ES2733576T3 - Nuevos compuestos de pirrolopirimidina como inhibidores de proteína cinasas - Google Patents

Nuevos compuestos de pirrolopirimidina como inhibidores de proteína cinasas Download PDF

Info

Publication number
ES2733576T3
ES2733576T3 ES16202341T ES16202341T ES2733576T3 ES 2733576 T3 ES2733576 T3 ES 2733576T3 ES 16202341 T ES16202341 T ES 16202341T ES 16202341 T ES16202341 T ES 16202341T ES 2733576 T3 ES2733576 T3 ES 2733576T3
Authority
ES
Spain
Prior art keywords
certain cases
alkyl
hydrogen
compound
halo
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.)
Active
Application number
ES16202341T
Other languages
English (en)
Spanish (es)
Inventor
Xiao Xu
Xiaobo Wang
Long Mao
Li Zhao
Biao Xi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Acea Therapeutics Inc
Original Assignee
Acea Therapeutics Inc
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
Priority claimed from US13/843,554 external-priority patent/US9034885B2/en
Application filed by Acea Therapeutics Inc filed Critical Acea Therapeutics Inc
Application granted granted Critical
Publication of ES2733576T3 publication Critical patent/ES2733576T3/es
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • A61P27/04Artificial tears; Irrigation solutions
    • 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
    • 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
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Transplantation (AREA)
  • Ophthalmology & Optometry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Epidemiology (AREA)
ES16202341T 2012-08-06 2013-07-11 Nuevos compuestos de pirrolopirimidina como inhibidores de proteína cinasas Active ES2733576T3 (es)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201261680231P 2012-08-06 2012-08-06
US13/843,554 US9034885B2 (en) 2012-01-13 2013-03-15 EGFR modulators and uses thereof
US201361814147P 2013-04-19 2013-04-19
US13/917,514 US8685988B2 (en) 2012-08-06 2013-06-13 EGFR modulators and uses thereof

Publications (1)

Publication Number Publication Date
ES2733576T3 true ES2733576T3 (es) 2019-12-02

Family

ID=50068479

Family Applications (2)

Application Number Title Priority Date Filing Date
ES16202341T Active ES2733576T3 (es) 2012-08-06 2013-07-11 Nuevos compuestos de pirrolopirimidina como inhibidores de proteína cinasas
ES13745491.4T Active ES2618007T3 (es) 2012-08-06 2013-07-11 Nuevos compuestos de pirrolopirimidina como inhibidores de proteína cinasas

Family Applications After (1)

Application Number Title Priority Date Filing Date
ES13745491.4T Active ES2618007T3 (es) 2012-08-06 2013-07-11 Nuevos compuestos de pirrolopirimidina como inhibidores de proteína cinasas

Country Status (22)

Country Link
EP (2) EP2880035B9 (cg-RX-API-DMAC7.html)
JP (2) JP6215938B2 (cg-RX-API-DMAC7.html)
KR (1) KR102181365B1 (cg-RX-API-DMAC7.html)
CN (2) CN107266453B (cg-RX-API-DMAC7.html)
AU (1) AU2013300106B2 (cg-RX-API-DMAC7.html)
BR (1) BR112015002709B1 (cg-RX-API-DMAC7.html)
CA (1) CA2881275C (cg-RX-API-DMAC7.html)
CY (1) CY1120844T1 (cg-RX-API-DMAC7.html)
DK (1) DK2880035T3 (cg-RX-API-DMAC7.html)
ES (2) ES2733576T3 (cg-RX-API-DMAC7.html)
HR (1) HRP20170311T1 (cg-RX-API-DMAC7.html)
HU (1) HUE031955T2 (cg-RX-API-DMAC7.html)
IN (1) IN2015DN00914A (cg-RX-API-DMAC7.html)
LT (1) LT2880035T (cg-RX-API-DMAC7.html)
MX (1) MX361992B (cg-RX-API-DMAC7.html)
NZ (1) NZ629807A (cg-RX-API-DMAC7.html)
PT (1) PT2880035T (cg-RX-API-DMAC7.html)
RU (2) RU2018104702A (cg-RX-API-DMAC7.html)
SG (1) SG11201500872SA (cg-RX-API-DMAC7.html)
SM (1) SMT201700136T1 (cg-RX-API-DMAC7.html)
WO (1) WO2014025486A1 (cg-RX-API-DMAC7.html)
ZA (2) ZA201500762B (cg-RX-API-DMAC7.html)

Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3409278B8 (en) 2011-07-21 2020-11-04 Sumitomo Dainippon Pharma Oncology, Inc. Heterocyclic protein kinase inhibitors
US9034885B2 (en) 2012-01-13 2015-05-19 Acea Biosciences Inc. EGFR modulators and uses thereof
US9464089B2 (en) 2012-01-13 2016-10-11 Acea Biosciences Inc. Heterocyclic compounds and uses thereof
WO2013106792A1 (en) 2012-01-13 2013-07-18 Acea Biosciences Inc. Heterocyclic compounds and uses as anticancer agents.
ES2638179T3 (es) * 2013-01-16 2017-10-19 Signal Pharmaceuticals, Llc Compuestos de pirrolopirimidina sustituidos, composiciones de los mismos, y métodos de tratamiento con los mismos
HUE044558T2 (hu) 2013-03-14 2019-11-28 Tolero Pharmaceuticals Inc JAK és ALK2 inhibitorok és eljárások alkalmazásukra
CN105916851A (zh) * 2013-07-11 2016-08-31 艾森生物科学公司 嘧啶衍生物作为激酶抑制剂
WO2015127234A1 (en) * 2014-02-20 2015-08-27 Board Of Regents, The University Of Texas System Use of ibrutinib to treat egfr mutant cancer
NZ629796A (en) 2014-07-14 2015-12-24 Signal Pharm Llc Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use
CN106715427A (zh) 2014-07-14 2017-05-24 西格诺药品有限公司 利用取代的吡咯并嘧啶化合物、其组合物治疗癌症的方法
CN107801397B (zh) * 2015-02-13 2021-07-30 达纳-法伯癌症研究所公司 Lrrk2抑制剂及其制备和使用方法
JP2018104290A (ja) * 2015-04-28 2018-07-05 アステラス製薬株式会社 ピラジンカルボキサミド化合物を有効成分とする医薬組成物
EP3312179B1 (en) 2015-04-29 2019-07-10 Nanjing Sanhome Pharmaceutical Co., Ltd. Fused-ring or tricyclic aryl pyrimidine compound used as kinase inhibitor
WO2017011720A1 (en) * 2015-07-16 2017-01-19 Signal Pharmaceuticals, Llc Solod forms 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d] oxazol-6-yl)17h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use
AU2016334141B2 (en) * 2015-10-09 2019-12-19 ACEA Therapeutics, Inc. Pharmaceutical salts, physical forms, and compositions of pyrrolopyrimidine kinase inhibitors, and methods of making same
CN105646496B (zh) * 2016-01-20 2018-07-20 华侨大学 一种7H-吡咯并[2,3-d]嘧啶衍生物、其合成方法及应用
CN107540661A (zh) * 2016-06-24 2018-01-05 正大天晴药业集团股份有限公司 作为egfr抑制剂的苯胺嘧啶化合物的结晶
CN107663208B (zh) * 2016-07-27 2021-10-15 南京圣和药业股份有限公司 一种新型egfr激酶抑制剂的药用盐及其制备方法与用途
CN107663207B (zh) * 2016-07-27 2021-07-30 南京圣和药业股份有限公司 一种egfr激酶抑制剂的甲磺酸盐结晶及制备方法
CN107955019B (zh) * 2016-10-17 2021-09-14 广东众生药业股份有限公司 一种egfr抑制剂的盐型、晶型及其制备方法
CN106749266B (zh) * 2016-11-14 2019-01-22 山东大学 吡咯并[2,3-d]嘧啶类化合物的高效制备方法
CN108299419B (zh) * 2017-01-11 2022-04-26 南京圣和药业股份有限公司 一种新型egfr激酶抑制剂的几种新晶型及其制备方法
EP3556761B1 (en) * 2017-02-08 2021-03-03 The National Institutes Of Pharmaceutical Research Pyrrolo-aromatic heterocyclic compound, preparation method therefor, and medical use thereof
US11498922B2 (en) 2017-04-07 2022-11-15 ACEA Therapeutics, Inc. Pharmaceutical composition comprising N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenylacrylamide
CN109422751B (zh) * 2017-09-03 2022-04-22 上海美志医药科技有限公司 一类具有降解酪氨酸蛋白激酶jak3活性的化合物
US12180581B2 (en) 2017-09-18 2024-12-31 Waters Technologies Corporation Use of vapor deposition coated flow paths for improved chromatography of metal interacting analytes
US12181452B2 (en) 2017-09-18 2024-12-31 Waters Technologies Corporation Use of vapor deposition coated flow paths for improved chromatography of metal interacting analytes
US11709156B2 (en) 2017-09-18 2023-07-25 Waters Technologies Corporation Use of vapor deposition coated flow paths for improved analytical analysis
US11709155B2 (en) 2017-09-18 2023-07-25 Waters Technologies Corporation Use of vapor deposition coated flow paths for improved chromatography of metal interacting analytes
IL275207B (en) 2017-12-28 2022-09-01 Daewoong Pharmaceutical Co Ltd An oxy-fluoropiperidine derivative as a kinase inhibitor
KR102577241B1 (ko) * 2017-12-28 2023-09-11 주식회사 대웅제약 카이네이즈 저해제로서의 아미노-플루오로피페리딘 유도체
KR102577242B1 (ko) 2017-12-28 2023-09-11 주식회사 대웅제약 카이네이즈 저해제로서의 아미노-메틸피페리딘 유도체
WO2019195753A1 (en) 2018-04-05 2019-10-10 Tolero Pharmaceuticals, Inc. Axl kinase inhibitors and use of the same
US20210113562A1 (en) 2018-04-13 2021-04-22 Sumitomo Dainippon Pharma Oncology, Inc. Pim kinase inhibitors for treatment of myeloproliferative neoplasms and fibrosis associated with cancer
CN108530450B (zh) * 2018-05-03 2021-03-30 赖建智 具有egfr抑制活性的化合物、制备方法及其在疾病治疗中的应用
MX2021000977A (es) 2018-07-26 2021-04-12 Sumitomo Pharma Oncology Inc Metodos para tratar enfermedades asociadas con expresion anormal de receptor de activina a tipo 1 (acvr1) e inhibidores de acvr1 para uso en los mismos.
EP3613738A1 (en) * 2018-08-23 2020-02-26 Lead Discovery Center GmbH 4-substituted pyrrolo[2,3-b]pyridine as erbb modulators useful for treating cancer
JP7662528B2 (ja) 2019-02-12 2025-04-15 スミトモ ファーマ アメリカ, インコーポレイテッド 複素環式タンパク質キナーゼ阻害剤を含む製剤
CN111747931A (zh) * 2019-03-29 2020-10-09 深圳福沃药业有限公司 用于治疗癌症的氮杂芳环酰胺衍生物
CN110407840A (zh) * 2019-08-15 2019-11-05 重庆化工职业学院 一种艾维替尼的制备方法
EP4059935A4 (en) * 2019-11-13 2024-02-28 Zhejiang Longcharm Bio-Tech Pharma. Co., Ltd. PYRROLOPYRIMIDINE COMPOUND USED AS BTK INHIBITOR AND USE THEREOF
US11918936B2 (en) 2020-01-17 2024-03-05 Waters Technologies Corporation Performance and dynamic range for oligonucleotide bioanalysis through reduction of non specific binding
CN115023428B (zh) * 2020-01-21 2025-04-08 江苏先声药业有限公司 嘧啶并吡咯类化合物
CN111848631B (zh) * 2020-08-28 2022-04-19 四川大学华西医院 一种靶向EGFR突变的吡咯并[2,3-d]嘧啶衍生物及其制备方法和用途
US12352734B2 (en) 2020-09-24 2025-07-08 Waters Technologies Corporation Chromatographic hardware improvements for separation of reactive molecules
US20240100172A1 (en) 2020-12-21 2024-03-28 Hangzhou Jijing Pharmaceutical Technology Limited Methods and compounds for targeted autophagy
JP7621624B2 (ja) * 2021-01-11 2025-01-27 広州力▲しん▼生物科技有限公司 2-アミノピリミジン系化合物、その医薬組成物、及び使用
CN114957248B (zh) * 2022-05-09 2023-12-29 南开大学 一种吡咯并嘧啶化合物及其制备方法、药物组合物和应用
CN115611989B (zh) * 2022-10-09 2023-08-01 武汉理工大学 机械活化淀粉衍生物抑制剂的优化制备方法及应用
WO2024092047A1 (en) 2022-10-26 2024-05-02 Sorrento Therapeutics, Inc. Administration of pyrrolopyrimidine-based kinase inhibitors for treatment of psoriasis
WO2024097653A1 (en) 2022-10-31 2024-05-10 Sumitomo Pharma America, Inc. Pim1 inhibitor for treating myeloproliferative neoplasms

