HK1134486A1 - 作為用於治療增殖病症的蛋白激酶 抑制劑的 -二氫- 三唑並 蝶啶 - Google Patents

作為用於治療增殖病症的蛋白激酶 抑制劑的 -二氫- 三唑並 蝶啶

Info

Publication number
HK1134486A1
HK1134486A1 HK10100194.2A HK10100194A HK1134486A1 HK 1134486 A1 HK1134486 A1 HK 1134486A1 HK 10100194 A HK10100194 A HK 10100194A HK 1134486 A1 HK1134486 A1 HK 1134486A1
Authority
HK
Hong Kong
Prior art keywords
plk1
pteridines
triazolo
dihydro
treatment
Prior art date
Application number
HK10100194.2A
Other languages
English (en)
Inventor
Jean-Damien Charrier
David Kay
Ronald Knegtel
Original Assignee
Vertex Pharma
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Vertex Pharma filed Critical Vertex Pharma
Publication of HK1134486A1 publication Critical patent/HK1134486A1/zh

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12Heterocyclic 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 three hetero rings
    • C07D487/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic 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
    • C07D491/12Heterocyclic 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 three hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Transplantation (AREA)
  • Virology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
HK10100194.2A 2006-04-12 2010-01-08 作為用於治療增殖病症的蛋白激酶 抑制劑的 -二氫- 三唑並 蝶啶 HK1134486A1 (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US79132706P 2006-04-12 2006-04-12
US83872006P 2006-08-18 2006-08-18
PCT/US2007/009006 WO2007120752A2 (en) 2006-04-12 2007-04-12 4, 5-dihydro- [1, 2, 4] triazolo [4, 3-f] pteridines as protein kinase plk1 inhibitors for the treatment of proliferative disorders

Publications (1)

Publication Number Publication Date
HK1134486A1 true HK1134486A1 (zh) 2010-04-30

Family

ID=38544378

Family Applications (1)

Application Number Title Priority Date Filing Date
HK10100194.2A HK1134486A1 (zh) 2006-04-12 2010-01-08 作為用於治療增殖病症的蛋白激酶 抑制劑的 -二氫- 三唑並 蝶啶

Country Status (17)

