948A CA2899948A CA2899948C CA 2899948 C CA2899948 C CA 2899948C CA 2899948 A CA2899948 A CA 2899948A CA 2899948 A CA2899948 A CA 2899948A CA 2899948 C CA2899948 C CA 2899948C
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- CA
- Canada
- Prior art keywords
- triazol
- compound
- tautomer
- independently selected
- pharmaceutically acceptable
- 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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- 125000004076 pyridyl group Chemical group 0.000 title description 6
- DKHMDUDREAVQOQ-UHFFFAOYSA-N 5-pyridin-2-yltriazol-4-one Chemical class O=C1N=NN=C1C1=CC=CC=N1 DKHMDUDREAVQOQ-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 408
- 150000003839 salts Chemical class 0.000 claims abstract description 96
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 61
- 208000035475 disorder Diseases 0.000 claims abstract description 32
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 11
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- 230000003211 malignant effect Effects 0.000 claims abstract description 6
- 208000010216 atopic IgE responsiveness Diseases 0.000 claims abstract description 5
- 230000002062 proliferating effect Effects 0.000 claims abstract description 5
- -1 R10 Chemical group 0.000 claims description 161
- 125000005843 halogen group Chemical group 0.000 claims description 118
- 125000001424 substituent group Chemical group 0.000 claims description 117
- 125000000217 alkyl group Chemical group 0.000 claims description 111
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 239000001257 hydrogen Substances 0.000 claims description 92
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 89
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 69
- 125000004432 carbon atom Chemical group C* 0.000 claims description 65
- 125000001188 haloalkyl group Chemical group 0.000 claims description 59
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 56
- 125000003386 piperidinyl group Chemical group 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 239000002988 disease modifying antirheumatic drug Substances 0.000 claims description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 8
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 5
- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 claims description 5
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 5
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 229960000485 methotrexate Drugs 0.000 claims description 5
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 4
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 4
- 208000009137 Behcet syndrome Diseases 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000005024 Castleman disease Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- 208000028622 Immune thrombocytopenia Diseases 0.000 claims description 3
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
- 201000011152 Pemphigus Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 201000001976 pemphigus vulgaris Diseases 0.000 claims description 3
- 101100240518 Caenorhabditis elegans nhr-12 gene Proteins 0.000 claims description 2
- 101100079984 Caenorhabditis elegans nhr-9 gene Proteins 0.000 claims description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
- 208000024908 graft versus host disease Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 15
- HOUPMJUJPOUWRQ-CWQZNGJJSA-N 5-[1-[(3S)-1-prop-2-enoylpiperidin-3-yl]oxyisoquinolin-3-yl]-1,2,4-triazolidin-3-one Chemical compound C=CC(=O)N1CCC[C@@H](C1)Oc1nc(cc2ccccc12)C1NNC(=O)N1 HOUPMJUJPOUWRQ-CWQZNGJJSA-N 0.000 claims 1
- UTLIHPPCVYRXDA-CHPOKUKFSA-N 5-[1-[[(3S)-1-(2-chloroacetyl)pyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2,4-triazolidin-3-one Chemical compound ClCC(=O)N1CC[C@@H](C1)Nc1nc(cc2ccccc12)C1NNC(=O)N1 UTLIHPPCVYRXDA-CHPOKUKFSA-N 0.000 claims 1
- ZLWLFHUPLISYBJ-XLLULAGJSA-N 5-[4-methyl-6-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]oxypyridin-2-yl]-1,2,4-triazolidin-3-one Chemical compound Cc1cc(O[C@H]2CCN(C2)C(=O)C=C)nc(c1)C1NNC(=O)N1 ZLWLFHUPLISYBJ-XLLULAGJSA-N 0.000 claims 1
- IWLBOOQOHPAHJE-NKUHCKNESA-N 5-[5-methyl-6-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]oxypyridin-2-yl]-1,2,4-triazolidin-3-one Chemical compound Cc1ccc(nc1O[C@H]1CCN(C1)C(=O)C=C)C1NNC(=O)N1 IWLBOOQOHPAHJE-NKUHCKNESA-N 0.000 claims 1
- NKPZVXJYRKMJIY-LLTODGECSA-N 5-[6-[(3S)-1-prop-2-enoylpyrrolidin-3-yl]oxypyridin-2-yl]-1,2,4-triazolidin-3-one Chemical compound C=CC(=O)N1CC[C@@H](C1)Oc1cccc(n1)C1NNC(=O)N1 NKPZVXJYRKMJIY-LLTODGECSA-N 0.000 claims 1
- OUXQVZPHPUFGSB-LBPRGKRZSA-N 5-[7-chloro-1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C12=CC(Cl)=CC=C2C=C(C=2NC(=O)NN=2)N=C1O[C@H]1CCN(C(=O)C=C)C1 OUXQVZPHPUFGSB-LBPRGKRZSA-N 0.000 claims 1
- FNCLMGJYUVZZML-LBPRGKRZSA-N 5-[7-chloro-1-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C12=CC(Cl)=CC=C2C=C(C=2NC(=O)NN=2)N=C1N[C@H]1CCN(C(=O)C=C)C1 FNCLMGJYUVZZML-LBPRGKRZSA-N 0.000 claims 1
