WO2019233941A1 - Tetrahydro-1 h-pyrazino[2,1 -ajisoindolylquinoline compounds for the treatment of autoimmune disease - Google Patents

Tetrahydro-1 h-pyrazino[2,1 -ajisoindolylquinoline compounds for the treatment of autoimmune disease Download PDF

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Publication number
WO2019233941A1
WO2019233941A1 PCT/EP2019/064323 EP2019064323W WO2019233941A1 WO 2019233941 A1 WO2019233941 A1 WO 2019233941A1 EP 2019064323 W EP2019064323 W EP 2019064323W WO 2019233941 A1 WO2019233941 A1 WO 2019233941A1
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WIPO (PCT)
Prior art keywords
methyl
amino
tetrahydro
pyrazino
carbonitrile
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Ceased
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PCT/EP2019/064323
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English (en)
French (fr)
Inventor
Fabian Dey
Hong Shen
Hongtao Xu
Hongying Yun
Ge Zou
Wei Zhu
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Publication date
Priority to BR112020024782-0A priority Critical patent/BR112020024782A2/pt
Priority to KR1020207034855A priority patent/KR20210018818A/ko
Priority to CR20200584A priority patent/CR20200584A/es
Priority to AU2019280728A priority patent/AU2019280728A1/en
Priority to CN201980035182.7A priority patent/CN112204028B/zh
Priority to PE2020001875A priority patent/PE20210131A1/es
Priority to SG11202011137SA priority patent/SG11202011137SA/en
Priority to US16/972,556 priority patent/US12157746B2/en
Priority to CA3098291A priority patent/CA3098291A1/en
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Priority to MX2020012827A priority patent/MX2020012827A/es
Priority to JP2020567772A priority patent/JP7374130B2/ja
Priority to EP19729220.4A priority patent/EP3802539B1/en
Publication of WO2019233941A1 publication Critical patent/WO2019233941A1/en
Priority to CONC2020/0014677A priority patent/CO2020014677A2/es
Priority to IL279144A priority patent/IL279144A/en
Priority to PH12020552092A priority patent/PH12020552092A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • 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
    • C07D471/08—Bridged systems
    • 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
    • C07D471/10—Spiro-condensed systems
    • 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
    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • n 1, 2, 3 or 4;
  • the“ds-isomers” refers to a mixture of
  • R 5 is H, piperazinyl, halogen, Ci -6 alkyl, halopyrrolidinylamino or hydroxypyrrolidinylCi- 6alkyl amino;
  • R 4 is H
  • halopyrrolidinyloxy hydroxy(Ci- 6 alkyl)-l ,4-diazepanyl; hydroxy(Ci -6 alkylamino)pyrrolidinyl; hydroxy- 1 ,4-diazepanyl; hydroxypyrrolidinylCi ⁇ alkylamino; morpholinylC i _ 6 alkylammo;
  • a further embodiment of present invention is (vi) a compound of formula (I) or (la) or (lb) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 1
  • R 4 is H
  • Another embodiment of present invention is (ii’) a compound of fonnula (la),
  • R 3 is H; R 4 is H;
  • azetidinyl amino amino; azetidinyloxy; piperazinyl; piperidinyl or pyrrolidinyl which is once or twice substituted by substituents independently selected from amino, hydroxy, hydroxyCi- 6alkyl, Ci -6 alkoxy and C ⁇ alkyl amino;
  • R 2 is Ci- 6 alkyl
  • R 5 is H or piperazinyl
  • R 4 is H
  • X is halogen or leaving group, for example, OTf or OMs; m is 0, 1, 2, or 3; n is 1, 2, 3 or 4; m+n ⁇ 4; R 7 and R 8 are protecting groups, for example, R 7 is Boc and R 8 is benzyl; R 9 is alkylsilyl, for example, trimethylsilyl.
  • the amide coupling of protected amino acid (II) and silylamine (III) can be achieved using coupling reagents, such as HATU and DIPEA, to afford intermediate (IV).