Country Link
US (3) US7763629B2 (zh)
EP (1) EP2010542B1 (zh)
JP (1) JP5313875B2 (zh)
KR (1) KR101432316B1 (zh)
AR (1) AR060432A1 (zh)
AT (1) ATE542823T1 (zh)
AU (1) AU2007238690B2 (zh)
CA (1) CA2649324A1 (zh)
ES (1) ES2381212T3 (zh)
HK (1) HK1134486A1 (zh)
IL (1) IL194699A (zh)
MX (1) MX2008013110A (zh)
NO (1) NO20084747L (zh)
NZ (1) NZ571969A (zh)
RU (1) RU2441006C2 (zh)
TW (1) TW200808805A (zh)
WO (1) WO2007120752A2 (zh)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023269A2 (en) * 2007-08-15 2009-02-19 Vertex Pharmaceuticals Incorporated 4-(9-(3, 3-difluorocyclopentyl) -5, 7, 7-trimethyl-6-oxo-6, 7, 8, 9-tetrahydro-5h-pyrimido [4, 5-b[1, 4] diazepin-2-ylamino)-3-methoxybenzamide derivatives as inhibitors of the human protein kinases plk1 to plk4 for the treatment of proliferative diseases
JP5537439B2 (ja) 2007-12-19 2014-07-02 アムジエン・インコーポレーテツド 細胞周期阻害剤としての縮合ピリジン、ピリミジンおよびトリアジン化合物
EP2278973B1 (en) 2008-04-07 2011-11-02 Amgen Inc. Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors
AU2009271663B2 (en) * 2008-06-23 2014-04-17 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors
CN102076690A (zh) * 2008-06-23 2011-05-25 维泰克斯制药公司 蛋白激酶抑制剂
AU2010299579A1 (en) 2009-09-25 2012-05-03 Vertex Pharmaceuticals Incorporated Methods for preparing pyrimidine derivatives useful as protein kinase inhibitors
JP2013512860A (ja) * 2009-09-25 2013-04-18 バーテックス ファーマシューティカルズ インコーポレイテッド プロテインキナーゼ阻害剤として有用なピリミジン誘導体の調製方法
SG181908A1 (en) 2009-12-23 2012-08-30 Elan Pharm Inc Pteridinones as inhibitors of polo-like kinase
EP2535059A4 (en) 2010-02-10 2014-03-12 Public Univ Corp Yokohama City USE OF A MSIN3B-BINDING COMPOUND WHICH BINDES SPECIFICLY TO THE SILENCER FACTOR OF NRSF NEURONIC SPECIFICATION
US8933070B2 (en) 2010-07-02 2015-01-13 University Health Network Methods of targeting PTEN mutant diseases and compositions therefor
CA2814084A1 (en) 2010-10-08 2012-04-12 Elan Pharmaceuticals Inc. Inhibitors of polo-like kinase
US8569331B2 (en) 2010-11-01 2013-10-29 Arqule, Inc. Substituted benzo[f]lmidazo[1,2-d]pyrido[2,3-b][1,4]diazepine compounds
ES2620521T3 (es) 2011-03-23 2017-06-28 Amgen Inc. Inhibidores duales tricíclicos condensados de CDK 4/6 y FLT3
MD4300C1 (ro) * 2012-12-28 2015-03-31 Государственный Университет Молд0 Inhibitor al proliferării celulelor HepG2 în cancerul hepatic în bază de cloro-[2-fenil(piridin-2-il)metanon-4-(3-metoxifenil)tiosemicarbazono]nichel
WO2016183071A1 (en) 2015-05-11 2016-11-17 Incyte Corporation Hetero-tricyclic compounds and their use for the treatment of cancer
US9708333B2 (en) 2015-08-12 2017-07-18 Incyte Corporation Fused bicyclic 1,2,4-triazine compounds as TAM inhibitors
WO2017035366A1 (en) 2015-08-26 2017-03-02 Incyte Corporation Pyrrolopyrimidine derivatives as tam inhibitors
SI3436461T1 (sl) 2016-03-28 2024-03-29 Incyte Corporation Pirolotriazinske spojine kot tam-inhibitorji
PE20210002A1 (es) 2017-09-27 2021-01-05 Incyte Corp Sales de derivados de pirrolotriazina utiles como inhibidores tam
EP3813800A1 (en) 2018-06-29 2021-05-05 Incyte Corporation Formulations of an axl/mer inhibitor
CN109734809A (zh) * 2019-02-27 2019-05-10 南方科技大学 治疗性的人Plk1蛋白单克隆抗体及其制备方法
WO2023017442A1 (en) * 2021-08-10 2023-02-16 Uppthera, Inc. Novel plk1 degradation inducing compound

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA973884B (en) * 1996-05-23 1998-11-06 Du Pont Merck Pharma Tetrahydropteridines and pyridylpiperazines for treatment of neurological disorders
US6184226B1 (en) * 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
WO2002076985A1 (en) * 2001-03-23 2002-10-03 Smithkline Beecham Corporation Compounds useful as kinase inhibitors for the treatment of hyperproliferative diseases
WO2004030635A2 (en) * 2002-10-03 2004-04-15 Targegen, Inc. Vasculostatic agents and methods of use thereof
BRPI0411347A (pt) 2003-06-10 2006-07-11 Pfizer combinações terapêuticas compreendendo inibidores de pde e antagonistas dos receptores de vasopressina para o tratamanento de dismenorréia
GB0315966D0 (en) * 2003-07-08 2003-08-13 Cyclacel Ltd Compounds
GB0400700D0 (en) 2004-01-13 2004-02-18 Pfizer Ltd Compounds useful in therapy
GB0412874D0 (en) 2004-06-09 2004-07-14 Pfizer Ltd Novel pharmaceuticals
DE102004029784A1 (de) 2004-06-21 2006-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 2-Benzylaminodihydropteridinone, Verfahren zur deren Herstellung und deren Verwendung als Arzneimittel

Also Published As

Publication number Publication date
US20090062292A1 (en) 2009-03-05
AU2007238690B2 (en) 2013-05-02
US7763629B2 (en) 2010-07-27
IL194699A (en) 2014-07-31
EP2010542B1 (en) 2012-01-25
NO20084747L (no) 2008-11-25
WO2007120752A2 (en) 2007-10-25
ES2381212T3 (es) 2012-05-24
JP5313875B2 (ja) 2013-10-09
US8524902B2 (en) 2013-09-03
NZ571969A (en) 2011-10-28
US8067417B2 (en) 2011-11-29
KR20080109919A (ko) 2008-12-17
CA2649324A1 (en) 2007-10-25
KR101432316B1 (ko) 2014-08-29
MX2008013110A (es) 2009-03-06
EP2010542A2 (en) 2009-01-07
ATE542823T1 (de) 2012-02-15
AR060432A1 (es) 2008-06-18
WO2007120752A3 (en) 2008-05-08
RU2008144584A (ru) 2010-05-20
US20120277425A1 (en) 2012-11-01
TW200808805A (en) 2008-02-16
IL194699A0 (en) 2009-08-03
AU2007238690A1 (en) 2007-10-25
RU2441006C2 (ru) 2012-01-27
US20110021519A1 (en) 2011-01-27
JP2009536155A (ja) 2009-10-08