- IQQZPESQANJEIH-LBPRGKRZSA-N 5-[7-fluoro-1-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C12=CC(F)=CC=C2C=C(C=2NC(=O)NN=2)N=C1N[C@H]1CCN(C(=O)C=C)C1 IQQZPESQANJEIH-LBPRGKRZSA-N 0.000 claims 1
- KLOPMWUFPGQSEQ-NSHDSACASA-N 5-[8-chloro-1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=12C(Cl)=CC=CC2=CC(C=2NC(=O)NN=2)=NC=1O[C@H]1CCN(C(=O)C=C)C1 KLOPMWUFPGQSEQ-NSHDSACASA-N 0.000 claims 1
- OUBGQRGWUQEITD-NSHDSACASA-N 5-[8-chloro-1-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=12C(Cl)=CC=CC2=CC(C=2NC(=O)NN=2)=NC=1N[C@H]1CCN(C(=O)C=C)C1 OUBGQRGWUQEITD-NSHDSACASA-N 0.000 claims 1
- FLDYREMAARAHTJ-LBPRGKRZSA-N 5-[8-methoxy-1-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=12C(OC)=CC=CC2=CC(C=2NC(=O)NN=2)=NC=1N[C@H]1CCN(C(=O)C=C)C1 FLDYREMAARAHTJ-LBPRGKRZSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 31
- 239000000463 material Substances 0.000 abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 228
- 239000000203 mixture Substances 0.000 description 182
- 239000011541 reaction mixture Substances 0.000 description 126
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 123
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
- 239000000243 solution Substances 0.000 description 91
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 85
- 239000012043 crude product Substances 0.000 description 80
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 79
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 78
- 239000002904 solvent Substances 0.000 description 69
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 53
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 45
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
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- 101150041968 CDC13 gene Proteins 0.000 description 18
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- 229910000104 sodium hydride Inorganic materials 0.000 description 18
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- 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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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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| PCT/US2014/022801 WO2014164558A1 (en) | 2013-03-11 | 2014-03-10 | Pyridinyl and fused pyridinyl triazolone derivatives |
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| SMT201900344T1 (it) | 2012-09-10 | 2019-07-11 | Principia Biopharma Inc | Composti di pirazolopirimidina come inibitori di chinasi |
| JO3377B1 (ar) * | 2013-03-11 | 2019-03-13 | Takeda Pharmaceuticals Co | مشتقات بيريدينيل وبيريدينيل مندمج |
| KR20220027271A (ko) | 2014-02-21 | 2022-03-07 | 프린시피아 바이오파마, 인코퍼레이티드 | Btk 억제제의 염 및 고체 형태 |
| CN104447530A (zh) * | 2014-12-11 | 2015-03-25 | 苏州欧凯医药技术有限公司 | 4-甲基-2,6-二羧基吡啶的制备方法 |
| CA2970723C (en) | 2014-12-18 | 2023-09-05 | Principia Biopharma Inc. | Treatment of pemphigus |
| MA42242A (fr) | 2015-06-24 | 2018-05-02 | Principia Biopharma Inc | Inhibiteurs de la tyrosine kinase |
| UY37046A (es) | 2015-12-24 | 2017-07-31 | Takeda Pharmaceuticals Co | Cocristal, método de produccion del mismo,y medicamento que contiene dicho cocristal |
| WO2017122175A1 (en) * | 2016-01-13 | 2017-07-20 | Acerta Pharma B.V. | Therapeutic combinations of an antifolate and a btk inhibitor |
| DK3436447T3 (da) * | 2016-03-31 | 2021-09-13 | Takeda Pharmaceuticals Co | Isoquinolinyl-triazolon-komplekser |
| WO2018005849A1 (en) | 2016-06-29 | 2018-01-04 | Principia Biopharma Inc. | Modified release formulations of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile |
| BR112021000964A2 (pt) | 2018-07-25 | 2021-04-20 | Novartis Ag | inibidores do inflamassoma de nlrp3 |
| KR20210142154A (ko) | 2019-03-21 | 2021-11-24 | 옹쎄오 | 암 치료를 위한 키나제 억제제와 조합된 dbait 분자 |
| KR102459858B1 (ko) * | 2019-04-02 | 2022-10-27 | 연세대학교 산학협력단 | 신규 화합물 및 이를 유효성분으로 포함하는 호흡기 질환의 예방 또는 치료용 조성물 |
| AR119731A1 (es) | 2019-05-17 | 2022-01-05 | Novartis Ag | Inhibidores del inflamasoma nlrp3 |
| TWI877239B (zh) | 2019-10-14 | 2025-03-21 | 美商普林斯匹亞生物製藥公司 | 藉由投予(R)-2-[3-[4-胺基-3-(2-氟-4-苯氧基-苯基)吡唑并[3,4-d]嘧啶-1-基]哌啶-1-羰基]-4-甲基-4-[4-(氧呾-3-基)哌-1-基]戊-2-烯腈來治療免疫血小板減少症之方法 |
| CN114761006A (zh) | 2019-11-08 | 2022-07-15 | Inserm(法国国家健康医学研究院) | 对激酶抑制剂产生耐药性的癌症的治疗方法 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| BR112022014149A2 (pt) | 2020-01-22 | 2022-09-27 | Principia Biopharma Inc | Formas cristalinas de 2-[3-[4-amino-3-(2-fluoro-4-fenóxi-fenil)-1h-pirazolo[3,4-d]pirimidina-1-il]piperidina-1-carbonil]-4-metil-4-[4-(oxetan-3-il)piperazin-1-il]pent-2-enenitrila |
| AU2021325431B2 (en) | 2020-08-14 | 2024-01-18 | Novartis Ag | Heteroaryl substituted spiropiperidinyl derivatives and pharmaceutical uses thereof |
| UY40374A (es) | 2022-08-03 | 2024-02-15 | Novartis Ag | Inhibidores de inflamasoma nlrp3 |
| WO2025116652A1 (ko) * | 2023-11-30 | 2025-06-05 | 주식회사 지엔티파마 | 자가면역 질환 치료용 조성물 및 방법 |
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