  • coupling reagents such as HATU and DIPEA
  • R 7 is removed by selective deprotection, the amide bond in the resulting intermediate (V) can be reduced under reductive conditions, such as treatment of LAH, to afford diamine (VI).
  • Buchwald-Hartwig animation conditions ref: Acc. Chem. Res. 1998, 31, 805-818; Chem. Rev. 2016, 116, 12564-12649; Topics in Current Chemistry, 2002, 219, 131-209; and references cited therein
  • a catalyst such as Ruphos Pd-G2
  • a base such as Cs 2 C0 3
  • the resulting compound of formula (XII) can be submitted to nucleophilic aromatic substitution conditions (e.g. heating with halide (XIII) in the presence of DIEPA in DMSO), or Buchwald-Hartwig amination conditions (e.g. heating with halide (XIII) in the presence of a catalyst, such as Ruphos Pd-G2, and a base, such as Cs 2 C0 3 , to afford compound of formula (I).
  • the compound of formula (XII) may contain a protecting group, e.g. Boc, which will be removed before affording the final compound of formula (I).
  • Example 3 (19.7 mg) was obtained.
  • Step 2 preparation of 4- [(4/?, 10/>5 -4-methy l-8-piperazin-l -yl-3,4,6,1 Ob-tetrahydro- l/ -pyrazino [2, l-a]isoindoI-2-yl] pyrazolo [1,5-a] pyridine-7-carbonitriIe (Example 5)
  • Step 2 preparation of tert- butyl 4-
  • Step 3 preparation of tert- butyl (3/?)-4-[(4/?, 10M , )-2-(8-cyano-5-quinolyI)-4-methyl- 3 ,4, 6,1 Ob-tetrahydro-l//-pyrazino [2, 1-a] isoindol-8-yl] -3-(hydroxymethyl)-piperazine- 1- carboxylate (compound 10c)
  • Example 14 (7.2 mg) was obtained.
  • Example 25 (9.4 mg) was obtained.
  • Example 30 (46 mg) was obtained.
  • Example 41 The title compound was prepared in analogy to the preparation of Example 10 by using tert-butyl 3a-methoxy-l,2,3,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate instead of tert- butyl (3/ )-3-(hydiOxymethyl)piperazine-l -carboxyl ate.
  • Example 41 (8.8 mg) was obtained.
  • Example 45A (18 mg) was obtained. MS: calc’d 455 [(M+H) + ], measured 455 [(M+H)']. ' H NMR (400 MHz, METHANOL-7 ⁇ ) d ppm 'll NMR (400
  • Example 46 (35 mg) was obtained. MS: calc’d 443 [(M+H) + ], measured 443 [(M+H) ].
  • Example 48 (8.8 mg) was obtained.
  • Example 49 (58 mg) was obtained. MS: calc’d 443 [(M+H) + ], measured 443 [(M+H) + ]. !
  • Example 50 (5.4 mg) was obtained.
  • Example 56A (24 mg) was obtained.
  • Example 60 (70 mg) was obtained.
  • Example 61 (61 mg) was obtained. MS: ealc’d 455 [(M+H) + ], measured 455 [(M+H) + J.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
PCT/EP2019/064323 2018-06-05 2019-06-03 Tetrahydro-1 h-pyrazino[2,1 -ajisoindolylquinoline compounds for the treatment of autoimmune disease Ceased WO2019233941A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
CA3098291A CA3098291A1 (en) 2018-06-05 2019-06-03 Tetrahydro-1 h-pyrazino[2,1 -ajisoindolylquinoline compounds for the treatment of autoimmune disease
CR20200584A CR20200584A (es) 2018-06-05 2019-06-03 Compuestos tetrahidro-1h-pirazino [2,1-a] isoindolilquinolina para el tratamiento de enfermedades autoinmunes
MX2020012827A MX2020012827A (es) 2018-06-05 2019-06-03 Compuestos tetrahidro-1h-pirazino[2,1-a]isoindolilquinolina para el tratamiento de enfermedades autoinmunes.