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563905A (en) 1992-09-24 1996-10-08 Hughes Aircraft Company Network communication system having time-sliced protocol
DE60330022D1 (de) 2002-07-20 2009-12-24 Acea Biosciences Inc Vorrichtungen auf impedanzbasis sowie verfahren zur verwendung in assays
US7470533B2 (en) 2002-12-20 2008-12-30 Acea Biosciences Impedance based devices and methods for use in assays
US7468255B2 (en) 2002-12-20 2008-12-23 Acea Biosciences Method for assaying for natural killer, cytotoxic T-lymphocyte and neutrophil-mediated killing of target cells using real-time microelectronic cell sensing technology
US7560269B2 (en) 2002-12-20 2009-07-14 Acea Biosciences, Inc. Real time electronic cell sensing system and applications for cytotoxicity profiling and compound assays
US7732127B2 (en) 2002-12-20 2010-06-08 Acea Biosciences, Inc. Dynamic monitoring of cell adhesion and spreading using the RT-CES system
EP1692258A4 (en) 2003-11-12 2007-03-21 Xiao Xu REAL-TIME ELECTRONIC CELL DETECTION SYSTEMS FOR CELL-BASED TESTS
US8232297B2 (en) * 2005-09-21 2012-07-31 4Sc Ag Sulphonylpyrroles as inhibitors of HDACs novel sulphonylpyrroles
KR101705158B1 (ko) * 2009-05-05 2017-02-09 다나-파버 캔서 인스티튜트 인크. Egfr 억제제 및 질환 치료방법
WO2011079231A1 (en) * 2009-12-23 2011-06-30 Gatekeeper Pharmaceutical, Inc. Compounds that modulate egfr activity and methods for treating or preventing conditions therewith