Similar Documents

Publication Publication Date Title
HK1134486A1 (zh) 作為用於治療增殖病症的蛋白激酶 抑制劑的 -二氫- 三唑並 蝶啶
ZA200802998B (en) Use of pyrazolo [1,5-a] pyrimidine derivatives for inhibiting protein kinases methods for inhibiting protein kinases
WO2007111904A3 (en) C-met protein kinase inhibitors for the treatment of proliferative disorders
IL176737A0 (en) Pyrazolo[1,5-a] pyrimidin-7-yl-amine derivatives for use in the treatment of protein kinase dependent diseases
IL190061A0 (en) 5-amino-4-hydroxy-7-(imidazo[1,2-a]pyridin-6-ylmethyl)-8-methyl-nonamide derivatives and related compounds as renin inhibitors for the treatment of hypertension
HK1143154A1 (zh) 作為蛋白激酶 抑制劑的吡咯並 嘧啶衍生物
EP1796467A4 (en) INHIBITORS IMIDAZO {4,5-B} PYRAZINONE PROTEIN KINASES
IL189980A0 (en) Novel imidazo [4,5-b]pyridine derivatives as inhibitors of glycogen synthase kinase 3 for use in the treatment of dementia and neurodegenerative disorders
IL204693A0 (en) Imidazo[1, 2 - a] pyrimidine derivatives for the treatment of diseases such as diabetes
SI1893612T1 (sl) Pirolo b piridin derivati kot protein kinazni inhibitorji
EP1945222A4 (en) PYRROLO [2,1-F] [1,2,4] TRIAZIN-4-YLAMINE DERIVATIVES INHIBITORS OF IGF-1R KINASE FOR THE TREATMENT OF CANCER AND OTHER HYPERPROLIFERATIVE DISEASES
HK1122808A1 (en) Preparation and use of tetrahydropyrrolo [3, 2-c]t pyridin-4-one derivatives for treatment of obesitty, psychiatric and neurological disorders
AP2010005346A0 (en) 3H-[1,2,3]triazolo[4,5-D]pyrimidine compounds, their use as mTOR kinase and P13 kinase inhibitors, and their synthesis.
IL195238A0 (en) Pyrazolo [1,5-a]pyrimidines as cdk inhibitors
EP1899342A4 (en) [1, 2, 4] TRIAZOLO [1, 5-A] PYRIMIDINE DERIVATIVES AS IGF SELECTIVE ADSORPTION CHROMATOGRAPHIC ADSORBENTS
EP1670466A4 (en) PREPARATION OF 1,6,7-TRISUBSTITUTED AZABENIC ZIMIDAZOLES AS KINASE-INHIBITORS
EP2142544B8 (en) Pyrido [2, 3-d]pyrimidin-7-one compounds as inhibitors of pi3k-alpha for the treatment of cancer
EP2142543B8 (en) Pyrido [2, 3-d]pyrimidin-7-one compounds as inhibitors of pi3k-alpha for the treatment of cancer
HK1129888A1 (zh) 作為 調節劑用於治療疼通的 -四氫- -嘧啶並 氮雜䓬- -基 -胺衍生物
AU2003242860A8 (en) 2-aminopyrazine derivatives as inhibitors of cyclin dependent kinases for the treatment of proliferative disorders
ZA200802637B (en) Novel 2-phenyl-imidazo [4,5-b] pyridine derivatives as inhibitors of glycogen synthase kinase for the treatment of dementia and neurodegenerative disorders
IL188390A0 (en) Imidazolyl-pyrimidine compounds for use in the treatment of proliferative disorders
ZA200809016B (en) 4, 5-Dihydro-[1,2,4] Triazolo [4,3-F] PteridinesS as protein kinase PLK1 inhibitors for the treatment of proliferative disorders
ZA200603113B (en) Process for the preparation of risperidone
ZA200800409B (en) Imidazolyl-pyrimidine compounds for use in the treatment of proliferative disorders

Legal Events

Date Code Title Description
PC Patent ceased (i.e. patent has lapsed due to the failure to pay the renewal fee)

Effective date: 20190418