CN201980035182.7A CN112204028B (zh) 2018-06-05 2019-06-03 用于治疗自身免疫性疾病的四氢-1H-吡嗪并[2,1-a]异吲哚基喹啉化合物
PE2020001875A PE20210131A1 (es) 2018-06-05 2019-06-03 COMPUESTOS TETRAHIDRO-1H-PIRAZINO[2,1-a]ISOINDOLILQUINOLINA PARA EL TRATAMIENTO DE ENFERMEDADES AUTOINMUNES
SG11202011137SA SG11202011137SA (en) 2018-06-05 2019-06-03 Tetrahydro-1 h-pyrazino[2,1 -ajisoindolylquinoline compounds for the treatment of autoimmune disease
US16/972,556 US12157746B2 (en) 2018-06-05 2019-06-03 Tetrahydro-1H-pyrazino[2,1-a]isoindolylquinoline compounds for the treatment of autoimmune disease
BR112020024782-0A BR112020024782A2 (pt) 2018-06-05 2019-06-03 compostos de tetra-hidro-1h-pirazino[2,1-a]isoindolilquinolina para o tratamento de doença autoimune
AU2019280728A AU2019280728A1 (en) 2018-06-05 2019-06-03 Tetrahydro-1 H-pyrazino[2,1 -ajisoindolylquinoline compounds for the treatment of autoimmune disease
KR1020207034855A KR20210018818A (ko) 2018-06-05 2019-06-03 자가면역 질환의 치료를 위한 테트라하이드로-1H-피라지노[2,1-a]이소인돌릴퀴놀린 화합물
JP2020567772A JP7374130B2 (ja) 2018-06-05 2019-06-03 自己免疫疾患治療用の新規なテトラヒドロ－１Ｈ－ピラジノ［２，１－ａ］イソインドリルキノリン化合物
EP19729220.4A EP3802539B1 (en) 2018-06-05 2019-06-03 Tetrahydro-1h-pyrazino[2,1-a]isoindolylquinoline compounds for the treatment of autoimmune disease
CONC2020/0014677A CO2020014677A2 (es) 2018-06-05 2020-11-26 Compuestos tetrahidro-1h-pirazino[2,1-a]isoindolilquinolina para el tratamiento de enfermedades autoinmunes
IL279144A IL279144A (en) 2018-06-05 2020-12-01 Tetrahydro-1H-pyrazino[2,1-azisoindolylquinoline compounds for the treatment of immune system disease
PH12020552092A PH12020552092A1 (en) 2018-06-05 2020-12-04 Tetrahydro-1h-pyrazino[2,1-a]isoindolylquinoline compounds for the treatment of autoimmune disease

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN2018090004 2018-06-05
CNPCT/CN2018/090004 2018-06-05
EP18193916.6 2018-09-12
EP18193916 2018-09-12
CN2019086019 2019-05-08
CNPCT/CN2019/086019 2019-05-08

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US (1) US12157746B2 (enExample)
EP (1) EP3802539B1 (enExample)
JP (1) JP7374130B2 (enExample)
KR (1) KR20210018818A (enExample)
CN (1) CN112204028B (enExample)
AU (1) AU2019280728A1 (enExample)
BR (1) BR112020024782A2 (enExample)
CA (1) CA3098291A1 (enExample)
CL (1) CL2020003065A1 (enExample)
CO (1) CO2020014677A2 (enExample)
CR (1) CR20200584A (enExample)
IL (1) IL279144A (enExample)
MA (1) MA52747A (enExample)
MX (1) MX2020012827A (enExample)
PE (1) PE20210131A1 (enExample)
PH (1) PH12020552092A1 (enExample)
SG (1) SG11202011137SA (enExample)
TW (1) TW202016111A (enExample)