Also Published As

Publication number Publication date
CA2881275A1 (en) 2014-02-13
ES2618007T3 (es) 2017-06-20
RU2015107831A (ru) 2016-09-27
KR102181365B1 (ko) 2020-11-23
JP6215938B2 (ja) 2017-10-18
CN107266453A (zh) 2017-10-20
ZA201600648B (en) 2021-09-29
IN2015DN00914A (cg-RX-API-DMAC7.html) 2015-06-12
CA2881275C (en) 2020-10-20
LT2880035T (lt) 2017-03-27
SG11201500872SA (en) 2015-03-30
AU2013300106A1 (en) 2015-02-19
JP2017061581A (ja) 2017-03-30
EP2880035A1 (en) 2015-06-10
RU2645672C2 (ru) 2018-02-27
KR20150068949A (ko) 2015-06-22
BR112015002709A2 (pt) 2017-07-04
JP2015524468A (ja) 2015-08-24
MX361992B (es) 2018-12-19
EP2880035B1 (en) 2016-12-07
HK1210471A1 (en) 2016-04-22
CN103748096B (zh) 2017-10-20
SMT201700136T1 (it) 2017-05-08
DK2880035T3 (en) 2017-03-06
EP3170825A1 (en) 2017-05-24
RU2018104702A (ru) 2019-02-22
PT2880035T (pt) 2017-03-10
CN103748096A (zh) 2014-04-23
AU2013300106B2 (en) 2017-11-30
CN107266453B (zh) 2020-02-07
EP3170825B1 (en) 2019-04-10
MX2015001715A (es) 2015-07-06
BR112015002709B1 (pt) 2022-09-20
EP2880035B9 (en) 2017-05-17
ZA201500762B (en) 2021-09-29
HUE031955T2 (en) 2017-08-28
WO2014025486A1 (en) 2014-02-13
HRP20170311T1 (hr) 2017-04-21
CY1120844T1 (el) 2019-12-11
NZ629807A (en) 2017-04-28

Similar Documents

Publication Publication Date Title
ES2733576T3 (es) Nuevos compuestos de pirrolopirimidina como inhibidores de proteína cinasas
US10596174B2 (en) Pyrrolopyrimidine compounds as inhibitors of protein kinases
US11007197B2 (en) EGFR modulators and uses thereof
JP2023519815A (ja) スピロ環含有キナゾリン化合物
WO2021249563A1 (zh) 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
US9586965B2 (en) Pyrrolo[2,3-d]pyrimidine compounds as inhibitors of protein kinases
ES3048702T3 (en) Salt and crystal form of nitrogen-containing heterocyclic derivative, preparation method therefor and application thereof
US12384795B2 (en) Pyrimido[5,4-b]pyrrolizin compound, optical isomer thereof, preparation method therefor and use thereof
HK1238243B (en) Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
HK1238243A1 (en) Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
HK1210471B (en) Novel pyrrolopyrimidine compounds as inhibitors of protein kinases