WO (1) WO2019233941A1 (enExample)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021094301A1 (en) * 2019-11-12 2021-05-20 F. Hoffmann-La Roche Ag Hydropyrazino[1,2-b]isoquinoline compounds for the treatment of autoimmune disease
WO2021099284A1 (en) * 2019-11-19 2021-05-27 F. Hoffmann-La Roche Ag Hydro-1h-pyrrolo[1,2-a]pyrazine compounds for the treatment of autoimmune disease
WO2021099285A1 (en) * 2019-11-19 2021-05-27 F. Hoffmann-La Roche Ag Triazatricycle compounds for the treatment of autoimmune disease
WO2022013136A1 (en) 2020-07-14 2022-01-20 F. Hoffmann-La Roche Ag Hydroisoquinoline or hydronaphthyridine compounds for the treatment of autoimmune disease
WO2022022489A1 (zh) * 2020-07-27 2022-02-03 江苏恒瑞医药股份有限公司 吲哚稠环类衍生物、其制备方法及其在医药上的应用
CN114057759A (zh) * 2020-08-07 2022-02-18 江苏恒瑞医药股份有限公司 稠合四环类衍生物、其制备方法及其在医药上的应用
WO2022111636A1 (zh) 2020-11-26 2022-06-02 江苏恒瑞医药股份有限公司 稠合三环化合物、其制备方法及其在医药上的应用
CN114656363A (zh) * 2022-03-28 2022-06-24 南京林业大学 一种钯催化芳香酯类化合物的合成方法
US12421229B2 (en) 2019-12-03 2025-09-23 Hoffmann-La Roche Inc. Hydropyrido[1,2-α]pyrazine compounds for the treatment of autoimmune disease
US12421240B2 (en) 2019-10-31 2025-09-23 Hoffmann-La Roche Inc. Hydropyrazino[1,2-d][1,4]diazepine compounds for the treatment of autoimmune disease

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023025109A1 (zh) * 2021-08-23 2023-03-02 上海维申医药有限公司 一类Toll样受体抑制剂及其制备和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150105370A1 (en) * 2013-10-14 2015-04-16 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273773A (en) 1979-09-24 1981-06-16 American Home Products Corporation Antihypertensive tricyclic isoindole derivatives
NZ551468A (en) 2003-12-24 2010-05-28 Biota Scient Management Polycyclic agents for the treatment of respiratory syncytial virus infections
WO2011106276A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Task channel antagonists
SG11201509520QA (en) 2013-05-24 2015-12-30 Janssen Sciences Ireland Uc Pyridone derivatives for the treatment of viral infections and further diseases
ES2670550T3 (es) 2013-10-14 2018-05-30 Eisai R&D Management Co., Ltd. Derivados de quinolina selectivamente sustituidos
PT3889145T (pt) 2015-12-17 2024-04-02 Merck Patent Gmbh 8-ciano-5-piperidino-quinolinas como antagonistas de tlr7/8 e suas utilizações para tratamento de distúrbios imunitários
US10071079B2 (en) 2016-06-29 2018-09-11 Bristol-Myers Squibb Company [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds
MX391344B (es) 2016-07-30 2025-03-21 Bristol Myers Squibb Co Compuestos indol sustituidos con dimetoxifenilo como inhibidores de receptores tipo toll 7, 8 o 9 (tlr7, tlr8 o tlr9).
EP4198031A1 (en) 2016-08-08 2023-06-21 Merck Patent GmbH Tlr7/8 antagonists and uses thereof
KR102519535B1 (ko) 2016-09-09 2023-04-06 브리스톨-마이어스 스큅 컴퍼니 피리딜 치환된 인돌 화합물
CR20190119A (es) 2016-09-09 2019-06-03 Novartis Ag Compuestos y composiciones como inhibidores de los receptores endosomales tipo peaje
ES2965044T3 (es) 2017-07-18 2024-04-10 Merck Patent Gmbh Antagonistas de TLR7/8 y sus usos
ES2921020T3 (es) 2017-08-04 2022-08-16 Bristol Myers Squibb Co Compuestos de indol sustituidos con [1,2,4]triazolo[4,3-a]piridinilo
CN110997656B (zh) 2017-08-04 2023-04-14 百时美施贵宝公司 用作tlr7/8/9抑制剂的取代的吲哚化合物
FI3692040T3 (fi) 2017-10-05 2023-03-29 Glaxosmithkline Ip Dev Ltd Kemiallisia yhdisteitä
CN111448190B (zh) 2017-11-14 2023-09-26 百时美施贵宝公司 取代的吲哚化合物
BR112020011668A2 (pt) 2017-12-15 2020-11-17 Bristol-Myers Squibb Company compostos de éter de indol substituído
FI3728252T3 (fi) 2017-12-18 2023-10-18 Bristol Myers Squibb Co 4-atsaindoliyhdisteitä
WO2019126082A1 (en) 2017-12-19 2019-06-27 Bristol-Myers Squibb Company 6-azaindole compounds
CN111511729A (zh) 2017-12-19 2020-08-07 默克专利股份公司 Tlr7/8拮抗剂及其用途
JP7313354B2 (ja) 2017-12-19 2023-07-24 ブリストル－マイヤーズ スクイブ カンパニー Ｔｌｒ阻害剤として有用なアミド置換されたインドール化合物
BR112020012084A2 (pt) 2017-12-19 2020-11-24 Bristol-Myers Squibb Company compostos de indol substituído úteis como inibidores de tlr
US11299501B2 (en) 2017-12-20 2022-04-12 Bristol-Myers Squibb Company Diazaindole compounds
BR112020011984A2 (pt) 2017-12-20 2020-11-17 Bristol-Myers Squibb Company compostos de amino indol úteis como inibidores de tlr
CA3085942A1 (en) 2017-12-20 2019-06-27 Bristol-Myers Squibb Company Aryl and heteroaryl substituted indole compounds
JP2021507889A (ja) 2017-12-22 2021-02-25 ノバルティス アーゲー ピラゾロピペリジン誘導体の新規な使用
JP7407740B2 (ja) 2018-05-18 2024-01-04 ノバルティス アーゲー Ｔｌｒ７／ｔｌｒ８阻害剤の結晶形態
WO2019236710A1 (en) 2018-06-05 2019-12-12 Praxis Biotech LLC Inhibitors of integrated stress response pathway
TWI825144B (zh) 2018-08-10 2023-12-11 美商思達利醫藥公司 第二型轉麩醯胺酸酶(tg2)抑制劑
WO2021094301A1 (en) 2019-11-12 2021-05-20 F. Hoffmann-La Roche Ag Hydropyrazino[1,2-b]isoquinoline compounds for the treatment of autoimmune disease
US12503471B2 (en) 2019-11-19 2025-12-23 Hoffmann-La Roche Inc. Triazatricycle compounds for the treatment of autoimmune disease
BR112022009856A2 (pt) 2019-11-26 2022-08-02 Hoffmann La Roche Compostos de 1,8-naftiridin-2-ona para o tratamento de doença autoimune

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150105370A1 (en) * 2013-10-14 2015-04-16 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Alternative Methods in Toxicology", 1994, MARY ANN LIEBERT PUBL, pages: 243 - 251
ACC. CHEM. RES., vol. 31, 1998, pages 805 - 818
BORENFREUND, EPUERNER JA: "Toxicity determined in vitro by morphological alterations and Neutral Red absorption", TOXICOLOGY LETT., vol. 24, 1985, pages 119 - 124, XP025521855, DOI: doi:10.1016/0378-4274(85)90046-3
CHEM. REV., vol. 116, 2016, pages 12564 - 12649
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1820575-70-9
CHEN, J. Q. ET AL., CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY, vol. 50, 2016, pages 1
JIMENEZ-DALMARONI, M. J. ET AL., AUTOIMMUN REV., vol. 15, 2016, pages 1
KRIEG, A. M. ET AL., IMMUNOL. REV., vol. 220, 2007, pages 251
LIEBSCH MSPIELMANN HBALLS MBRAND MDORING BDUPUIS JHOLZHUTER HGKLECAK GL.EPLATTENIER HLOVELL W: "First results of the EC/COLIPA Validation Project. In Vitro Phototoxicity Testing", IN VITRO SKIN TOXICOLOGY: IRRITATION, PHOTOTOXICITY, SENSITIZATION, vol. 10
NAVARRA, S. V. ET AL., LANCET, vol. 377, 2011, pages 721
REDFERN WSCARLSSON LDAVIS ASLYNCH WGMACKENZIE IPALETHORPE SSIEGL PKSTRANG ISULLIVAN ATWALLIS R: "Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development", CARDIOVASC. RES., vol. 58, 2003, pages 32 - 45, XP004722301, DOI: doi:10.1016/S0008-6363(02)00846-5
SANGUINETTI MCTRISTANI-FIROUZI M.: "hERG potassium channels and cardiac arrhythmia", NATURE, vol. 440, 2006, pages 463 - 469
SPIELMANN HBALLS MDUPUIS JPAPE WJWPECHOVITCH GSILVA DEOHOLZHUTTER, HGCLOTHIER RDESOLLE PGERBERICK F: "The international EU/COLIPA in vitro phototoxicity validation study: Results of phase II (blind trial). Part 1: The 3T3 NRU phototoxicity test", TOXICOLOGY IN VITRO, vol. 12, 1998, pages 305 - 327, XP055149225, DOI: doi:10.1016/S0887-2333(98)00006-X
TOPICS IN CURRENT CHEMISTRY, vol. 219, 2002, pages 131 - 209
WEBSTER RLEISHMAN DWALKER D.: "owards a drug concentration effect relationship for QT prolongation and torsades de pointes", CURR. OPIN. DRUG DISCOV. DEVEL., vol. 5, 2002, pages 116 - 26

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12421240B2 (en) 2019-10-31 2025-09-23 Hoffmann-La Roche Inc. Hydropyrazino[1,2-d][1,4]diazepine compounds for the treatment of autoimmune disease
WO2021094301A1 (en) * 2019-11-12 2021-05-20 F. Hoffmann-La Roche Ag Hydropyrazino[1,2-b]isoquinoline compounds for the treatment of autoimmune disease
CN114728959A (zh) * 2019-11-12 2022-07-08 豪夫迈·罗氏有限公司 用于治疗自身免疫性疾病的氢吡嗪并[1,2-b]异喹啉化合物
CN114728959B (zh) * 2019-11-12 2024-11-12 豪夫迈·罗氏有限公司 用于治疗自身免疫性疾病的氢吡嗪并[1,2-b]异喹啉化合物
WO2021099284A1 (en) * 2019-11-19 2021-05-27 F. Hoffmann-La Roche Ag Hydro-1h-pyrrolo[1,2-a]pyrazine compounds for the treatment of autoimmune disease
WO2021099285A1 (en) * 2019-11-19 2021-05-27 F. Hoffmann-La Roche Ag Triazatricycle compounds for the treatment of autoimmune disease
US12503471B2 (en) 2019-11-19 2025-12-23 Hoffmann-La Roche Inc. Triazatricycle compounds for the treatment of autoimmune disease
US12486273B2 (en) 2019-11-19 2025-12-02 Hoffmann-La Roche Inc. Hydro-1H-pyrrolo[1,2-a]pyrazine compounds for the treatment of autoimmune disease
US12421229B2 (en) 2019-12-03 2025-09-23 Hoffmann-La Roche Inc. Hydropyrido[1,2-α]pyrazine compounds for the treatment of autoimmune disease
WO2022013136A1 (en) 2020-07-14 2022-01-20 F. Hoffmann-La Roche Ag Hydroisoquinoline or hydronaphthyridine compounds for the treatment of autoimmune disease
WO2022022489A1 (zh) * 2020-07-27 2022-02-03 江苏恒瑞医药股份有限公司 吲哚稠环类衍生物、其制备方法及其在医药上的应用
CN114057759A (zh) * 2020-08-07 2022-02-18 江苏恒瑞医药股份有限公司 稠合四环类衍生物、其制备方法及其在医药上的应用
WO2022111636A1 (zh) 2020-11-26 2022-06-02 江苏恒瑞医药股份有限公司 稠合三环化合物、其制备方法及其在医药上的应用
EP4253387A4 (en) * 2020-11-26 2024-05-15 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Fused tricyclic compound, preparation method therefor and application thereof in medicine
CN114656363A (zh) * 2022-03-28 2022-06-24 南京林业大学 一种钯催化芳香酯类化合物的合成方法

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